vitamin-k-semiquinone-radical and Neoplasms

Each year, cancer claims the lives of around 10.0 million people worldwide. Food components have been shown to alter numerous intracellular signaling events that frequently go awry during carcinogenesis. Many studies suggest that dietary behaviors involving the consumption of antioxidant-rich foods, as well as caloric restriction, may play an important role in cancer prevention. Gene expression patterns, such as genetic polymorphisms, can influence the response to food components by altering their specific action on targets, as well as absorption, metabolism, and distribution, among other things. This review discusses two significant cancer prevention techniques: a vitamin-rich diet and caloric restriction. It also discusses the possible molecular interactions between the two dietary strategies and the first clues of a probable synergy that would come from combining caloric restriction with antioxidant use. Caloric restriction diets have positive effects on life expectancy and enable avoidance of age-related illnesses. As a result, this manuscript is based on the degenerative nature of cancer and intends to shed light on the biochemical features of not just calorie restriction but also vitamins. Both are thought to have an effect on oxidative stress, autophagy, and signaling pathways involved in energy metabolism and mitochondrial functions.

Topics: Antioxidants; Caloric Restriction; Diet; Humans; Neoplasms; Vitamin K; Vitamins

Are there any evidence-based medicine (EBM)-supported treatment approaches of complementary and alternative medicine (CAM) methods for urological oncologists?. We reviewed the actual German S3 guidelines "Supportive Care" and "Complementary Medicine" as well as the online-tool Onkopedia for recommendations about essential trace elements (Zn, Se, Mn, Fe), vitamins (A, B, C, D, E), and electrolytes (Mg, Ca). Furthermore, we added results of randomized trials to present potential future developments.. Each therapy with micronutrients should be based on laboratory observation of a deficit. There are selected guideline recommendations for selenium, iron and vitamin D. Potential indications were registered for manganese, vitamin A derivates, and vitamin C. No benefit was observed for vitamin B, zinc, and vitamin E.. Micronutrients should be substituted in the case of deficit. General supplementation of daily nutrition is not recommended for cancer patients.. FRAGESTELLUNG: Gibt es evidenzbasierte Behandlungsansätze für den Umgang mit Mikronährstoffen in der urologischen Onkologie?. Die bestehenden S3-Leitlinien „Supportive Therapie“, „Komplementärmedizin“ und die Online-Plattform Onkopedia werden zu den einzelnen Spurenelementen (Zn, Se, Mn, Fe), Vitaminen (A, B, C, D, E) und Elektrolyten (Mg, Ca) durchsucht, die Aussagen zusammengestellt und um andere, in Studien geprüfte Ansätze in diesem Bereich erweitert.. Einer Therapie mit Mikronährstoffen sollte eine Serumbestimmung vorausgehen. Für Selen, Eisen und Vitamin D gibt es Leitlinienempfehlungen. Potenzielle Indikationen lassen sich aus kleineren Untersuchungen für Mangan, Vitamin A und C ableiten. Kein Benefit wird für Zink, Vitamin B und E gesehen.. Mikronährstoffe sollten bei Mangel immer substituiert werden. Von einer generellen Supplementation der Nahrung wird auch im urologischen Bereich abgeraten.

Topics: Complementary Therapies; Dietary Supplements; Electrolytes; Humans; Micronutrients; Neoplasms; Trace Elements; Vitamin A; Vitamin B Complex; Vitamin K

Thromboembolic events in myeloproliferative neoplasms (MPNs) are one of the most important causes of mortality and morbidity, in which vitamin K antagonists (VKAs) have been used mostly. Recently, direct oral anticoagulants (DOACs) are used in venous thromboembolism (VTE) and cancer-associated thrombosis (CAT). With the adoption of data from CAT and VTE, the usage of DOACs in MPNs is increasing.. In this paper, we performed a systematic review to the current literature regarding the usage of DOACs in MPNs. Eleven studies involving 944 patients were included. The reasons for initiating DOACs were secondary prophylaxis for thrombosis (arterial or venous) and atrial fibrillation (AF) in 562 and 382 patients, respectively. A total of 84 (8.9%) recurrent thrombotic (arterial or venous) events recorded. Forty-six (8.1%) events occurred in the thrombosis group (arterial or venous) and 38 (9.9%) events occurred in patients with AF.. Ease of management and patient comfort should be regarded as benefits of DOACs compared to VKAs. However, it would be appropriate to bring an individualized approach until we obtain high-quality data with prospectively designed studies involving more patients and longer follow-up time concerning the use of DOACs in patients with MPNs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Myeloproliferative Disorders; Neoplasms; Thrombosis; Venous Thromboembolism; Vitamin K

Cancer is an escalating global issue, with 19.3 million new cases and 9.9 million deaths in 2020. Therefore, effective approaches to prevent cancer are urgently required. Diet plays a significant role in determining cancer risk. Nutrients and food bioactives influence specific signaling pathways in the body. Recently, there have been significant advances in cancer prevention research through nutrigenomics or with the effects of dietary components on the genome. Google Scholar, PubMed, and Scopus databases were used to search for peer-reviewed articles between 2017 and 2023. Criteria used were vitamins, minerals, tumors, cancer, genes, inflammation, signaling pathways, and nutrigenomics. Among the total of 1857 articles available, the highest relevant 90 articles that specifically discussed signaling pathways and genes on cancer cell lines and human cancer patients were selected and reviewed. Food sources are rich in antioxidant micronutrients, which are effective in activating or regulating signaling pathways involved in pathogenesis and cancer therapy by activating enzymes such as mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and phosphatidylinositol 3-kinase (PI3K). The micronutrients are involved in the regulation of β-catenin (WNT/β-catenin) including mutations in Kras and epidermal growth factor receptor (EGFR) alongside inhibition of the NF-kB pathway. The most common mechanism of cancer prevention by these micronutrients is their antioxidative, anti-inflammation, and anti-apoptosis effects. This review discusses how nutrigenomics is essential and beneficial for developing cancer prevention and treatment approaches.

Topics: Antioxidants; beta Catenin; Humans; Micronutrients; Neoplasms; Phosphatidylinositol 3-Kinases; Signal Transduction; Vitamin A; Vitamin K; Vitamins

Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered one of the major obstacles in the successful treatment of cancer by chemotherapy. Combination therapy by the amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in a synergistic or additive manner. Vitamin K is an essential nutrient and has recently been investigated as a potential anticancer agent. The combination of vitamin K analogs, such as vitamins K1, K2, K3, and K5, with other chemotherapeutic drugs have demonstrated a safe, cost-effective, and most efficient way to overcome drug resistance and improved the outcomes of prevailing chemotherapy. Published reports have shown that vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcoming drug resistance by inhibiting P-glycoprotein. In this review, we discuss the mechanism, cellular targets, and possible ways to develop vitamin K subtypes into effective cancer chemosensitizers. Finally, this review will provide a scientific basis for exploiting vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs.

Topics: Antineoplastic Agents; Humans; Neoplasms; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K 3

This paper aims to provide a narrative review of the risks, diagnosis, and management of recurrent venous thromboembolism (VTE) in cancer patients. There is an established association between cancer and VTE, with cancer being a major risk factor for VTE. A history of VTE, short duration of oral anticoagulation, and a proximal DVT are all associated with increased risk for recurrent VTE. Studies have shown that certain cancers (e.g., metastatic genitourinary, lung, and colorectal cancers) are associated with recurrent VTE. Published literature shows that cancer is prothrombotic, and various mechanisms have been postulated as pathways for increased thrombogenesis and hence recurrent VTE in cancer. The symptoms, signs, laboratory information, and imaging results for the diagnosis of recurrent VTE are similar to those of an initial VTE. Management of recurrent VTE involves using low molecular weight heparin (LMWH) or a direct oral anticoagulant (DOAC). Vitamin K antagonists (VKA) or inferior vena cava (IVC) filters are less commonly used.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Thrombosis; Venous Thromboembolism; Vitamin K

The main function of vitamin K in the human organism is its activity in the blood clotting cascade. Epidemiological studies suggest that reduced intake of vitamin K may contribute to an increased risk of geriatric diseases such as atherosclerosis, dementia, osteoporosis, and osteoarthritis. A growing number of studies also indicate that vitamin K may be involved not only in preventing the development of certain cancers but it may also support classical cancer chemotherapy. This review article summarizes the results of studies on the anticancer effects of vitamin K on selected female malignancies, i.e., breast, cervical, and ovarian cancer, published over the past 20 years. The promising effects of vitamin K on cancer cells observed so far indicate its great potential, but also the need for expansion of our knowledge in this area by conducting extensive research, including clinical trials.

Topics: Aged; Blood Coagulation; Female; Humans; Neoplasms; Osteoporosis; Ovarian Neoplasms; Vitamin K; Vitamin K 1; Vitamin K 2

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.

Topics: Biology; Humans; Neoplasms; Pregnane X Receptor; Proteins; Vitamin K; Vitamin K 1; Vitamin K 2

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as 'hidden hunger'), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Topics: Ascorbic Acid; Biomarkers, Tumor; Diet, Western; Female; Humans; Male; Micronutrients; Neoplasms; Risk Factors; Vitamin A; Vitamin B Complex; Vitamin E; Vitamin K; Vitamins

Cancer-associated thrombosis (CAT) is a common complication in patients with malignancy. Although direct oral anticoagulants (DOACs) have emerged as a treatment option for CAT, there have not been head-to-head comparisons of these agents. We searched MEDLINE and EMBASE from inception to April 2020 for studies comparing the effect of different long-term anticoagulation strategies for venous thromboembolism (VTE) in patients with cancer. We performed a network meta-analysis comparing the antithrombotic strategies in the selected studies using random-effects model. We identified a total of 20 studies [9 randomized control trials (RCTs) and 11 subgroup analyses from other unique RCTs] with total of 6699 patients for inclusion in our analysis. There was no significant difference in recurrent VTE, all-cause death, major bleeding and clinically relevant non-major bleeding among DOACs. When DOACs were combined, recurrent VTE was significantly decreased in DOACs compared to low-molecular weight heparin (LMWH) and Vitamin K antagonist (VKA) [RR (95% CI) 0.75 (0.59-0.94); RR (95% CI) 0.51 (0.39-0.66), respectively] without significant increase in major bleeding or clinically relevant non-major bleeding. In patients with CAT, there was no significant difference in recurrent thrombotic event among different DOACs. Bleeding risk was comparable among all anticoagulation strategies. When DOACs were combined, DOACs were associated with a significant decrease in recurrent VTE with comparable bleeding risk to LMWH and VKA.

Topics: Anticoagulants; Blood Coagulation; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Recent clinical guidelines suggest direct oral anticoagulants (DOACs) as treatment for cancer-associated thrombosis (CAT), but the strength of such recommendations was not clear. Newly released trials add uncertainties to the benefit and risk assessment between DOACs and conventional therapy (low-molecular-weight heparin [LMWH] or vitamin K antagonists [VKAs]).. To evaluate the efficacy and safety of DOACs in patients with CAT, as compared with LMWH and VKAs.. PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) that reported outcomes of DOACs for treating CAT were included. Relative risk (RR), risk difference, and 95% CIs were pooled using the Mantel-Haenszel method.. A total of 8 RCTs were included. DOACs significantly reduced VTE recurrence (RR = 0.59; 95% CI = 0.48-0.73) compared with conventional therapy. Results were similar in the LMWH and VKA subgroups. DOACs had a higher, though nonsignificant, risk of major bleeding compared with LMWH (RR = 1.33; 95% CI = 0.94-1.89) but lower risk of major bleeding compared with VKAs (RR = 0.60; 95% CI = 0.39-0.93). Findings were consistent across patients with active cancer and history of cancer.. DOACs have better efficacy to prevent recurrent VTE compared with conventional therapy. Regarding the safety profile, DOACs may carry higher risk of bleeding compared with LMWH but lower risk of bleeding compared with VKAs. Further studies are needed to inform the optimal anticoagulation approach for different types of cancers.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Assessment; Secondary Prevention; Treatment Outcome; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established.. We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF.. An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users.. The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52-0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74-0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52-0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50-0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47-0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78-1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78-1.06; p 0.24).. In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Treatment Outcome; Vitamin K

Redox dysregulation originating from metabolic alterations in cancer cells contributes to their proliferation, invasion, and resistance to therapy. Conversely, these features represent a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. Amongst them, Vitamin K (VitK) carries the potential against cancer stem cells, in addition to the rest of tumor mass.. To assess the possible benefits and safety of VitK for cancer treatment using a systematic review and meta-analysis with a mixed-methods approach.. We performed a systematic search on several electronic databases for studies comparing VitK treatment with and without combination to the control groups. For quantitative studies, fully or partially reported clinical outcomes such as recurrence rates, survival, overall response and adverse reactions were assessed. For qualitative studies, a narrative synthesis was accomplished.. Our analysis suggested that the clinical outcome of efficacy, the pooled hazard ratio for progression-free survival, and the pooled relative risk for overall survival, and overall response were significantly higher in the VitK therapy group compared to the placebo group (p<0.05). We did not observe any significant difference in the occurrence of adverse events between groups. Among qualitative studies, VitK treatment targeting myelodysplastic syndrome and advanced solid tumors resulted in 24.1% and 10% of clinical response, respectively.. VitK not only exerts antitumor effects against a wide range of tumor types, but it also has excellent synergism with other therapeutic agents.

Topics: Humans; Neoplasms; Vitamin K

 In this study-level meta-analysis, we evaluated the clinical outcome with nonvitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients with cancer..  Anticoagulation in AF patients with cancer is challenging given the coexistence of elevated thrombotic and bleeding risk. The efficacy and safety of NOACs in this setting remain unclear..  We included three randomized trials in our primary analysis (.  In AF patients with malignancy, NOACs appear at least as effective as VKAs in preventing thrombotic events and reduce intracranial bleeding. NOACs may represent a valid and more practical alternative to VKAs in this setting of high-risk patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Data Interpretation, Statistical; Embolism; Hemorrhage; Humans; Intracranial Hemorrhages; Neoplasms; Observational Studies as Topic; Odds Ratio; Patient Safety; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Thromboembolism; Venous Thromboembolism; Vitamin K

Non-vitamin K antagonist oral anticoagulants (NOACs), or direct oral anticoagulants have not been tested in randomized trials conducted in patients with atrial fibrillation (AF), who had malignant disease. However, their use in cancer patients increases and real-life evidence for their effectiveness and safety in this vulnerable subset of patients is growing. The challenges of the use of NOACs in cancer patients with AF and the current expert opinions on this subject have been summarized in this review article.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Neoplasms; Vitamin K

"Acute venous thromboembolism is a common disease seen by nearly all hospitalists. The advent of low molecular weight heparin (LMWH) several decades ago ushered in the era of early hospital discharge and home treatment. More recently, the direct oral anticoagulants (DOACs) have further simplified outpatient treatment and some offer treatment without parenteral therapy. Use of DOACs for cancer-associated venous thromboembolism is emerging and is a welcome evolution of care to spare oncologic patients the burden of daily LMWH injections."

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Risk Assessment; Surgical Procedures, Operative; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

Topics: Anticoagulants; Child; Heparin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Thrombophilia; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) may be good alternatives to low molecular weight heparin (LMWH) or vitamin K antagonists (VKA) for treatment of cancer associated thrombosis (CAT). We conducted a meta-analysis of ten randomized clinical trials to evaluate the efficacy and safety of DOACs in patients with CAT. All had study populations composed in entirety or in part of patients with CAT. The primary outcome (efficacy) was recurrent VTE and the secondary outcomes (safety outcomes) included major bleeding, clinically relevant non-major bleeding (CRNMB), and all bleeding (major bleeding + CRNMB). Participants treated with DOACs had lower risk of recurrent VTE, overall (RR 0.63; 95% CI 0.51-0.79; p < 0.0001), compared to LMWH (RR 0.57; 95% CI 0.40-0.83; p = 0.003), but not compared to VKA (RR 0.69; 95% CI 0.44-1.06; p = 0.09). Compared to LMWH, DOACs showed no difference in major bleeding risk (RR 1.31; 95% CI 0.78-2.18; p = 0.31), though had higher risk of CRNMB (RR 1.60; 95% CI 1.13-2.26; p = 0.008) and all bleeding (RR 1.49; 95% CI 1.10-2.01; p = 0.010). These results indicate that DOACs are more effective than LMWH for prevention of recurrent VTE with CAT though carry an increased risk for non-major bleeding compared to standard of care, LMWH.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Secondary Prevention; Thrombosis; Venous Thrombosis; Vitamin K

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

Topics: Anticoagulants; Central Venous Catheters; Factor Xa Inhibitors; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Vena Cava Filters; Venous Thromboembolism; Vitamin K

Thromboembolism (TE) is a well-recognized complication of pediatric cancer and can lead to mortality and excess morbidity. There is conflicting evidence about the effectiveness and safety of thromboprophylaxis in children. We conducted a systematic literature review and network meta-analysis of primary pharmacological thromboprophylaxis in children and adolescents (0-21 years) with cancer. The primary outcomes were objectively proven TE and major bleeding. The network meta-analysis included comparisons of multiple alternatives simultaneously: antithrombin (AT) replacement, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and standard of care (SOC) defined as no thromboprophylaxis or low-dose heparin for catheter patency. Six articles describing 1,318 patients were included (mean age: 6.7 years, 56.7% male). Acute lymphoblastic leukemia was the underlying diagnosis in 97.5% of patients. All studies were considered at moderate or high risk of bias. LMWH was the only agent associated with lower odds of TE compared with SOC (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 0.06-0.81). No statistically significant difference was detected between other thromboprophylaxis modalities and SOC. Tau

Topics: Adolescent; Anticoagulants; Antithrombins; Child; Child, Preschool; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Infant; Infant, Newborn; Male; Neoplasms; Network Meta-Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboembolism; Thrombosis; Vitamin K; Young Adult

Atrial fibrillation (AF) is commonly diagnosed in the setting of active cancer. Because of an increased risk of either thromboembolic events or bleeding, the decision to initiate therapeutic anticoagulation in patients with active cancer can be challenging. Moreover, little is still known about the optimal anticoagulation therapy in the setting of AF and cancer, and no guidelines are as yet available. Considering that nonvitamin K antagonist oral anticoagulants (NOACs) are recommended as alternatives to vitamin K antagonists for stroke prevention in AF patients with CHA

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Neoplasms; Risk Factors; Stroke; Thromboembolism; Vitamin K

Cancer is associated with an increased risk of venous thromboembolism of four to sixfold. Cancer-related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of venous thromboembolism. Low molecular weight heparin for at least 3-6 months is the current standard of care for the treatment of cancer associated venous thromboembolism. Anticoagulation should be continued as long as the cancer is active. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In the randomized controlled trials comparing direct oral anticoagulants with vitamin K antagonists, the direct oral anticoagulants all provide non-inferior in prevention of thromboembolic events in patients with atrial fibrillation, for the prevention and treatment of venous thromboembolism and in acute coronary syndrome. In people with cancer, these drugs have emerged as attractive alternatives for the treatment of venous thromboembolism with the potential to overcome the limitations of low molecular weight heparin. Randomized controlled studies comparing direct oral anticoagulants to low molecular weight heparin in cancer patients are still limited and direct oral anticoagulants are not recommended for the treatment of cancer associated venous thromboembolism yet. However, new emerging data are supporting the use of direct oral anticoagulants in cancer-associated thrombosis. Here, we review recent data on the evidence related to the efficacy and safety of direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer.

Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Thrombosis; Venous Thromboembolism; Vitamin K

Cancer-associated venous thromboembolism (CAT) is a common complication associated with high morbidity and mortality. In accordance with major clinical trials comparing low-molecular-weight heparin (LMWH) with a vitamin K antagonist (VKA), LMWH is currently the standard treatment for CAT, owing to its efficacy for thrombosis recurrence and improved safety profile compared to VKA. Over the past few years, direct oral anticoagulants (DOACs) have emerged as potential alternative therapies to LMWH due to their convenient route of administration and predictable pharmacokinetics, but evidence for their use in CAT is inconclusive, as only a small fraction of the study populations in these trials had CAT. Recently, two large head-to-head trials comparing DOACs to LMWH in CAT patients reported comparable efficacies of DOACs with increased bleeding risk. Occasionally, CAT treatment can be challenging due to the heterogeneity of underlying malignancies and comorbidities. Renal insufficiency and gastrointestinal defects are the main obstacles in anticoagulant selection. Careful choice of treatment candidates and proper anticoagulant strategies are critical for the treatment of CAT; hence, more studies are required to address these challenges.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Renal Insufficiency; Risk Factors; Venous Thromboembolism; Vitamin K

Low-molecular-weight heparin (LMWH) is usually recommended for the treatment of cancer-associated thrombosis (CAT) but this treatment requires burdensome daily injections. We did a systematic review to compare the efficacy and safety of direct oral anticoagulants (DOAC), vitamin K antagonists (VKA) and LMWH in patients with CAT.. We searched Pubmed, Embase and CENTRAL for randomised controlled trials comparing DOAC, VKA and LMWH in patients with CAT. Pairwise and network meta-analyses were computed for venous thromboembolism (VTE) recurrence and bleeding complications.. We identified 14 studies, including 4,661 patients. In pairwise comparison, DOAC were superior to LMWH to prevent VTE recurrence (HR 0.63; 95% CI 0.42-0.96) and LMWH was superior to VKA (HR 0.53; 95% CI 0.40-0.70). The rate of major bleeding was higher with DOAC compared to LMWH (HR 1.78; 95% CI 1.11-2.87). In the network meta-analysis, DOAC had a lower, but non-significant, rate of VTE recurrence compared to LMWH (HR 0.74; 95% CI 0.54-1.01). Both DOAC (HR 0.42; 95% CI 0.29-0.61) and LMWH (HR 0.57; 95% CI 0.44-0.75) were associated with lower rates of recurrence compared to VKA. No significant difference in major bleeding rate was observed in the network meta-analysis. Inconsistency was observed between pairwise and network meta-analysis comparisons for major bleeding.. DOAC are effective to prevent VTE recurrence in patients with CAT but are associated with an increased risk of bleeding compared to LMWH. The choice of anticoagulant should be personalised, taking into account the patient's bleeding risk, including cancer site, and patient's values and preferences.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Network Meta-Analysis; Recurrence; Risk Factors; Safety; Secondary Prevention; Venous Thromboembolism; Vitamin K

The aim was to review the relative efficacy and safety of anticoagulation for managing venous thromboembolism (VTE) in patients with cancer.. A systematic review and meta-analysis was carried out. On 17 May 2018 the MEDLINE and Scopus databases were searched for randomised controlled trials (RCTs). Eligible RCTs had to be performed in patients with cancer exclusively or to report results on a subset of patients with cancer. The main study outcomes (efficacy/recurrent VTE and safety/bleeding events) were expressed as risk ratios (RR) with a 95% confidence interval (CI). The quality of evidence was assessed following the GRADE method.. Twenty-three RCTs with 6980 patients were identified. Low molecular weight heparins (LMWHs) were more effective than vitamin K antagonists (VKAs) in preventing recurrent VTE (RR 0.58, 95% CI 0.45-0.75) and deep vein thrombosis (RR 0.44, 95% CI 0.29-0.69) but not pulmonary embolism (PE), bleeding, or overall mortality. Direct oral anticoagulants (DOACs) were more effective than VKAs in preventing recurrent VTE (RR 0.65, 95% CI 0.45-0.95) but not DVT, PE, overall mortality, or bleeding. However, anti-Xa DOACs were more effective (RR for VTE 0.64, 95% CI 0.42-0.97) and caused less bleeding than VKAs, although major bleeding was reduced only with DOACs not requiring initial parenteral anticoagulation (RR 0.45, 95% CI 0.21-0.97). In a direct comparison, DOACs were more effective than LMWHs in preventing VTE recurrence (RR 0.64, 95% CI 0.45-0.90) but caused more major bleeding (RR 1.75, 95% CI 1.10-2.77), with no difference in fatal bleeding and overall mortality. Quality of evidence, where sufficient, was mostly moderate or high.. Compared with VKAs, LMWHs and DOACs are more effective in treating VTE, but the former caused less bleeding. DOACs are more effective than LMWHs in preventing VTE recurrence but may carry a higher risk of major bleeding, pending additional information by ongoing trials.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Pulmonary Embolism; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Vitamin K antagonists (VKAs) remain one of the most commonly used anticoagulation therapies. The potential anticancer effect of long-term use of VKAs has been a matter of debate with conflicting results. Our goal was to perform a systematic review and meta-analysis examining the association between long-term VKAs use and cancer risk.. Systematic searches of multiple major databases were performed from inception until January 2018. We included studies of adults that compared incidence of any cancer between ≥6 months use of VKAs (long-term group) and <6 months use of VKAs or nonuse (control group). Primary outcome was all-cancer incidence and secondary outcomes were cancer-specific incidence, all-cause death and cancer-specific mortality. Hazard ratios (HRs) were pooled using a random-effects model, and individual studies were weighted using inverse variance.. We identified 9 observational studies that included 1,521,408 patients. No randomized trials were identified. In comparison to control, long-term use of VKAs was associated with a significant reduction in incidence of all cancers (HR, 0.84; 95% confidence interval [CI], 0.81-0.88; P<0.001). In a prespecified subgroup analysis, long-term use of VKAs demonstrated a significant reduction in all-cancer incidence when compared with control in individuals whose indication for VKAs were venous thromboembolism (HR, 0.69; 95% CI, 0.52-0.90; P=0.007).. The use of long-term VKAs, for any indication, is associated with lower cancer incidence. This finding could have important clinical implications for the choice of oral anticoagulation therapies among specific patients with a higher baseline risk of cancer.

Topics: Anticoagulants; Canada; Humans; Incidence; Neoplasms; Prognosis; Risk Factors; Vitamin K

This review summarizes the available evidence concerning direct oral anticoagulant (DOAC) use to treat venous thromboembolism (VTE) in patients with cancer as well as pertinent safety data on the use of DOACs in patients with both cancer and atrial fibrillation.. The introduction of DOACs into clinical practice changed the way thrombotic complications are managed and prevented in diverse patient populations, including VTE and atrial fibrillation. Low-molecular-weight heparins have been the standard of care for treating VTE in cancer patients due to superiority over vitamin K antagonists in preventing recurrent VTE. Therefore, widespread DOAC use for VTE in patients with active cancer has not been adopted.. Recent randomized clinical trials (SELECT-D, Hokusai VTE Cancer) have provided evidence that DOACs may have a role in treating VTE in cancer patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Standard of Care; Treatment Outcome; Venous Thromboembolism; Vitamin K

This observational study aimed to investigate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with malignancy. A total of 76 patients (mean age: 73.2 ± 8.9; 28 females) with AF and malignancy treated with NOAC were included in the analysis. The mean CHA

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Databases, Factual; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Retrospective Studies; Vitamin K

Topics: Administration, Oral; Anticoagulants; Antithrombins; Drug Interactions; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Neoplastic Cells, Circulating; Prospective Studies; Pulmonary Embolism; Treatment Outcome; Venous Thrombosis; Vitamin K

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed.

Topics: Anticoagulants; Clinical Trials as Topic; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Gla-rich protein (GRP) or unique cartilage matrix-associated protein (Ucma), the newest member of vitamin K dependent proteins, carries exceptionally high number of γ-carboxyglutamic acid (Gla) residues which contributes to its outstanding capacity of binding with calcium in the extracellular environment indicating its potential role as a global calcium modulator. Recent studies demonstrated a critical function of GRP in the regulation of different pathophysiological conditions associated with vascular and soft tissue calcification including cardiovascular diseases, osteoarthritis, inflammation, and skin and breast carcinomas. These findings established an important relationship between γ-carboxylation of GRP and calcification associated disease pathology suggesting a critical role of vitamin K in the pathophysiological features of various health disorders. This review for the first time summarizes all of the updated findings related to the functional activities of GRP in the pathogenesis of several diseases associated with vascular and soft tissue mineralization, osteoarthritis, inflammation, and carcinoma. The outcome of this review will improve the understanding about the role of GRP in the pathogenesis of tissue calcification and its associated health disorders, which should in turn lead to the design of clinical interventions to improve the condition of patients associated with these health disorders.

Topics: Animals; Calcinosis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Neoplasms; Osteoarthritis; Proteins; Vitamin K

This review is directed to the redox-modulating properties and anticancer effect of vitamin K. The concept is focused on two aspects: (i) redox-cycle of vitamin K and its effect on the calcium homeostasis, "oncogenic" and "onco-suppressive" reactive oxygen species and the specific induction of oxidative stress in cancer; (ii) vitamin K plus C as a powerful redox-system, which forms a bypass between mitochondrial complexes II and III and thus prevents mitochondrial dysfunction, restores oxidative phosphorylation and aerobic glycolysis, modulates the redox-state of endogenous redox-pairs, eliminates the hypoxic environment of cancer cells and induces cell death. The analyzed data suggest that vitamin C&K can sensitize cancer cells to conventional chemotherapy, which allows achievement of a lower effective dose of the drug and minimizing the harmful side-effects. The review is intended for a wide audience of readers - from students to specialists in the field.

