vitamin-k-semiquinone-radical and Cerebral-Hemorrhage

As intracerebral hemorrahge becomes more frequent as a result of an aging population with greater comorbidities, rapid identification and reversal of precipitators becomes increasingly paramount. The aformentioned population will ever more likely be on some form of anticoagulant therapy. Understanding the mechanisms of these agents and means by which to reverse them early on is critical in managing the acute intracerebral hemorrhage.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Humans; Plasma; Recombinant Proteins; Treatment Outcome; Vitamin K; Warfarin

The objective of this paper is to assess the clinical outcomes between non-traumatic intracerebral hemorrhage(ICH) in patients using direct oral anticoagulants(DOAC) versus vitamin K antagonists(VKA) for non-valvular atrial fibrillation. We also evaluated the predictors of the poor post-ICH outcomes.. We have performed pooled meta-analysis to assess long-term clinical outcomes in patients with DOAC-ICH as compared to those with VKA-ICH. A systematic literature search was conducted by searching the full-text English literature in PubMed, EMBASE, and Cochrane databases for observational studies reporting outcomes on interest. MOOSE guidelines were used to collect data till December 31, 2019 and random effects analysis was carried out to account for heterogeneity. For outcomes, risk ratios(RR) and the mean differences were pooled using a random-effects model and weighted mean differences (WMDs), respectively.. Seventeen studies met the inclusion criteria (n = 25,354 patients; DOAC-ICH arms = 5,631; VKA-ICH arm = 19,273). Patients with DOAC-ICH had smaller hematoma volumes (WMD=-9.59; 95%CI=-15.33--3.85; I2 = 68.6%) and reduced mortality rate at discharge (RR = 0.82; 95%CI = 0.71-0.96; I2 = 9.4%). There was no significant difference between the two groups in rate of hematoma expansion (RR = 0.79; 95%CI = 0.56-1.11; I2 = 50.9%), unfavorable functional outcome(Modified Rankin Scale) at discharge (RR = 0.82; 95%CI = 0.56-1.18; I2 = 80.2%), unfavorable outcome at 3-months (RR = 0.77; 95%CI = 0.56-1.06; I2 = 63.9), and mortality at 3-months (RR = 0.90; 95%CI = 0.73-1.10; I2 = 35∙8%). Multivariate meta-regression revealed that the average age of patient population had a significantly negative correlation with(RR=-0.202; p = 0.017) hematoma expansion.. We conclude that use of DOAC is associated with reduced hematoma volume and mortality rate at discharge. Age is a predictor of the poor outcome of hematoma expansion.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hematoma; Humans; Male; Treatment Outcome; Vitamin K

To obtain precise estimates of age, haematoma volume, secondary haematoma expansion (HE) and mortality for patients with intracerebral haemorrhage (ICH) taking oral anticoagulants [Vitamin K antagonists (VKA-ICH) or non-Vitamin K antagonist oral anticoagulants (NOAC-ICH)] and those not taking oral anticoagulants (non-OAC ICH) at ICH symptom onset.. We conducted a systematic review and meta-analysis of studies comparing VKA-ICH or NOAC-ICH or both with non-OAC ICH. Primary outcomes were haematoma volume (in ml), HE, and mortality (in-hospital and 3-month). We calculated odds ratios (ORs) using the Mantel-Haenszel random-effects method and corresponding 95% confidence intervals (95%CI) and determined the mean ICH volume difference.. We identified 19 studies including data from 16,546 patients with VKA-ICH and 128,561 patients with non-OAC ICH. Only 2 studies reported data on 4943 patients with NOAC-ICH. Patients with VKA-ICH were significantly older than patients with non-OAC ICH (mean age difference: 5.55 years, 95%CI 4.03-7.07, p < 0.0001, I. This meta-analysis confirms, refines and expands findings from prior studies. We provide precise estimates of key prognostic factors and outcomes for VKA-ICH, which has larger haematoma volume, increased rate of HE and higher mortality compared to non-OAC ICH. There are insufficient data on NOACs.

