warfarin and Multiple-Myeloma

With the introduction of thalidomide and multi-agent chemotherapy in the treatment of multiple myeloma around 15years ago a strongly increased risk of venous thrombosis was observed. The occurrence of venous thrombosis in multiple myeloma is not only determined by the kind of treatment, but also by several other factors, including disease specific factors, patient-specific factors, changes in pro-and anticoagulant factors and fibrinolysis. Studies showed a prevalence of up to 25% in patients with newly diagnosed multiple myeloma. Therefore these patients nowadays receive prophylaxis with aspirin, low molecular weight heparin or warfarin in order to reduce the risk of venous thrombosis. It is however still debatable which patients should receive prophylaxis and what the best kind of prophylaxis is, considering both the risk of thrombosis and the risk of bleeding. In recent years several new anti-myeloma agents have been developed and investigated in large clinical studies. The risk of thrombosis using these new drugs seems less than with thalidomide and lenalidomide-based regimens. In this article an update on prevention and management of thrombotic events in patients with multiple myeloma is given.

Topics: Anticoagulants; Antineoplastic Agents; Aspirin; Heparin, Low-Molecular-Weight; Humans; Lenalidomide; Multiple Myeloma; Thalidomide; Thrombosis; Warfarin

Patients with multiple myeloma (MM) have an increased risk of venous thromboembolic (VTE) complications. The first reports of high VTE rates date back to 1999 but became more apparent with the introduction of novel agents in the treatment of MM and mostly with immunomodulatory drugs (IMiDs; thalidomide, lenalidomide and pomalidomide).. Currently thromboprophylaxis is recommended for patients who receive IMiDs-based regimens and the type of thrombophrophylaxis is based on patient-, disease- and treatment-related risk factors. Making the distinction between the intrinsic risk of thrombosis in MM and the effect of therapy is crucial. The use of aspirin, low molecular weight heparins and warfarin are the recommended drugs but despite their appropriate use the rates of VTE are not completely eliminated. Expert commentary: Research into biomarkers of increased coagulability and their incorporation in risk assessment models could identify patients most likely to benefit from thromboprophylaxis but such models are not widely used in myeloma.

Topics: Antineoplastic Agents; Biomarkers; Blood Coagulation; Genetic Predisposition to Disease; Heparin, Low-Molecular-Weight; Humans; Immunologic Factors; Multiple Myeloma; Premedication; Risk Factors; Venous Thromboembolism; Warfarin

Currently multiple antithrombotic agents are used for thalidomide thromboprophylaxis in multiple myeloma patients. Agents used include low-dose aspirin, fixed low-dose and therapeutic warfarin and prophylactic low molecular weight heparin. To evaluate the evidence for the efficacy and safety of aspirin, warfarin and low molecular weight heparin thromboprophylaxis in multiple myeloma patients on thalidomide a literature search was conducted in May and June 2011. Databases searched included the Cochrane Database of Systemic Reviews and the Database of Abstracts of Reviews of Effects, Evidence Based Medicine Reviews and Ovid MEDLINE. The search was restricted to English language articles and limited to articles published from 2005 to 2011. Most studies consisted of small prospective cohort studies not originally designed to assess thromboprophylaxis as an outcome. A single comparative randomized trial, several retrospective review articles, two meta-analyses and two clinical practice guidelines were also identified. Current evidence fails to demonstrate a clear advantage of any particular thromboprophylaxis strategy. Results from the only prospective comparative randomized trial found no significant differences among aspirin, warfarin and low molecular weight heparin. More studies are required that consider not only efficacy and safety, but also costs, lifestyle burden and patient preference.