Topics: Ascorbic Acid; Humans; Mitochondria; Neoplasms; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Vitamin K

Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality. This is an update of the Cochrane Review published in 2014.. To evaluate the efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC.. We conducted a comprehensive literature search in May 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. This update of the systematic review was based on the findings of a literature search conducted on 14 May 2018.. Randomized controlled trials (RCTs) assessing the benefits and harms of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux or comparing the effects of two of these anticoagulants in people with cancer and a CVC.. Using a standardized form, we extracted data and assessed risk of bias. Outcomes included all-cause mortality, symptomatic catheter-related venous thromboembolism (VTE), pulmonary embolism (PE), major bleeding, minor bleeding, catheter-related infection, thrombocytopenia, and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (Balshem 2011).. Thirteen RCTs (23 papers) fulfilled the inclusion criteria. These trials enrolled 3420 participants. Seven RCTs compared LMWH to no LMWH (six in adults and one in children), six RCTs compared VKA to no VKA (five in adults and one in children), and three RCTs compared LMWH to VKA in adults.LMWH versus no LMWHSix RCTs (1537 participants) compared LMWH to no LMWH in adults. The meta-analyses showed that LMWH probably decreased the incidence of symptomatic catheter-related VTE up to three months of follow-up compared to no LMWH (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.22 to 0.81; risk difference (RD) 38 fewer per 1000, 95% CI 13 fewer to 52 fewer; moderate-certainty evidence). However, the analysis did not confirm or exclude a beneficial or detrimental effect of LMWH on mortality at three months of follow-up (RR 0.82, 95% CI 0.53 to 1.26; RD 14 fewer per 1000, 95% CI 36 fewer to 20 more; low-certainty evidence), major bleeding (RR 1.49, 95% CI 0.06 to 36.28; RD 0 more per 1000, 95% CI 1 fewer to 35 more; very low-certainty evidence), minor bleeding (RR 1.35, 95% CI 0.62 to 2.92; RD 14 more per 1000, 95% CI 16 fewer to 79 more; low-certainty evidence), and thrombocytopenia (RR 1.03, 95% CI 0.80 to 1.33; RD 5 more per 1000, 95% CI 35 fewer to 58 more; low-certainty evidence).VKA versus no VKAFive RCTs (1599 participants) compared low-dose VKA to no VKA in adults. The meta-analyses did not confirm or exclude a beneficial or detrimental effect of low-dose VKA compared to no VKA on mortality (RR 0.99, 95% CI 0.64 to 1.55; RD 1 fewer per 1000, 95% CI 34 fewer to 52 more; low-certainty evidence), symptomatic catheter-related VTE (RR 0.61, 95% CI 0.23 to 1.64; RD 31 fewer per 1000, 95% CI 62 fewer to 51 more; low-certainty evidence), major bleeding (RR 7.14, 95% CI 0.88 to 57.78; RD 12 more per 1000, 95% CI 0 fewer to 110 more; low-certainty evidence), minor bleeding (RR 0.69, 95% CI 0.38 to 1.26; RD 15 fewer per 1000, 95% CI 30 fewer to 13 more; low-certainty evidence), premature catheter removal (RR 0.82, 95% CI 0.30 to 2.24; RD 29 fewer per 1000, 95% CI 114 fewer to 202 more; low-certainty evidence), and catheter-related infection (RR 1.17, 95% CI 0.74 to 1.85; RD 71 more per 1000, 95% CI 109 fewer to 356; low-certainty evidence).LMWH versus VKAThree RCTs (641 participants) compared LMWH to VKA in adults. The available evidence did not confirm or exclude a beneficial or detrimental effect of LMWH relative to VKA on mortality (RR 0.94, 95% CI 0.56 to 1. The evidence was not conclusive for the effect of LMWH on mortality, the effect of VKA on mortality and catheter-related VTE, and the effect of LMWH compared to VKA on mortality and catheter-related VTE. We found moderate-certainty evidence that LMWH reduces catheter-related VTE compared to no LMWH. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Topics: Adult; Anticoagulants; Catheter-Related Infections; Catheterization, Central Venous; Child; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Secondary Prevention; Thrombocytopenia; Venous Thrombosis; Vitamin K

Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.. To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.. We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.. Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.. We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).. Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months. For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

To perform a systematic review and network meta-analysis evaluating the efficacy and safety of low-molecular-weight heparins (LMWHs), vitamin K antagonists (VKAs), and direct-acting oral anticoagulants (DOACs) for the treatment of cancer-associated thrombosis (CAT). We searched MEDLINE, Cochrane Central Register of Controlled Trials, and conference abstracts through March 2018. Randomized controlled trials (RCTs) enrolling adults with CAT comparing 2 or more full-dose anticoagulants (LMWH, VKA, and DOAC) and evaluating recurrent venous thromboembolism (VTE), major bleeding, and/or all-cause mortality were included. Reviewers identified studies, extracted data, and assessed the quality of the evidence in duplicate. A frequentist network meta-analysis, which uses direct and indirect evidence to simultaneously compare multiple interventions, was performed using a random-effects approach. Results are reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). We included 13 RCTs (n = 6292): 7 compared LMWHs with VKAs, 4 compared DOACs with VKAs, and 2 compared DOACs with LMWHs. The risk of recurrent VTE was significantly reduced by 28% and 54% with a DOAC compared to an LMWH and a VKA, respectively. Low-molecular-weight heparins significantly reduced the risk of recurrent VTE by 36% versus VKAs. The risk of major bleeding was 14% higher with DOACs compared to LMWHs and 15% and 25% lower with DOACs and LMWHs versus VKAs, although 95% CIs included unity for each. The risk of all-cause mortality appeared similar for all 3 comparisons (RR = 1.0 for each comparison). Direct-acting oral anticoagulants appeared superior in reducing recurrent VTE in patients with CAT compared to LMWH and VKAs, but an increased risk of major bleeding versus LMWH cannot be ruled out.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Thrombosis; Vitamin K

Cancer patients appear to be at increased risk for atrial fibrillation. Although surgery and chemotherapy exacerbate this risk, this association is observed even in the absence of any cancer-specific treatment. The underlying mechanism of this is likely multifactorial, but systemic inflammation and autonomic dysregulation are hypothesized to play critical roles. Cancer and atrial fibrillation are both independent risk factors for ischemic stroke; however, it is not clear whether this translates to an increased risk of stroke in patients with both comorbidities. As such, commonly used risk stratification tools including the CHADS2 score currently do not take cancer into account as a variable and it is possible that stroke risk is underestimated in this population. There is a paucity of data regarding anticoagulant choice in cancer patients with atrial fibrillation. Vitamin K antagonists are often preferred over direct oral anticoagulants; however, this may be changing in the near future as new trials specific to this patient population emerge.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Neoplasms; Risk Factors; Stroke; Vitamin K

Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation - what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Topics: Animals; Carcinogenesis; Cell Proliferation; Humans; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency

To update on new data for low-molecular weight heparins (LMWHs) and the direct oral anticoagulants (DOACs) for the treatment and prevention of cancer-associated thrombosis (CAT), to discuss progress with the risk-adaptive management scores (RAMS) and update on increased dose primary thromboprophylaxis (IDPTP).. In a pooled meta-analysis of 1132 cancer patients who received DOACs vs. vitamin K analogues (VKAs), recurrence of venous thromboembolism (VTE) was reduced from 6.0% on VKA schedules to 3.9% on DOACs. In a randomized trial of warfarin vs. once daily sc. tinzaparin (175 IU/kg), cumulative 6-month VTE incidence reduced from 10.5 to 7.2% [hazard ratio, 0.65 (95% confidence interval, 0.41-1.03); P = 0.07]. Despite early suggestions that DOACs may have a role in CAT, 3-6 months of LMWH remain the standard for initial treatment of CAT. A prospective comparison of RAMS found the Vienna CATS or the PROTECHT scores superior to the Khorana score but concluded that RAMS did not perform well enough to be used in the clinic. An efficacy scale of LMWHs in pancreatic cancer facilitates IDPTP. Practical implementation of IDPTP was needed to control the 40% VTE incidence of the HALO-109-202 study in metastatic pancreatic cancer.. DOACs have some encouraging data, but LMWHs remain the standard for CAT treatment. RAMS generated to predict VTE occurrence or recurrence are still of unproven significance and IDPTP for advanced pancreatic cancer has tools and guidance for implementation.

Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Risk Assessment; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. The treatment of VTE complications in cancer patients remains a difficult clinical task. Low-molecular-weight heparins (LMWH) are the cornerstone of VTE treatment in cancer patients, including the treatment of catheter-related thrombosis. LMWH dose adjustment is effective in treating recurrent thrombosis and in patients with bleeding or thrombocytopenia. The duration of treatment is dependent on several factors that need to be individually evaluated. The novel anticoagulants should be investigated more carefully before being routinely implemented in the treatment of cancer-associated VTE. Incidentally detected isolated sub-segmental pulmonary embolism is unlikely to require systematic full-dose anticoagulation. Whether the long-term use of LMWHs has the potential to prolong survival in subgroups of cancer patients requires further investigations.

Topics: Administration, Oral; Anticoagulants; Drug Administration Schedule; Drug Dosage Calculations; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Vascular Access Devices; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Intracranial hemorrhage (ICH) in cancer patients can result from tumor bleeding and from antitumor and anticoagulation therapy. The effect of anticoagulation on the incidence of ICH in cancer patients has not been quantified. Our objective was to determine the risk of intracranial hemorrhage associated with anticoagulation therapy for cancer-associated venous thromboembolism (VTE). Systematic review and meta-analysis of studies assessing the safety of anticoagulation therapy in patients with cancer-associated VTE. The primary endpoint of interest was the incidence of ICH and secondary outcomes included all major bleeding, and the time to ICH and major bleeding. After identifying 595 studies, five studies and 2089 patients were included in the analyses. We found that the relative risk (RR) for ICH was 0.494, 95 % CI (0.105-2.331) when low molecular weight heparin (LMWH) with vitamin K antagonist (VKA) anticoagulants were compared. No statistically significant differences in risk were measured. The risk of major bleeding using any type of anticoagulation therapy in patients with cancer-associated VTE was RR 0.853, 95 % CI (0.549, 1.327). After meta-analytic review of data published through August 2015, we conclude that therapeutic anticoagulation with LMWH given ≤6 months does not increase the risk of ICH in cancer patients compared to VKA. The risk of ICH in cancer patients is also similar to that of non-cancer patients. Available data were insufficient to determine if the ICH risk increase changes when the duration of anticoagulation is >6 months.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Intracranial Hemorrhages; Neoplasms; Risk; Venous Thromboembolism; Vitamin K

Cancer associated thrombosis (CAT) is a frequent complication among cancer patients. It is associated with increased morbidity, mortality, and psychological burden. Areas covered: Low-molecular-weight heparin monotherapy for the initial 6 months is considered the standard of care for the acute and long-term management of CAT. For patients at high risk of recurrent CAT (e.g. active cancer or still undergoing anticancer therapy) beyond the initial 6 months of treatment, continuation of anticoagulation therapy for secondary prevention is usually recommended. The management of anticoagulation therapy is more challenging in patients with cancer. Cancer patients are more likely to have recurrent events despite anticoagulation, thrombocytopenia due to their chemotherapy regimens or have incidental pulmonary embolism diagnosed on their staging imaging. Expert commentary: We will review expert consensuses and opinions in order to guide clinicians on how to tailor the management of CAT in these special circumstances.

Topics: Anticoagulants; Disease Management; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Secondary Prevention; Thrombocytopenia; Thrombosis; Time Factors; Vitamin K

Cancer-associated venous thromboembolism (VTE) is primarily treated with low-molecular weight heparin (LMWH), a strategy based on studies showing it to be superior to the vitamin K antagonist (VKA) warfarin for preventing VTE recurrence. Subsequent analyses suggest that the magnitude of this benefit might be less than previously determined. Neither patient-focused measures of utility nor the costs of each strategy have been evaluated in the current treatment era.. This is a cost-effectiveness analysis of VKA and LMWH for the treatment of cancer-associated thrombosis through use of a microsimulation model of outcomes for competing anticoagulation management strategies from a 2014 United States societal perspective.. LMWH therapy added 0.27 QALYs relative to VKA treatment with an ICER of $217,007. One-way sensitivity analysis evaluating the utility of LMWH revealed that VKA was always the preferred strategy at a willingness to pay (WTP) threshold of $100,000 per QALY. Limitations include that the model incorporates a low VKA time in therapeutic range (TTR) and that the TTR in some centers may be higher thereby increasing the cost-effectiveness of the VKA strategy. Utilities for anticoagulation strategies were not derived from cancer patients, and preference is known to vary depending on how anticoagulation method is integrated with cancer treatment.. Our findings suggest that compared to LMWH, warfarin is a more cost-effective strategy to treat cancer-associated VTE. Although LMWH is associated with a modest increase in life expectancy, this increase comes at significant cost.

Topics: Anticoagulants; Cost-Benefit Analysis; Heparin, Low-Molecular-Weight; Humans; Markov Chains; Neoplasms; Quality-Adjusted Life Years; Thrombosis; Vitamin K

Prior meta-analysis studies showed that direct oral anticoagulants (DOAs) are as effective and safe as warfarin for the prevention of recurrences in patients with venous thrombo-embolism(VTE) and cancer. However, randomized studies also showed that low-molecular-weight-heparin (LMWH) performs better than warfarin in subjects with cancer. We therefore aimed to assess whether, even after pooling data with warfarin and LMWH, the use of DOAs remains safe and effective.. We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. Data on recurrent VTE and major and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs.. Nine studies were included in the meta-analysis, seven in comparison with VKI, 2 with LMWH, accounting for a total of 1952 patients. VTE recurred in 5.4% and in 5.9% of patients with cancer treated with DOAs and conventional treatment, respectively (OR 0.79; 95% CI, 0.53-1.17; I. DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer in comparison with VKI. Higher bleeding rates were found when DOAs are compared with LMWH.

Topics: Administration, Oral; Anticoagulants; Dose-Response Relationship, Drug; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Patients with cancer are at increased risk of venous thromboembolism, and emergency physicians can play a significant role in addressing one of the leading causes of morbidity and mortality in this patient population. However, there are no comprehensive guidelines addressing the approach to cancer-associated venous thromboembolism in the emergency department. Here, we review the guidelines put forth by various national and international cancer societies and highlight how emergency physicians can help institute appropriate treatment and prevent the recurrence of venous thromboembolism in cancer patients. We also address areas of controversy and highlight topics that require further research.

Topics: Anticoagulants; Contraindications; Emergency Service, Hospital; Guidelines as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Recurrence; Risk Factors; Secondary Prevention; Venous Thromboembolism; Vitamin K

Isolated acquired factor VII (FVII) deficiency is a rare haemorrhagic disorder. We report what is currently known about the pathogenesis, clinical features, diagnosis, treatment and prognosis of acquired FVII deficiency.. We performed a literature search and included all articles published between 1980 and August 2015.. Acquired FVII deficiency has been reported in 42 patients. There are well-established clinical diseases associated with acquired FVII deficiency, most notably infections, malignancy and haematological stem cell transplantation. The exact pathogenesis of the diseases is still unknown, but different pathophysiological hypotheses have been suggested. The clinical manifestation of acquired FVII deficiency varies greatly in severity; asymptomatic course as well as severe life-threatening bleeding diathesis and fatal bleedings have been described.

Topics: Factor VII Deficiency; Factor VIIa; Female; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infections; Male; Neoplasms; Prognosis; Vitamin K

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2-3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.

Topics: Administration, Oral; Anticoagulants; Asian; Black or African American; Disease Management; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Polysaccharides; Prevalence; Quality of Life; Recurrence; Risk Factors; Taiwan; Thrombosis; United States; Venous Thromboembolism; Vitamin K; Warfarin; White People

Cancer and venous thromboembolism (VTE) are closely related, with a high risk of VTE associated with cancer and a strong impact of VTE on cancer prognosis. The management and treatment of cancer-associated VTE are particularly challenging and, in many cases, are not guided by a high level of evidence.. In this review, we present the best therapeutic approach to acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and to some controversial issues, such as home treatment, optimal duration of anticoagulation, management of VTE recurrence during anticoagulant treatment, and of unsuspected PE. Then, the available evidence on other cancer-related VTE manifestations is presented, such as catheter-related thrombosis and splanchnic vein thrombosis.. While solid evidence exists on the advantage of low molecular weight heparin (LMWH) over vitamin K antagonists (VKAs) during the first 3 to 6 months after acute DVT and/or PE, several issues have not been sufficiently investigated yet. These include the role of LMWH beyond the first 3 to 6 months, whether it is still more effective than VKA and if its intensity could be safely reduced, the strategies to identifying accurate predictors of VTE recurrence and the role of direct oral anticoagulants.

Topics: Acute Disease; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Simply providing anticoagulation therapy is not as straightforward of a solution in cancer patients who have concurrent thrombocytopenia owing to the increased risk of bleeding complications. Currently, few guidelines are in place to assist clinicians in safely managing thrombocytopenic cancer patients on anticoagulation. The purpose of this review is to critically examine the available body of biomedical literature surrounding anticoagulant use against the backdrop of cancer-related thrombocytopenia in adult patients. Available evidence for the use of parenteral anticoagulants (low molecular weight heparins, unfractionated heparin, pentasaccharides, and direct thrombin inhibitors) and oral anticoagulants (vitamin K antagonists and novel oral anticoagulants) in thrombocytopenic cancer patients is described. The review revealed many inconsistencies between reports on this topic, which made it difficult to draw firm conclusions as to, for example, the ideal well tolerated anticoagulant dose in thrombocytopenic cancer patients? Intriguingly, critical clinical information including (but not limited) patient platelet nadirs, platelet counts during bleeding episodes, and platelet transfusion support was absent from a not-so-insignificant number of publications. Despite these shortcomings, the review sets out to formulate recommendations on the management of anticoagulation, at prophylactic or treatment doses, in adult cancer patients who also have concurrent thrombocytopenia. It also enlists a call for the medical community, by mapping select clinical guideposts, for further research in this setting. With the inclusion of these criteria in future studies, only then formal recommendations on the ideal safe dosage of anticoagulants in cancer patients, based on solid evidence, are conceived.

Topics: Adult; Anticoagulants; Antithrombins; Blood Coagulation; Blood Platelets; Drug Dosage Calculations; Guidelines as Topic; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Platelet Count; Platelet Transfusion; Thrombocytopenia; Vitamin K

Venous thromboembolism (VTE) and cancer are strongly associated, and present a major challenge in cancer patient treatment. Cancer patients have a higher risk of developing VTE, although the risk differs widely between tumour types. VTE prophylaxis is routinely given to cancer patients, in the form of vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). Several studies have reported that cancer patients receiving anticoagulants show prolonged survival and this effect was more pronounced in patients with a good prognosis, although the mechanism is poorly understood. Tissue Factor (TF) is the initiator of extrinsic coagulation, but its non-haemostatic signalling via protease-activated receptors (PARs) is a potent driver of tumour angiogenesis. Furthermore, coagulation activation is strongly implicated in tumour cell migration and metastasis. This review discusses the effects of anticoagulants on cancer progression in patients, tumour cell behaviour, angiogenesis, and metastasis in in vitro and in vivo models. Inhibition of TF signalling shows great promise in curbing angiogenesis and in vivo tumour growth, but whether this translates to patients is not yet known. Furthermore, non-haemostatic properties of coagulation factors in cancer progression are discussed, which provide exciting opportunities on limiting oncologic processes without affecting blood coagulation.

Topics: Animals; Anticoagulants; Blood Coagulation; Coumarins; Heparin, Low-Molecular-Weight; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Thromboplastin; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is one of the leading causes of death in cancer patients, which are known to have a 5- to 7-fold increased risk for VTE. The anticoagulant treatment of VTE in cancer patients is less effective with a three-fold increased risk of VTE recurrence compared to non-cancer patients, and it is less safe with more than double rates of major bleeding. Compared to vitamin-K antagonists (VKA), long-term secondary prevention with low molecular weight heparin (LMWH) has been shown to reduce the risk of recurrent VTE in cancer-associated thrombosis (CAT), and therefore, current international guidelines recommend the use of LMWH over VKA. With increasing age, cancer prevalence and VTE incidence increase while renal function decreases. Anti-cancer treatment may impair renal function additionally. Therefore, renal insufficiency is a frequent challenge in CAT patients, which is associated with a higher risk of both bleeding and recurrent VTE. Both VKA and LMWH may be associated with less efficacy and higher bleeding risk in renal insufficiency. Unfortunately, there is a lack of prospective data on renal insufficiency and CAT. A recent sub-analysis from a large randomized controlled trial shows that the bleeding risk in patients with severe renal insufficiency in CAT is not elevated with the use of LMWH compared to VKA while efficacy is maintained. In addition, LMWH treatment has several practical advantages over VKA, particularly in patients with CAT while they are receiving anti-cancer treatment.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Renal Insufficiency; Venous Thromboembolism; Vitamin K; Warfarin

Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature.

Topics: Age Factors; Anticoagulants; Antithrombins; Arthroplasty, Replacement; Atrial Fibrillation; Comorbidity; Critical Illness; Drug Interactions; Drug Monitoring; Hemorrhage; Heparin; Humans; Neoplasms; Perioperative Care; Pulmonary Embolism; Stroke; Venous Thromboembolism; Vitamin K

Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress.

Topics: Animals; Cell Transformation, Neoplastic; Cholesterol; Dimethylallyltranstransferase; Enterocytes; Humans; Intestinal Absorption; Mice; Neoplasms; Oxidative Stress; Vitamin K; Vitamin K 2

Venous thromboembolism (VTE) is not uncommon among patients with cancer and is one of the major causes of mortality and morbidity. Treatment with low-molecular-weight heparin (LMWH) is effective, yet accompanied by the need for daily administration of injections for a prolonged time and (even rarely) thrombocytopenia. The discovery of novel oral anticoagulants (NOACs) was based on an effort to improve the pharmacodynamic and pharmacokinetic properties of previous generation anticoagulants while maintaining efficacy without the need for daily subcutaneous administration and frequent laboratory monitoring. The MEDLINE database was searched using PubMed in order to find relevant studies on the use of NOACs in patients with active malignancy and VTE. Furthermore, critical reading of references in recently published studies and reviews was performed. NOACs appear to be at least equivalent to coumarin anticoagulants in terms of efficacy and safety and their administration is easier, but data specifically concerning patients with active malignancy or comparing them to LMWH in this specific clinical setting are not yet available. Furthermore, patients with active cancer present several unique characteristics and drawing conclusions from studies involving other patient groups may not be appropriate. Specific studies in cancer patients are still pending that will help decide if NOACs will be the drugs of choice in this group of patients in need of efficient and simple to administer treatments.

Topics: Administration, Oral; Anticoagulants; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOAs) have been shown to be as effective and at least as safe as conventional anticoagulation for the prevention of recurrences in patients with VTE. Whether this is the case in patients with cancer-associated VTE remains undefined.. We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. MEDLINE, EMBASE, and CENTRAL were searched up to December 2013 with no language restriction. The primary outcome of the analysis was recurrent VTE. Data on major bleeding (MB) and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs.. Overall, 10 studies comparing DOAs with conventional anticoagulation for treatment of VTE including patients with cancer were included in the review. Six studies were included in the meta-analysis (two with dabigatran, two with rivaroxaban, one with edoxaban, and one with apixaban), accounting for a total of 1,132 patients. VTE recurred in 23 of 595 (3.9%) and in 32 of 537 (6.0%) patients with cancer treated with DOAs and conventional treatment, respectively (OR, 0.63; 95% CI, 0.37-1.10; I2, 0%). MB occurred in 3.2% and 4.2% of patients receiving DOAs and conventional treatment, respectively (OR, 0.77; 95% CI, 0.41-1.44; I2, 0%).. DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer. Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

Topics: Anticoagulants; Antithrombins; Factor Xa Inhibitors; Heparin; Humans; Neoplasms; Recurrence; Venous Thromboembolism; Vitamin K

Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non-vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug-drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Drug Interactions; Humans; Intestinal Absorption; Neoplasms; Venous Thromboembolism; Vitamin K

Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 .

Topics: 4-Hydroxycoumarins; Animals; Anti-Bacterial Agents; Anticoagulants; Antineoplastic Agents; Bacteria; Bacterial Infections; Drug Discovery; Folic Acid; Folic Acid Antagonists; Humans; Indenes; Models, Molecular; Neoplasms; Vitamin B 12; Vitamin K; Vitamins

Patients with cancer are at increased risk of (recurrent) venous thromboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging.. In this review, we will focus on the safety of anticoagulant treatment of VTE in cancer patients. We will discuss the absolute and relative bleeding risks associated with the various types of anticoagulants, specifically focusing on low-molecular-weight heparins (LMWH), vitamin K antagonist (VKA) and the new oral anticoagulants (NOACs).. Monotherapy with LMWH is recommended for treatment of acute VTE in cancer patients. The bleeding risk associated with LMWH is comparable to VKAs, but LMWH are more effective in preventing recurrent VTE. More evidence on the efficacy and safety of NOACs in cancer patients is needed.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Venous Thromboembolism; Vitamin K

Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE.. A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model.. LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies.. The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable.. Austrian Science Fund (FWF-SFB-54).

Topics: Anticoagulants; Causality; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Neoplasms; Risk Assessment; Treatment Outcome; Venous Thromboembolism; Vitamin K

The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin-induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and safety of DOACs in these high-risk populations are underway.

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Pulmonary Embolism; Recurrence; Renal Insufficiency; Risk; Thrombin; Thrombocytopenia; Thrombosis; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Cancer increases the risk of thromboembolic events in patients including those receiving anticoagulation treatments.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.. We conducted a comprehensive search for studies of anticoagulation in cancer patients including 1. a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL Issue 12, 2012), MEDLINE, and EMBASE; 2. a handsearch of conference proceedings; 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. a search of clinicaltrials.gov for ongoing studies.. We included randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE.. Using a standardized data form, we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.. Of 9559 identified citations, 10 RCTs (11 reports) were eligible and reported data for 1981 patients with cancer. We excluded 14 studies in which patients with cancer constituted study subgroups, but did not report outcome data for them. Meta-analysis of seven RCTs comparing LMWH with VKA found no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). The remaining findings did not exclude a beneficial or harmful effect of LMWH compared with VKA for the outcomes of major bleeding (RR 1.07; 95% CI 0.52 to 2.19), minor bleeding (RR 0.89; 95% CI 0.51 to 1.55), or thrombocytopenia (RR 0.98; 95% CI 0.57 to 1.66). We judged the quality of evidence as low for mortality, major bleeding, and minor bleeding, and as moderate for recurrent VTE.One RCT comparing dabigatran with VKA did not exclude beneficial or harmful effects of one agent over the other. One RCT comparing six months' extension of anticoagulation with 18 months of ximelagatran 24 mg twice daily versus no extended ximelagatran did not exclude beneficial or harmful effects for the outcomes of reduction in VTE, mortality, and minor bleeding. One RCT comparing once-weekly subcutaneous injection of idraparinux for three or six months versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) suggested a reduction in recurrent VTE (HR 0.39; 95% CI 0.14 to 1.11) at six months, but did not exclude beneficial or harmful effects for the outcomes of mortality (HR 0.99; 95% CI 0.66 to 1.48) and major bleeding (RR 1.04; 95% CI 0.39 to 2.83).. For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and harms and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality.. To evaluate the relative efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12, 2012), MEDLINE Ovid (January 1966 to February 2013), and EMBASE Ovid (1980 to February 2013). We handsearched conference proceedings, checked references of included studies, used the 'related citations' feature within PubMed, and searched clinicaltrials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing the effects of any dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux with no intervention or placebo or comparing the effects of two different anticoagulants in people with cancer and a CVC.. Teams of two review authors independently used a standardized form to extract data in duplicate. They resolved any disagreements by discussion. They extracted data on risk of bias, participants, interventions, and outcomes. Outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), asymptomatic DVT, major bleeding, minor bleeding, infection, and thrombocytopenia. Where possible, we conducted meta-analyses using the random-effects model.. Of 9559 identified citations, we included 12 RCTs (17 publications) reporting follow-up data on 2823 participants. Two of the RCTs included children. Of the 10 RCTs including 2564 adults, one compared prophylactic dose heparin with low-dose VKA. Three RCTs compared VKA with no VKA and four RCTs compared heparin with no heparin. Two additional trials had three separate arms comparing heparin, VKA, and no intervention. Prophylactic-dose heparin, compared with no heparin, was associated with a statistically significant reduction in symptomatic DVT (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.86; moderate-quality evidence). However, results did not confirm or exclude a beneficial or detrimental effect of heparin on mortality (RR 0.82; 95% CI 0.53 to 1.26; moderate-quality evidence), major bleeding (RR 0.49; 95% CI 0.03 to 7.84; low-quality evidence), infection (RR 1.00; 95% CI 0.54 to 1.85; moderate-quality evidence); thrombocytopenia (RR 1.03; 95% CI 0.80 to 1.33; moderate-quality evidence), or minor bleeding (RR 1.35; 95% CI: 0.62 to 2.92). Low-dose VKAs, compared with no VKAs, were associated with a statistically significant reduction in asymptomatic DVT (RR 0.43; 95% CI 0.30 to 0.62). Results did not confirm or exclude a beneficial or detrimental effect of VKAs on mortality (RR 1.04; 95% CI 0.89 to 1.22; low-quality evidence), symptomatic DVT (RR 0.51; 95% CI 0.21 to 1.22; low-quality evidence), major bleeding (RR 7.60; 95% CI 0.94 to 61.49; very-low-quality evidence), or minor bleeding (RR 3.14; 95% CI 0.14 to 71.51). The use of heparin, compared with VKA was associated with a statistically significant increase in thrombocytopenia (RR 3.73; 95% CI 2.26 to 6.16; low-quality evidence) and asymptomatic DVT (RR 1.74; 95% CI 1.20 to 2.52). However, results did not show or exclude a beneficial or detrimental effect on any of the other outcomes of interest (very-low-quality evidence).. Compared with no anticoagulation, we found a statistically significant reduction of symptomatic DVT with heparin and asymptomatic DVT with VKA. Heparin was associated with a higher risk of thrombocytopenia and asymptomatic DVT when compared with VKA. However, the findings did not rule out other clinically important benefits and harms. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Topics: Adult; Anticoagulants; Catheterization, Central Venous; Child; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Secondary Prevention; Venous Thrombosis; Vitamin K

This study sought to investigate the relative efficacy and safety of non-vitamin K oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) in cancer patients.. A systematic search of the PubMed, EMBASE, and ClinicalTrials.gov databases identified all multicentre, randomised phase III trials investigating the initial use of NOAC against a vitamin K antagonist (VKA) together with subcutaneous heparin or low molecular weight heparin (upstart) for treatment of VTE. Outcomes of interest were recurrent VTE (deep venous thrombosis or pulmonary embolism), and clinically relevant bleeding.. Four randomised controlled phase III trials were included, comprising a total of 19,060 patients randomised to either NOAC or VKA. For patients with active cancer (N = 759), the analysis on the efficacy outcomes demonstrated a trend in favour of NOAC (OR 0.56, 95% CI 0.28-1.13). Similar, analyses on the safety outcomes comparing NOAC to VKA and enoxaparin demonstrated a trend in favour of NOAC (OR 0.88, 95% CI 0.57-1.35).. Point estimates of the effect size suggest an important estimated beneficial effect of NOAC in the treatment of VTE in cancer, in terms of efficacy and safety, but given the small numbers of patients with cancer in the randomised trials, statistical significance was not achieved.