Topics: Anticoagulants; Cerebral Hemorrhage; Hematoma; Humans; Vitamin K

Direct Oral Anticoagulants (DOAC) are increasingly used as an alternative to vitamin-K antagonists (VKA) for anticoagulation and have shown lower rates of intracranial hemorrhage; however, there is disagreement in the literature over the outcomes of the intraparenchymal hemorrhages (IPH) associated with DOACs, and clinical concern regarding the lack of standardized reversal strategies for DOACs. Thus, the aim of this meta-analysis was to compare mortality, hematoma volume, and risk of hematoma expansion in patients who developed an IPH on DOACs versus VKA. A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Studies were selected that reported on mortality, hematoma expansion, and hematoma volume in DOAC-associated IPH. Pooled risk ratios (RR) were calculated for mortality and hematoma expansion and pooled mean difference (MD) was calculated for hematoma volume (ml) using random-effect models. 15 studies reporting on 1238 patients were included in the systematic review. Eleven of these compared DOAC-IPH to VKA-IPH and were pooled quantitatively. DOAC-IPH was not associated with increased mortality risk (RR: 0.95, 95%-CI: 0.72 -1.27) or increased hematoma expansion risk (RR: 0.92; 95%-CI: 0.75-1.12) compared to VKA-IPH. The hematoma volume of DOAC- IPH was statistically significantly smaller than VKA-IPH (MD: -12.14 ml; 95%-CI: -15.38; -8.89). In conclusion, DOAC-IPH was not associated with increased mortality or hematoma expansion compared to VKA-IPH and may be associated with a smaller hematoma volume.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Cerebral Hemorrhage; Hematoma; Humans; Male; Risk Factors; Vitamin K

The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH).. We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation.. Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted.. Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Topics: Anticoagulants; Antithrombins; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Hematoma; Humans; Mortality; Odds Ratio; Phenprocoumon; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Thiazoles; Vitamin K; Warfarin

The effect of rapid anticoagulation reversal on mortality and functional outcome in vitamin K antagonist-associated intracerebral hemorrhage (VKA-ICH) is uncertain. Given the approval of idarucizumab for dabigatran reversal and pending approval for andexanet alfa for reversal of factor Xa inhibitors, a systematic appraisal of the effectiveness of reversal for VKA-ICH would provide a bench mark for current practice. We performed PubMed searches and reviewed current guidelines. Using pre-specified inclusion and exclusion criteria, studies were reviewed by two physicians independently. Data elements abstracted included study design, sample size, inclusion and exclusion criteria; patient characteristics at presentation; time to presentation and therapy; dose and timing of warfarin reversal agents; functional outcome and mortality. Studies were assessed for risk of bias. Twenty-one studies met the selection criteria. The overall quality of the studies was poor with small sample size for the majority and all studies being either case series or retrospective observational in design. Inclusion criteria were not uniform. Interpretation of the effectiveness of vitamin K antagonist reversal on functional outcome was not feasible due to lack of standard protocols in the management of VKA-ICH including choice, dose, and timing of reversal agent, timing of subsequent INR monitoring, and decision for repeat imaging. Confounding by indication, lack of universal reporting of functional outcome, and use of varied scales for the endpoint further limited a summary interpretation. Despite availability of reversal agents, mortality and morbidity remain high following VKA-ICH. Evidence for improvement in neurological outcome is limited.

Topics: Anticoagulants; Cerebral Hemorrhage; Drug Interactions; Humans; Vitamin K

Whether intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOAC-ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA-ICH) is uncertain.. We performed a systematic review and individual patient data meta-analysis of cohort studies comparing clinical and radiological outcomes between NOAC-ICH and VKA-ICH patients. The primary outcome measure was 30-day all-cause mortality. All outcomes were assessed in multivariate regression analyses adjusted for age, sex, ICH location, and intraventricular hemorrhage extension.. Although functional outcome at discharge, 1 month, or 3 months was comparable after NOAC-ICH and VKA-ICH, patients with NOAC-ICH had smaller baseline hematoma volumes and less severe acute stroke syndromes. Ann Neurol 2018;84:702-712.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Neuroimaging; Vitamin K