Topics: Anticoagulants; Aspirin; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Multiple Myeloma; Thalidomide; Venous Thromboembolism; Warfarin

Immunomodulatory agents which include thalidomide and its analogue lenalidomide have recently emerged as an effective chemotherapy option for patients with Multiple Myeloma. The anti-tumor property of these molecules is probably related to action on tumor microenvironment, anti-angiogenesis and several other hitherto less understood mechanisms. Despite promising efficacy, their progress has been complicated by reports of venous thromboembolism in patients receiving these agents. The background rate of thromboembolism is 4-11% in patients with multiple myeloma, which increases to 15-20% in patients who received intensive treatment with Thalidomide. The exact mechanism of this phenomenon is not clear but possible explanations include up-regulation of pro-coagulant factors and selective endothelial damage. The development of thromboembolism is also influenced by disease state, performance status, type of chemotherapy and supportive therapy. Multiple treatment strategies for prevention of thromboembolic events in these patients have been proposed including aspirin, heparins and warfarin but there have been no prospective controlled trials comparing the superiority of one prophylactic measure over another. The diagnosis and treatment of thromboses in these patients involves standard guidelines but the optimal duration is not certain. This review discusses incidence, pathogenesis and management of thrombotic events with the use of immunomodulatory agents in the setting of multiple myeloma as well as recent recommendations regarding appropriate prophylaxis and preventive measures.

Topics: Anticoagulants; Antineoplastic Agents; Aspirin; Heparin, Low-Molecular-Weight; Humans; Immunologic Factors; Lenalidomide; Multiple Myeloma; Thalidomide; Thromboembolism; Warfarin

The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Topics: Antineoplastic Agents; Aspirin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Lenalidomide; Multiple Myeloma; Premedication; Risk Assessment; Risk Factors; Thalidomide; Thrombosis; Venous Thromboembolism; Warfarin

We presented a patient suffered from stroke related to thalidomide therapy. The patient was a 74-year-old man who had about two-year history of multiple myeloma and treated with 100 mg of oral thalidomide daily. He was diagnosed as having cryptogenic stroke attributable to patent foramen ovale, when he admitted to our hospital with sudden onset left-side hemiparesis. Antiplatelet and neuroprotective therapies were commenced along with the use of elastic stocking to prevent further embolic event. Then, warfarin was selected as secondary prevention to reduce the risk of paradoxical embolism during thalidomide therapy. Although the risk of deep vein thrombosis on thalidomide therapy has been well documented, only a few cases have been noted documenting the risk of stroke during thalidomide therapy. We need to be careful about the risk of deep vein thrombosis on thalidomide therapy, even as monotherapy, and consider using anticoagulant therapy while prescribing thalidomide.

Topics: Aged; Anticoagulants; Aspirin; Embolism, Paradoxical; Foramen Ovale, Patent; Humans; Male; Multiple Myeloma; Neuroprotective Agents; Risk; Stockings, Compression; Stroke; Thalidomide; Venous Thrombosis; Warfarin

Deep vein thrombosis and its lethal complication pulmonary embolism are manifestations of venous thromboembolism (VTE), which is typically associated with cancer and recent major surgery. Certain solid tumors and hematologic malignancies impose an inherently elevated risk of VTE that is compounded by chemotherapy and other risk factors. Multiple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their multiple hemostatic effects, including elevated interleukin-6 levels, pro-coagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance, and endothelial damage. The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported. Various VTE prophylaxis strategies with thalidomide- and lenalidomide-containing combinations have been investigated in clinical studies. This review discusses emerging results on the use of VTE prophylaxis to minimize VTE risks associated with MM treatment regimens containing thalidomide and lenalidomide.