Topics: Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Enoxaparin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.

Topics: Age Factors; Anticoagulants; Chronic Disease; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Male; Neoplasms; Sex Factors; Stroke; Substance-Related Disorders; Thromboembolism; Vitamin K; Warfarin

Vitamin K exists in the food supply as phylloquinone, a plant-based form and as menaquinones (MKs), a collection of isoprenologues mostly originating from bacterial synthesis. Although multiple bacterial species used as starter cultures for food fermentations synthesize MK, relatively little is known about the presence and distribution of MK in the food supply and the relative contribution of MK to total dietary vitamin K intake. Dairy products may be a predominant source of dietary MK in many regions of the world, and there is recent interest in enhancing the MK content of dairy products through identification and selection of MK-producing bacteria in dairy fermentations. This interest is increased by emerging evidence that current dietary recommendations based on the classic role of vitamin K as an enzyme cofactor for coagulation proteins may not be optimal for supporting vitamin K requirements in extrahepatic tissues and that MK may have unique bioactivity beyond that as an enzyme cofactor. Observational studies have reported favorable associations between MK intake and bone and cardiovascular health. Although randomized trials have provided some evidence to support the beneficial effects of MK on bone, the evidence to date is not definitive, and randomized trials have not yet examined MK intake in relation to cardiovascular outcomes. Food production practices provide a means to enhance dietary MK availability and intake. However, parallel research is needed to optimize these production practices, develop comprehensive food MK content databases, and test hypotheses of unique beneficial physiological roles of MK beyond that achieved by phylloquinone.

Topics: Animal Feed; Animals; Bacteria; Biological Availability; Bone and Bones; Cardiovascular System; Dairy Products; Diet; Fermentation; Food; Food Analysis; Health Promotion; Humans; Neoplasms; Nutrition Policy; Nutritional Requirements; Vitamin K; Vitamin K 2

Since its discovery in 1970, protein S (PS) has emerged as a key vitamin K-dependent natural anticoagulant protein at the crossroads of multiple biological processes, including coagulation, apoptosis, atherosclerosis, angiogenesis/vasculogenesis, and cancer progression. Following the binding to a unique family of protein tyrosine kinase receptors referred to as Tyro-3, Axl and Mer (TAM) receptors, PS can lead to regulation of coagulation, phagocytosis of apoptotic cells, cell survival, activation of innate immunity, vessel integrity and angiogenesis, and local invasion and metastasis. Because of these dynamics and multiple functions of PS, which are largely lost following invalidation of the mouse PROS1 gene, this molecule is currently intensively studied in biomedical research. The purpose of this review is to provide a brief chronicle of the discovery and current understanding of the mechanisms of PS signaling, and how PS and their signaling partners regulate various cellular functions, with a particular focus on TAM receptors.

Topics: Animals; Blood Coagulation; Gene Expression Regulation; Humans; Inflammation; Neoplasms; Neovascularization, Physiologic; Promoter Regions, Genetic; Protein S; Vitamin K

Venous thromboembolism (VTE) is a common complication of cancer. Prolonged use of low-molecular-weight heparin in cancer patients provides better VTE prophylaxis compared with vitamin K antagonists. Both therapeutic options have a similar safety profile. If patients on long-term oral anticoagulation are diagnosed with cancer, they should continue treatment with vitamin K antagonists.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Thromboembolism; Venous Thrombosis; Vitamin K

Due to its specific pharmacokinetic profile, tinzaparin, a low-molecular-weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding.. A systematic literature search identified randomized studies on long-term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed-effect model in the overall population and cancer population.. Five randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients.. Tinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE.

Topics: Adult; Aged; Aged, 80 and over; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

Central venous catheters (CVCs) are used extensively in cancer patients for the administration of therapy and phlebotomy. An important complication of CVCs is the development of catheter-related thrombosis (CRT), which becomes symptomatic in approximately 5% of the patients. Several factors, such as insertion location and position of the catheter tip, increase the risk of CRT. Prevention of CRT with systemic anticoagulant prophylaxis has largely been ineffective. In addition, the optimal diagnostic strategy and anticoagulant treatment are unclear due to the lack of well-designed studies. The most recent American College of Chest Physicians guidelines recommend (color) Doppler ultrasound more than venography as the initial diagnostic test in patients with suspected arm thrombosis. Only if the ultrasound is negative and clinical suspicion is high is further testing with D-dimer, serial ultrasound, or venography advocated. In case of CRT, removal of the catheter is not necessary if it is functional and needed for chemotherapy. Anticoagulant treatment of CRT consists of treatment with low-molecular-weight heparin (LMWH) followed by vitamin K antagonists for at least 3 months. Whether long-term treatment with LMWH is more effective than vitamin K antagonists in cancer patients with CRT is unknown, but LMWH may be advocated following the recommendations in lower limb thrombosis and cancer. In addition, the effect of new anticoagulants in CRT has not been studied.

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Fibrin Fibrinogen Degradation Products; Guidelines as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Odds Ratio; Probability; Randomized Controlled Trials as Topic; Risk; Risk Factors; Societies, Medical; Thrombosis; United States; Vitamin K

the development of venous thromboembolism (VTE) in patients with cancer adversely affects their prognosis. Several autopsy- and population-based studies have clearly shown a negative impact of VTE on patient outcome in cancer patients.. an up-to-date review of VTE prophylaxis and treatment in cancer patients is provided with some insights on areas of uncertainty to be answered in the near future. Particular attention is paid to recent cohort studies, randomized clinical trials and consensus guidelines.. cancer patients at a higher risk for VTE may be identified with five variables easily available before initiation of chemotherapy. Long-term treatment with low-molecular-weight heparin (LMWH) demonstrated a superior efficacy over vitamin K antagonists. The intensity and duration of anticoagulant therapy should be tailored to the risk of VTE recurrences or bleeding in an individual patient.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Prognosis; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is associated with a long term risk of recurrence. This risk is at least in part related to the presence of major identifiable risk factors at the time of the index event. It is generally low in the presence of removable risk factors, and very high in the presence of permanent risk factors such as active cancer. This categorization is important because it drives the duration of secondary prevention treatment with anticoagulant drugs. Unfortunately, up to 40-50% of VTE events remain classified as unprovoked. This large group of patients is obviously heterogeneous, with an unpredictable risk of recurrence. Evidences from clinical trials suggest that extending secondary prevention with vitamin K antagonists (VKAs) for 1 or 2 years after an initial course of treatment in patients with unprovoked VTE does not provide additional benefit in terms of reducing the long term risk of recurrence. Prolonging indefinitely the duration of treatment would likely be effective in reducing this risk, but at the cost of unnecessarily expose the majority of patients to several complications, there including major bleeding events, and inconveniences. A number of variables have been identified to predict the individual risk of recurrence in these patients and some clinical prediction rules have been proposed. Improved patients stratification, together with a better understanding of the mechanisms underlying unprovoked VTE, should allow physicians to individually tailor the optimal duration of secondary prevention and to identify those patients (likely the minority) for whom indefinite duration of treatment is warranted.

Topics: Anticoagulants; Clinical Trials as Topic; Humans; Neoplasms; Recurrence; Risk Factors; Venous Thromboembolism; Vitamin K

Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality.. To evaluate the efficacy and safety of anticoagulation in cancer patients with a CVC.. We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2010), MEDLINE (January 1966 to February 2010; accessed via OVID), EMBASE (January 1980 to February 2010; accessed via OVID) and ISI the Web of Science (1975 to February 2010). We handsearched conference proceedings, checked references of included studies and used the "related article" feature within PubMed.. Randomized controlled trials (RCTs) comparing any dose of unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux to no intervention or placebo or comparing two different anticoagulants in cancer patients with a CVC.. Two authors independently extracted data from each included study and resolved their disagreements by discussion.. Of 8187 identified citations, we included 12 RCTs enrolling 3611 patients and assessing either prophylactic dose heparin or low dose VKAs. Prophylactic dose heparin was not associated with a statistically significant effect on death (relative risk (RR) = 0.85; 95% confidence interval (CI): 0.53 to 1.37), symptomatic deep venous thrombosis (DVT) (RR = 0.54; 95% CI: 0.28 to 1.05) asymptomatic DVT (RR = 0.81; 95% CI: 0.64 to 1.02), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78), thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46), or infection (RR = 0.91; 95% CI: 0.49 to 1.68). Similarly, low dose VKAs were not associated with a statistically significant effect on death (RR = 0.97; 95% CI: 0.82 to 1.15), symptomatic DVT (RR = 0.63; 95% CI: 0.35 to 1.11) or major bleeding (RR = 6.93; 95% CI: 0.86 to 56.08). However, they were associated with a statistically significant reduction in asymptomatic DVT (RR = 0.42; 95% CI: 0.28 to 0.61). Studies comparing heparin to VKA found no effects on any of the outcomes of interest.. We found no statistically significant effect of heparin or VKA on the outcomes of interest. However, the findings did not rule out clinically important benefits and harms. Patients with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Topics: Anticoagulants; Catheterization, Central Venous; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K

Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality.. To evaluate the efficacy and safety of anticoagulation in cancer patients with a CVC.. We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2010), MEDLINE (January 1966 to February 2010; accessed via OVID), EMBASE (January 1980 to February 2010; accessed via OVID) and ISI the Web of Science (1975 to February 2010). We handsearched conference proceedings, checked references of included studies and used the "related article" feature within PubMed.. Randomized controlled trials (RCTs) comparing any dose of unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux to no intervention or placebo or comparing two different anticoagulants in cancer patients with a CVC.. Two authors independently extracted data from each included study and resolved their disagreements by discussion.. Of 8187 identified citations, we included 12 RCTs enrolling 3611 patients and assessing either prophylactic dose heparin or low dose VKAs. Prophylactic dose heparin was not associated with a statistically significant effect on death (relative risk (RR) = 0.85; 95% confidence interval (CI): 0.53 to 1.37), symptomatic deep venous thrombosis (DVT) (RR = 0.54; 95% CI: 0.28 to 1.05) asymptomatic DVT (RR = 0.81; 95% CI: 0.64 to 1.02), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78), thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46), or infection (RR = 0.91; 95% CI: 0.49 to 1.68). Similarly, low dose VKAs were not associated with a statistically significant effect on death (RR = 0.97; 95% CI: 0.82 to 1.15), symptomatic DVT (RR = 0.63; 95% CI: 0.35 to 1.11) or major bleeding (RR = 6.93; 95% CI: 0.86 to 56.08). However, they were associated with a statistically significant reduction in asymptomatic DVT (RR = 0.42; 95% CI: 0.28 to 0.61). Studies comparing heparin to VKA found no effects on any of the outcomes of interest.. We found no statistically significant effect of heparin or VKA on the outcomes of interest. However, the findings did not rule out clinically important benefits and harms. Patients with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Topics: Anticoagulants; Catheterization, Central Venous; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K

Vitamins are essential nutrients for human metabolism, playing an important role as coenzymes or enzymes in many vital processes for the normal functioning of the body. In recent years, it has become apparent that vitamins are crucial in health and human disease, due to several studies that studied this relationship. Currently, it is known that vitamins can have an important role in the prevention and treatment of cancer, but until now no conclusive results were obtained. In this review, we will present the work and more relevant conclusions obtained in recent years of investigation about the relationship between vitamins and cancer, namely vitamin A, vitamin B complex, vitamin C, vitamin D, vitamin E, and vitamin K.

Topics: Ascorbic Acid; Chemoprevention; Dietary Supplements; Humans; Neoplasms; Randomized Controlled Trials as Topic; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K; Vitamins

Cancer increases the risk of thromboembolic events even while on anticoagulation.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science.. Randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively-confirmed VTE.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.. Of 8187 identified citations, nine RCTs were eligible and reported data for 1908 patients with cancer. Meta-analysis of seven RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). Other results did not exclude a beneficial or harmful effect of LMWH compared to VKA for the outcomes of major bleeding (RR 1.05; 95% CI 0.53 to 2.10) or thrombocytopenia (RR 1.02; 95% CI 0.60 to 1.74). The quality of evidence was low for mortality, major bleeding and minor bleeding and moderate for recurrent VTE. One RCT comparing six months extension of anticoagulation with 18 months ximelagatran 24 mg twice daily versus placebo found a reduction in VTE (HR 0.16; 95% CI 0.09 to 0.30) but did not exclude beneficial or harmful effects for the outcomes of mortality and bleeding. One RCT, comparing dabigatran to VKA, did not exclude beneficial or harmful effect of one agent over the other.. For the long-term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Pulmonary embolism (PE) is common and the majority of patients survive the acute event. Survivors are at increased risk for adverse outcomes, including persistent thrombi, recurrent embolism, chronic thromboembolic pulmonary hypertension (CTEPH), and death. Anticoagulation protects against recurrence, which has a high mortality rate. The recommended duration of anticoagulation for patients with reversible PE risk factors is 3 months. For patients with idiopathic PE or persistent risk factors, extended duration of anticoagulation is preferred, balanced with an individual patient's risk of hemorrhage, which in itself is a major cause of morbidity and mortality. Among patients with malignancy who develop venous thromboembolism (VTE), low-molecular-weight heparin is preferred over oral vitamin K antagonists in the first 6 months. Thereafter, anticoagulation should be continued indefinitely with either low-molecular-weight heparin or oral vitamin K antagonists. Inferior vena cava filters are not routinely recommended and should only be used in patients who have a contraindication to anticoagulation. Patients who have had VTE and with persistent or recurrent dyspnea should be evaluated for recurrence of VTE or development of CTEPH. Patients with recurrent VTE should be anticoagulated indefinitely. Routine screening for CTEPH in asymptomatic patients is not recommended. Echocardiography often provides the first indication of the presence of pulmonary hypertension. Once presence of CTEPH is established by right-sided heart catheterization and perfusion imaging (ie, ventilation/perfusion scintigraphy, computed tomography angiography, or pulmonary angiography), patients should be referred early to a center with expertise, as it is potentially surgically curable by pulmonary endarterectomy. Those who are deemed inoperable after being evaluated may gain symptomatic benefit from drugs approved for idiopathic pulmonary arterial hypertension. Lung transplantation may also be an option for patients who are not candidates for pulmonary endarterectomy.

Topics: Anticoagulants; Blood Coagulation Tests; Chronic Disease; Drug Administration Schedule; Dyspnea; Heparin, Low-Molecular-Weight; Humans; Hypertension, Pulmonary; Neoplasms; Pulmonary Embolism; Risk Factors; Vena Cava Filters; Venous Thrombosis; Vitamin K

The risk of venous thromboembolic events (VTE) in cancer patients is higher than in the general population. Treatment may also increase this risk in these patients. Based on the appropriate criteria (of which the most important are the current ministerial guidelines) thrombosis prophylaxis should be started (given that there is no contraindication) on these patients and be continued while they are at risk. In the event of permanent risk thrombosis prophylaxis should be given lifelong. The drug of choice is low-molecular-weight heparin (LMWH) which is safer and more effective than the oral vitamin K antagonists. Platelet aggregation inhibitors have proved unsuccessful in this patient group. The evidence so far suggests that LMWH (during VTE prophylaxis) can have a positive impact on the course of cancer and perhaps it will be registered under the indication section for cancer patients in the future.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Assessment; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Infusions, Intravenous; Injections, Subcutaneous; Long-Term Care; Neoplasms; Patient Acceptance of Health Care; Randomized Controlled Trials as Topic; Secondary Prevention; Survival Analysis; Thrombin; Venous Thromboembolism; Vitamin K

The optimal course of oral anticoagulant therapy is determined according to the risk of recurrent venous thromboembolism after stopping therapy and the risk of anticoagulant-related bleeding. Clinical risk factors appear to be important in predicting the risk of recurrence whereas the influence of biochemical and morphological tests is uncertain. The risk of recurrent venous thromboembolism is low when the initial episode was provoked by a reversible major risk factor (surgery): 3 months of anticoagulation is sufficient. Conversely, the risk is high when venous thromboembolism was unprovoked or associated with persistent risk factor (cancer): 6 months or more prolonged anticoagulation is necessary. After this first estimation, the duration of anticoagulation may be modulated according to the presence or absence of certain additional risk factors (major thrombophilia, chronic pulmonary hypertension, massive pulmonary embolism): 6 months if pulmonary embolism was provoked and 12 to 24 months if pulmonary embolism was unprovoked. If the risk of anticoagulant-related bleeding is high, the duration of anticoagulation should be shortened (3 months if pulmonary embolism was provoked and 3 to 6 months if it was unprovoked). Lastly, if pulmonary embolism occurred in association with cancer, anticoagulation should be conducted for 6 months or more if the cancer is active or treatment is on going. Despite an increasing knowledge of the risk factors for recurrent venous thromboembolism, a number of issues remain unresolved. Randomised trials comparing different durations of anticoagulation are needed.

Topics: Age Factors; Anticoagulants; Antiphospholipid Syndrome; Cohort Studies; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hypertension, Pulmonary; Male; Neoplasms; Prospective Studies; Pulmonary Embolism; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Sex Factors; Thrombophilia; Time Factors; Vena Cava Filters; Venous Thrombosis; Vitamin K

Venous thromboembolism (VTE) is a major therapeutic issue in cancer patients. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines in the management of VTE in cancer patients according to the SOR (Standards, Options and Recommendations) methodology. A literature review of the studies published on this topic between 1999 and 2007 was performed. The guidelines were developed from the analysis of 38 out of 418 publications selected. They were peer-reviewed by 65 independent experts. The treatment of VTE in patients with cancer, including those with intracranial malignancies, should be based on low-molecular-weight heparins administered at therapeutic doses for at least 3 months. In the event of recurrent VTE, pulmonary embolism with hemodynamic failure or contra-indication to anticoagulant treatment, the indications and usages of vena cava filters and thrombolytic drugs should be the same as in non-cancer patients.

Topics: Antineoplastic Agents; France; Heparin; Humans; Neoplasms; Practice Guidelines as Topic; Venous Thromboembolism; Vitamin K

We evaluated whether the incidence of recurrent venous thromboembolic events (VTEs) during and after therapy differs for patients treated with full or reduced doses of low-molecular-weight heparin (LMWH) used long term compared with vitamin K antagonists (VKAs).. We identified randomized studies of long-term treatment with LMWH or VKA by searching MEDLINE, EMBASE, BIOSIS, and PASCAL. Seventeen studies were included, with 4,002 patients.. In the assessment at 12 months of 1,957 patients without cancer, the recurrence rates of VTE in the LMWH/VKA groups were 8.3%/7.6% in the studies using full doses and 12.3%/12.1% in those using prophylactic doses. However, combined analysis after treatment to 1 year showed a nonsignificant (NS) trend to lower recurrent symptomatic VTE in favor of VKA (RR = 1.46, 95% CI 0.96-2.23). In 1,292 patients with cancer the recurrence rates of VTE in the LMWH/VKA groups were 6.5%/17.9% (p = 0.005) in the studies using full doses, 7.1%/13.4% (p = 0.002) in the studies using intermediate doses, and 14.3%/19.1% (p = NS) in the studies using prophylactic doses. Furthermore, the recurrences of VTE after discontinuation of treatment in the LMWH/VKA groups were 1.6%/9.5% (RR = 0.25, 95% CI 0.06-1.1) in 252 patients with full doses and 12%/7.4% (RR = 1.49, 95% CI 0.3-7.48) in 52 patients with prophylactic doses. In this population with cancer, the full-treatment LMWH regimen did not produce more major bleeding events than intermediate or prophylactic doses (5.1% vs. 6.3% or 8.1%, respectively).. Full-dose LMWH for 3-6 months is as safe as intermediate and prophylactic doses for the long-term treatment of deep vein thrombosis. In patients with cancer it appears that there is an excess of VTE recurrence after treatment with prophylactic doses that does not occur with full therapeutic doses.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

The relation of cancer to thromboembolism has been described since the mid 1800s. Different studies in animal and in vitro models have confirmed the link between the haemostatic system and both tumor stroma formation and metastasis. Although the mechanisms of warfarin effects on cancer are not elucidated, but are based on hypothesis, various studies have reported interesting results in this setting. But does warfarin added to recommended anti-tumour therapy improve survival of cancer patients? For the time being it is difficult to answer this question. Data from the literature are few and sometimes contradictory. Trials are characterized by important differences in studied cohorts, histological types of cancers evaluated, and in the treatment protocols. Most studies show that there is benefit from the addition of warfarin to chemotherapy in the tumour development, expansion and on the patient survival, especially in particular types of cancers. These data, although fascinating, do not rationalize the use of anticoagulation in the routine prophylaxis of cancer, however, they call for efforts in preparing large scale randomized trials to elucidate the effect of anticoagulation in the setting of neoplastic disease.

Topics: Animals; Anticoagulants; Clinical Trials as Topic; Humans; Neoplasms; Thromboembolism; Vitamin K; Warfarin

The recommendations for anticoagulation in over 80 years old patients are based on the thromboembolic/bleeding risk relation. They add to the published recommendations for the specific indications. Low-molecular-weight heparin (LMWH) is used to prevent thromboembolism postoperatively. Compression stockings and/or intermittent pneumatic compression are used if bleeding risk is very high. The dose is increased starting at day two if the thromboembolic risk is very high. Bleeding and thromboembolic risks are re-evaluted daily. The antithrombotic therapy is adjusted accordingly. Prophylaxis of thromboembolism in patients with acute illnesses and bedrest is performed according postoperative care. Two-thirds of therapeutic doses of low-molecular-weight heparin are used to treat acute venous thromboembolism. Reduced renal function (creatinine clearance <30 ml/ min for most LMWHs or <20 ml/min for tinzaparin) should result in a further reduction of dose. Intensity and duration of prophylaxis of recurrent events with vitamin K antagonist or LMWH in malignancy follow current or herein described recommendations. Patients with atrial fibrillation are treated with vitamin K antagonists adjusted to an INR of 2-3 for prophylaxis of embolism. Further details of anticoagulant therapy should be in agreement with the national or international recommendations.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Kidney Function Tests; Neoplasms; Postoperative Complications; Risk Factors; Secondary Prevention; Stockings, Compression; Thromboembolism; Vitamin K

Long-term anticoagulant treatment is highly effective in preventing recurrent Venous Thrombo-Embolism (VTE) in patients with idiopathic Deep Vein Thrombosis (DVT) of the lower limbs, though associated with an increased risk for major bleeding that may offset the benefits of anticoagulation. Accordingly to recent guidelines, patients with idiopathic DVT should be treated for at least 3 months and then should be evaluated for the risk-benefit ratio of long-term therapy. However, such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. In recent studies, markers for the assessment of the individual risk for recurrent thrombosis have been proposed, which can be of help to establish the optimal duration of VKA treatment; among them, the D-dimer (D-d) assay and the Residual Vein Thrombosis (RVT) assessment by Compression Ultra-Sonography (CUS) were shown to be the most suitable. Studies' results showed that negative results of these parameters after 3 to 6 months of therapy, identify a group of patients at low-risk for recurrent thrombosis in whom VKA treatment can be withheld. In the present review we will discuss advantages and potential limits of using these individual markers for the management of patients with a first episode of DVT of the lower limbs.

Topics: Anticoagulants; Drug Administration Schedule; Fibrin Fibrinogen Degradation Products; Humans; Neoplasms; Risk Factors; Secondary Prevention; Ultrasonography; Venous Thrombosis; Vitamin K

Patients with malignancy have a 4-fold increase in the risk of developing a venous thrombosis and a 3-fold increase in risk of bleeding. Both low-molecular-weight-heparin (LMWH) and vitamin K antagonists (VKA) have been used for treatment of cancer-associated thrombosis. However, the best anticoagulation approach remains a matter of debate.. In adult patients with cancer and an acute venous thromboembolic event we sought to determine the rates of recurrent venous thromboembolism (VTE) and major hemorrhage when treated with prolonged LMWH therapy compared to vitamin-K antagonists.. A systematic literature search strategy was used to identify potential trials on MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Medline in-process using an OVID interface. Risk assessment of bias of randomized controlled trials (RCTs) was performed according to the Cochrane Collaboration-Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome measure was symptomatic VTE recurrence rate during the anticoagulation period. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated using random -effects and fixed-effects model.. Five articles met our inclusion criteria. All compared LMWH and VKA for secondary prevention of VTE. The pooled RR of VTE recurrence was 0.53 (95% CI: 0.36-0.76; p=0.007). The pooled RR of major bleeding was 0.98 (95% CI: 0.49-1.93, p=0.95). Minor bleeding events and all cause mortality were similar between the 2 intervention arms.. The results of our review suggest that the long term use of LMWH after the acute first week of treatment is superior to VKAs for secondary prevention of venous thromboembolism in adult patients with cancer.

Topics: Adult; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Adult; Aged; Anticoagulants; Antineoplastic Agents; Child; Clinical Trials as Topic; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Multicenter Studies as Topic; Neoplasms; Quality of Life; Recurrence; Thrombolytic Therapy; Venous Thromboembolism; Vitamin K

Cancer and its therapies increase the risk of venous thromboembolism. Compared to patients without cancer, patients with cancer anticoagulated for venous thromboembolism are more likely to develop recurrent thrombotic events and major bleeding. Addressing all important outcomes including harm is of great importance to make evidence based health care decisions. The objective of this study was to compare low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism in patients with cancer.. A systematic review of the medical literature. We followed the Cochrane Collaboration methodology for conducting systematic reviews. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.. Eight randomized controlled trials (RCTs) were eligible and reported data for patients with cancer. The quality of evidence was low for death and moderate for recurrent venous thromboembolism. LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in venous thromboembolism (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74).. For the long term treatment of venous thromboembolism in patients with cancer, LMWH compared to VKA reduces venous thromboembolism but not death.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Cancer is linked with hypercoagulability and risk of thrombosis and this close association was recognized by Armand Trousseau in 1865. The relation between cancer and blood coagulation is reciprocal: cancer induces a hypercoagulable state and predisposes to thrombosis and activation of platelets, blood coagulation and fibrinolysis interfere with tumor cell biology, tumor growth, angiogenesis and metastatic process. In the present article, we analyze the clinical trials which assessed the influence of anticoagulant treatment on the survival of patients with cancer. The available data show that low-molecular-weight heparins (LMWHs) tend to be more effective and safer than vitamin K antagonists (VKA) in improving survival in patients with cancer. The beneficial effect of anticoagulation with either LMWHs or VKA is not universal for all patients with cancer. There are some histological types of cancers which, at early stages, appear to be more sensitive than others to the effect of anticoagulant treatment. The available clinical trials, although limited, are encouraging for the beneficial effect of anticoagulant treatment on the survival of cancer patients. More clinical trials are needed, targeting groups of patients homogenous regarding the type of cancer, the stage of the disease and life expectancy. The forthcoming clinical trials have to address some issues regarding the optimal dose, the timing and the duration of treatment with LMWH in relation to chemotherapy or other anticancer therapies.