Hematoma expansion (HE), defined as a greater than 33% increase in intracerebral hemorrhage (ICH) volume within the first 24 hours, results in significant neurological deficits, and enhancement of ICH-induced primary and secondary brain injury. An escalation in the use of oral anticoagulants has led to a surge in the incidences of oral anticoagulation-associated ICH (OAT-ICH), which has been associated with a greater risk for HE and worse functional outcomes following ICH. The oral anticoagulants in use include vitamin K antagonists, and direct thrombin and factor Xa inhibitors. Fibrinolytic agents are also frequently administered. These all act via differing mechanisms and thus have varying degrees of impact on HE and ICH outcome. Additionally, antiplatelet medications have also been increasingly prescribed, and result in increased bleeding risks and worse outcomes after ICH. Aspirin, thienopyridines, and GPIIb/IIIa receptor blockers are some of the most common agents in use clinically, and also have different effects on ICH and hemorrhage growth, based on their mechanisms of action. Recent studies have found that reduced platelet activity may be more effective in predicting ICH risk, hemorrhage expansion, and outcomes, than antiplatelet agents, and activating platelets may thus be a novel target for ICH therapy. This review explores how dysfunctions or alterations in the coagulation and platelet cascades can lead to, and/or exacerbate, hematoma expansion following intracerebral hemorrhage, and describe the mechanisms behind these effects and the drugs that induce them. We also discuss potential future therapy aimed at increasing platelet activity after ICH.

Topics: Anticoagulants; Cerebral Hemorrhage; Factor Xa Inhibitors; Fibrinolytic Agents; Hematoma; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Thrombin; Vitamin K

To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF).. We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH.. We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSS. DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Brain; Cerebral Hemorrhage; Cross-Sectional Studies; Female; Humans; Male; Observational Studies as Topic; Prospective Studies; Stroke; Treatment Outcome; Vitamin K

In patients with acute intracerebral hemorrhage (ICH), one of the major concerns is ongoing bleeding or ICH expansion. Anticoagulated patients are at higher risk of ongoing expansion and worse outcome. It may be that rapid anticoagulation reversal can reduce the risk of expansion and improve clinical outcome. For those taking coumarins, the best available evidence suggests that intravenous vitamin K combined with four-factor prothrombin complex concentrate (4F-PCC) is the most rapid and effective regimen to restore hemostasis. For those on dabigatran, the highest quality data available for reversal are for idarucizumab, although it is not yet clear whether patients derive clinical benefit from this reversal. In the absence or failure of idarucizumab, activated prothrombin complex concentrate (aPCC) is recommended. For those on factor Xa inhibitors, the ideal reversal agent is not clear. Many providers use 4F-PCC or aPCC, but more specific agents are in clinical trials and may soon be available. In addition, the half-lives of the non-vitamin K antagonists are relatively short compared with warfarin, and so some patients may not have a clinically relevant coagulopathy at the time of presentation. Overall, the optimal reversal agent, when one is required, is a function of which anticoagulant the patient is taking.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Humans; Vitamin K

The use of vitamin K antagonists (VKAs) in hemodialysis patients with atrial fibrillation (AF) is controversial. No randomized trials are available and observational studies have yielded conflicting results, engendering a large clinical practice variability and physician uncertainty. An unresolved but highly relevant question is whether AF poses a true risk of ischemic stroke in hemodialysis and whether any form of oral anticoagulation is therefore warranted.. We conducted a systematic review of studies that compared the incidence of ischemic stroke and bleeding in hemodialysis patients with AF taking VKA and those not taking VKA. When hemodialysis patients had been pooled with peritoneal dialysis, kidney transplant, or stage V chronic kidney disease patients, unpublished outcome data of the hemodialysis subgroup were obtained through personal communication. The main outcome measures were ischemic stroke/thromboembolic events, all-cause mortality, major bleeding, and hemorrhagic stroke. Combined hazard ratios (HRs) and 95% CIs were calculated using a random-effects model.. Twelve prospective or retrospective cohort studies were included in the meta-analysis, totaling 17,380 hemodialysis patients of whom 4,010 (23.1%) received VKA. In VKA-treated patients, mean CHADS. Our meta-analysis revealed a trend for a reduction of the risk of ischemic stroke in hemodialysis patients with AF treated with VKA. The true protective effect may have been underestimated, owing to inclusion of low-risk patients not expected to benefit from anticoagulation and to suboptimal anticoagulation. However, assessment of the overall effect of VKA in hemodialysis patients should also take into account the increased risk of bleeding, in particular of hemorrhagic stroke. Whether new oral anticoagulants provide a better benefit-risk ratio in hemodialysis patients should be the subject of future trials.