Topics: Anticoagulants; Aspirin; Clinical Trials as Topic; Drug Therapy, Combination; Embolism; Factor V; Heparin, Low-Molecular-Weight; Humans; Immunologic Factors; Multiple Myeloma; Mutation; Prothrombin; Risk Reduction Behavior; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Angiogenesis Inhibitors; Drug Screening Assays, Antitumor; Heparin; Humans; Multiple Myeloma; Thalidomide; Thrombosis; Warfarin

In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens.. A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment.. Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded.. In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Cardiovascular Diseases; Enoxaparin; Female; Fibrinolytic Agents; Hemorrhage; Humans; Italy; Male; Middle Aged; Multiple Myeloma; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Thalidomide; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

Venous thromboembolism (VTE) is a major complication of myeloma therapy recently observed with the increasing use of up-front thalidomide and dexamethasone (thal-dex). The pathogenesis of thal-induced VTE is not well recognized, and the role of prothrombotic factors, especially of thrombophilic abnormalities, is not yet determined.. Two hundred and sixty-six patients with newly diagnosed multiple myeloma (MM) were primarily treated with thal-dex in preparation for subsequent high-dose therapy and autologous stem-cell transplantation. Out of these 266 patients, 190 were evaluated for thrombophilic alterations at baseline, and 125 of them were also re-assessed after thal-dex therapy.. The presence of genetic thrombophilic polymorphisms among patients with MM was superimposable to that of normal controls and was associated with a twofold increase in the relative risk of VTE. aAPCR and elevated factor VIII levels were frequent, albeit transient, alterations and were not associated with a significant increase in the risk of VTE. Two hundred and forty-six patients received a thromboprophylaxis with fixed low-dose warfarin (1.25 mg/day) during thal-dex therapy. Of these patients (or 10.6%), 26 had symptomatic VTE events. Their patients-years rate of VTE (35.5%) was significantly lower in comparison with the 86.2% rate recorded among the first 19 patients who initially entered the study and did not receive any kind of thromboprophylaxis (P = 0.043).. On the basis of these data, a baseline thrombophilic work up is not recommended in patients with receiving up-front thal-dex. For these patients, fixed low-dose warfarin may be a valuable prophylaxis against VTE.

Topics: Activated Protein C Resistance; Adult; Aged; Anticoagulants; Case-Control Studies; Dexamethasone; Factor V; Factor VIII; Female; Humans; Male; Middle Aged; Multiple Myeloma; Prothrombin; Risk Factors; Thalidomide; Thrombophilia; Thrombosis; Venous Thromboembolism; Warfarin

Patients with primary systemic (AL) amyloidosis or multiple myeloma are frequently treated with cyclic dexamethasone (DXM) courses and often require oral anticoagulants. We previously reported a strong potentiation of oral anticoagulants with intravenous methylprednisolone and observed a similar potentiation with DXM in 3 patients, which led us to prospectively investigate the interaction between DXM and oral anticoagulants.. Nine patients with multiple myeloma (n=6) or AL amyloidosis (n=3), including 6 prospective patients, taking fluindione (n=8) or warfarin (n=1), were studied for a total of 10 cycles. DXM (40 mg/day for 4 days every 28 days) was administered alone (n=4) or with melphalan (n=5). One patient was studied for 2 consecutive cycles after a moderate increase in the international normalized ratio (INR) during the first course of DXM. International normalized ratio (INR) was measured serially during DXM administration. Plasma oral anticoagulant concentrations were measured for 5 cycles.. The mean INR increased from 2.75 (range: 1.80-3.6) at baseline to 5.22 (3.09-7.07) after DXM. Oral anticoagulants were transiently stopped during 8 cycles and 1 mg oral vitamin K was given during 2. No serious bleeding was observed. Plasma oral anticoagulant concentrations increased after DXM administration. In controls receiving DXM without oral anticoagulants, DXM alone did not increase prothrombin time.. High dose DXM can potentiate oral anticoagulants and elevate INR substantially. INR should therefore be monitored repeatedly during concomitant administration of these 2 drugs to allow individual adaptation of oral anticoagulant doses.