Topics: Animals; Anticoagulants; Clinical Trials as Topic; Double-Blind Method; Drug Screening Assays, Antitumor; Fibrinolytic Agents; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Mice; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic; Research Design; Survival Analysis; Thrombophilia; Thrombosis; Vitamin K; Warfarin

Cancer increases the risk of thromboembolic events and the risk of recurrent thromboembolic events while on anticoagulation.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism (VTE) in patients with cancer.. A comprehensive search was undertaken including a January 2007 search of electronic databases; Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2007, Issue 1). MEDLINE (1966 onwards; accessed via OVID), EMBASE (1980 onwards; accessed via OVID) and ISI the Web of Science. Hand search of the proceedings of the American Society of Clinical Oncology and of the American Society of Hematology. Checking of references of included studies, relevant papers and related systematic reviews. Use of "related article" feature in PubMed; and (5) search of ISI the Web of Science for papers citing landmark studies.. Randomized controlled trials (RCTs) comparing long term treatment with LMWH versus oral anticoagulants (VKA or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome.. Of 3986 identified citations, eight RCTs were eligible and reported data for patients with cancer. Their overall methodological quality was moderate. Meta-analysis of six RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in VTE (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74). One RCT compared tinzaparin and dalteparin and showed no differences in the outcomes of interest. One RCT compared a six months extension of anticoagulation with 18 months Ximelagatran 24mg twice daily versus placebo. It showed a reduction in VTE (HR = 0.16; 95% CI 0.09 to 0.30) with no apparent effect on survival or bleeding.. For the long term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Tumourous diseases are associated with haemorrhagic as well as thrombotic complications. Trousseau described in 1865 a mutual association between tumourous diseases and venous thromboembolism. As many as 15-20% patients with venous thromboembolism have an undetected malignity, which equals a prevalence of 2-3% in the population. From this ensues the relative risk of a newly diagnosed malignity which is higher during the first year after venous thromboembolism. Migrating thrombophlebitis is a relatively specific sign in tumours, in particular in pancreatic tumours. In the pathogenesis of venous thromboembolisms in tumourous diseases, the following factors play a significant part: elevated coagulation parameters, reduced fibrinolysis, frequent immobilization, surgical operations in the case history, chemotherapy, hormonal therapy and central venous catheters. Conventional long term management of VTE involves the use of vitamin K antagonists, such as warfarin, to reduce the risk of recurrence. Recent evidence-based approach in long term management of VTE in patients with tumorous disease shows that the use of LMWH offers an effective alternative to VKAs with higher efficacy, without a significantly increased risk of bleeding, and without the need for regular laboratory monitoring.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Factors; Thromboembolism; Vitamin K

Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality.. To evaluate the efficacy and safety of anticoagulation in reducing venous thromboembolic (VTE) events in cancer patients with CVC.. A comprehensive search for studies of anticoagulation in cancer patients up to January 2006 was conducted in the following databases: The Cochrane Central Register of Controlled Trials ( CENTRAL), MEDLINE, EMBASE and ISI the Web of Science.. Randomized controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), fondaparinux or ximelagatran to no intervention or placebo in cancer patients with a CVC or comparing two different anticoagulants.. Data was extracted on methodological quality, patients, interventions and outcomes including all cause mortality (primary outcome), premature CVC removal, catheter-related infections, CVC site and non CVC site deep venous thrombosis (DVT), pulmonary embolism (PE), major and minor bleeding and thrombocytopenia.. Of 3986 identified citations nine RCTs were included in the meta-analysis including one published as an abstract and one focusing on paediatric patients not included in the meta-analysis. None of these RCTs tested fondaparinux or ximelagatran. The use of heparin in cancer patients with CVC was associated with a trend towards a reduction in symptomatic DVT (Relative Risk (RR) = 0.43; 95% Confidence Interval (CI): 0.18 to 1.06), but the data did not show any statistically significant effect on mortality (RR = 0.74; 95% CI: 0.40 to 1.36), infection (RR = 0.91; 95% CI: 0.36 to 2.28), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78) or thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46). The effect warfarin on symptomatic DVT was not statistically significant (RR = 0.62; 95% CI: 0.30 to 1.27). When studies assessing different types of anticoagulants were pooled, symptomatic DVT rates were significantly reduced (RR = 0.56; 95% CI: 0.34 to 0.92).. Cancer patients with CVC considering anticoagulation, should consider the possible benefit of reduced incidence of thromboembolic complications with the burden and harms of anticoagulation. Future studies should be adequately powered and evaluate the effects of newer anticoagulants such as fondaparinux and ximelagatran in cancer patients with CVC.

Topics: Anticoagulants; Catheterization, Central Venous; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K

Pathology studies of human cancers suggested to early investigators that the hemostatic system may play an important role in cancer metastasis. Subsequent studies in animal models have demonstrated a reduction of tumor metastasis and improved animal survival with systemic anticoagulation. In many of these experiments, vitamin K antagonists (VKAs) were utilized. Although warfarin was effective in reducing metastasis in a majority of these animal models, effects on the growth of the primary tumor and on animal survival have been less consistent. Clinical studies on the effect of warfarin in human malignancy are limited and less than conclusive. Several small, uncontrolled and controlled clinical studies have been reported but do not definitively suggest a benefit in most malignancies. However, none of the studies of VKAs in humans are adequately designed or sufficiently powered to definitively exclude an impact of oral anticoagulants on cancer survival. Because of the difficulties in managing VKA oral anticoagulation in cancer patients and recent studies suggesting a positive effect on cancer survival with low-molecular-weight heparins, it unlikely that further studies on the use of VKAs in cancer patients will be undertaken.

Topics: Animals; Anticoagulants; Disease Progression; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Survival Rate; Vitamin K; Warfarin

Venous thromboembolism (VTE) in patients with cancer follows an aggressive course, and it is often resistant to traditional regimens of pharmacological prophylaxis and treatment. Anticoagulant-related bleeding is also common and can complicate VTE treatment as well as cancer therapy. Consequently, the most effective approach to reducing the burden of VTE and its associated morbidity and mortality is to provide appropriate prophylaxis. Few clinical trials have focused on the prevention of VTE in this high-risk patient population, and they consistently demonstrate the efficacy and safety of anticoagulant prophylaxis in reducing thrombotic complications. Currently, low-molecular-weight heparins and oral vitamin K antagonists are the most commonly used anticoagulants for primary prevention in patients with cancer, but compliance with consensus guidelines is poor. Novel anticoagulants with a convenient and favorable risk/benefit profile may help to improve prophylaxis utilization and treatment. This review will provide a summary of the evidence on the primary prevention of VTE in patients with cancer.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Calcific arteriolopathy (CA), also known as " Calciphylaxis " describes a phenomenon of necrosis, mainly cutaneous and sometimes systemic, due to the obliteration of the arteriole's lumen. Initially there are under-intimal calcium deposits, and then the thrombosis occurs leading to the necrosis. CA affects mainly the renal insufficient hemodialysed patient, but not exclusively. We present 4 cases which illustrate well the etiologic spectrum of CA: terminal renal insufficiency, neoplasia, primary hyperparathyroidism, proteinuria, vitamin K inhibitors. We describe the AC's epidemiology, its cutaneous and systemic clinical presentations, its treatment. We make the hypothesis that CA is a strong risk marker in matter of cardiac mortality and we discuss this point.. In this article we describe the numerous breakthroughs that have been made in matter of research about calcification over the past few years: inhibitors of calcium phosphate deposition, vitamin D and PTH1R, protein-calcium complexes, cell death, induction of bone formation. These data are analysed from a clinical point of view with practical purposes. We present CA not only as a cutaneous disease but as a systemic pathology.. The CA epidemiology is an incentive to more diagnosis suspicion in front of organ infarct involving a patient likely to be concerned by CA. The scientific and therapeutic breakthroughs in matter of calcification enable a better prevention of the disease. Nevertheless it remains very difficult to cure when installed.

Topics: Aged; Arterioles; Biopsy; Calciphylaxis; Calcium; Coronary Artery Disease; Fatal Outcome; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Leg Ulcer; Male; Middle Aged; Neoplasms; Phosphates; Proteinuria; Skin; Vitamin K

The risk of venous thromboembolism (VTE) is increased in association with malignancy, and has a potential to produce significant morbidity and mortality. Treatment of such patients with anticoagulants is associated with both benefit and a high rate of complications. In the early phase, the treatment is usually achieved with low molecular weight heparin (LMWH), which has a number of advantages over unfractionated heparin (UFH): once or twice daily administration, no necessary laboratory monitoring, lesser risk of bleeding and no drugs interactions. Nevertheless, the UFH is the anticoagulant of choice when a rapid anticoagulant effect or stop of anticoagulant effect is required, in the treatment of massive pulmonary embolism or severe renal insufficiency. Prolonged anticoagulation with LMWH (over 3 or 6 months) appears to be beneficial on survival for such patients. The subject of anticoagulation in patients with primary or secondary brain tumours is controversial. The long-term anticoagulation mainly use LMWH or vitamin K antagonist. The last ones are more difficult to use because of an unpredictable response with higher rate of recurrence and bleeding. The optimal duration of treatment is not known but the patients should be treated for at least 6 months, even at least 12 months after a second episode of venous thromboembolism. On the primary prevention in high-risk surgical oncology, the LMWH are at least as effective and safer as UFH when the optimal dose was administered. For the medical patients, the use of prophylactic anticoagulant treatment is less clear except the patients who are bedridden for prolonged periods of time. For the secondary prevention, the LMWH seems to be more effective over vitamin K antagonists. For these patients, the anticoagulant therapy is recommended indefinitely or until cancer is resolved.

Topics: Anticoagulants; Antineoplastic Agents, Hormonal; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Postoperative Complications; Tamoxifen; Thromboembolism; Venous Thrombosis; Vitamin K

The promising theoretical possibilities of antioxidant prevention and protection against vascular diseases and neoplasms could not have been realized as yet. The author searches into the causes of this failure by analyzing data of recent literature. Previous preventive trials as well as newly discovered pharmacological and molecular biological effects of antioxidants are reviewed. Results of meta-analyses on prevention trials of vascular disease by vitamin-E and those of gastrointestinal cancers are also included. The lately recognized properties of antioxidants are surveyed with special regard to their capability of modulating apoptosis, inducing gene expressions and their transformation into pro-oxidants. The harmful consequence of high doses of a single antioxidant is emphasized. The retinoids, vitamins D and K possess both pro-apoptotic and antiproliferative activity, while N-acetylcysteine exerts mainly anti-apoptotic effects. Since the effects of the eight vitamin E homologues are different in many respects, alpha-tocopherol can not be regarded as vitamin E of full value. Antioxidant supply from natural sources does not seem to be sufficient for an adequate preventive effect. The author recommends such a combination in which physiological amounts of vitamins C, D, K and B-complex, N-acetylcysteine, vitamin E of natural origin might be complemented by allopurinol, co-enzyme Q-10 and alpha-lipoic acid. A diet rich in flavonoids and carotenoids is essential. Application of appropriate laboratory methods is of great value in the individualization, monitoring and control of antioxidant treatment.

Topics: Acetylcysteine; Allopurinol; Antioxidants; Apoptosis; Ascorbic Acid; Cardiovascular Diseases; Clinical Trials as Topic; Coenzymes; Flavonoids; Humans; Meta-Analysis as Topic; Neoplasms; Selenium; Ubiquinone; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

Venous thromboembolism (VTE) is a common complication in cancer patients that results in significant morbidity and mortality. Long-term treatment options for cancer patients who experience VTE include vitamin K antagonists (VKAs), low molecular weight heparins (LMWHs), and inferior vena caval (IVC) filters. Cancer patients have a two- to fourfold higher risk for experiencing recurrent VTE and major bleeding during chronic VKA therapy than patients without malignancies. Recent randomized clinical trials have shown that LMWHs rather than oral VKAs are preferred for initial chronic treatment of VTE in patients with advanced cancer. One factor potentially limiting the broader use of LMWH for chronic therapy in the United States is its higher acquisition cost. Efficacy, cost, drug availability, patient comorbidities, and concomitant medications all need to be considered when selecting chronic VTE therapy. Cancer patients with VTE should be treated for as long as their disease is active to minimize the incidence of recurrence. Use of IVC filters should generally be reserved for patients at high risk for recurrent VTE who have contraindications to anticoagulation. Several new anticoagulants are being investigated that promise greater therapeutic choices and potentially better outcomes for cancer patients with VTE.

Topics: Heparin, Low-Molecular-Weight; Humans; Neoplasms; Thromboembolism; Vena Cava Filters; Venous Thrombosis; Vitamin K

Gas6 and protein S are two homologous secreted proteins that depend on vitamin K for their execution of a range of biological functions. A discrete subset of these functions is mediated through their binding to and activation of the receptor tyrosine kinases Axl, Sky and Mer. Furthermore, a hallmark of the Gas6-Axl system is the unique ability of Gas6 and protein S to tether their non receptor-binding regions to the negatively charged membranes of apoptotic cells. Numerous studies have shown the Gas6-Axl system to regulate cell survival, proliferation, migration, adhesion and phagocytosis. Consequently, altered activity/expression of its components has been detected in a variety of pathologies such as cancer and vascular, autoimmune and kidney disorders. Moreover, Axl overactivation can equally occur without ligand binding, which has implications for tumorigenesis. Further knowledge of this exquisite ligand-receptor system and the circumstances of its activation should provide the basis for development of novel therapies for the above diseases.

Topics: Animals; Apoptosis; Axl Receptor Tyrosine Kinase; c-Mer Tyrosine Kinase; Cell Adhesion; Crystallography, X-Ray; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Models, Biological; Neoplasms; Oncogene Proteins; Protein S; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Saccharomyces cerevisiae Proteins; Signal Transduction; Vitamin K

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Postoperative Complications; Premedication; Thromboembolism; Venous Thrombosis; Vitamin K

The aim of this review is to perform a critical analysis of all completed studies evaluating the role of anticoagulant agents in improving survival in patients with cancer. Furthermore, the rationale for testing anticoagulant drugs in this setting, and the recent basic research studies providing new evidence for a link between tissue malignant transformation of tissues and hemostatic proteins, are also briefly reviewed.. Four prospective randomized clinical studies to test the impact of low-molecular-weight heparin on mortality in cancer patients have been published. The results suggest a benefit from treatment, particularly in patients with nonadvanced disease. Inhibition of specific clotting pathways by anticoagulants may be hypothesized, particularly those involved in the malignant behavior of tissues. In the same vein, a direct action of anticoagulants on mechanisms of tumor growth and progression can be considered.. An antineoplastic effect of anticoagulant agents has often been suggested. Heparin and vitamin K antagonists have both been tested in this context. Heparin has been more extensively studied. Data from clinical trials of thromboprophylaxis in cancer patients have suggested that heparin may have beneficial effects on survival in these patients, with a major role for low-molecular-weight heparin compared with unfractionated heparin. Recently, the results of new prospective randomized clinical trials to evaluate the effect of low-molecular-weight heparin on cancer survival have become available. The published data look promising and provide an important step forward in the research knowledge in this field.

Topics: Anticoagulants; Blood Coagulation; Disease Progression; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Vitamin K

Topics: Animals; Clinical Trials as Topic; Humans; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Pharmacogenetics; Polymorphism, Genetic; Protective Agents; Quinones; Vitamin K

Bleeding occurs in up to 10% of patients with advanced cancer. It can present in many different ways. This article provides a qualitative review of treatment options available to manage visible bleeding. Local modalities, such as hemostatic agents and dressings, radiotherapy, endoscopic ligation and coagulation, and transcutaneous arterial embolization, are reviewed in the context of advanced cancer, as are systemic treatments such as vitamin K, vasopressin/desmopressin, octreotide/somatostatin, antifibrinolytic agents (tranexamic acid and aminocaproic acid), and blood products. Considerations at the end of life are described.

Topics: Antifibrinolytic Agents; Bandages; Blood Transfusion; Endoscopy; Hemorrhage; Hemostatic Techniques; Humans; Neoplasms; Radiotherapy; Somatostatin; Terminal Care; Vasopressins; Vitamin K

Topics: Aging; Anti-Bacterial Agents; Biomarkers; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Kidney Diseases; Neoplasms; Protein Precursors; Prothrombin; Reference Values; Risk Factors; Specimen Handling; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Policies for giving babies vitamin K prophylactically at birth have been dictated, over the last 60 years, more by what manufacturers decided on commercial grounds to put on the market, than by any informed understanding of what babies actually need, or how it can most easily be given. By a pure fluke a 1 mg IM dose, designed to prevent early vitamin deficiency bleeding ("haemorrhagic disease of the newborn") has been found to protect against late deficiency bleeding-a condition unrecognised at the time this policy took hold. Alternative strategies for oral prophylaxis are now opening up (see pp 109 and 113), but these are also, at the moment, dictated more by what the manufacturers choose to provide than by what would make for ease of delivery either in poor countries, or in the developed world.

Topics: Antifibrinolytic Agents; Humans; Infant, Newborn; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Although it has been widely known that extracellular signal-regulated kinase (ERK) pathway stimulates cell growth and have a protective effect from cell death, recent findings propose pro-apoptotic action of ERK phosphorylation. Since it was found that Vitamin K3 (VK3) or its analog was a potent growth inhibitor and inducer for ERK phosphorylation through specific pathway in cancer cell line, the critical role of ERK phosphorylation in growth inhibitory actions can be discussed. VK3 induced receptor tyrosine phosphorylation and occurred at growth inhibitory concentrations. The phosphorylation of growth factor receptor by VK3 was indicated to be functional, since these were connected with growth factor receptor-bound protein 2 (Grb2) and SOS1. The growth factor stimulated to induce cyclin D1 protein and increase DNA contents. In addition, ERK inhibitor antagonized increase of cyclin D1, suggesting that ERK phosphorylation by growth factor might play an essential role for cell growth. By contrast, ERK phosphorylation by VK3 was more prolonged and intense than the signal induced by growth factors and the antagonize ERK phosphorylation protected from growth inhibition by VK3. The additional and extra ERK spot by VK3, compared with those obtained from growth factor, was detected on two dimensional gels, and this was completely and selectively antagonized by ERK inhibitor. Therefore, the overexpressed ERK phosphorylation was suggested to originate from the additional spot, which played a critical role in growth inhibitory action, despite ERK phosphorylation by growth factor had an essential association with cell growth. The new approach to consider the signal transduction can be one of the most favorite strategies for cancer therapy in the future.

Topics: Animals; Humans; Mitogen-Activated Protein Kinases; Neoplasms; Phosphorylation; Receptor Protein-Tyrosine Kinases; Signal Transduction; Vitamin K

Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential. Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects. Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos. Tyrosine kinases associated with cyclins have also been shown to be affected by vitamin K, which can lead to cell cycle arrest and cell death.

Topics: Animals; Anticarcinogenic Agents; Cell Cycle; Humans; Mice; Neoplasms; Rats; Transcription Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K 3

Vitamin C (VC) and vitamin K(3) (VK(3)) administered in a VC:VK(3) ratio of 100:1 exhibit synergistic antitumor activity and preferentially kill tumor cells by autoschizis, a novel type of necrosis characterized by exaggerated membrane damage and progressive loss of organelle-free cytoplasm through a series of self-excisions. During this process, the nucleus becomes smaller, cell size decreases one-half to one-third of its original size, and most organelles surround an intact nucleus in a narrow rim of cytoplasm. While the mitochondria are condensed, tumor cell death does not result from ATP depletion. However, vitamin treatment induces a G(1)/S block, diminishes DNA synthesis, increases H(2)O(2) production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H(2)O(2). There is a concurrent 8- to 10-fold increase in intracellular Ca(2+) levels. Electrophoretic analysis of DNA reveals degradation due to the caspase-3-independent reactivation of deoxyribonuclease I and II (DNase I, DNase II). Redox cycling of the vitamins is believed to increase oxidative stress until it surpasses the reducing ability of cellular thiols and induces Ca(2+) release, which triggers activation of Ca(2+)-dependent DNase and leads to degradation of DNA. Recent experiments indicate that oral VC:VK(3) increases the life-span of tumor-bearing nude mice and significantly reduces the growth rate of solid tumors without any significant toxicity by reactivating DNase I and II and inducing autoschizis. This report discusses the mechanisms of action employed by these vitamins to induce tumor-specific death by autoschizis.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Death; Humans; Necrosis; Neoplasms; Oxidative Stress; Vitamin K

Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.. To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.. We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.. Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.. Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis

Topics: Ascorbic Acid; Avitaminosis; Blood Coagulation; Breast Neoplasms; Carotenoids; Chronic Disease; Colorectal Neoplasms; Coronary Disease; Dietary Supplements; Female; Folic Acid; Fractures, Bone; Humans; Lung Neoplasms; Male; Neoplasms; Neural Tube Defects; Prostatic Neoplasms; Risk Factors; Vitamin A; Vitamin B 12; Vitamin B 6; Vitamin D; Vitamin E; Vitamin K; Vitamins

Vitamin K-dependent factors are lower in neonates than in adults, and these anomalies are more prevalent in preterm neonates and in breast-fed infants. Vitamin K deficiency can account for vitamin K deficiency bleeding (VKDB) which occurs in 3 forms--early, classic and late. Vitamin K should be administered to all neonates at birth or immediately afterwards. However, the protocols for administration (route of administration, dosage, number of doses) remain a subject of discussion. Oral administration of a single dose of vitamin K protects against classical and early VKDB, but is less effective than intramuscular (IM) prophylaxis for the prevention of late VKDB. Although an increased risk of solid tumour, associated vitamin K administration, can be definitively excluded, a low potential risk of lymphoblastic leukaemia in childhood can not be ruled out. For formula-fed neonates without risk of haemorrhage, a 2 mg oral dose of vitamin K at birth, followed by a second 2 mg oral dose between day 2 and 7, is probably sufficient to prevent VKDB. For infants who are exclusively or nearly exclusively breast-fed, weekly oral administration of 2mg (or 25 microg/day) vitamin K after the initial 2 oral doses is justified at completion of breast-feeding. For neonates at high risk of haemorrhage (premature, neonatal disease, birth asphyxia, difficult delivery, any illness which will delay feeding, known hepatic disease, maternal drugs inhibiting vitamin K activity), the first dose must be administered by the IM or slow intravenous route. Doses should be repeated, particularly in premature infants, by a route of administration decided for each dose according to the clinical state of the infant. For infants of mothers treated with drugs inhibiting vitamin K activity, antenatal maternal prophylaxis (10 to 20 mg/day orally for 15 to 30 days before delivery) prevents early VKDB. After neonatal prophylaxis, as for infants at high risk of haemorrhage, doses need to be repeated at a rate and route of administration decided for each dose, according to the clotting factor profile specific for each infant.

Topics: Anticonvulsants; Female; Hemorrhage; Humans; Infant, Newborn; Neoplasms; Pregnancy; Prenatal Care; Risk Factors; Vitamin K; Vitamin K Deficiency

Topics: Adenocarcinoma; Anticoagulants; Carcinoma, Small Cell; Clinical Trials as Topic; Colorectal Neoplasms; Heparin; Humans; Lung Neoplasms; Neoplasms; Odds Ratio; Thrombophilia; Vitamin K

Topics: Blood Coagulation; Carcinogens; Child; Child, Preschool; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Hemorrhage; Humans; Incidence; Infant, Newborn; Neoplasms; Reproducibility of Results; Vitamin K

Topics: Animals; Antineoplastic Agents; Antisickling Agents; Carcinogens; Cathartics; Disease Models, Animal; Evidence-Based Medicine; Humans; Hydroxyurea; Indicators and Reagents; Intestinal Absorption; Neoplasms; Nucleic Acid Synthesis Inhibitors; Phenolphthalein; Research Design; Risk Factors; Tissue Distribution; Vitamin K

Topics: Administration, Oral; Female; Humans; Infant, Newborn; Injections, Intramuscular; Male; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Newborn babies are born vitamin K deficient; however, the deficiency is not sufficiently severe to cause a vitamin K deficiency coagulopathy and haemorrhagic disease of the newborn (HDN). Severe vitamin K deficiency can develop quickly in breast-fed newborns and can result in the appearance of classic HDN during the first week of life or late HDN during the first 2 months of life. Both forms of the disease can be severe, causing brain damage and death. Classic and late HDN are prevented by the intramuscular administration of vitamin K at birth. Oral prophylaxis prevents classic HDN but is ineffective in preventing late HDN. Despite proven effectiveness of intramuscular vitamin K prophylaxis there have been concerns about the need for, and safety of, this therapy. This review provides evidence that there is need for intramuscular vitamin K prophylaxis for all babies in order to eradicate haemorrhagic disease of the newborn and concludes that there is no evidence that this therapy is harmful.

Topics: Administration, Oral; Blood Coagulation; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Vitamin K deficiency remains a world-wide problem in the newborn. Vitamin K traverses the placenta from mother to infant very poorly and is present only in very low concentrations in human milk. Thus, it is not surprising that the newborn infant has undetectable vitamin K serum levels with abnormal amounts of the coagulation proteins and undercarboxylated prothrombin. Hemorrhagic disease of the newborn, secondary to vitamin K deficiency, remains largely a disease of breastfed infants. Lactating mothers easily achieve the recommended dietary allowance for vitamin K (1 microg kg(-1) d(-1)) and the breast milk concentration is readily increased by increasing maternal vitamin K intake. Breastfed infants do not receive the recommended vitamin K intake via human milk. To prevent vitamin K deficiency in the newborn, intramuscular or oral vitamin K prophylaxis is necessary.

Topics: Adult; Breast Feeding; Comorbidity; Female; Humans; Incidence; Infant, Newborn; Male; Milk, Human; Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Socioeconomic Factors; United States; Vitamin K; Vitamin K Deficiency; World Health Organization

There is considerable evidence that the hemostatic system is involved in the growth and spread of malignant disease. There is an increased incidence of thromboembolic disease in patients with cancers and hemostatic abnormalities are extremely common in such patients. Antihemostatic agents have been successfully used to treat a variety of experimental tumors, and several clinical trials in humans have been initiated. Although metastasis is undoubtedly multifactorial, intravascular coagulation activation and peritumor fibrin deposition seem to be important. The mechanisms by which hemostatic activation facilitates the malignant process remain to be completely elucidated. Of central importance may be the presence on malignant cells of tissue factor and urokinase receptor. Recent studies have suggested that these proteins, and others, may be involved at several stages of metastasis, including the key event of neovascularization. Tissue factor, the principal initiator of coagulation, may have additional roles, outside of fibrin formation, that are central to the biology of some solid tumors.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Biomarkers; Blood Coagulation Tests; Cell Adhesion; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor Xa; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Monocytes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, Thrombin; Thrombophilia; Thrombophlebitis; Thromboplastin; Vitamin K

Newborn babies are at risk of bleeding as a result of vitamin K deficiency. Vitamin K supplements given at birth reduce this risk but it is not clear which preparation should be used. Until the early 1990s, it was standard practice to give vitamin K as a single intramuscular injection at birth (Konakion Ampoules 1 mg/0.5 ml-Roche). Studies published in 1990 and 1992 suggested a possible link between intramuscular vitamin K injection and childhood cancers, particularly leukaemias. Our response was to recommend that vitamin K injection be given orally (not then a licensed route) until a licensed oral preparation became available. Such a preparation is now marketed as Konakion MM Paediatric (Roche). In addition, the suggested association between intramuscular vitamin K and cancer has been further investigated. In this article, we update our advice.

Topics: Administration, Oral; Hemostatics; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Perinatal Care; Vitamin K; Vitamin K Deficiency Bleeding

To determine (1) the most effective method of administering vitamin K to infants to prevent hemorrhagic disease of the newborn (HDNB) and (2) the safest method, in light of preliminary evidence suggesting that intramuscular administration of vitamin K is associated with childhood cancer.. A MEDLINE search of articles published between Jan. 1, 1991, and Apr. 30, 1994, with the use of MeSH terms "hemorrhagic disease of the newborn", articles were limited to those involving human subjects, from birth to adolescence, and to articles from journals indexed through Index Medicus and written in English. References of all articles found through the initial search, the earliest of which was published in 1967, were also reviewed.. Six controlled trials met the selection criteria: a minimum 4-week follow-up period, a minimum of 60 subjects and a comparison of oral and intramuscular administration or of regimens of single and multiple doses taken orally. All retrospective case reviews were evaluated. Because of its thoroughness, the authors selected a meta-analysis of almost all cases involving patients more than 7 days old published from 1967 to 1992. Only five studies that concerned safety were found, and all of these were reviewed.. In controlled trials, the risk of HDNB caused by vitamin K deficiency among infants receiving different regimens of vitamin K; in case studies, method of vitamin K administration and incidence of hemorrhagic disease; and in studies concerning safety, odds ratios and relative risks of childhood cancer following intramuscular administration of vitamin K.. Vitamin K (1 mg, administered intramuscularly) is currently the most effective method of preventing HDNB. The previously reported relation between intramuscular administration of vitamin K and childhood cancer has not been substantiated. An oral regimen (three doses of 1 to 2 mg, the first given at the first feeding, the second at 2 to 4 weeks and the third at 8 weeks) may be an acceptable alternative but needs further testing in large clinical trials.. There is no compelling evidence to alter the current practice of administering vitamin K intramuscularly to newborns.

Topics: Administration, Oral; Child; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Age Factors; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Odds Ratio; Risk Assessment; Vitamin K; Vitamin K Deficiency Bleeding

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.