Topics: Anticoagulants; Atrial Fibrillation; Cause of Death; Cerebral Hemorrhage; Hemorrhage; Humans; Kidney Failure, Chronic; Mortality; Proportional Hazards Models; Renal Dialysis; Stroke; Thromboembolism; Vitamin K; Warfarin

Intracerebral hemorrhage (ICH) in patients with oral anticoagulation therapy is an increasingly prevalent problem in large part due to the aging population and the increased use of anticoagulants for patients at high risk of thrombosis. Warfarin has been virtually the only outpatient anticoagulant choice until fairly recently. The development of subcutaneously injected heparinoids, and more recently, of direct thrombin inhibitors, has made the treatment and prognostication of ICH in anticoagulated patients more difficult. In this review, we will review the current state of diagnosis, prognostication, and treatment for patients with this often-devastating type of bleeding. We will focus on warfarin therapy, because the preponderance of evidence comes from studies of warfarin treatment. Where there is evidence, we will contrast warfarin with some of the newer treatment modalities. We review the evidence of the 4 major reversal agents for warfarin, vitamin K, prothrombin complex concentrates, activated factor VII, and fresh frozen plasma as well as rational treatment choices. We offer possible treatments for the newer anticoagulants based on the limited evidence available. Finally, we review recommendations from the major societies and studies that support early and aggressive therapies in intensive care units with dedicated neurological specialists.

Topics: Administration, Oral; Age Factors; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Critical Care; Factor VIIa; Humans; Plasma; Thrombosis; Tomography, X-Ray Computed; Vitamin K; Warfarin

As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In 'real world' clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a 'real world' cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on 'real world' data.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Clopidogrel; Drug Synergism; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Humans; Mortality; Numbers Needed To Treat; Observational Studies as Topic; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk; Risk Assessment; Stroke; Thiazoles; Thrombophilia; Ticlopidine; Vitamin K

Newborn infants are born with an immature innate immunity. They are less likely to develop anaphylaxis since their immune system is weaker than older infants and children. There are only a few reports of side effects after vitamin K injection in neonates although prophylaxis against hemorrhagic disease of the newborn with this drug has been in routine practice in all over the world for many years. We herein report a case of anaphylactic shock developing after the intramuscular administration of vitamin K1 in a newborn. To our knowledge, this patient is the first case of neonatal anaphylactic shock developing due to intramuscular administration of vitamin K1. We suggest the clinicians should be aware of this possibility of potentially fatal adverse effect occurring with intramuscular administration of vitamin K1.

Topics: Anaphylaxis; Cerebral Hemorrhage; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Injections, Intramuscular; Male; Pregnancy; Vitamin K; Young Adult

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Embolism; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K; Warfarin