Topics: Aged; Amyloidosis; Anticoagulants; Blood Coagulation; Creatinine; Dexamethasone; Drug Synergism; Female; Glucocorticoids; Humans; International Normalized Ratio; Male; Middle Aged; Multiple Myeloma; Patient Selection; Phenindione; Prothrombin Time; Warfarin

Venous thromboemobolism (VTE) is an important complication of thalidomide therapy especially when it is combined with steroids or chemotherapy. Currently there is no consensus on the most appropriate prophylactic approach. We prospectively investigated the use of low-dose warfarin sodium in prevention of thalidomide-associated VTE in patients receiving thalidomide-based combination therapies. Patients with multiple myeloma or chronic lymphocytic leukemia who were treated on thalidomide based-combination therapies were treated on low-dose warfarin (1 or 2 mg) continuously through the duration of their therapy. Among the 68 patients enrolled, four developed an episode of VTE, an overall incidence of 5.9% (odds = 0.063). Median duration of thalidomide therapy was 4 months. Low-does warfarin decreases the incidence of VTE compared to historical control and is an effective mechanism of prevention of VTE in thalidomide-based chemotherapy regimens.

Topics: Aged; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Multiple Myeloma; Thalidomide; Venous Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Gastrointestinal Hemorrhage; Hematoma; Humans; Male; Multiple Myeloma; Warfarin

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Bortezomib; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Female; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Multiple Myeloma; Retrospective Studies; Survival Rate; Thromboembolism; Warfarin

A 77-year-old man with a mechanical mitral valve on warfarin presented with an acute drop in haemoglobin and large spontaneous haematoma. He was found to have a new coagulopathy with initial labs notable for a prolonged activated partial thromboplastin time (APTT). Further workup revealed factor VIII levels less than 1%, abnormal mixing studies and elevated Bethesda titres, which was consistent with an acquired factor VIII inhibitor. Given his bone marrow biopsy result, which was positive for plasma cell myeloma, this coagulopathy was thought to be an acquired haemophilia A secondary to multiple myeloma. Anticoagulation was a challenge in this patient given his mechanical mitral valve and acquired haemophilia A. Although the patient was at risk of thrombosis due to a mechanical mitral valve, he had a bleeding diathesis and anaemia not responsive to transfusion. The decision was made to hold anticoagulation and the patient was started on myeloma treatment which included CyBorD, rituximab and daratumumab. After initiation of treatment APTT and factor VIII normalised. He eventually restarted anticoagulation under direction of his primary care doctor.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Drug Therapy, Combination; Heart Valve Prosthesis; Hematoma; Hemophilia A; Humans; Male; Multiple Myeloma; Partial Thromboplastin Time; Warfarin

BACKGROUND Currently available antithrombotic prophylaxis is not perfectly reliable in elderly patients. The aim of this retrospective study was to evaluate the efficacy and safety of Compound Danshen Tablet (CDT) in preventing thromboembolism in multiple myeloma (MM) patients treated with thalidomide-based regimens. MATERIAL AND METHODS MM patients treated with thalidomide-based regimens were retrospectively reviewed between January 2008 and March 2015. Patients were categorized into 3 cohorts based on thromboembolic prophylaxis used: CDT, Warfarin Tablet, and no prophylaxis. Venous thromboembolism (VTE), other adverse effects (AEs), and the changes of D-dimer and fibrinogen levels were monitored. RESULTS Seven out of 313 MM patients (2.24%) developed venous thrombosis events (VTE) in this retrospective study, all clustering in the no prophylaxis cohort. Three patients of the Warfarin cohort (3.19%) experienced hemorrhage. Neither VTE events nor serious AEs were observed in the CDT cohort. Following Compound Danshen or Warfarin treatment for 3 months, the D-dimer and fibrinogen levels (in particular the D-dimer level) (all P<0.05), were obviously decreased relative to their respective baselines and the no prophylaxis cohort. In contrast, the 2 blotting parameters were significantly increased in the no prophylaxis cohort relative to the baseline level (All P<0.05), and were even higher in the patients experiencing VTE compared to the no VTE patients (P<0.0001 and P=0.016, respectively). CONCLUSIONS Our findings indicate CDT is an effective therapy for preventing VTE in MM patients treated with thalidomide-based regimens, and is well tolerated in long-term use.