Topics: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Adult; Animals; Biotransformation; Carcinogens; Chick Embryo; Cocarcinogenesis; DNA Adducts; Female; Fetal Diseases; Fetus; Humans; Infant, Newborn; Liver; Maternal Exposure; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Microsomes, Liver; Mixed Function Oxygenases; Neoplasms; Neoplasms, Experimental; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Smoking; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin; Xenobiotics

Coumarin derivatives and anticonvulsants administered during pregnancy enter the fetal circulation, interfering with the action of vitamin K. Vitamin K plays a crucial part in the gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors prothrombin, FVII, FIX, and FX. Other vitamin K-dependent proteins in the coagulation cascade are protein C and protein S. Vitamin K-dependent bone proteins are osteocalcin and gamma-carboxyglutamate matrix protein. Administration of coumarol derivatives results in under carboxylation of the vitamin K-dependent proteins. Anticoagulation therapy with warfarin is followed by an increased risk of embryopathy, which has been shown to be greatest between gestational weeks 6 and 12. Administration of warfarin is also followed by an increased risk both of fetal intraventricular hemorrhage, and of cerebral microbleedings, which may result in microencephaly and mental retardation. Treatment with coumarol derivatives should therefore be avoided during pregnancy, even in pregnant women with artificial heart valves, and replaced by heparin. Hemorrhage in the newborn related to the use of anticonvulsant drugs during pregnancy occurs very early within the first 24 hours, probably due to increased degradation of vitamin K. Transplacental administration of vitamin K has been shown to prevent neonatal hemorrhage induced by maternal anticonvulsant therapy. Prophylactic administration of vitamin K, especially by intramuscular injection, has been reported to be associated with an increased risk of childhood cancer. However, subsequent extensive studies have yielded no evidence of any relationship between prophylactic vitamin K administration and the occurrence of childhood cancer.

Topics: Abnormalities, Drug-Induced; Anticoagulants; Anticonvulsants; Blood Coagulation Factors; Child; Cohort Studies; Coumarins; Epilepsy; Female; Fetal Diseases; Hemorrhage; Humans; Infant, Newborn; Maternal-Fetal Exchange; Neoplasms; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Protein Processing, Post-Translational; Sweden; Thrombosis; United Kingdom; Vitamin K; Vitamin K Deficiency

Discussion about the efficacy and safety of vitamin K prophylaxis has recently restarted. In this review, new developments in diagnosis of vitamin K deficiency (including vitamin K plasma levels and protein induced by vitamin K absence [PIVKA]-II detection) and therapy of early, classic, and late hemorrhagic disease of the newborn are highlighted. Special attention is brought to the efficacy of preventing early and late hemorrhagic disease. The recently described association between intramuscular vitamin K administration and cancer is debated. The very high plasma levels, the intramuscular injection itself, or the adjuvants in the solution might all be responsible. These factors are all absent in oral administration. Therefore, we recommend repeated oral administration for preventing classic and late hemorrhagic disease of the newborn. Additionally, we recommend maternal supplementation of vitamin K for preventing early hemorrhagic disease of the newborn, especially when the mother is using medications that interfere with vitamin K metabolism.

Topics: Administration, Oral; Clinical Protocols; Humans; Infant, Newborn; Injections, Intramuscular; Intestinal Absorption; Neoplasms; Primary Prevention; Risk Factors; Time Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Vitamin K is given to many babies born in the United Kingdom, but we still do not know if it has substantial hazards. Because the population exposed to vitamin K is very large even quite small hazards would involve many adverse events. It is therefore important to be able to put reasonably close bounds on the potential damage that vitamin K prophylaxis could cause. Past research has not allowed us to do this but a large randomised controlled clinical trial of vitamin K against no vitamin K, enrolling only infants at low risk of haemorrhagic disease, would do so. There is no question that vitamin K is a useful treatment in babies at highest risk of haemorrhagic disease: the question is whether the trend towards use of vitamin K in lower risk babies should be encouraged.

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; England; Humans; Incidence; Infant; Infant, Newborn; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding; Wales

Topics: Age Factors; Europe; Hemostasis; Humans; Incidence; Infant; Infant, Newborn; Japan; Neoplasms; Practice Guidelines as Topic; Vitamin K; Vitamin K 1; Vitamin K Deficiency Bleeding

Tumor cells are known to interfere with blood coagulation pathways of the host by producing procoagulants and other substances, thereby deriving certain advantages relating to tumor growth, metastasis, and angiogenesis. Anticoagulants may diminish these advantages under certain conditions. The interaction between coumarin anticoagulants and tumor cells has been reviewed with respect to procoagulants and their vitamin K-dependent properties. Evidence is also presented which suggests that vitamin K-dependent protein carboxylation is a general property of tumor cells.

Topics: Animals; Anticoagulants; Carbon-Carbon Ligases; Cathepsin B; Hemostasis; Humans; Ligases; Neoplasm Proteins; Neoplasms; Vitamin K

Topics: Carcinogens; Combined Modality Therapy; Humans; Neoplasms; Tumor Stem Cell Assay; Vitamin K

Vitamins are a group of organic compounds occurring naturally in food and are necessary for good health. Lack of a vitamin may lead to a specific deficiency syndrome, which may be primary (due to inadequate diet) or secondary (due to malabsorption or to increased metabolic need), and it is rational to use high-dose vitamin supplementation in situations where these clinical conditions exist. However, pharmacological doses of vitamins are claimed to be of value in a wide variety of conditions which have no, or only a superficial, resemblance to the classic vitamin deficiency syndromes. The enormous literature on which these claims are based consists mainly of uncontrolled clinical trials or anecdotal reports. Only a few studies have made use of the techniques of randomisation and double-blinding. Evidence from such studies reveals a beneficial therapeutic effect of vitamin E in intermittent claudication and fibrocystic breast disease and of vitamin C in pressure sores, but the use of vitamin A in acne vulgaris, vitamin E in angina pectoris, hyperlipidaemia and enhancement of athletic capacity, of vitamin C in advanced cancer, and niacin in schizophrenia has been rejected. Evidence is conflicting or inconclusive as to the use of vitamin C in the common cold, asthma and enhancement of athletic capacity, of pantothenic acid in osteoarthritis, and folic acid (folacin) in neural tube defects. Most of the vitamins have been reported to cause adverse effects when ingested in excessive doses. It is therefore worthwhile to consider the risk-benefit ratio before embarking upon the use of high-dose vitamin supplementation for disorders were proof of efficacy is lacking.

Topics: Acne Vulgaris; Ascorbic Acid; Asthma; Cardiovascular Diseases; Common Cold; Fibrocystic Breast Disease; Humans; Neoplasms; Osteoporosis; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K; Vitamins

Topics: Antithrombin III Deficiency; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Fibrinolysis; Hemostasis; Humans; Neoplasms; Thrombosis; Vitamin K

Topics: Antifibrinolytic Agents; Bromodeoxyuridine; Dactinomycin; DNA; DNA, Neoplasm; Ethylmaleimide; Hyperbaric Oxygenation; Naphthoquinones; Neoplasms; Retinoids; Vitamin K

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Black or African American; Blood Coagulation; Data Interpretation, Statistical; Enoxaparin; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemoglobins; Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasms; Platelet Aggregation Inhibitors; Prognosis; Proportional Hazards Models; Regression Analysis; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dalteparin; Female; Humans; Kidney Diseases; Male; Middle Aged; Neoplasms; Venous Thromboembolism; Vitamin K; Warfarin

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Postthrombotic Syndrome; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Vitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03-3.49), active cancer at baseline (OR=1.52; CI1.05-2.19), secondary VTE (OR=1.42; CI1.20-1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09-1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06-3.63 and OR=1.95; CI1.36-2.80, respectively). ORs of early (≤ 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31-2.80) and instability (OR=1.55; CI1.07-2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09-1.69) and instability (OR=1.25; CI1.01-1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57-2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Prognosis; Recurrence; Risk Factors; Thrombophilia; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Treatment of splanchnic vein thrombosis (SVT) is a clinical challenge due to heterogeneity of clinical presentations, increased bleeding risk, and lack of evidences from clinical trials. We performed an international registry to describe current treatment strategies and factors associated with therapeutic decisions in a large prospective cohort of unselected SVT patients. A total of 613 patients were enrolled (mean age 53.1 years, standard deviation ± 14.8); 62.6% males; the majority (468 patients) had portal vein thrombosis. Most common risk factors included cirrhosis (27.8%), solid cancer (22.3%), and intra-abdominal inflammation/infection (11.7%); in 27.4% of patients, SVT was idiopathic. During the acute phase, 470 (76.7%) patients received anticoagulant drugs, 136 patients (22.2%) remained untreated. Incidental diagnosis, single vein thrombosis, gastrointestinal bleeding, thrombocytopenia, cancer, and cirrhosis were significantly associated with no anticoagulant treatment. Decision to start patients on vitamin K antagonists after an initial course of parenteral anticoagulation was significantly associated with younger age, symptomatic onset, multiple veins involvement, and unprovoked thrombosis. Although a nonnegligible proportion of SVT patients did not receive anticoagulant treatment, the majority received the same therapies recommended for patients with usual sites thrombosis, with some differences driven by the site of thrombosis and the pathogenesis of the disease.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Female; Fibrinolytic Agents; Fibrosis; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Registries; Retrospective Studies; Risk Factors; Splanchnic Circulation; Venous Thrombosis; Vitamin K

Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aim of the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95% CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Mediterranean; Female; Follow-Up Studies; Humans; Incidence; Male; Mediterranean Region; Middle Aged; Neoplasms; Plant Oils; Proportional Hazards Models; Prospective Studies; Risk Factors; Vegetables; Vitamin K; Vitamin K 1; Vitamin K 2

Based on the activity of menadione (M) in the human tumor stem cell assay, we conducted a phase I trial of M in patients with advanced cancer. Forty patients (19 men, 21 women) were treated with 90 courses of M; 82 treatment courses are evaluable for toxicity. The median patient age, Karnofsky performance status, and number of prior chemotherapy regimens were 61 years (range 32-74 years), 80% (range 50-100%), and two, respectively. M was given by a short (1-5 h) intravenous infusion every 3 weeks, starting at 40 mg/m2 and escalating by modified Fibonacci scheme to 1360 mg/m2. Toxicity was graded according to the Southwest Oncology Group toxicity scale with defined hypersensitivity reaction (HSR) scales. No grade > or =2 hematologic toxicity was observed. Non-hematologic toxicity consisted of a HSR syndrome of paresthesiae of the extremities, facial flushing, burning of the eyes and mucous membranes, chest pain and dyspnea. HSR was defined as Grade I toxicity by the presence of facial numbness, flushing, and/or a tingling sensation or burning of the eyes and mucous membranes. Grade II toxicity was defined as the presence of the same above symptoms plus chest tightness, paresthesiae of extremities and/or dyspnea and chest pain. These toxicities were grade 1 in 3 of 4 patients at a dose of 840 mg/m2. At 1360 mg/m2, 2 of 13 patients suffered grade 1 HSR and 7 of 13 grade 2 HSR. No objective partial or complete responses were observed. Plasma menadione concentrations peaked at 1.9-7.4 microM during the infusion in 3 patients receiving 1360 mg/m2. Further phase 1 and 2 combination trials using longer infusion durations have resulted from this trial.

Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Karnofsky Performance Status; Male; Middle Aged; Neoplasms; Vitamin K

The length of time after an episode of venous thromboembolism during which the risk of newly diagnosed cancer is increased is not known, and whether vitamin K antagonists have an antineoplastic effect is controversial.. In a prospective, randomized study of the duration of oral anticoagulation (six weeks or six months) after a first episode of venous thromboembolism, patients were questioned annually about any newly diagnosed cancer. After a mean follow-up of 8.1 years, we used the Swedish Cancer Registry to identify all diagnoses of cancer and causes of death in the study population. The observed numbers of cases of cancer were compared with expected numbers based on national incidence rates, and the standardized incidence ratios were calculated.. A first cancer was diagnosed in 111 of 854 patients (13.0 percent) during follow-up. The standardized incidence ratio for newly diagnosed cancer was 3.4 (95 percent confidence interval, 2.2 to 4.6) during the first year after the thromboembolic event and remained between 1.3 and 2.2 for the following five years. Cancer was diagnosed in 66 of 419 patients (15.8 percent) who were treated for six weeks with oral anticoagulants, as compared with 45 of 435 patients (10.3 percent) who were treated for six months (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The difference was mainly due to the occurrence of new urogenital cancers, of which there were 28 cases in the six-week group (6.7 percent) and 12 cases in the six-month group (2.8 percent) (odds ratio, 2.5; 95 percent confidence interval, 1.3 to 5.0). The difference in the incidence of cancer between the treatment groups became evident only after two years of follow-up, and it remained significant after adjustment for sex, age, and whether the thromboembolism was idiopathic or nonidiopathic. Older age at the time of the venous thrombosis and an idiopathic thromboembolism were also independent risk factors for a diagnosis of cancer. No difference in the incidence of cancer-related deaths was detected.. The risk of newly diagnosed cancer after a first episode of venous thromboembolism is elevated during at least the following two years. Subsequently, the risk seems to be lower among patients treated with oral anticoagulants for six months than among those treated for six weeks.

Topics: Administration, Oral; Age Factors; Anticoagulants; Drug Administration Schedule; Humans; Incidence; Neoplasms; Prospective Studies; Pulmonary Embolism; Retrospective Studies; Risk Factors; Thromboembolism; Time Factors; Urogenital Neoplasms; Venous Thrombosis; Vitamin K; Warfarin

A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n = 51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1-2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors, for which treatment with single-agent mitomycin C is appropriate.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Erythrocytes; Female; Glucosephosphate Dehydrogenase; Glutathione; Hemolysis; Humans; Infusions, Intravenous; Male; Middle Aged; Mitomycin; Neoplasms; Vitamin K

In 34 cancer patients with 40 neutropenic febrile episodes requiring broad-spectrum antimicrobial therapy, detailed dietary assessments revealed that deficient and severely deficient phylloquinone intakes (less than or equal to 70 and less than or equal to 25 micrograms/d) were identified during 88% and 38% of all days recorded, respectively. Serum phylloquinone levels and serial prothrombin times (PT) drawn in a similar group of 32 patients revealed that an elevated PT (greater than or equal to 2 s beyond control) was significantly associated (p less than 0.01) with a serum phylloquinone level of less than 4.4 nmol/L. Patients on antimicrobial regimens that suppressed menaquinone-producing intestinal microflora and that contained an N-methylthiotetrazole (NMTT) moiety had an elevated PT significantly more often than did patients receiving antimicrobial agents that preserved the microflora and contained no NMTT moiety (3 of 10 vs 10 of 11, respectively; p = 0.02 Fisher's exact). These data suggest that these patients have a profound deficiency of oral vitamin K intake that may be further augmented by antimicrobial therapy.

Topics: Agranulocytosis; Anti-Bacterial Agents; Diet; Fever; Humans; Hypoprothrombinemias; Intestines; Neoplasms; Neutropenia; Prothrombin Time; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Chromatography, Liquid; Doxorubicin; Mice; Neoplasms; Tandem Mass Spectrometry; Vitamin A; Vitamin B Complex; Vitamin K

Natural health products (NHPs), including vitamins, minerals, and herbal supplements, are the most common complementary and alternative medicine (CAM) among cancer patients. Our survey determined the attitudes and behaviors of cancer patients toward natural complementary therapies that should be considered to implement an integrative approach in the future.. Our survey was conducted in four hospitals in Belgium. Questionnaires were posted online from October 2020 to October 2021 for cancer patients. Descriptive statistics were used to analyze the data. A [Formula: see text] test was applied to study the type of NHP consumed according to diagnosis time. Fischer's exact test compared patients who had changed their consumption since diagnosis and those who had not.. Out of 349 questionnaires collected, only 59 met all inclusion criteria. 83.1 % of the patients agreed that conventional medicine (CM) could benefit from complementary therapies, but they did not estimate (72.3 % of the patients) that those latter are more effective than conventional medicine. More than half of the patients used five or more NHPs. The most frequent NHPs consumed daily were vitamins (64.4 %), followed by other products (i.e., probiotics, gemmotherapy, birch sap and omega 3/6) (42.4 %) and herbs (40.7 %). Almost all patients started taking NHPs before their cancer diagnosis, but 72.7 % have changed their consumption significantly (p = 0.009) since their diagnosis. Boosting the immune system (79.7 %) and limiting conventional treatment side effects (76.9 %) were the most common reasons for NHPs' use. 74.4 % of the patients did not take complementary therapies to delay or avoid conventional treatment.. The combination and high diversity of NHPs consumption highlight the importance of educating patients and healthcare providers (HCPs) about the risk of drug interactions associated with these natural products. Most cancer patients are more interested in using this non-mainstream medicine to complement their conventional treatment than as an alternative. Knowing the patients' reasons and understanding patients' attitudes toward NHPs will be essential for HCPs to address NHPs' use.

Topics: Biological Products; Complementary Therapies; Dietary Supplements; Humans; Neoplasms; Vitamin A; Vitamin K; Vitamins

Despite patients with cancer having a higher incidence of atrial fibrillation (AF), little is known about the predictors of outcomes in this population. This study aimed to assess the incidence and predictors of bleeding in patients with AF and cancer. The study population comprised 16,056 patients from a Spanish health area diagnosed with AF between 2014 and 2018 (1,137 with cancer). Competing risk analysis were used to evaluate the association of cancer and bleeding. Discrimination and calibration of bleeding risk scores were assessed by the concordance statistic and the Brier score, respectively. During a median follow-up of 4.9 years, the incidence of bleeding in patients with cancer was 13.2 per 100 patients/year. After multivariate adjustment, a significant association between cancer and bleeding was detected (subdistribution hazard ratio [sHR] 1.18, 95% CI 1.07 to 1.30, p = 0.001), specifically in patients with active cancer or previous radiotherapy. Early age, male gender, diabetes, and anticoagulation were independent predictors of bleeding. However, only anticoagulation with vitamin K antagonist (sHR 1.36, 95% CI 1.03 to 1.78, p = 0.026), not with direct oral anticoagulants (sHR 1.25, 95% CI 0.84 to 1.85, p = 0.270), was associated with bleeding. Discrimination and calibration of Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, and Drugs/alcohol concomitantly (HAS-BLED), AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA), and Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age ≥75 years), Reduced platelet count or function, Rebleeding risk, Hypertension, Anaemia, Genetic factors, Excessive fall risk and Stroke (HEMORR

Topics: Aged; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Incidence; Male; Neoplasms; Risk Assessment; Risk Factors; Stroke; Vitamin K

Cancer patients have an increased risk of bleeding compared to non-cancer patients with anticoagulant therapy. A bleeding risk assessment before initiation of anticoagulation is recommended. Currently low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) are the mainstays of treatment for cancer-associated venous thromboembolism (VTE). Since DOACs are administered orally, they offer some convenience and ease of administration; however, LMWH may be preferred in certain cancers. Given the prevalence of anticoagulant therapies in cancer patients, clinical providers must be able to recognize potentially critical bleeding sites and modalities to reverse major hemorrhage. Reversal agents or antidotes to bleeding may be required when bleeding is persistent or life-threatening. These include vitamin K, fresh frozen plasma (FFP), protamine, prothrombin complex concentrate (PCC) or andexanet alfa, and idarucizumab. Inferior vena cava (IVC) filter insertion can be also considered in those with major bleeding. Evidence for timing and need for re-initiation of anticoagulant therapy after a major bleeding remains sparse, but a multi-disciplinary approach and shared decision-making can be implemented in the interim.

Topics: Administration, Oral; Anticoagulants; Antidotes; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Protamines; Vitamin K

Mertk, a type I Receptor Tyrosine Kinase (RTK) and member of the TAM (Tyro3, Axl, and Mertk) family of homologous tyrosine kinases, has important roles in signal transduction both homeostatically on normal cells as well as patho-physiologically on both tumor-associated macrophages and malignant cells by its overexpression in a wide array of cancers. The main ligands of Mertk are Vitamin K-modified endogenous proteins Gas6 and Protein S (ProS1), heterobifunctional modular proteins that bind Mertk via two carboxyl-terminal laminin-like globular (LG) domains, and an N-terminal Gla domain that binds anionic phospholipids, whereby externalized phosphatidylserine (PS) on stressed viable and caspase-activated apoptotic cells is most emblematic. Recent studies indicate that Vitamin K-dependent γ-carboxylation on the N-terminal Gla domain of Gas6 and Protein S is necessary for PS binding and Mertk activation, implying that Mertk is preferentially active in tissues where there is high externalized PS, such as the tumor microenvironment (TME) and acute virally infected tissues. Once stimulated, activated Mertk can provide a survival advantage for cancer cells as well as drive compensatory proliferation. On monocytes and tumor-associated macrophages, Mertk promotes efferocytosis and acts as an inhibitory receptor that impairs host anti-tumor immunity, functioning akin to a myeloid checkpoint inhibitor. In recent years, inhibition of Mertk has been implicated in a dual role to enhance the sensitivity of cancer cells to cytotoxic agents along with improving host anti-tumor immunity with anti-PD-1/PD-L1 immunotherapy. Here, we examine the rationale of Mertk-targeted immunotherapies, the current and potential therapeutic strategies, the clinical status of Mertk-specific therapies, and potential challenges and obstacles for Mertk-focused therapies.

Topics: Biology; c-Mer Tyrosine Kinase; Humans; Neoplasms; Protein S; Proto-Oncogene Proteins; Tumor Microenvironment; Vitamin K

Topics: Cardiovascular Diseases; Dietary Supplements; Humans; Minerals; Neoplasms; Vitamin K; Vitamins

Topics: Humans; Neoplasms; Vitamin K; Vitamins

Thrombosis is common in subjects suffering from cardiovascular diseases (CVD) and cancer. Hypercoagulation plays a pivotal role in the pathophysiology of thrombosis. Therefore, the inactivation of thrombin, the key enzyme in coagulation, is tightly regulated via antithrombin (AT). AT deficiency is related to thrombosis and cardiovascular death. In this study we investigated the association between AT levels and mortality, in particularly cardiovascular-related and cancer-related death in the general population.. We studied the association of AT levels and mortality in a prospective cohort sampled from the general Italian population (n = 19,676). AT levels were measured in the baseline samples, and mortality was recorded during a median follow-up period of 8.2 years. Cox regression was performed to investigate the association of all-cause, CVD-related and cancer-related mortality with variations in AT levels.. In total, 989 subjects died during follow-up, of which 373 subjects of CVD and 353 of cancer-related causes. Cox analysis revealed that, after adjustment for age, sex, current smoking, BMI, diabetes, hypertension, hypercholesterolemia, history of cardiovascular disease, history of cancer, vitamin K antagonists, antiplatelet medication, heparin and oral contraceptives AT levels were not associated with all-cause mortality (HRQ1vsQ5: 0.92, 95% CI:0.74-1.15). Interestingly, the risk of CVD-related mortality was reduced in subjects with low AT levels compared to subjects with higher AT levels, after adjustment for age and sex and other confounders did not change the association (HRQ1vsQ5: 0.64, 95% CI:0.44-0.91). Moreover, low AT levels were associated with increased cancer mortality in a fully adjusted model (HRQ1vsQ2-5: 1.26, 95% CI:0.88-1.81).. Low AT levels are associated to a lower risk of fatal cardiovascular events in the general population, regardless of age, sex and medication use. In contrast, low AT levels are associated with lower cancer survival. For the first time we show that AT levels lower than the normal range in the general population, even before the development or diagnosis of cancer, are associated with an elevated risk of cancer death.

Topics: Antithrombins; Cardiovascular Diseases; Contraceptives, Oral; Heparin; Humans; Neoplasms; Prospective Studies; Risk Factors; Thrombin; Vitamin K

Certain popular supplements, notably beta carotene and vitamin E, may even cause harm.

Topics: beta Carotene; Cardiovascular Diseases; Dietary Supplements; Humans; Minerals; Neoplasms; Vitamin A; Vitamin E; Vitamin K; Vitamins

Venous thromboembolic disease (VTD) is currently the second leading cause of death in cancer patients with a prevalence of approximately 20% compared with that of 5% in the entire adult population. Cancer patients are a heterogeneous group with significant differences in the risk of VTD which is, in particular, determined by the type of tumour, its extent, location, and the presence of metastases. Some tumours represent a mean 3- to 5-fold increase in risk, while in others the risk of developing VTD is even several times higher. In comparison with non-cancer patients, those with a tumour are not only at an increased risk of an initial thromboembolic event, but also of its recurrence, regardless of ongoing anticoagulation which is associated with a higher risk of bleeding, particularly in mucosal involvement. Venous thrombosis and its treatment may interfere with the ongoing diagnosis and treatment. In cancer patients, VTD is a frequent incidental finding on imaging studies. Primary thromboprophylaxis (apixaban, rivaroxaban, LMWH) is currently recommended in selected groups of cancer patients who are either hospitalized for acute internal disease or immobilized and have an active malignancy, undergo outpatient systemic chemotherapy for a tumour with a high risk of VTD (a Khorana score of 2) or surgery and are not at high risk of bleeding. DOACs should be administered six months after the initiation of chemotherapy. If there is a risk of drug interactions or mucosal bleeding, LMWHs are recommended. At present, DOACs (apixaban, edoxaban, rivaroxaban) and LMWHs are the first-choice drugs in treating VTD. LMWHs are preferred in mucosal tumours, when there is a high risk of bleeding, in progressive malignancy, concomitant emetogenic therapy, and dyspeptic difficulties. In severe renal insufficiency (CrCl < 15 ml/min), vitamin K antagonists may be of value. Individualized treatment should take into consideration the patients general condition, prognosis, and personal preferences.