Patients receiving anticoagulation therapy who present with any type of intracranial hemorrhage--including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, and intracerebral hemorrhage (ICH)--require urgent correction of their coagulopathy to prevent hemorrhage expansion, limit tissue damage, and facilitate surgical intervention as necessary. The focus of this review is acute ICH, but the principles of management for anticoagulation-associated ICH (AAICH) apply to patients with all types of intracranial hemorrhage, whether acute or chronic. A number of therapies--including fresh frozen plasma (FFP), intravenous vitamin K, activated and inactivated prothrombin complex concentrates (PCCs), and recombinant activated factor VII (rFVIIa)--have been used alone or in combination to treat AAICH to reverse anticoagulation, help achieve hemodynamic stability, limit hematoma expansion, and prepare the patient for possible surgical intervention. However, there is a paucity of high-quality data to direct such therapy. The use of 3-factor PCC (activated and inactivated) and rFVIIa to treat AAICH constitutes off-label use of these therapies in the United States. However, in April 2013, the US Food and Drug Administration (FDA) approved Kcentra (a 4-factor PCC) for the urgent reversal of vitamin K antagonist (VKA) anticoagulation in adults with acute major bleeding. Plasma is the only other product approved for this use in the United States. (1) Inconsistent recommendations, significant barriers (e.g., clinician-, therapy-, or logistics-based barriers), and a lack of approved treatment pathways in some institutions can be potential impediments to timely and evidence-based management of AAICH with available therapies. Patient assessment, therapy selection, whether to use a reversal or factor repletion agent alone or in combination with other agents, determination of site-of-care management, eligibility for neurosurgery, and potential hematoma evacuation are the responsibilities of the neurosurgeon, but ultimate success requires a multidisciplinary approach with consultation from the emergency department (ED) physician, pharmacist, hematologist, intensivist, neurologist, and, in some cases, the trauma surgeon.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Factor VIIa; Humans; Plasma; Recombinant Proteins; Time Factors; Vitamin K

Intraventricular hemorrhage (IVH) is a major complication of preterm birth, and large hemorrhages may yield significant future disability. During the last few decades, the survival of preterm infants has increased dramatically. Nevertheless, morbidity is still a major problem especially for very young and extremely low birth weight infants. As both, mortality and incidence of morbidities known to influence outcome, show a weekly decline with increasing gestational age, prematurity and low birth weight have been identified as major risk factors for IVH occurrence. This stems probably from the increased vulnerability of the premature germinal matrix as well as the physiologically impaired hemostasis, demonstrated in neonates. The hypothesis that a severe coagulation deficiency in the premature newborn could be a major contributing factor for IVH has been suggested, and small open label interventional studies targeting the premature coagulation system have been conducted with ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII and prothrombin complex concentrate. Nevertheless, potential venous origin of hemorrhages, which may be related to thrombophilic risk factors, has also been discussed. The following manuscript will focus upon IVH pathogenesis and address potential therapies.

Topics: Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Ethamsylate; Factor VIIa; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prothrombin; Recombinant Proteins; Risk Factors; Treatment Outcome; Vitamin K

New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications.

Topics: Anticoagulants; Cerebral Hemorrhage; Humans; Neurosurgical Procedures; Platelet Aggregation Inhibitors; Vitamin K

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Morpholines; Prodrugs; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Vitamin K; Warfarin

Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Drugs, Investigational; Half-Life; Humans; Intracranial Embolism; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Stroke is a common disease, which is associated with high morbidity and high mortality. Up to 25% of cerebral ischaemic infarcts are caused by cardio-embolic events, most commonly associated with atrial fibrillation. It has previously been shown that antithrombotic therapy is insufficiently used in patients at increased risk of stroke. This article reviews evidence and practical management of anticoagulant therapy in stroke patients and provides an update on risk stratification for thromboembolism and bleeding complications in patients with atrial fibrillation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Morpholines; Pyrazoles; Pyridones; Radiography; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Thiophenes; Thromboembolism; Vitamin K

Dabigatran etexilate is emerging as an alternative for vitamin K antagonists, but evidence-based guidelines for management of intracerebral hemorrhage and acute ischemic stroke in patients taking this drug are nonexistent. This review summarizes current knowledge on key pharmacological features and the assessment of dabigatran activity. Pragmatic approaches are provided for individualized decision taking with regard to hemostatic therapy and reperfusion strategies in acute stroke patients.