Topics: Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Multiple Myeloma; Phytotherapy; Plant Preparations; Retrospective Studies; Risk Factors; Salvia miltiorrhiza; Tablets; Thalidomide; Venous Thromboembolism; Warfarin

Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer(+) BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy.

Topics: Animals; Axl Receptor Tyrosine Kinase; Bone Marrow Cells; c-Mer Tyrosine Kinase; Case-Control Studies; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Multiple Myeloma; Neoplasm Transplantation; Plasma Cells; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Signal Transduction; Stromal Cells; Survival Analysis; Warfarin

Treatment with thalidomide is associated with vascular thrombosis. The effect of thalidomide on platelet activation is unclear, although the use of aspirin is justified for thromboprophylaxis. A study on platelet activation markers was done among multiple myeloma patients receiving thalidomide therapy with warfarin as thromboprophylaxis. Strict criteria and procedure were set to avoid misinterpretation of platelet activation other than due to the thalidomide's effect. Blood specimen pre and post thalidomide therapy were used for flow cytometric analysis. Platelet surface P-selectin, CD62P expression and PAC-1 (antibody that recognizes conformational change of the GPIIb/IIIa complex) were examined by using three-colour flowcytometer. Increased expression marker for PAC-1 was observed after 4 weeks of thalidomide treatment (P < 0.05) indicating one aspect of platelet activation activity seen in these patients. The mechanism of thrombosis by thalidomide is probably multifactorial and one of them is likely through platelet activation. Further study on the affected pathway/s in the platelet activation process would confirm the exact mechanism of thalidomide-induced thrombosis and potential extended usage of this drug in future.

Topics: Aged; Antibodies, Monoclonal; Anticoagulants; Blood Platelets; Female; Gene Expression; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Thalidomide; Thrombosis; Warfarin

To assess thromboprophylaxis prescribing patterns against current guidelines and report thromboembolism (TE) incidence in multiple myeloma (MM) patients treated with thalidomide (thal) or lenalidomide (len) at a specialist cancer hospital over a one-year period.. Dispensing records of thal and len, diagnosis of MM, patients' characteristics, disease status, co-prescribed medicines including thromboprophylaxis and incidence of TE were extracted from patients' records and a patient survey conducted to identify patients who sourced thromboprophylactic medicines outside the hospital.. Enoxaparin was most the commonly prescribed thromboprophylactic agent (43%), followed by low-dose aspirin (26%) and therapeutic warfarin (6%). The thromboprophylactic strategy (including no prophylaxis) could not be determined for 22% of patients. TE incidence (with any thromboprophylaxis) was 9.3 and 9.1% in thal-based and len-based regimens, respectively.. Both aspirin and enoxaparin thromboprophylaxis were prescribed for patients on both low-risk and high-risk immunomodulatory drug-based regimens, deviating from current consensus guidelines. Treatment of comorbidities constituted the rationale for maintenance on therapeutic warfarin. Fixed low-dose warfarin was not prescribed. TE event rates (with any thromboprophylaxis) were consistent with those reported in the literature. Documentation of a chosen strategy was lacking for nearly a quarter of patients, resulting in uncertainty of treatment plan for other members of the multidisciplinary treating team. Centers need to work towards evidence-based institutional guidelines and improving documentation practices for thromboprophylaxis in their MM patients.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anticoagulants; Aspirin; Cancer Care Facilities; Enoxaparin; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Incidence; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Practice Patterns, Physicians'; Prognosis; Retrospective Studies; Specialization; Thalidomide; Thrombosis; Warfarin