Topics: Administration, Oral; Adult; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Atrial fibrillation (AF) may be a pre-existing disease before cancer diagnosis, may be a direct effect of the neoplasm or, more often, appears as a post-surgical complication, especially after thoracic surgery. AF may also develop as a consequence of chemotherapy or radiotherapy. The management of the anticoagulation in cancer patients with AF is challenging, and data on these patients are lacking. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and/or changes in renal or hepatic function. Low molecular weight heparins and direct oral anticoagulants (DOACs) could be preferred. However, the possible pharmacological interactions of DOACs with anti-cancer and anti-arrhythmic drugs and the bleeding risks in thrombocytopenic patients should be considered. Based on these considerations, a careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed in cancer patients and anticoagulation for AF should be tailored individually. An ongoing consultation of oncologists/hematologists with cardiologists and coagulation experts in a multidisciplinary approach, with a periodic re-assessment of the benefits of anticoagulation with changes in cancer status/advancement and treatment plans is needed.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Stroke; Vitamin K

Patients with cancer have increased risks of venous and arterial thromboembolism and/or atrial fibrillation, for which anticoagulation is commonly used. For these indications, three main types of anticoagulants are recommended or used: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and vitamin K antagonists (VKAs), all have different advantages and disadvantages. Drug-drug interactions (DDIs) with anticoagulation are often cautioned against by major guidelines, but evidence remains scarce regarding the best management approach for specific drug combinations, particularly with DOACs. Significant DDIs might affect the efficacy and safety of anticoagulants and/or anticancer therapies as well as other interfering medications, and more studies are needed. This paper will review the available evidence and guidelines on DDIs with anticoagulants, focusing on the cancer population whenever possible, and propose directions for future research.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

The association between the use of vitamin K antagonists (VKAs) and cancer risk reduction remains unclear. We aimed to assess the association between the use of VKAs or direct oral anticoagulants (DOACs) and the incidence of cancer in a large cohort of patients with atrial fibrillation (AF) by means of a population-based, propensity-weighted cohort study using population-wide databases including patients diagnosed with nonvalvular AF (NVAF) followed for up of 5 years (median 2.94 years). We created two cohorts based on the initiation therapy (VKA or DOAC). Initiation with VKA or DOAC was defined as filling a prescription with no previous exposure in the preceding 12 months. Cancer diagnoses of any type and for specific tumors (lung, colon, prostate, bladder, and breast). We included 39,989 patients, 31,200 (78.0%) in the VKA cohort. Incidence rate for any cancer was 12.45 per 1,000 person-year in the DOAC cohort vs. 14.55 in the VKA cohort (adjusted hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.02-1.32). In secondary outcomes, no differences were found for specific types of cancer, such as lung (HR: 1.28, CI: 0.89-1.83), colon (HR: 0.84, CI: 0.62-1.13), prostate (HR: 1.40, CI: 0.94-2.10), bladder (HR: 1.07, CI: 0.76-1.52), and breast (HR: 1.05, CI: 0.66-1.69). Sensitivity analyses yielded similar results. Subgroup analyses also produced consistent findings, except for men, for whom VKA was associated with a lower risk of colon cancer (HR: 0.68, 95% CI: 0.48-0.96). Our results do not confirm a chemoprotective effect of VKA when compared with DOAC in a large, real-world cohort of patients with NVAF followed for up to 5 years.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Correlation of Data; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Male; Neoplasms; Proportional Hazards Models; Risk Assessment; Risk Factors; Vitamin K

Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer.. In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups.. There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50–0.80]; P=0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24–0.70]; P=0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23–0.61]; P<0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56–0.94]; P=0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer (P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years (P interaction <0.05).. Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Cohort Studies; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Propensity Score; Retrospective Studies; Stroke; Taiwan; Treatment Outcome; Venous Thrombosis; Vitamin K; Warfarin

Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy.. This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event.. We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plus LMWH. A total of 21 patients (17%) were receiving a subtherapeutic dose of an anticoagulant. The main regimens to treat recurrence in patients on VKA were: switch to LMWH (33%), temporary double treatment with LMWH and VKA (23%), and VKA with a higher target INR (19%). In patients with a breakthrough on LMWH, the most frequently chosen regimen was a permanent dose increase (74%). During 3-month follow-up, 7% of patients had a second breakthrough event and 8% experienced major or clinically relevant non-major bleeding.. There is wide variation in the management of VTE during anticoagulant treatment, reflecting a heterogeneous and complex clinical situation. Despite intensifying anticoagulation, the risk of a second breakthrough event in this population is 7%.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Venous Thromboembolism; Vitamin K; Young Adult

Topics: 4-Hydroxycoumarins; Adult; Aftercare; Anticoagulants; Antiphospholipid Syndrome; England; Factor Xa Inhibitors; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Incidence; Indenes; International Normalized Ratio; Neoplasms; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; State Medicine; Systematic Reviews as Topic; Thrombophilia; Vena Cava Filters; Venous Thromboembolism; Vitamin K

Cancer may complicate the clinical course of nonvalvular atrial fibrillation (AF) but its association with cardiovascular events (CVEs) remains unclear. We performed a prospective cohort study including 2092 consecutive AF patients on vitamin K antagonists. Principal endpoint was the occurrence of CVEs including fatal/nonfatal myocardial infarction and ischemic stroke/transient ischemic attack and cardiovascular death. Secondary endpoints were major adverse cardiac events (MACEs) and thromboembolism (TE). Mean age was 73.7 ± 9.1 years and 42.1% were women; 367 (17.5%) patients had cancer: 21% gastrointestinal (GI), 10% respiratory, 28% genitourinary and 41% had other localization. Cancer patients were older but with similar comorbidities than those without. During a mean of 35.9 months, 203 CVEs occurred (incidence rate [IR] = 3.24 per 100 patient-years): 133 MACEs (IR = 2.12 per 100 patient-years) and 70 TE (IR = 1.12 per 100 patient-years). Multivariable Cox proportional hazards regression analysis showed an association between GI cancer and MACE occurrence (hazard ratio [HR] = 3.22, 95% confidence interval [CI] = 1.59-6.52, P = .001) and between respiratory cancer and TE (HR = 3.37, 95% CI = 1.30-8.75, P = .013). These associations were confirmed at competing risk analysis. In conclusion, AF patients with cancer have specific vascular outcomes according to cancer site, as indicated by the higher risk of MACE and TE in patients with gastrointestinal and respiratory cancer, respectively.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Comorbidity; Cross-Sectional Studies; Female; Humans; Male; Myocardial Ischemia; Neoplasms; Proportional Hazards Models; Prospective Studies; Thromboembolism; Vitamin K

 Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence..  Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models..  Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91-1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93-1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01-2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72-6.44). Results were consistent in the head-to-head comparison..  Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Vitamin K

Topics: 4-Hydroxycoumarins; Administration, Oral; Anticoagulants; Clinical Trials as Topic; Dalteparin; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Indenes; Medical Oncology; Neoadjuvant Therapy; Neoplasms; Prognosis; Pyrazoles; Pyridones; Risk Assessment; Venous Thromboembolism; Vitamin K

To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs).. PubMed was searched using terms "venous thromboembolism," "cancer," and "anticoagulation." This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations.. English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer.. Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered.. DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Prospective Studies; Retrospective Studies; Venous Thromboembolism; Vitamin K

The safety and efficacy of direct oral anticoagulants in cancer patients is currently unclear. Low-molecular-weight heparin remains the standard of care for cancer patients with venous thromboembolism, with warfarin, a vitamin K antagonist, as an alternative. Clear recommendations do not exist for patients with both active cancer and non-valvular atrial fibrillation. The objectives of this study were to report safety and efficacy outcomes of direct oral anticoagulants, low-molecular-weight heparin, and vitamin K antagonist in cancer patients with venous thromboembolism or non-valvular atrial fibrillation.. Retrospective chart review of adult cancer patients from 2012 to 2015 who received an antineoplastic agent and an anticoagulant.. A total of 258 patients were reviewed: 80 patients in direct oral anticoagulant group, 95 patients in low-molecular-weight heparin group, and 83 patients in vitamin K antagonist group. Sixty-seven percent of patients were on an anticoagulant for acute or chronic venous thromboembolism. Major bleeding events were similar across the groups (15% direct oral anticoagulant vs 17% low-molecular-weight heparin vs 18% vitamin K antagonist). The most common type of major bleeding event was gastrointestinal bleeding. A total of five fatal bleeding events occurred. Venous thromboembolism recurrence rates were higher in both direct oral anticoagulant (18%) and low-molecular-weight heparin (12%) groups while lower in vitamin K antagonist group (10%) compared to previous studies.. Cancer patients receiving direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonist had similar rates of major bleeding events, with gastrointestinal bleeding being the most common event. Venous thromboembolism recurrence rates were higher in direct oral anticoagulant and low-molecular-weight heparin groups than prior studies. Randomized trials are warranted to establish clear safety and efficacy in this population.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Treatment Outcome; United States; Venous Thromboembolism; Vitamin K; Warfarin

Whether bleeding should be considered a sufficient sign to justify thorough cancer surveillance in atrial fibrillation (AF) patients receiving nonvitamin K antagonist oral anticoagulants (NOACs) remains unclear. We investigated the relationships between bleeding events and new-onset cancers in AF patients receiving NOACs in a prospective cohort (n = 395, mean follow-up duration of 2.8 years). There were 18 patients who were diagnosed with new-onset cancers 584 ± 372 days after the initiation of NOACs. The patients with new-onset cancers had higher HAS-BLED scores (no, preexisting and new-onset cancer: 1.51 ± 0.81, 1.69 ± 0.87, and 2.11 ± 0.96, respectively; p = 0.006) and a higher incidence of bleeding events (22%, 33%, 67%, respectively; p<0.001) than did patients without new-onset cancers. Bleeding events that preceded the diagnosis of new-onset cancers were independently correlated with new-onset cancers (odds ratio: 7.89, p = 0.001) in the multivariate logistic regression. More than half of the patients (61%) with new-onset cancers had either a significant period of drug interruption for at least 2 months or discontinued NOACs. In conclusions, bleeding in AF patients receiving NOACs could be an alerting sign of new-onset cancers and should prompt the initiation of thorough surveillance to detect early cancers.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Incidence; Male; Neoplasms; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Taiwan; Time Factors; Vitamin K

Mechanical heart valves (MHV) require life-long anticoagulation with vitamin K antagonists (VKA), but anticoagulation management is complex in patients with cancer due to a high risk of thrombosis and bleeding. This is a retrospective, single-center study to assess anticoagulation management and thrombotic (stroke/valve thrombosis) and bleeding events in patients with active cancer and MHV. The incidence of thrombotic complications was compared to a control group (matched 1:1) of patients with MHV but without cancer. We included 48 patients, 60% of whom had aortic prostheses, 23% mitral prostheses and 17% both types. All patients received VKA as anticoagulant. With a median follow-up of 5.12 years, we observed two arterial thrombotic events (two strokes and no heart valve thrombosis). The 5-year incidence (95% confidence interval [CI]) of stroke/valve thrombosis was 5.7% (0.9-17.9%). The control group had a similar incidence of stroke/valve thrombosis (5-year incidence 7.9% [95%CI 2-19.8], p = 0.16). There were also 15 major bleeding episodes in the cancer group, 11 of which were related to a surgical procedure. The 5-year incidence (95% CI) of major bleeding was 32.9% (18.5-48%), and that of major bleeding unrelated to any procedure was 10.3% (3-23%). We found a low incidence of thrombotic events in this series of patients with active cancer and MHV who were anticoagulated with VKA. However, the incidence of bleeding was high, particularly in relation to invasive procedures.

Topics: Aged; Anticoagulants; Case-Control Studies; Female; Follow-Up Studies; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Incidence; Male; Middle Aged; Neoplasms; Retrospective Studies; Surgical Procedures, Operative; Thromboembolism; Vitamin K

Low-molecular-weight heparins (LMWH) are the drug of choice for treatment of cancer-associated thrombosis (CAT), however non-vitamin K antagonist oral anticoagulants (NOAC) seem to be a reasonable alternative. We investigated the safety and efficacy of NOAC versus LMWH in patients with a history of CAT.. In a prospective cohort study 128 consecutive patients with active cancer who experienced CAT were enrolled following LMWH treatment for ≥3 months. Symptomatic recurrent venous thromboembolism (VTE), bleeding and death were recorded during follow-up.. 65 (50.8%) patients were switched to NOAC and 63 (49.2%) continued with LMWH. During a median follow-up of 17 (interquartile range, 15-21) months, recurrent VTE was observed in 6 (9.2%) patients on NOAC and in 12 (19.0%) on LMWH (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.16-1.16). The rate of major bleeding was 9.2% and 4.8%, respectively (HR 2.00, 95% CI 0.50-8.00). The median time to bleeding was shorter in patients on NOAC (3 [2.25-5.5] months) versus on LMWH (9 [6.5-13.0] months). The mortality rates were similar in both groups (15.4% versus 15.9%, respectively, HR 0.76, 95% CI 0.32-1.84).. In patients following CAT, extended treatment with NOAC, compared with LMWH, appears to be associated with similar effectiveness and safety.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Comparative Effectiveness Research; Dabigatran; Drug Administration Schedule; Enoxaparin; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Low-molecular-weight heparin (LMWH) is the treatment of choice in cancer patients with venous thromboembolism. However, data on continuing LMWH treatment beyond 6 months remain scanty.. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the rate of venous thromboembolism recurrences and major bleeding appearing beyond the first 6 months of anticoagulant therapy in cancer patients with venous thromboembolism, according to therapy with LMWH or vitamin K antagonists (VKA). We performed a propensity score-matched cohort study.. After propensity matching, 482 cancer patients continued to receive LMWH and 482 switched to VKA. During the course of anticoagulant therapy (mean 275.5 days), 57 patients developed venous thrombosis recurrences (recurrent pulmonary embolism 26, recurrent deep vein thrombosis 29, both 2), 28 had major bleeding, 38 had nonmajor bleeding, and 129 died. No patient died of recurrent venous thrombosis, and 5 patients died of bleeding (2 were on LMWH, 3 on VKA). Patients who continued with LMWH had a similar rate of deep vein thrombosis recurrences (relative risk [RR] 1.41; 95% confidence interval [CI], 0.68-2.93), pulmonary embolism recurrences (RR 0.73; 95% CI, 0.34-1.58), major bleeding (RR 0.96; 95% CI, 0.51-1.79), or nonmajor bleeding (RR 1.15; 95% CI, 0.55-2.40), compared with those who switched to VKA, but a higher mortality rate (RR 1.58; 95% CI, 1.13-2.20).. In cancer patients with venous thromboembolism who completed 6 months of LMWH therapy, switching to VKA was associated with a similar risk of venous thrombosis recurrences or bleeding when compared with patients who continued LMWH.

Topics: Aged; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Propensity Score; Recurrence; Registries; Retrospective Studies; Venous Thromboembolism; Vitamin K

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Denmark; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Thromboembolism; Vitamin K

Since several trials have demonstrated that low-molecular-weight-heparin (LMWH) is superior to vitamin K antagonist (VKA) in preventing recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, guidelines now recommend LMWH monotherapy in this setting. We evaluated whether this shift resulted in improved outcomes in routine clinical practice. We performed a cohort study of consecutive patients with cancer-associated VTE during 2001 and 2010. We compared the risks for recurrent VTE, major bleeding and mortality between patients diagnosed before and after 2008 during a 6-month routine follow-up. A total of 381 patients were included, of which 234 (61.4%) were diagnosed before 2008. Before 2008, 23% of the patients were treated with LMWH; thereafter, this percentage was higher: 67%. The 6-month incidence for recurrent VTE was 8.6% in patients diagnosed before 2008 versus 7.5% for patients diagnosed after 2008 (risk difference [RD]: -1.1%; 95% confidence interval [CI]: -6.3, 5.3). The respective risks for major bleeding were 6.4 versus 4.8% (RD: -1.6%; 95% CI: -3.8 to 5.8), and 39.7 versus 41.5% (RD: 1.8%; 95% CI: -8.8, 12) for overall mortality. The mean time in therapeutic range (TTR) of patients treated with VKA was 61%. Despite a clear shift toward LMWH as agent of choice for cancer-associated VTE, we did not observe a clear improvement in terms of recurrent VTE and bleeding complications.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Clinical Decision-Making; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Netherlands; Recurrence; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Vitamin K has been associated with various health outcomes, including non-fatal cardiovascular diseases (CVD) and cancer. However, little is known about the association between vitamin K intake and all-cause and cause specific mortality. This study aims to investigate the association between vitamin K intake and all-cause and cause-specific mortality.. This prospective cohort study included 33,289 participants from the EPIC-NL cohort, aged 20-70 years at baseline and recruited between 1993 and 1997. Dietary intake was assessed at baseline with a validated food frequency questionnaire and intakes of phylloquinone, and total, short chain and long chain menaquinones were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazards, adjusted for risk factors for chronic diseases and nutrient intake.. During a mean follow-up of 16.8 years, 2863 deaths occurred, including 625 from CVD (256 from coronary heart disease (CHD)), 1346 from cancer and 892 from other causes. After multivariable adjustment, phylloquinone and menaquinones were not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of intake of 1.04 (0.92;1.17) and 0.94 (0.82;1.07) respectively. Neither phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. Higher intake of long chain menaquinones was borderline significantly associated (p. Vitamin K intake was not associated with all-cause mortality, cancer mortality and mortality from other causes.

Topics: Adult; Aged; Body Mass Index; Cardiovascular Diseases; Chronic Disease; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Mortality; Neoplasms; Nutrition Assessment; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Factors; Surveys and Questionnaires; Vitamin K; Vitamin K 1; Vitamin K 2; Young Adult

International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146-53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR = 0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates = 3% vs. 17%; p = 0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives.. Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained.. The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin = €2687 vs. VKA = €2012; France: dalteparin = €2053 vs. VKA = €1352: p < 0.001). However, when the incremental costs were combined with the utility gain, dalteparin had a cost of €6600 and €4900 per QALY gained in Austria and France, respectively. The analyses in patients with renal impairment suggested an even better economic profile, with the cost per QALY gained being less than €4000 in both countries.. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

Topics: Anticoagulants; Austria; Cost-Benefit Analysis; Dalteparin; Female; France; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Recurrence; Venous Thromboembolism; Vitamin K

ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE.. Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management.. Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed.. In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4).. These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Data Interpretation, Statistical; Female; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Recurrence; Registries; Risk Factors; Tomography, X-Ray Computed; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

There has been a concern that major bleeding events (MBE) on direct-acting oral anticoagulants (DOACs) will be more difficult to manage than on vitamin K antagonists. Patients with cancer and DOAC-associated bleeding may be even more of a challenge to manage. We therefore reviewed the literature on bleeding in patients with cancer on DOACs. In addition, we performed an analysis of individual patient data from 5 phase III trials on treatment with dabigatran with focus on those with cancer. In 6 randomized trials the risk of MBE in patients with cancer was similar on treatment with DOACs compared to vitamin K antagonists. Bleeding was in the majority of patients managed with supportive therapy alone. In the individual patient data analysis there were no significant differences in use of hemostatic products, transfusion of red cells, effectiveness of management, bleeding-related mortality or 30-day all-cause mortality between patients with cancer treated with dabigatran or with warfarin. Local hemostatic therapy, including resection of the cancer site was more common in patients with gastrointestinal bleeding with cancer than among those without cancer. We conclude that management of bleeding in patients with cancer and on a DOAC does not pose a greater challenge than management of bleeding in patients without cancer.

Topics: Anticoagulants; Dabigatran; Hemorrhage; Humans; Neoplasms; Venous Thromboembolism; Vitamin K; Warfarin

Cancer and venous thrombo-embolic disease (VTE) are closely related. Indeed, cancer can reveal VTE and VTE can be the first sign of cancer. Low molecular weight heparin (LWMH) is now the first line treatment in cancer patients. Compliance with marketing authorizations and guidelines are crucial for patient-centered decision-making. This work deals with the prescription of LWMH in patients who develop VTE during cancer in order to better recognize what should or should not be done. The patient's wishes must be taken into consideration when making the final therapeutic decision. The other treatments are discussed: vitamin K antagonists and direct oral anticoagulants (DOACs) may be useful.

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Risk Factors; Venous Thromboembolism; Venous Thrombosis; Vitamin K

After 6months, little is known about the optimal anticoagulant strategy for an acute episode of VTE in cancer patients.. The objective was to determine the risk of recurrent VTE and anticoagulant-related bleeding at 6months of follow-up and after 6months, in cancer patients who received tinzaparin during at least 3months for an acute episode of VTE. We conducted a multicenter retrospective cohort study from January 2004 to March 2011.. Two hundred fifty patients were included. Stopping anticoagulation before 6months in patients considered at low risk by physicians (i.e.; patients who had prior cancer surgery) and for another reason than bleeding or death was the only factor associated with a significant increased risk of recurrent VTE (OR 7.2 95%CI, 2.0-25.7; p=0.002). The type of anticoagulation did not influence the risk of recurrent VTE. We found a trend towards an increased risk of recurrent VTE when anticoagulation was stopped because of major bleeding while on anticoagulant therapy and patients with metastatic cancer (OR 2.3, 95%CI, 0.9-5.4; p=0.07; and OR 1.8 95%CI, 1.0-3.3; p=0.07; respectively). No factors were found to increase the risk of major bleeding at 6months and after. The overall mortality was 42.8%.. The risk of recurrent VTE was mainly related to early discontinuation of anticoagulation in patients considered at low risk of recurrence (after surgery). When the anticoagulation was stopped before the sixth month, the risk was eight fold higher. After 6month, the risks of recurrent VTE, major bleeding and death were similar in patients with either VKA or tinzaparin when patients were treated according to the guidelines.

Topics: Anticoagulants; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasm Metastasis; Neoplasms; Recurrence; Retrospective Studies; Risk Factors; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Vitamin K

Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies.. Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression.. We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation.. Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Topics: Aged; Anticoagulants; Chi-Square Distribution; Drug Substitution; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Prospective Studies; Recurrence; Registries; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism occurs in up to 10% of patients with cancer. The incidence of thrombosis is varying with the nature, the histologic type and the stage of the disease. The risk of thrombosis is also increased by most of anticancer treatments and supportive care. Although long-term prophylactic treatment is able to decrease the rate of venous thromboembolism in patients with cancer, the absolute reduction is too low to give long-term prophylaxis, except for some rare exceptions. The treatment of cancer associated thrombosis is based on the use of low-molecular weight heparin for at least three to six months. In most cases, anticoagulation should be given for a longer period but the choice of the drug should be indi- vidualized on the basis of the evolution of the underlying cancer, overall prognosis, tolerance of injections and patient's preference. Recurrent venous thromboembolism during treatment with low-molecular weight heparin can be treated with a 10% dose escalation. Dose should be adjusted during periods of thrombocytopenia. Finally, the direct oral anticoagulants have not been compared with low-molecular weight heparins for the treatment of cancer associated thrombosis.

Topics: Anticoagulants; Humans; Neoplasms; Pulmonary Embolism; Venous Thromboembolism; Vitamin K

Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion.

Topics: Aged; Anticoagulants; Antithrombin III; Blood Coagulation Factors; Blood Platelets; Female; Follow-Up Studies; Gangrene; Heparin; Humans; International Normalized Ratio; Ischemia; Leg; Male; Middle Aged; Neoplasms; Peptide Hydrolases; Prognosis; Protein C Deficiency; Syndrome; Venous Thrombosis; Vitamin K; Warfarin

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.

Topics: Aged; Aged, 80 and over; Anticoagulants; Drug Prescriptions; Female; Fibrinolytic Agents; Follow-Up Studies; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Time Factors; Venous Thromboembolism; Vitamin K

Periprocedural management of patients on long-term warfarin therapy remains a common and important clinical issue, with little high-quality data to guide this complex process. The current accepted practice is cessation of warfarin five days preoperatively, but this is not without risk and can be complicated, particularly if bridging is required. An alternative method utilising low-dose intravenous vitamin K the day before surgery has been shown previously to be efficacious, safe and convenient in an elective surgical population receiving chronic warfarin therapy. The efficacy and utility of this 'fast-track' warfarin reversal protocol in surgical patients with cancer, who were at high risk of both thromboembolism and bleeding was investigated in a prospective, single-arm study at a dedicated cancer centre. Seventy-one patients underwent 82 episodes of fast-track warfarin reversal (3 mg intravenous vitamin K 18 to 24 hours before surgery). No patient suffered an adverse reaction to intravenous vitamin K, all but one achieved an International Normalized Ratio =1.5 on the day of surgery, and no surgery was deferred. Assays of vitamin K-dependent factor levels pre- and post-vitamin K demonstrated restoration of functional activity to within an acceptable range for surgical haemostasis. While this alternative method requires further validation in a larger prospective randomised study, we have now extended our use of fast-track warfarin reversal using vitamin K to patients with cancer, on the basis of our experience of its safety, convenience, reliability and efficacy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Elective Surgical Procedures; Female; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Vitamin K; Warfarin

Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed with a malignant disease. Two patients died, the other has been improving and anticoagulant therapy with VKA was continued, in 4 VKA were changed to low-molecular-weight heparin, and on 4 commissioned new generation anticoagulant (rivaroxaban).

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Cognition Disorders; Dementia; Drug Interactions; Drug Overdose; Female; Humans; Male; Neoplasms; Poland; Suicide, Attempted; Vitamin K; Warfarin

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3-6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.

Topics: Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Postoperative Complications; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Thrombocytopenia; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Algorithms; Anticoagulants; Biomarkers; Chronic Disease; Clinical Laboratory Techniques; Diagnostic Imaging; Embolectomy; Endovascular Procedures; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Heart Failure; Home Care Services; Humans; Hypertension, Pulmonary; Long-Term Care; Neoplasms; Pregnancy; Pregnancy Complications, Cardiovascular; Prognosis; Pulmonary Embolism; Risk Factors; Vasoconstrictor Agents; Vasodilator Agents; Vitamin K

Since 2004, guidelines recommend long-term treatment with low-molecular-weight heparin (LMWH) in patients with cancer and pulmonary embolism (PE). We assessed the proportion of cancer patients with PE actually treated with LMWH and the duration of anticoagulant treatment in the Netherlands.. A retrospective cohort study in patients that were hospitalised for PE between 1998-2008. Patients with PE were selected from national hospital discharge records, after linkage to a national pharmacy database. Cancer patients with PE were matched for age, sex and year of diagnosis of PE to subjects with PE without cancer.. 600 cancer patients with PE were matched to 1200 patients with PE without cancer. Long-term LMWH was prescribed in 82 (13.7%) of the cancer patients and in eight (0.7%) of the cancer-free patients (p < 0.001); all the other patients received vitamin K antagonists (VKA). From 1998-2008, there was an increase in the use of LMWH in cancer patients: in 2007-2008, LMWH was prescribed in 42 (32%) cases, compared with one (1.7%) of the cancer patients with PE in 1998-1999. Median duration of treatment was 5.8 months (interquartile range 3.1-8.8) in cancer patients, compared with 7.0 months (4.9-11) in patients without cancer (p < 0.001), a difference that persisted after adjustment for mortality.. Although the use of LMWH in patients with cancer and PE is increasing, in 2008, patients in the Netherlands are still mostly treated with VKA, and not with LMWH as recommended by guidelines. Cancer patients with PE on average receive shorter treatment than matched patients without cancer.

Topics: Aged; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Netherlands; Practice Guidelines as Topic; Pulmonary Embolism; Retrospective Studies; Time Factors; Vitamin K

Injectable anticoagulation therapy is indicated for several months following diagnosis of venous thromboembolic disease (VTE) in a context of active neoplasia. Certain studies have shown an improvement in patient compliance using self-injections.. Allow patients to safely make their own injections of anticoagulants after checking their aptitude and motivation.. At the prescribing physician's request, the GRANTED network provided patients and/or the resource person with specific education and training. The educational program was proposed to patients with an indication for a treatment for at least 3 months. After becoming familiar with the injection material and its manipulation, the patient and/or resource person performed sham injections on test materials. Patients were then allowed to decide for themselves whether or not to participate in the self-injection protocol. The prescribing physician received a report from the training team.. From November 2010 to July 2012, 39 patients participated in the educational program, generally in a context of vitamin K antagonist prescriptions. Sixteen of these patients had a neoplasia. The educational program corrected erroneous or imprecise points of information, particularly concerning syringe purging.. The education program proved to be interesting for points other than those initially foreseen and allowed the team to rectify a certain number of erroneous messages unrecognized by the prescribing physicians. This result goes in line with the need for accompanying patients who have a prescription for self-injections and also emphasizes the need for careful follow-up.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Feasibility Studies; Female; Humans; Injections; Male; Middle Aged; Neoplasms; Patient Education as Topic; Self Administration; Venous Thromboembolism; Vitamin K

Information on recurrent venous thromboembolic events (VTEs) and major bleeding risks during anticoagulant treatment in patients with cancer-associated VTEs and chronic kidney disease (CKD) is scarce, although it is of relevance in establishing better tailored management strategies in these patients.. We compared risks of recurrent VTEs and major bleeds in cancer-associated VTE patients with and without CKD.. A total of 1684 patients diagnosed with a cancer-associated VTE between 2001 and 2011 were followed for 180 days after VTE diagnosis. Patients were treated mainly with low-molecular-weight heparin (LMWH) or vitamin-K antagonists (VKA). Primary outcomes were recurrent VTE and major bleeding. Secondary outcome was fatal bleeding.. Recurrent VTEs occurred in 15.9/100 patient years (py) in patients without CKD (eGFR > 60 mL min(-1) ), 19.5/100 py in those with CKD stage 3A (eGFR 45-60 mL min(-1) ), 14.9/100 py in those with CKD 3B (eGFR 30-45 mL min(-1) ), and 6.8/100 py in patients with CKD 4-5 (eGFR < 30 mL min(-1) ). Major bleeding occurred in 11.4/100 py in patients without CKD, 18.5/100 py in those with CKD stage 3A, 16.0/100 py in those with CKD 3B, and 40.8/100 py in patients with CKD 4-5. Fatal bleeding occurred in 1.1/100 py, 3.4/100 py, 6.3/100 py and 15.7/100 py, respectively. These increased bleeding risks in CKD patients were mainly observed in those on LMWH treatment, not VKA.. The risk of major bleeding was increased in CKD patients with VTE and cancer, and was most prominent in those treated with LMWH and an eGFR < 30 mL min(-1) . These results indicate that LMWH should be used with caution in this specific population.

Topics: Aged; Anticoagulants; Cohort Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Recurrence; Registries; Risk; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Some evidence suggests that long-term use of vitamin K antagonists (VKAs) has a cancer chemopreventive effect. Such an effect would have considerable implications in terms of understanding tumor biology. To evaluate if long-term VKA treatment influences the risk of developing cancer, we performed a matched case-control analysis. We used data from four Danish nationwide registers. Cases were all Danish individuals with a first-time cancer diagnosis (except nonmelanoma skin cancer) between 2000 and 2009. For each case, eight controls, matched by birth year and gender, were selected from the source population by risk-set sampling. Long-term VKA use was defined as exposure to VKA for a period of 3 or more years. Conditional logistic regression was used to compute odds ratios (ORs) for cancer associated with long-term VKA exposure, adjusting for potential confounders. Prespecified subanalyses were performed for selected cancer sites, subgroups and measures of exposure. A total of 238,196 cases and 1,713,176 controls were included. The adjusted OR for cancer associated with long-term VKA exposure was 0.99 (95% CI: 0.95-1.02). Long-term VKA use was associated with increased ORs for alcohol- or obesity-related cancer sites, whereas we observed a decreased risk of prostate cancer (OR: 0.86; 95% CI: 0.78-0.95). Our study does not support a general chemopreventive effect of VKA drugs. However, in accordance with findings from previous studies, we found an inverse association between use of VKA and prostate cancer.

Topics: Aged; Anticoagulants; Case-Control Studies; Denmark; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Prognosis; Risk Factors; Vitamin K

Topics: Aged; Aged, 80 and over; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Pilot Projects; Treatment Outcome; Vitamin K; Vitamin K Deficiency

Bias analysis serves multiple objectives in epidemiologic data analysis. The objectives most often emphasized are quantification of uncertainty due to systematic errors and reduction in overconfidence by specifying hypotheses that compete with the causal hypothesis. A third objective is the utility of bias analysis to identify strategies for new data collection that will be productive in evaluating the validity of an association. The authors illustrate the value of this objective using two examples. The first example examines the value of comprehensive CYP2D6 genotyping in a study of tamoxifen resistance. Tamoxifen is metabolized primarily by CYP2D6 to more active forms. More than thirty polymorphisms in the CYP2D6 gene reduce its function. We genotyped the most prevalent CYP2D6 polymorphism and found a null association between genotype and breast cancer recurrence in a Danish population. One possibility is that incomplete genotyping of the multiple functional polymorphisms introduced non-differential misclassification and biased the association toward the null. We used bias analysis to evaluate the plausibility of this explanation and to guide a decision about devoting study resources toward more comprehensive genotyping of other polymorphisms in the CYP2D6 gene. The second example examines the association between vitamin K antagonist (VKA) therapy and the incidence of 24 site-specific cancers, using heart valve replacement as an instrumental variable. Earlier studies suggested a protective association between VKA anticoagulants and the incidence of cancer. We observed a null-centered distribution of associations, which may be due to non-differential misclassification of VKA therapy by the instrument. We used bias analysis to evaluate whether this misclassification was likely to explain the null-centered distribution of associations and to guide decisions about conducting a more expensive validation study. In the first example, the bias analysis showed that new data collection would be required to resolve the uncertainty, whereas the second example showed that new data collection was unlikely to be a productive use of scarce study resources.

Topics: Anticoagulants; Bias; Biostatistics; Breast Neoplasms; Causality; Cytochrome P-450 CYP2D6; Data Collection; Drug Resistance, Neoplasm; Epidemiologic Methods; Female; Humans; Male; Neoplasms; Polymorphism, Genetic; Tamoxifen; Vitamin K

Topics: Anticoagulants; Drug Administration Schedule; Evidence-Based Medicine; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Practice Guidelines as Topic; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Secondary Prevention; Venous Thromboembolism; Vitamin K

Whether long-term use of vitamin K antagonists (VKAs) might affect the incidence of cancer is a longstanding hypothesis. We conducted a population-based study including all cancer- and thromboembolism-free patients of our health area; study groups were defined according to chronic anticoagulant use to VKA-exposed and control groups. Cancer incidence and cancer-related and overall mortality was assessed in both groups. 76 008 patients (3231 VKA-exposed and 72 777 control subjects) were followed-up for 8.2 (± 3.2) years. After adjusting for age, sex, and time-to-event, the hazard ratio of newly diagnosed cancer in the exposed group was 0.88 (95% confidence interval [95% CI] 0.80-0.98; P < .015). VKA-exposed patients were less likely to develop prostate cancer, 0.69 (95% CI 0.50-0.97; P = .008). The adjusted hazard ratio for cancer-related and overall mortality was 1.07 (95% CI 0.92-1.24) and 1.12 (95% CI 1.05-1.19), respectively. These results support the hypothesis that anticoagulation might have a protective effect on cancer development, especially prostate cancer.

Topics: Aged; Anticoagulants; Cohort Studies; Female; Humans; Incidence; Italy; Male; Neoplasms; Survival Rate; Time Factors; Vitamin K

Earlier studies suggest a protective association between vitamin K antagonist (VKA) anticoagulants and the incidence of cancer. The authors examined the associations between VKA therapy and incidence of 24 site-specific cancers with a Danish population-based cohort study, using heart valve replacement as an instrumental variable. The authors enrolled 9,727 Danish residents who received a replacement heart valve between 1989 and 2006. The heart valve recipients were matched with 95,481 unexposed individuals on age and sex. The authors used the heart valve replacement instrument to estimate rate ratios associating VKA therapy with incidence of the 24 site-specific cancers using Poisson regression models. Direct associations between VKA therapy and incidence of the 24 cancers were estimated in a prescription validation subset. The instrumental variable associations were plotted according to the inverse normal of rank percentile and subjected to semi-Bayes shrinkage adjustment for multiple comparisons. The pattern of associations was consistent with a null-centered Gaussian distribution. No individual cancer site showed a substantial positive or negative association with VKA therapy in the prescription validation subset, the instrumental variable analysis, or the analysis with semi-Bayes adjustment. These results do not support the existing hypothesis that VKA therapy is associated with reduced cancer risk.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cohort Studies; Denmark; Female; Heart Valve Prosthesis Implantation; Humans; Incidence; Male; Middle Aged; Neoplasms; Vitamin K; Young Adult

Anticarcinogenic activities of vitamin K have been observed in animal and cell studies.. On the basis of the growth inhibitory effects of vitamin K as observed in a variety of cancer cell lines, we hypothesized that dietary intake of phylloquinone (vitamin K(1)) and menaquinones (vitamin K(2)) may be associated with overall cancer incidence and mortality.. In the prospective EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition-Heidelberg) cohort study, 24,340 participants aged 35-64 y and free of cancer at enrollment (1994-1998) were actively followed up for cancer incidence and mortality through 2008. Dietary vitamin K intake was estimated from food-frequency questionnaires completed at baseline by using HPLC-based food-composition data. Multivariate-adjusted hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards models.. During a median follow-up time of >10 y, 1755 incident cancer cases occurred, of which 458 were fatal. Dietary intake of menaquinones was nonsignificantly inversely associated with overall cancer incidence (HR for the highest compared with the lowest quartile: 0.86; 95% CI: 0.73, 1.01; P for trend = 0.08), and the association was stronger for cancer mortality (HR: 0.72; 95% CI: 0.53, 0.98; P for trend = 0.03). Cancer risk reduction with increasing intake of menaquinones was more pronounced in men than in women, mainly driven by significant inverse associations with prostate (P for trend = 0.03) and lung (P for trend = 0.002) cancer. We found no association with phylloquinone intake.. These findings suggest that dietary intake of menaquinones, which is highly determined by the consumption of cheese, is associated with a reduced risk of incident and fatal cancer.

Topics: Adult; Cell Division; Cheese; Diet; Educational Status; Exercise; Female; Follow-Up Studies; Germany; Humans; Male; Middle Aged; Neoplasms; Postmenopause; Risk Reduction Behavior; Smoking; Vitamin K; Vitamin K 1; Vitamin K 2

Topics: Europe; General Surgery; Heparin, Low-Molecular-Weight; Humans; Incidence; Neoplasms; Prognosis; Risk Factors; Secondary Prevention; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Animals; Antineoplastic Agents; Diet; Humans; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamins

The current approach for deciding the duration of vitamin K antagonist (VKA) treatment after an episode of venous thrombo-embolism (VTE) is mainly based on the characteristic of the index event (3 months or longer in case of unknown/persistent risk factors, 3 months or less in case of removable causes). However, the length of anticoagulation should be tailored on the patient's risk for recurrent thrombosis as well as for bleeding, but such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. The presence of persistent residual vein thrombosis and increased D-dimer levels after stopping therapy are predictors for recurrent deep vein thrombosis (DVT). Management strategies based on these parameters have been demonstrated to optimize the decision for VKA duration, as they establish the patient's intrinsic risk for recurrent events. This annotation discusses current practice and upcoming approaches regarding the length of VKA treatment after a first episode of DVT.

Topics: Biomarkers; Drug Administration Schedule; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Neoplasms; Recurrence; Risk Assessment; Time Factors; Venous Thrombosis; Vitamin K; Vitamins

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K; Warfarin

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Polysaccharides; Proportional Hazards Models; Pulmonary Embolism; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Secondary Prevention; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Young Adult

Factor V Leiden (R506Q) mutation is the most commonly observed inherited genetic abnormality related to vein thrombosis. Lebanon has one of the highest frequencies of this mutation in the world with a prevalence of 14.4% in the general population. The aim of this study is to define risk factors including inherited genetic abnormalities among Lebanese patients with lower extremity deep vein thrombosis. We report the clinical outcome of patients with thrombophilia.. From January 1998 to January 2008, 162 patients (61 males and 101 females) were diagnosed with lower extremity deep vein thrombosis. Mean age was 61 years (range: 21 to 95 years).. The most frequent risk factors for vein thrombosis were surgery, advanced age, obesity, and cancer. Twenty-five patients had thrombophilia, 16 patients had factor V Leiden (R506Q) mutation, and seven patients had MTHFR C677T mutation. Ninety-two percent of patients screened for thrombophilia were positive. Screening was requested in young patients (16), patients with recurrent (11), spontaneous (8), and extensive (5) venous thrombosis, familial history (5), pregnancy (4), estroprogestative treatment (3), and air travel (1). Nine patients had one, 11 patients had two, and five had three of these conditions. Follow-up (6 to 120 months) of these 25 patients treated with antivitamin K did not reveal recurrences or complications related to venous thromboembolism.. Factor V Leiden mutation followed by MTHFR mutation are the most commonly observed genetic abnormalities in these series. Defining risk factors and screening for thrombophilia when indicated reduce recurrence rate and complications. Recommendations for thrombophilia screening will be proposed.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Asian People; Factor V; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Incidence; Lebanon; Lower Extremity; Male; Mass Screening; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation; Neoplasms; Obesity; Recurrence; Risk Assessment; Risk Factors; Surgical Procedures, Operative; Thrombophilia; Treatment Outcome; Venous Thrombosis; Vitamin K; Young Adult

Topics: Acute Disease; Anticoagulants; Cardiovascular Diseases; Chronic Disease; Fibrinolytic Agents; Humans; Hungary; Internal Medicine; Mass Screening; Neoplasms; Nervous System Diseases; Platelet Aggregation Inhibitors; Primary Prevention; Risk Assessment; Risk Factors; Secondary Prevention; Surgical Procedures, Operative; Thromboembolism; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Female; Follow-Up Studies; Humans; Male; Neoplasms; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Anticoagulants; Cohort Studies; Hemorrhage; Humans; Neoplasms; Quality of Life; Recurrence; Registries; Research Design; Risk; Thrombosis; Treatment Outcome; Vitamin K

Little is known about the consequences of a first venous thrombosis in the upper extremity. We studied the incidence of, survival, and risk factors for recurrence in a follow-up study.. We followed up 224 patients 18 to 70 years of age after a first venous thrombosis of the arm. Information was collected through anticoagulation clinics, the national death registry, discharge letters, and questionnaires. The median follow-up was 3 years, during which time 30 patients experienced a recurrent event, yielding an incidence rate of 43.2 per 1000 person-years. Survival was reduced: 55 of 224 patients died, which was 5.4-fold higher than age- and sex-adjusted population rates (standardized mortality ratio, 5.4; 95% CI, 4.2 to 7.0). The risk of recurrence was 2-fold higher in women than in men (hazard ratio, 1.8; 95% CI, 0.9 to 3.9). A central venous catheter at the time of first thrombosis was associated with a reduced risk of recurrence. A body mass index > or =25 kg/m(2) and a first nonsubclavian thrombosis appeared to increase the risk of a recurrent event. Prothrombotic mutation carriers did not appear to have an increased recurrence risk.. The risk of recurrence was high, with women, patients with body mass index > or =25 kg/m(2), and patients with a first nonsubclavian vein thrombosis having a higher risk of recurrence. Patients with a first venous thrombosis of the arm have a poor vital prognosis.

Topics: Adolescent; Adult; Aged; Axillary Vein; Blood Coagulation Tests; Female; Follow-Up Studies; Humans; Incidence; Jugular Veins; Male; Middle Aged; Neoplasms; Recurrence; Risk Factors; Sex Distribution; Subclavian Vein; Survival Analysis; Upper Extremity; Veins; Venous Thrombosis; Vitamin K

A critical obstacle for efficient gene therapy and virotherapy of cancer with adenoviral vectors and oncolytic adenoviruses is to target tumor cells in vivo. Recent reports indicate that, contrary to the natural airborne infection of epithelial cells with adenovirus type 5 mediated by coxsackievirus B and adenovirus receptor (CAR) and integrins, blood-borne adenovirus infects hepatocytes mainly through an indirect pathway that involves blood coagulation factors. In this report we have studied whether adenovirus also infects tumor cells in vivo by this pathway. In vitro and in vivo analyses show that vitamin K-dependent coagulation zymogens mediate tumor transduction and that the elimination of these factors abrogates tumor transduction. This finding imposes new challenges to retarget adenoviruses in vivo.

Topics: Adenoviridae; Blood Coagulation; Enterovirus B, Human; Genetic Therapy; Genetic Vectors; Humans; Neoplasms; Transduction, Genetic; Vitamin K

Coumarin or anti-vitamin K oral anticoagulants have been used in anticoagulation therapy for more than 50 years. Well-designed studies have demonstrated the effectiveness of these drugs in the primary and secondary prevention of venous thromboembolic disease (VTD). Because of greater life expectancy and the increase in the indications for oral anticoagulation therapy (OAT), more and more patients are receiving this type of treatment. In Spain, approximately 1% of the population receives OAT. The mechanism of action of coumarin anticoagulants is based on inhibition of the interconversion of vitamin K and its 2,3-epoxide (vitamin K epoxide, which modulates gamma-carboxylation of the glutamic acid residues in the N-terminal regions of vitamin-K-dependent factors, namely, II, VII, IX, X, protein C, protein S and protein Z). Due to the lack of gamma-carboxylation, these factors lose their procoagulant activity. Major hemorrhagic complications of OAT in VTD after 3-6 months of treatment, with an INR of 2-3, occur in nearly 2% of patients. The hemorrhagic complications of OAT are related to the intensity of anticoagulation, patient characteristics, the concomitant use of drugs that interfere with hemostasis, and treatment duration. The risk of VTD recurrence after 3-6 months of OAT is high and can be more than 10% in patients with idiopathic thromboembolism or irreversible risk factors such as thrombophilia, cancer and other situations conferring permanent risk. The risk of recurrence is more frequent in men, in patients with thrombophilia especially in antithrombin deficiency, and in patients with cancer, residual venous obstruction, or elevated D dimer.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Coumarins; Drug Interactions; Female; Hemorrhage; Humans; Male; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Sex Factors; Spain; Thrombophilia; Time Factors; Venous Thromboembolism; Vitamin K

This study examined the prevalence of vitamin K deficiency in children pre-bone marrow transplantation (BMT). Vitamin K status was measured by the PIVKA-II assay and prothrombin times. Blood samples were obtained before vitamin-containing TPN was infused. Results indicated that eight of 26 patients (31%) were vitamin K deficient; four cases were attributed to drug antagonism (phenytoin) and four were due to inadequate vitamin K intake, synthesis or malabsorption. Only one patient had a prolonged prothrombin time. Prothrombin time, in our study, is shown to be an ineffective screening tool to determine vitamin K status. All patients receiving phenytoin and chemotherapy are at increased risk of vitamin K deficiency.

Topics: Adolescent; Anticonvulsants; Bone Marrow Transplantation; Child; Child, Preschool; Drug Antagonism; Female; Humans; Infant; Male; Neoplasms; Phenytoin; Prevalence; Prothrombin Time; Retrospective Studies; Risk Factors; Vitamin K; Vitamin K Deficiency

Topics: Administration, Oral; Anticoagulants; Electric Countershock; Heart Valve Prosthesis; Hemoglobinuria; Heparin, Low-Molecular-Weight; Humans; Medical Audit; Neoplasms; Perioperative Care; Self Administration; Thromboembolism; Thrombophilia; Thrombosis; Vitamin K; Warfarin

About 30% of patients with an episode of adequately treated deep venous thrombosis (DVT) develop the postthrombotic syndrome (PTS) within 2 years. During treatment with vitamin K antagonists (VKA) patients spend only 60% of time between an International Normalized Ratio (INR) of 2.0 and 3.0. We hypothesized that patients who spend a large amount of their time beneath this range will have an increased risk of the PTS.. To investigate the relation between the quality of anticoagulant therapy with VKA and the risk of the development of the PTS.. The time spent beneath the therapeutic range was calculated for patients with a first episode of DVT, who were treated with VKA for at least 3 months. At follow-up assessments for a maximum of 5 years, presence and severity of signs and symptoms of PTS were recorded.. A total of 244 patients, with a median duration of follow-up of 4.9 years were included for analysis. Of these, 81 patients (33%) developed the PTS. The multivariate model showed that patients who spend more than 50% of their time beneath an INR level of 2.0 are at higher risk for PTS [odds ratio (OR): 2.71, 95% CI: 1.44-5.10].. Low quality treatment with VKA, which is a common condition, is related to the occurrence of the PTS in patients with DVT. Strategies aimed at improving the quality of long-term anticoagulation might have the potential to reduce the incidence of this complication.

Topics: Aged; Anticoagulants; Bandages; Clinical Trials as Topic; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Neoplasms; Odds Ratio; Postphlebitic Syndrome; Quality Control; Retrospective Studies; Risk; Time Factors; Venous Thrombosis; Vitamin K

Topics: Humans; Neoplasms; Patient Selection; Research Design; Vitamin K; Warfarin

In this Minisymposium three principles for anticoagulant therapy are discussed and examples of novel, selective coagulation inhibitors at the stage of advanced clinical trials are given. This introduction attempts to explain the different mechanisms of action on a broad scale, and also includes a brief look at effects on inflammation and cancer.

Topics: Anti-Inflammatory Agents; Anticoagulants; Antineoplastic Agents; Blood Coagulation; Heparin; Heparin, Low-Molecular-Weight; Humans; Inflammation; Neoplasms; Thrombin; Thrombosis; Vitamin K

The relationship between neonatal vitamin K received by the intramuscular (i.m.) route and the development of leukaemia or other cancers was investigated as part of a national case-control study of childhood cancer, using data abstracted from obstetric and neonatal records. The analyses included 2530 children diagnosed with cancer before 15 years of age, 1174 of whom had leukaemia and 4487 control children without cancer. Overall, 39% of cases and 42% of controls had records of i.m. vitamin K administration, while 24% of cases and 22% of controls had no record of whether or not they had received vitamin K. Using subjects who received i.m. vitamin K as the baseline group, our analyses found no association between the administration of i.m. vitamin K and either leukaemia or other cancers as a group. We conclude that there is no convincing evidence that neonatal vitamin K administration, irrespective of the route by which it is given, influences the risk of children developing leukaemia or any other cancer.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Leukemia; Male; Neoplasms; Odds Ratio; United Kingdom; Vitamin K

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Neoplasms; Survival Rate; Vitamin K; Warfarin

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Platelets; Humans; Indenes; Neoplasms; Survival Analysis; Thrombosis; Vitamin K

To investigate the hypothesis that neonates who receive intramuscular vitamin K are at an increased risk of developing cancer, particularly leukaemia, a pooled analysis of individual patient data from six case-control studies conducted in Great Britain and Germany has been undertaken. Subjects comprised 2431 case children diagnosed with cancer before 15 years of age and 6338 control children. The retrospective assessment of whether or not an individual baby received vitamin K is not straightforward. In many cases no record was found in stored medical notes and two types of analysis were therefore conducted; in the first it was assumed that where no written record of vitamin K was found it had not been given, and in the second, where no written record of administration was found, information on hospital policy and perinatal morbidity was used to 'impute' whether or not vitamin K had been given. In the first analysis, no association was found between neonatal administration of intramuscular. vitamin K and childhood cancer: odds ratios adjusted for mode of delivery, admission to special care baby unit and low birth weight were 1.09 (95% confidence interval 0.92-1.28) for leukaemia and 1.05 (0.92-1.20) for other cancers. In the second analysis, the adjusted odds ratios increased to 1.21 (1.02-1.44) for leukaemia and 1.10 (0.95-1.26) for other cancers. This shift did not occur in all studies, and when data from the hypothesis generating Bristol study were excluded, the adjusted odds ratios for leukaemia became 1.06 (0.89-1.25) in the first analysis and 1.16 (0.97-1.39) when data on prophylaxis imputed from hospital policy and perinatal morbidity were used. We conclude that whilst the broad nature of the diagnostic groups and the poor quality of some of the vitamin K data mean that small effects cannot be entirely ruled out, our analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Leukemia; Neoplasms; Vitamin K

Topics: Hemorrhage; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency

Topics: Anticoagulants; Humans; International Normalized Ratio; Neoplasms; Thromboembolism; Vitamin K; Warfarin

2-(2-hydroxy-ethylsulfanyl)-3-methyl-1,4-naphthoquinone or CPD-5, a K vitamin analog, was previously indicated to be a potent growth inhibitor for Hep 3B hepatoma cells in vitro. Here, we show that CPD-5 and two newly synthesized analogs, 2-(2-hydroxy-ethylsulfanyl)-3-methyl-5- nitro-1,4-naphthoquinone (PD-37) and 2-(2-hydroxy-ethylsulfanyl)-3- methyl-5-acetylamino-1,4-naphthoquinone (PD-42), are potent growth inhibitors of 13 different human cancer cell lines, with IC50 values in the range of 3-54 microM. Phospho-ERK was induced by each of three K vitamin analogs in every cell line in a dose-dependent manner, at growth inhibitory doses. ERK phosphorylation and growth inhibitory effects were strongly correlated, with p=0.0080 for CPD-5, p=0.0076 for PD-37 and p=0.0251 for PD-42. The induction of phospho-ERK and growth inhibition were antagonized by thiol-containing anti-oxidants, but not by catalase, consistent with a possible arylating mechanism. The data show a novel class of growth inhibitors with a wide spectrum of action that induces ERK hyper-phosphorylation, as a possible new growth inhibitory feature.

Topics: Antioxidants; Blotting, Western; Cell Division; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Inhibitory Concentration 50; Liver Neoplasms; Mitogen-Activated Protein Kinases; Neoplasms; Phosphorylation; Precipitin Tests; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins c-met; Sulfhydryl Compounds; Tumor Cells, Cultured; Vitamin K

Initial heparinization followed by vitamin K antagonists is the treatment of choice for patients with venous thromboembolism. There is controversy whether known malignancy is a risk factor for recurrences and bleeding complications during this treatment. Furthermore, the incidence of such events in these patients is dependent on the achieved International Normalized Ratio (INR). The aim of this study was to assess the incidence of venous thromboembolic recurrence and major bleeding among patients with venous thromboembolism in relation to both malignancy and the achieved INR.. In a retrospective analysis, the INR-specific incidence of venous thromboembolic and major bleeding events during oral anticoagulant therapy was calculated separately for patients with and without malignancy. Eligible patients participated in two multicenter, randomized clinical trials on the initial treatment of venous thromboembolism. Patients were initially treated with heparin (standard or low-molecular weight). Treatment with vitamin K antagonists was started within 1 day and continued for 3 months, with a target INR of 2.0 to 3.0.. In 1,303 eligible patients (264 with malignancy), 35 recurrences and 12 bleeds occurred. Patients with malignancy, compared with nonmalignant patients, had a clinically and statistically significantly increased overall incidence of recurrence (27.1 v 9.0, respectively, per 100 patient-years) as well as bleeding (13.3 v 2.1, respectively, per 100 patient-years). In both groups of patients, the incidence of recurrence was lower when the INR was above 2.0 compared with below 2.0.. Although adequately dosed vitamin K antagonists are effective in patients with malignant disease, the incidence of thrombotic and bleeding complications remains higher than in patients without malignancy.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; International Normalized Ratio; Male; Middle Aged; Multicenter Studies as Topic; Neoplasms; Pulmonary Embolism; Randomized Controlled Trials as Topic; Recurrence; Retrospective Studies; Risk Factors; Venous Thrombosis; Vitamin K

Topics: Humans; Infant, Newborn; Leukemia; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

To test the hypothesis of an association between neonatal intramuscular vitamin K and childhood leukaemia and other cancers.. Population based case-control study with data abstracted from hospital records.. Scotland.. Children aged 0-14 years resident in Scotland from 1991-4 and diagnosed with leukaemia (150), lymphomas (46), central nervous system tumours (79), a range of other solid tumours (142), and a subset of acute lymphoblastic leukaemia (129). Controls were 777 children matched for age and sex, providing 417 matched sets (360 triplets and 57 pairs) for analysis.. Odds ratios for the risk of childhood leukaemia and cancer and intramuscular vitamin K versus a combined group of oral doses, none, and no record. Results are given for information recorded in medical notes and data supplemented by hospital policy.. Odds ratios based on medical record abstractions showed no significant positive association for leukaemias (odds ratio 1.30; 95% confidence interval 0.83 to 2.03), acute lymphoblastic leukaemia (1.21; 0.74 to 1.97), lymphomas (1.06; 0.46 to 2.42), central nervous system tumours (0.74; 0.40 to 1.34), and other solid tumours (0.59; 0.37 to 0.96). There was no association with acute lymphoblastic leukaemia in children aged 1 to 6 years. Imputation of exposure from hospital policy gave similar results. Adjustment for deprivation and type of delivery moved risk estimates closer to unity for all major diagnostic groups.. The observation of an increased risk of childhood leukaemia and cancer associated with intramuscular vitamin K is not confirmed by this independent population based study.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Leukemia; Neoplasms; Odds Ratio; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Scotland; Vitamin K; Vitamin K Deficiency

To investigate the possible link between neonatal administration of intramuscular vitamin K and childhood cancer.. Matched case-control study.. Selected large maternity units in England and Wales.. Children with cancer born 1968-85, diagnosed 1969-86; controls matched for sex, month of birth, and hospital of birth.. Neonatal administration of vitamin K, length of gestation, birth weight, type of delivery, admission to special care baby unit.. After exclusion of cases with missing notes or unknown hospital vitamin K policy, 597 cases and matched controls were studied. Written records on the use of vitamin K were available for only about 40% of these, and to avoid possible bias from selective recording it was assumed that the stated hospital policy was followed. The association between cancer generally and intramuscular vitamin K was of borderline significance (odds ratio 1.44, P = 0.05); the association was strongest for leukaemia. There was, however, also an effect of abnormal delivery, which could explain some of the findings.. The lack of consistency between the various studies so far published, including this one, and the low relative risks found in most of them suggest that the risk, if any, attributable to the use of vitamin K cannot be large, but the possibility that there is some risk cannot be excluded. A comparison of the predicted consequences of various policies shows that even a 10% increase would imply that prophylaxis using the commonly recommended 1 mg intramuscular dose should be restricted to babies at particularly high risk of vitamin K deficiency bleeding; alternatively a lower dose might be given to a larger proportion of those at risk.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; England; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Odds Ratio; Risk Factors; Vitamin K; Vitamin K Deficiency; Wales

To investigate the possible link between neonatal administration of intramuscular vitamin K and childhood cancer.. Ecological studies comparing incidence of cancer in groups of children classified by the vitamin K policy in operation at their hospital of birth.. Selected large maternity units in England, Scotland, and Wales.. Children born in these units in varying periods between 1966 and 1991.. Cancer occurring among these children before age 15 years identified by using the National Registry of Childhood Tumours. Ratios of observed to expected numbers of these conditions calculated for hospitals where the policy was to give all babies intramuscular vitamin K (non-selective) and where the policy was to use this treatment only for a selected minority of babies at increased risk of vitamin K deficiency bleeding (selective).. These ratios were calculated for children born in 94 hospitals with varying vitamin K policies. A raised risk was occasionally associated with vitamin K, but the overall results were not significant, and there was no evidence to support the previously suggested doubling of the risk of childhood cancer.. On the basis of the results reported here it is unlikely that there is a greatly increased risk of childhood cancer attributable to intramuscular vitamin K given to newborns, if indeed there is any.

Topics: Adolescent; Child; Child, Preschool; England; Follow-Up Studies; Humans; Incidence; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Nurseries, Hospital; Organizational Policy; Risk Factors; Scotland; Surveys and Questionnaires; Vitamin K; Vitamin K Deficiency; Wales

To explore the possible association between intramuscular vitamin K given to neonates and the subsequent development of childhood cancer.. Retrospective case-control study on the basis of hospital records.. The former Northern Health region of England.. 685 children who were born and lived in the region and who developed cancer before their 15th birthday, and 3442 controls also born between 1960 and 1991 and matched only for date and hospital of birth. The notes of a further 701 index cases were untraceable.. Administration of intramuscular vitamin K versus no exposure to vitamin K.. There was no association between the administration of vitamin K and the development of all childhood cancers (unadjusted odds ratio 0.89; 95% confidence interval 0.69 to 1.15) or for all acute lymphoblastic leukaemia (1.20; 0.75 to 1.92), but there was a raised odds ratio for acute lymphoblastic leukaemia developing 1-6 years after birth (1.79; 1.02 to 3.15). No such association was seen in a separate cohort-based study not dependent on case note retrieval in which the rates of acute lymphoblastic leukaemia in children born in hospital units where all babies received vitamin K were compared with those born in units where less than a third received prophylaxis.. It is not possible, on the basis of currently published evidence, to refute the suggestion that neonatal intramuscular vitamin K administration increases the risk of early childhood leukaemia. Any association may have been masked in earlier studies that did not use controls matched for time and locality by other unidentified factors affecting the spatiotemporal variations in incidence of leukaemia.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Cohort Studies; England; Humans; Incidence; Infant; Infant, Newborn; Neoplasms; Nurseries, Hospital; Odds Ratio; Organizational Policy; Retrospective Studies; Vitamin K; Vitamin K Deficiency

The role of lipid peroxidation, intracellular glutathione and Ca2+ concentration in menadione-mediated toxicity was investigated in human hepatoma cell lines, Hep G2 and Hep 3B, and in human leukemia cell lines, CCRF-CEM and MOLT-3. Incubation of these cells with 80 microM menadione at 37 degrees C resulted in depletion of intracellular glutathione, increased intracellular Ca2+, and increased lipid peroxidation, events leading to cell degeneration. The sensitivity of these cells to menadione, in order, was: Hep G2 cells > Hep 3B cells > CCRF-CEM cells and MOLT-3 cells. The extent of menadione-induced lipid peroxidation in different cell types followed the same order as did their susceptibility to menadione-induced cell degeneration. The menadione-induced depletion in glutathione level was in the following sequence: Hep G2 cells > MOLT-3 and CCRF-CEM cells > Hep 3B cells. The extent of the menadione-induced increase in the intracellular Ca2+ concentration was: Hep G2 cells > Molt-3 cells > CCRF-CEM cells and Hep 3B cells. Pre-treatment of Hep G2 cells with 20 mM deferoxamine mesylate, an iron chelator, reduced both the menadione-induced cell degeneration and lipid peroxidation; however, it did not prevent the menadione-induced increase in intracellular Ca2+ nor the depletion of glutathione. These data suggest that menadione-induced cell degeneration is directly linked to lipid peroxidation, and that it is less related to the rise in intracellular Ca2+ and the depletion in glutathione content. Dicumarol (an inhibitor of DT diaphorase) enhanced the capacity of menadione to induce Hep 3B cell degeneration from 71.3% to 86.2% after 120 min of menadione treatment at 37 degrees C, but did not have this effect in Hep G2, CCRF-CEM or MOLT-3 cells. The activities of DT diaphorase were 52.4, 39.6, 1.5 and 1.8 nmol cytochrome c reduced/min/mg protein in Hep G2, Hep 3B, CCRF-CEM and MOLT-3 cells, respectively. The activity of DT diaphorase was much higher in Hep G2 cells than in the other cells. It seems that DT diaphorase may not, as suggested by others, protect against cell degeneration by quinones, such as menadione.