Rate of thalidomide-related VTE and risk factors in Japanese myeloma patients are not clear and effects of thromboprophylaxis remain controvertial.. We retrospectively analyzed a cohort data of registered Japanese myeloma patients treated with thalidomide-based regimens between 2009 and 2010. Primary endpoint was rate of symptomatic VTE. Secondary endpoints were associations between VTE and clinical factors including age, gender, disease characteristics and duration, history of VTE, immobilization, comorbidities, treatment regimens, and laboratory parameters of Hb, leukocyte, platelet and FDP or D-dimer level, and effects of thromboprophylaxis with aspirin or warfarin. Statistical analysis was performed by Fischer's exact test and Cochran-Mantel-Haenszel test to control for confounders, and t test for dichotomous and continuous variables, respectively.. 1035 refractory or relapsed myeloma patients were followed up for a median of 112days(range 2-311days), and 14 (1.4%) developed VTE with a median treatment of 31days (range 9-134days) with thalidomide. Treatments with or without other agents lead to similar rates of VTE, 1.7% and 1.1%, respectively (p=0.43) and no specific clinical factors influenced development of VTE. Thromboprophylaxis with aspirin or warfarin did not reduce risk of VTE; VTE with or without aspirin: 1.4% and 1.3% (p=1.00), and warfarin: 2.4% and 1.3% (0.31), respectively.. Rate of VTE is low in Japanese myeloma patients treated with thalidomide. Risk factors and effects of thromboprophylaxis with aspirin or warfarin are not apparent, however, controlled randomized studies of larger scale are needed for statistically valid conclusion.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Cohort Studies; Female; Humans; Incidence; Japan; Male; Middle Aged; Multiple Myeloma; Retrospective Studies; Risk Factors; Thalidomide; Venous Thromboembolism; Warfarin

Topics: Antineoplastic Agents; Aspirin; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Immunomodulation; Multiple Myeloma; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Adjustment; Secondary Prevention; Thalidomide; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a disease with a high prevalence in elderly people, affecting > 5% of the population > 65 years of age. Cancer patients have a 4.3-fold higher incidence of thrombotic complications, due to multiple risk factors that are not always related to the disease. Among hematologic malignancies, multiple myeloma (MM) confers a high risk of developing such complications, with a VTE rate of nearly 10%. Multiple factors are involved in MM-related VTE, such as increased blood viscosity, high levels of immunoglobulin, procoagulant activity of monoclonal protein, and inflammatory cytokines. Since the introduction of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide in the therapeutic armamentarium of MM, VTE has emerged as one of the leading complications, in particular in patients with newly diagnosed MM. In this setting, IMiDs-based treatments are associated with rates of VTE reaching values up to 14 to 26%, particularly when dexamethasone or chemotherapy are added. The optimal prophylaxis for patients receiving these antiangiogenetic agents is still a matter of debate. Due to the lack of prospective randomized clinical trials, different studies have used various anticoagulant prophylaxes, including fixed low-dose warfarin (1 mg or 1.25 mg), therapeutic doses of warfarin (international normalized ratio between 2.0 and 3.0), low molecular weight heparin, or low-dose aspirin. As yet, no study has clearly demonstrated a significant superiority of one prophylactic regimen in comparison with the others. Further investigation and more randomized clinical trials are needed to define the best thromboprophylaxis.

Topics: Activated Protein C Resistance; Aged; Anticoagulants; Aspirin; Boronic Acids; Bortezomib; Dexamethasone; Humans; Immunologic Factors; International Normalized Ratio; Lenalidomide; Multiple Myeloma; Proteasome Inhibitors; Pyrazines; Risk Factors; Thalidomide; Thrombosis; Venous Thromboembolism; Warfarin

Topics: Aged; Anticoagulants; Female; Heparin; Humans; Multiple Myeloma; Pulmonary Embolism; Thalidomide; Tomography, X-Ray Computed; Warfarin