Topics: Calcium; Carcinoma, Hepatocellular; Cell Death; Chelating Agents; Deferoxamine; Dicumarol; Glutathione; Glutathione Disulfide; Humans; Intracellular Fluid; Leukemia; Lipid Peroxidation; Liver Neoplasms; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Tumor Cells, Cultured; Vitamin K

Topics: Administration, Oral; Drug Administration Schedule; Hemorrhage; Humans; Infant Food; Infant, Newborn; Injections, Intramuscular; Leukemia; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency

Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

The review by Drs. Brousson and Klein (see pages 307 to 315 of this issue) identifies controversies surrounding the administration of vitamin K to babies shortly after birth. Controlled studies comparing the effect of oral and intramuscular administration are unlikely to be conducted because of the large number of subjects needed. The evidence presented in the review should dispel concerns that intramuscular administration may be associated with childhood cancer. Oral administration of a single dose of vitamin K soon after is associated with significant biochemical vitamin K deficiency by 1 month of age, but the relation of biochemical abnormality to clinical manifestations of late hemorrhagic disease of the newborn is less clear. Epidemiologic studies indicate a small, but significant, increase in the incidence rate of hemorrhagic disease after oral administration of vitamin K (1.0 to 6.4 incidents per 1000 000 infants), compared with the incidence rate after intramuscular administration (0.25 incidents per 100 000 infants). Although repeated oral doses of vitamin K may be and effective alternative regimen, there is no approved oral vitamin K formulation, there are concerns about patient compliance, and there has been limited investigation of such regimen. Therefore, intramuscular administration of a single dose of 1.0 mg of vitamin K shortly after birth is recommended.

Topics: Administration, Oral; Child; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Erythroblastosis, Fetal; Humans; Infant, Newborn; Leukemia; Neoplasms; Vitamin K; Vitamin K Deficiency

To confirm or refute a possible association of parenteral vitamin K prophylaxis and childhood cancer.. Population based case-control study. Comparison of vitamin K exposure in children with leukaemia or other common tumours with two control groups.. State of Lower Saxony (north western part of Germany); case recruitment from the German childhood cancer registry.. 272 children with leukaemia, nephroblastoma, neuroblastoma, rhabdomyosarcoma, and tumours of the central nervous system diagnosed between 1 July 1988 and 30 June 1993; children were aged between 30 days and 15 years at diagnosis. 334 population based controls without diagnoses of cancer matched to the leukaemia cases for age and sex.. Parenteral vitamin K prophylaxis (intramuscular and subcutaneous) versus oral and no vitamin K prophylaxis.. An association between parenteral vitamin K exposure and childhood cancer (leukaemias and other tumours combined) could not be confirmed (odds ratio 1.04, 95% confidence interval 0.74 to 1.48). For leukaemias the observed odds ratio was only 0.98 (0.64 to 1.50) (comparison of leukaemia cases with local controls 1.24 (0.68 to 2.25); state controls 0.82 (0.50 to 1.36)). These odds ratios remained almost unchanged when several potential confounders were considered in the logistic regression model.. This population based study adds substantial evidence that there is no association between parenteral vitamin K and childhood cancer.

Topics: Adolescent; Case-Control Studies; Central Nervous System Neoplasms; Child; Child, Preschool; Female; Germany; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Injections, Subcutaneous; Kidney Neoplasms; Leukemia; Male; Neoplasms; Neuroblastoma; Population Surveillance; Rhabdomyosarcoma; Risk Factors; Vitamin K; Vitamin K Deficiency; Wilms Tumor

In order to evaluate the efficiency of classical anticoagulant therapy for venous thromboembolic disease in cancer patients, we retrospectively analysed 71 patients treated with intravenous heparin first and then with antivitamin K. After a mean follow-up of 185 +/- 25 days, 23 patients (33%) were dead; nine patients (12%) had suffered from major haemorrhagic complications, which were not fatal, four of which were due to heparin overdosage; 17 patients (24%) showed recurrent venous thromboembolic disease. According to univariate statistical analysis, risk of major bleeding was not associated with the presence of either thrombocytopenia, abnormal blood coagulation, metastases and/or any other hemorrhagic risk factors; recurrence of venous thromboembolic disease was not associated with the presence of other risk factors for venous thromboembolic disease, nor with the presence or absence of metastases and/or of ongoing chemotherapy. Such results suggest that classical anticoagulant therapy for venous thromboembolic disease in cancer patients is neither effective nor safe. The present retrospective study underlines needs for further prospective analyses in order to evaluate potential benefit from other therapeutic strategies, such as use of low molecular weight heparins and/or vena cava filter placement.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Hemorrhage; Heparin; Humans; Indenes; Male; Middle Aged; Neoplasms; Retrospective Studies; Risk Factors; Thrombophlebitis; Vitamin K

Topics: Administration, Oral; Australia; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Child; Female; Hemorrhage; Humans; Infant, Newborn; Neoplasms; Nurse Midwives; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Vitamin K

Topics: Buspirone; Humans; Lactation; Metronidazole; Neoplasms; Nicotine; Paclitaxel; Substance-Related Disorders; Vitamin K

Topics: Bias; Causality; Child; Humans; Neoplasms; Research Design; Vitamin K

Topics: Administration, Oral; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Denmark; Humans; Incidence; Infant; Infant, Newborn; Leukemia; Lymphoma; Neoplasms; Risk Factors; Vitamin K

Topics: Administration, Oral; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Administration, Oral; Case-Control Studies; Child; Child, Preschool; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Reproducibility of Results; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Administration, Oral; Child; Confounding Factors, Epidemiologic; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K

Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Neoplasms; Vitamin K

Topics: Administration, Oral; Child; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K

To investigate whether childhood cancer is associated with intramuscular administration of vitamin K to newborn infants.. Routines for administration of vitamin K to infants born after normal deliveries during 1973-89 were obtained from maternity hospitals. Occurrence of cancer up to the end of 1991 was identified by comparing these records with the national cancer registry. Adherence to the routine method of administering vitamin K was checked with the medical records of a sample of 396 infants (196 who had developed childhood cancer and 200 controls).. All maternity hospitals in Sweden.. 1,384,424 full term infants born after non-instrumental deliveries, 1,085,654 of whom were born in units where vitamin K was routinely given by intramuscular injection and 272,080 of whom were born where it was given orally.. Odds ratios for cancer after intramuscular administration of vitamin K versus oral administration after stratification for year of birth.. Adherence to routine method of administering vitamin K was 92% in the 235 cases where individual information could be found. The risk of cancer after intramuscular administration of vitamin K was not elevated compared with that after oral administration: odds ratios of 1.01 (95% confidence interval 0.88 to 1.17) for all childhood cancers and 0.90 (0.70 to 1.16) for childhood leukaemia.. The alleged association between intramuscular vitamin K prophylaxis to newborn infants and childhood cancer could not be verified in the present study of full term infants born after non-instrumental delivery.

Topics: Administration, Oral; Child; Child, Preschool; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Sweden; Vitamin K

Topics: Child; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Sweden; Vitamin K

Two recent studies have found that infants who received intramuscular vitamin K were at twice the expected risk for cancer during childhood. Since nearly all newborns in the United States receive this drug, the public health implications of this association, if confirmed, would be substantial.. We examined the relation between vitamin K and cancer in a nested case-control study that used data from the Collaborative Perinatal Project, a multi-center, prospective study of pregnancy, delivery, and childhood. Among 54,795 children born from 1959 through 1966, 48 cases of cancer were diagnosed after the first day of life and before the eighth birthday. Each case child was matched with five randomly selected controls whose last study visit occurred at or after the age when the case child's cancer was diagnosed. Exposure to vitamin K was determined from study forms and medical records.. Vitamin K had been administered to 68 percent of the 44 case children and 71 percent of the 226 controls for whom data were available (matched odds ratio, 0.84; 95 percent confidence interval, 0.41 to 1.71). The odds ratio was 0.47 (95 percent confidence interval, 0.14 to 1.55) for leukemia and 1.08 (95 percent confidence interval, 0.45 to 2.61) for other cancers. Sequential adjustment for potential confounding factors did not change the results substantially.. We found no association between exposure to vitamin K and an increased risk of any childhood cancer or of all childhood cancers combined, although a slightly increased risk could not be ruled out. The benefits of neonatal vitamin K prophylaxis against hemorrhagic disease have been well described. Unless other evidence supporting an association between vitamin K and cancer appears, there is no reason to abandon the routine administration of vitamin K to newborns.

Topics: Case-Control Studies; Child; Confidence Intervals; Confounding Factors, Epidemiologic; Female; Humans; Infant, Newborn; Injections, Intramuscular; Male; Neoplasms; Odds Ratio; Prospective Studies; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Child; Humans; Incidence; Infant, Newborn; Neoplasms; Odds Ratio; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Child; Clinical Protocols; Community Health Nursing; Drug and Narcotic Control; Humans; Injections, Intramuscular; Neoplasms; United Kingdom; Vitamin K

Topics: Child; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Odds Ratio; Vitamin K

Topics: Administration, Oral; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K

Topics: Case-Control Studies; Humans; Infant, Newborn; Neoplasms; Retrospective Studies; Vitamin K

Topics: Administration, Oral; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency

Topics: Humans; Incidence; Infant; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K

Topics: Administration, Oral; Case-Control Studies; Child; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Odds Ratio; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Breast Feeding; Child; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Administration, Oral; Humans; Infant, Newborn; Injections, Intramuscular; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Child; Child, Preschool; Humans; Incidence; Neoplasms; Risk Factors; Vitamin K

Topics: Humans; Infant, Newborn; Neoplasms; Risk Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Attitude to Health; Child; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Meperidine; Neoplasms; Pregnancy; Publishing; Vitamin K

The spectrum of cytotoxicity of menadione (MD) was examined in a panel of human cancer cell lines. MD was equipotent against multidrug-resistant and parental leukemia cell lines with IC50 values of 13.5 +/- 3.6 and 18 +/- 2.4 microM respectively. A cervical carcinoma cell line resistant to the antimetabolite, methotrexate (MTX), was as sensitive to MD as its parental cell line. The interactions of fifteen clinically utilized anticancer drugs with MD were examined in vitro and the majority were found to be additive, with four agents exhibiting synergism and one agent exhibiting antagonism. MD inhibited the incorporation of radioactive thymidine, uridine and amino acids into DNA, RNA and protein, respectively, in three human cancer cell lines. Some possible reasons for the inhibition of DNA synthesis including effects of MD on intracellular deoxyribonucleoside triphosphate pools were examined and ruled out. Although results from previous studies using rat hepatocytes suggested that mitochondria may be a target of MD, no significant effect of this compound on total intracellular adenosine triphosphate (ATP) pools in human cancer cell lines was observed. Collectively, these in vitro results demonstrate that MD possesses a broad spectrum of anticancer activity and suggest the potential utility of this agent in cancer therapy. Future studies directed at elucidation of the mechanism of MD action in human cancer cells are warranted and are under study.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nucleotides; Tumor Cells, Cultured; Vitamin K

Des-gamma-carboxy prothrombin [DCP], a protein induced by vitamin K absence or antagonist-II and also abbreviated PIVKA-II, was evaluated as a serologic marker for hepatocellular carcinoma (HCC). Its plasma levels were measured by enzyme immunoassay (E-1023) using an anti-DCP monoclonal antibody in 514 patients with various diseases. Of 120 patients with HCC, 76 (63%) had abnormal DCP levels greater than 0.1 arbitrary unit (AU)/ml and 58 (48%) showed levels greater than 0.3 AU/ml. When a diagnostic minimum level of 0.3 AU/ml was applied for DCP, false-positive cases of HCC were virtually eliminated. In some patients with HCC, plasma DCP levels normalized after surgical resection of the tumor. However, they rose again later with recurrence of the disease. The sensitivity of DCP in the diagnosis and monitoring of HCC was increased by serial and simultaneous determinations of alpha-fetoprotein (AFP), because high DCP levels were observed more often in low AFP-producing HCC patients. Elevated plasma DCP levels were not related to low vitamin K concentration in the serum. In fact, in many patients vitamin K administration resulted in only a moderate reduction of DCP levels. These results suggested strongly that DCP was synthesized by the hepatoma cells.

Topics: Adenoma, Bile Duct; alpha-Fetoproteins; Antibodies, Monoclonal; Biomarkers; Carcinoma, Hepatocellular; Female; Hepatitis, Chronic; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Neoplasm Proteins; Neoplasms; Protein Precursors; Prothrombin; Vitamin K

Anticoagulants of the coumarin type have long been reported to inhibit metastasis growth in experimental animals; however, the mechanisms of such effects has not been clarified. Systemic anticoagulation per se does not appear to account completely for such metastasis growth depression. More recent information gathered on a cell procoagulant activity, which is vitamin K-dependent, could probably supply a fresh insight into this problem. Indeed, vitamin K deficiency induced either dietarily or pharmacologically by warfarin, does inhibit the activity of a cysteine protease with direct factor-X-activating properties. This protease is only present in warfarin-sensitive tumors. The correlation of this activity with cancer cell invasiveness is supported by experimental data in metastatic variants and, lately, also by the observation of markedly higher cancer procoagulant activity in extracts from metastases than from primary human melanomas.

Topics: Animals; Antineoplastic Agents; Blood Coagulation Factors; Cysteine Endopeptidases; Endopeptidases; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Protease Inhibitors; Vitamin K; Warfarin

From the results of the alpha-particle track autoradiography, the alkaline phosphatase studies, the biodistribution investigations and the therapeutic experiments with the transplanted Franks and Hemmings (1978) adenocarcinoma of the rectum in mice, an important finding is the striking selectivity of the uptake of the compound 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt), after intraperitoneal injection into the tumour cell nuclei and in many cases into the nuclei of tumour stem cells, together with negligible uptake into normal colon and narrow. The compound, 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt) has been found to cure about two-thirds of the transplanted adenocarcinoma of the rectum in mice after a single intra-peritoneal injection of 3-4 microCi. This approach can be regarded as a form of metabolically-directed drug targetting on to a tumour product which is an enzyme, an alkaline phosphatase isozyme, present in the cells of some tumours. The compound is being studied further from the point of view of possible human therapeutic applications.

Topics: Alkaline Phosphatase; Animals; Astatine; Bromine; Energy Transfer; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Neoplasms; Phosphorylation; Radioisotopes; Vitamin K

Topics: Antineoplastic Agents; Colonic Neoplasms; Energy Transfer; Humans; Melanoma; Naphthols; Neoplasms; Pancreatic Neoplasms; Skin Neoplasms; Vitamin K

This report was prepared at the request of the International Atomic Energy Agency and presented at an Advisory Group Meeting on "Applications of Recent Radiobiological Research in Radiotherapy" held in Vienna, Austria, from 24-28 September 1979. Based on the recommendations of the Advisory Group, the I.A.E.A. has decided to initiate a coordinated international research programme entitled "Exploration of the Possibility of high LET RAdiation for Nonconventional Radiotherapy in Cancers". This programme will explore possible applications of corpuscular radiations (neutrons, protons, accelerated heavy ions, negative pi-mesons, thermal and epithermal neutrons) in cancer therapy. In addition, the programme will include research on in situ radiotherapy with unsealed radionuclides and thermal neutron capture. For further information on the programme, please contact Dr T. IWASAKI, Section of Radiation Biology, Division of Life Sciences, International Atomic Energy Agency, Wagramerstrasse 5, P. O. Box 100, A-1400 Vienna, Austria.

Topics: Animals; Antibodies, Neoplasm; Astatine; Cricetinae; Gallium Radioisotopes; Humans; Idoxuridine; Iodine Radioisotopes; Liposomes; Mice; Neoplasms; Radioisotopes; Tamoxifen; Tritium; Vitamin K

Topics: 4-Nitroquinoline-1-oxide; Animals; Mitochondria, Liver; Neoplasms; Oxidative Phosphorylation; Rats; Vitamin K

Topics: Carcinogens; Humans; Microsomes; Neoplasms; Vitamin K

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Autoradiography; Dihydroxyphenylalanine; Female; Humans; Isotope Labeling; Male; Middle Aged; Neoplasms; Organophosphorus Compounds; Tritium; Vitamin K

Topics: Humans; Neoplasms; Vitamin K

The coagulopathy induced by vitamin K deficiency commonly results from our lack of awareness of the clinical setting associated with vitamin K deficiency. Thirteen cases are reviewed to illustrate the clinical correlates most frequently observed. Dietary deficiency was always present, but concomitant antibiotic therapy was not an absolute requirement. The postoperative patient is at high risk, as is the patient with cancer or renal failure. Abnormal bleeding was common, but significant hemorrhage occurred only in postoperative patients. Factor assays were helpful and occasionally necessary to make the diagnosis, but a therapeutic trial with parenteral vitamin K was often enough to provide the right diagnosis. Greater awareness of this deficiency syndrome is necessary to avoid the serious morbidity that often results.

Topics: Adult; Aged; Anti-Bacterial Agents; Blood Coagulation Disorders; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Nutrition Disorders; Preoperative Care; Risk; Surgical Procedures, Operative; Vitamin K; Vitamin K Deficiency

Topics: Arteriosclerosis; Female; Humans; Hypertension; Liver Cirrhosis; Male; Neoplasms; Rheumatic Diseases; Vitamin K

An attempt has been made to develop tritiated derivatives of Synkavit (menadiol sodium diphosphate, MNDP) of high specific activity as a radioactive drug.This paper summarizes the preliminary biological and physical studies, with emphasis on approximate radiation dosimetry and the necessary preliminary testing, and then gives an account of the clinical investigations and the trials carried out so far, which correspond essentially to Phases I and II trials for a chemotherapeutic agent.In all, 214 patients with different sites and types of advanced and recurrent, inoperable, histologically verified malignant tumours including reticuloses have been treated with doses of at least 1 Ci of the various preparations. Among the 203 evaluable treated cases, some form of response was observed in 23 out of 151 (15·2%) receiving the drug by intravenous injections and 13 out of 52 (25%) after intra-arterial injections. For the sites and types of malignant diseases which showed responses after either intravenous or intra-arterial administration among the 55 patients surviving at least 3 months after the first injection, some form of response was observed in 32 but only 5 of these showed either a "complete" or a "partial" response.It is concluded that further investigation is desirable. It is suggested that clinical trials with randomization should be carried out for inoperable cases of carcinoma of the colon and of the pancreas.

Topics: Adult; Aged; Animals; Breast Neoplasms; Carcinoma 256, Walker; Colonic Neoplasms; Culture Techniques; Dose-Response Relationship, Radiation; Female; Half-Life; Hodgkin Disease; Humans; Injections, Intra-Arterial; Injections, Intraperitoneal; Injections, Intravenous; Male; Methods; Middle Aged; Neoplasms; Ovarian Neoplasms; Palatal Neoplasms; Radionuclide Imaging; Rectal Neoplasms; Testicular Neoplasms; Tongue Neoplasms; Tritium; Vitamin K

Topics: Animals; Bleomycin; Dactinomycin; Drug Therapy, Combination; Humans; Neoplasms; Pyrimidines; Radiation-Sensitizing Agents; Vitamin K

Topics: Brain Neoplasms; Bromodeoxyuridine; Dactinomycin; DNA; Fluorouracil; Glycogen; Humans; Neoplasms; Oxygen; Radiation-Sensitizing Agents; RNA; Vitamin K

Topics: Animals; Avitaminosis; Body Height; Body Weight; Growth; Longevity; Neoplasms; Rats; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K; Vitamins

In a previous paper, the exact conditions under which the radioactive drug 2-methyl-6,7-ditritio-1,4-naphthaquinol bis disodium phosphate could be selectively incorporated into HEp/2 cells were reported. This work has now been extended and suggests that the selective property associated with two human tumour cell lines established in culture, HEp/2 and HeLa, and two forms of mouse ascites tumour cells propagated in vivo, is a metabolic conversion of the drug (priming stage) to a form which can probably be freely incorporated by all cell types. It is suggested that the observed variations in uptake of label with changes in pH, cell concentration and the inorganic phosphate concentration of the medium indicate that the "priming" stage is critically dependent on the conditions of the experiment.Work with the non-radioactive analogue, Synkavit, indicates that under conditions where the drug is incorporated selectively into cells, incubations in excess of 20 minutes cause a large percentage of the population to lose its reproductive integrity.

Topics: Animals; Carcinoma; Carcinoma, Ehrlich Tumor; Cell Division; Cell Line; Culture Techniques; Haplorhini; HeLa Cells; Humans; Hydrogen-Ion Concentration; Kidney; Laryngeal Neoplasms; Male; Mice; Neoplasms; Phosphates; Tritium; Vitamin K

Topics: Adult; Antineoplastic Agents; Arsenicals; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Choriocarcinoma; Colonic Neoplasms; Drug Synergism; Female; Fluorides; Heparin; Humans; Lung Neoplasms; Male; Malonates; Melanoma; Neoplasms; Ovarian Neoplasms; Pharyngeal Neoplasms; Pregnancy; Rectal Neoplasms; Sarcoma; Stomach Neoplasms; Testicular Neoplasms; Thyroid Neoplasms; Time Factors; Vitamin K

Topics: Adenocarcinoma; Adult; Aged; Animals; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cystadenoma; Female; Humans; Iodine Radioisotopes; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Mice; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peritoneal Neoplasms; Radiation-Sensitizing Agents; Radionuclide Imaging; Rats; Rectal Neoplasms; Sigmoid Neoplasms; Stomach Neoplasms; Vitamin K

Topics: Cell Transformation, Neoplastic; Cybernetics; Diethylstilbestrol; Hot Temperature; Hydrogen Peroxide; Hydrogen-Ion Concentration; Membranes; Naphthoquinones; Neoplasms; Vitamin K

Topics: Animals; Bone Marrow; Bone Marrow Cells; Bronchial Neoplasms; Carcinoma, Ehrlich Tumor; Chickens; Cricetinae; Culture Techniques; Digestive System; Disulfiram; Fibrosarcoma; Hot Temperature; Humans; Kidney; Lung; Mice; Myocardium; Neoplasms; Neoplasms, Experimental; Organ Specificity; Sarcoma, Experimental; Spleen; Vitamin K

Topics: Adenocarcinoma; Adult; Animals; Arsenicals; Carcinoma, Ehrlich Tumor; Carcinoma, Squamous Cell; Choriocarcinoma; DNA, Neoplasm; Female; Fluorides; Heparin; Humans; Lung Neoplasms; Lymphoma; Male; Malonates; Mandibular Neoplasms; Mice; Middle Aged; Neoplasms; Pregnancy; RNA, Neoplasm; Sarcoma; Testicular Neoplasms; Vitamin K

Topics: Animals; Carcinogens; Carcinoma, Ehrlich Tumor; Fever; Methylene Blue; Mice; Neoplasms; Trypan Blue; Vitamin K

Topics: Adenocarcinoma; Autoradiography; Colonic Neoplasms; Dysgerminoma; Female; Gallbladder Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Injections, Intravenous; Melanoma; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Radiotherapy Dosage; Skin Neoplasms; Tritium; Vitamin K

Topics: Animals; Ascites; Biochemical Phenomena; Biochemistry; Carcinoma; Carcinoma, Ehrlich Tumor; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Radiation-Protective Agents; Radiation-Sensitizing Agents; Research; Sulfhydryl Compounds; Tritium; Vitamin K

Topics: Autoradiography; Female; Humans; Leg; Melanoma; Middle Aged; Neoplasms; Radiation Protection; Radioisotopes; Radiotherapy Dosage; Tritium; Ubiquinone; Vitamin K

Topics: Adult; Aged; Hemorrhage; Humans; Injections, Intravenous; Middle Aged; Neoplasms; Vitamin K

Topics: Anticoagulants; Breast Neoplasms; Dicumarol; Hematuria; Humans; Mastectomy; Neoplasms; Thrombosis; Toxicology; Ureteral Obstruction; Urinary Catheterization; Vitamin K

Topics: Electrophoresis; Humans; Leukemia; Liver Cirrhosis; Neoplasms; Pyridoxine; Vitamin A; Vitamin K; Vitamins

Topics: Amino Acids; Cobalt Isotopes; Esophageal Neoplasms; Glucose; Humans; Nandrolone; Neoplasms; Parenteral Nutrition; Radioisotope Teletherapy; Radiotherapy Dosage; Vitamin K; Vitamins

Topics: Carcinoma, Basal Cell; Cheek; Facial Neoplasms; Geriatrics; Humans; Neoplasms; Pathology; Skin Neoplasms; Vitamin K

A simple, rapid, quantitative test procedure to measure induction of phage production in lysogenic Escherichia coli K-12 (lambda) was described. This test was used in a study of 209 substances, including antibiotics, pyrimirines, purines, alkylating agents, thiols, amino acids, vitamins, and miscellaneous compounds. Minimal inducing concentrations for the 26 (12.5% of total tested) substances found to be effective inducing agents, as well as a listing of the inactive compounds, are presented. Since 21 of the 26 active agents reportedly have antineoplastic activity in rodent tumor systems, it was concluded that the induction test may provide a useful screen for the detection of potentially useful antitumor compounds.

Topics: Alkylating Agents; Amino Acids; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antineoplastic Agents; Bacteriophage lambda; Coliphages; Culture Media; Escherichia coli; Escherichia coli K12; Lysogeny; Neoplasms; Neoplasms, Experimental; Pharmacology; Purines; Pyrimidines; Research; Rodentia; Sulfhydryl Compounds; Vitamin A; Vitamin K; Vitamins

Topics: Carcinoma; Carcinoma, Squamous Cell; Cheek; Cobalt Isotopes; Humans; Injections, Intravenous; Mouth Neoplasms; Neoplasms; Tongue Neoplasms; Vitamin K

Topics: Antineoplastic Agents; Leukopenia; Mechlorethamine; Neoplasms; Thiamine; Vitamin K; Vitamins

Topics: Antineoplastic Agents; Autoradiography; Humans; Naphthoquinones; Neoplasms; Radiopharmaceuticals; Retinoids; Tritium; Vitamin K

Topics: Antifibrinolytic Agents; Blood Transfusion; Diagnosis; Hodgkin Disease; Mucormycosis; Neoplasms; Pathology; Phenylbutazone; Prednisone; Triethylenemelamine; Vitamin K

Topics: Animals; Antifibrinolytic Agents; Characidae; Leukemia; Leukemia, Lymphoid; Naphthoquinones; Neoplasms; Neoplasms, Experimental; Sodium; Tritium; Vitamin K

Topics: Antifibrinolytic Agents; Combined Modality Therapy; Neoplasms; Radiotherapy; Trachea; Tracheal Neoplasms; Vitamin K

Topics: Ascorbic Acid; Neoplasms; Vitamin A; Vitamin K; Vitamins

Topics: Antifibrinolytic Agents; Humans; Naphthoquinones; Neoplasms; Retinoids; Vitamin K

Topics: Analgesics; Hemostatics; Humans; Neoplasms; Vitamin K

Topics: Ascorbic Acid; Folic Acid; Humans; Neoplasms; Niacin; Nicotinic Acids; Vitamin A; Vitamin B Complex; Vitamin K; Vitamins

Topics: Animals; Characidae; Diphosphates; Naphthoquinones; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy; Sodium; Vitamin K

Topics: Humans; Neoplasms; Physiological Phenomena; Vitamin A; Vitamin K; Vitamins

Topics: Animals; Humans; Neoplasms; Neoplasms, Experimental; Vitamin A; Vitamin K; Vitamins

Topics: Animals; Humans; Neoplasms; Neoplasms, Experimental; Solanum lycopersicum; Vitamin E; Vitamin K; Vitamins

Topics: Antifibrinolytic Agents; Heparin Antagonists; Neoplasms; Pelargonium; Plants; Vitamin K

Topics: Cardiovascular Diseases; Humans; Neoplasms; Vitamin A; Vitamin K; Vitamins

Topics: Humans; Neoplasms; Vitamin K; Vitamin K Deficiency

Topics: Animals; Characidae; Diphosphates; Drug Therapy; Neoplasms; Sodium; Vitamin K

Topics: Neoplasms; Vitamin A; Vitamin B Complex; Vitamin K; Vitamins

Topics: Humans; Neoplasms; Vitamin A; Vitamin K; Vitamins