The effects of prednisone on the International Normalized Ratio (INR) values of a patient were examined.. A 66-year-old white man with a history of multiple myeloma was treated in an ambulatory care anticoagulation clinic for deep vein thrombosis. His INR values were normal during therapy with warfarin 14 mg weekly and thalidomide 300 mg daily. His INR values began to increase after three months of starting prednisone 10 mg daily. His weekly dose of warfarin was changed over the next two years, and his dietary intake of vitamin K was increased. For every INR value that was below the therapeutic goal, the patient was not taking prednisone; every time the INR value was above the therapeutic goal, he was taking prednisone. In November 2004, the prednisone and thalidomide were stopped and only the warfarin was continued. After a few dosage increases, ending with a weekly warfarin dose of 21 mg, the patient's INR values remained in the therapeutic range. Multiple variables must be examined when assessing INR values, as many things interact with warfarin. For example, tobacco use, alcohol consumption, and changes in vitamin K intake can affect the INR. Since this patient did not use tobacco or consume alcohol and had a fairly consistent dietary intake of vitamin K, these variables were ruled out as influencing the INR. In this case, the changes in his INR values corresponded to the addition or deletion of prednisone.. A patient's INR values increased after the addition of prednisone to his warfarin regimen.

Topics: Aged; Anti-Inflammatory Agents; Anticoagulants; Antineoplastic Agents, Hormonal; Glucocorticoids; Humans; International Normalized Ratio; Male; Multiple Myeloma; Prednisone; Venous Thrombosis; Warfarin

Thalidomide has been associated with venous thrombotic events, as reported in the post-marketing surveillance reports by Celgene Corporation; as well as case reports in the literature. Seven arterial thrombotic events have been reported in patients receiving thalidomide with 3 cases occurring in patients with other predisposing conditions. We report 4 additional cases of arterial thromboses in 1 lymphoma and 3 myeloma patients treated with thalidomide. The mechanism for these events is unclear; however, it is significant that 2 patients were receiving concomitant anticoagulation with aspirin and warfarin.

Topics: Aged; Arterial Occlusive Diseases; Aspirin; Drug Therapy, Combination; Female; Humans; Intracranial Thrombosis; Lymphoma; Male; Middle Aged; Multiple Myeloma; Thalidomide; Thrombosis; Warfarin

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Dexamethasone; Enoxaparin; Humans; Male; Middle Aged; Multiple Myeloma; Prognosis; Thalidomide; Venous Thrombosis; Warfarin

Among 199 patients treated with thalidomide for multiple myeloma, four thromboses occurred in 49 cases during erythropoietin therapy (prevalence 8.1%; annual rate 7.25%), and another 14 events occurred in patients not on erythropoietin (9.3%; 7.56%). Thus, erythropoietin would seem not to increase the risk of thrombosis of myeloma patients receiving thalidomide.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antineoplastic Agents; Drug Synergism; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Risk; Thalidomide; Thrombosis; Venous Thrombosis; Warfarin

Bone marrow transplant (BMT) recipients have risk factors for deep vein thrombosis (DVT) including venous stasis caused by immobilization in the sterile unit, vessel wall damage caused by preparative regimen or indwelling catheters, and hypercoagulability caused by decreased natural anticoagulants. We successfully treated a patient who developed massive DVT in the superior vena cava after BMT with anticoagulation and the use of temporary vena caval filters. Considering the delayed complications, permanent filter is not appropriate for BMT recipients, because the risk factors for DVT associated with BMT are transient. We considered that temporary vena caval filter is a safe and useful device to prevent pulmonary embolism after DVT in BMT recipients.

Topics: Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Catheterization, Central Venous; Coagulation Protein Disorders; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Endothelium, Vascular; Heparin; Humans; Immobilization; Male; Melphalan; Middle Aged; Multiple Myeloma; Radiography; Salvage Therapy; Thrombophilia; Transplantation, Homologous; Vena Cava Filters; Vena Cava, Superior; Venous Thrombosis; Vincristine; Warfarin