Topics: Anticoagulants; Benzimidazoles; Blood Coagulation Disorders; Case Management; Cerebral Hemorrhage; Cerebral Infarction; Dabigatran; Guidelines as Topic; Hemostasis; Hemostatics; Humans; Off-Label Use; Pyridines; Renal Dialysis; Reperfusion; Stroke; Vitamin K

Intracerebral hemorrhage in patients with warfarin-associated coagulopathy is an increasingly common life-threatening condition that requires emergent management. The evolution of therapeutic options in this setting, as well as recently published guidelines, has resulted in some heterogeneity in recommendations by professional societies. This heterogeneity can be attributed to lack of evidence-based support for plasma therapy; the variability in availability of prothrombin complex concentrates; the variability in the coagulation factor levels and contents of prothrombin complex concentrates; ambiguity about the optimal dose and route of administration of vitamin K; and the lack of standardized clinical care pathways, particularly in community hospitals, for the management of these critical care patients. In this review, we summarize the relevant literature about these controversies and present recommendations for management of patients with warfarin-associated coagulopathy and intracerebral hemorrhage.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Cerebral Hemorrhage; Female; Humans; Male; Vitamin K; Warfarin

Oral anticoagulant-associated intracerebral hemorrhage is increasing in incidence and is the most feared complication of therapy with vitamin K1 antagonists. Anticoagulant-associated intracerebral hemorrhage has a high risk of ongoing bleeding, death, or disability. The most important aspect of clinical management of anticoagulant-associated intracerebral hemorrhage is represented by urgent reversal of coagulopathy, decreasing as quickly as possible the international normalized ratio to values ≤1·4, preferably ≤1·2, together with life support and surgical therapy, when indicated. Protocols for anticoagulant-associated intracerebral hemorrhage emphasize the immediate discontinuation of anticoagulant medication and the immediate intravenous administration of vitamin K1 (mean dose: 10-20 mg), and the use of prothrombin complex concentrates (variable doses calculated estimate circulating functional prothrombin complex) or fresh-frozen plasma (15-30 ml/kg) or recombinant activated factor VII (15-120 μg/kg). Because of cost and availability, there is limited randomized evidence comparing different reversal strategies that support a specific treatment regimen. In this paper, we emphasize the growing importance of anticoagulant-associated intracerebral hemorrhage and describe options for acute coagulopathy reversal in this setting. Additionally, emphasis is placed on understanding current consensus-based guidelines for coagulopathy reversal and the challenges of determining best evidence for these treatments. On the basis of the available knowledge, inappropriate adherence to current consensus-based guidelines for coagulopathy reversal may expose the physician to medico-legal implications.

Topics: Administration, Oral; Algorithms; Anticoagulants; Cerebral Hemorrhage; Factor VIIa; Guidelines as Topic; Humans; Neurosurgical Procedures; Plasma; Prothrombin; Risk Assessment; Stroke; Vitamin K

This review describes some natural proteins, which can be employed, either as factor concentrates derived from human plasma or as recombinant drug, to modulate the coagulation system. I will address some biochemical characteristics and the physiological role of von Willebrand factor, the coagulation factors of the extrinsic and intrinsic pathways, and the physiological anticoagulant protein C. In addition, I will detail the pharmacological compounds, which are available for influencing or substituting the coagulation proteins: desmopressin (DDAVP), single coagulation factor concentrates, prothrombin complex concentrates, and protein C concentrate. In particular, I will address some treatment topics of general medical interest, such as the treatment of massive bleeding, the correction of the coagulopathy induced by vitamin K-antagonists in patients with cerebral haemorrhage, and of the coagulopathy of meningococcemia. Finally, I will describe some properties and practical clinical applications of the recombinant anticoagulans lepirudin and bivalirudin, which are derived from hirudin, the natural anticoagulant of the medical leech.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Proteins; Cerebral Hemorrhage; Hemorrhage; Hirudins; Humans; Peptide Fragments; Protein C; Recombinant Proteins; Vitamin K; von Willebrand Factor

It has long been considered that a severe coagulation deficiency in premature newborns could be a major contributing factor in the occurrence of intraventricular hemorrhage (IVH). High-grade IVH has also been shown to coincide with severe derangement of coagulation in extremely low birth weight infants. This review focuses on the relevance of the physiologically developing immature hemostatic system to IVH, and the potential benefit of agents affecting hemostasis for IVH therapy or prevention in preterm infants. The findings of small, open-label interventional studies on the effect of ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII, and prothrombin complex concentrate on the premature coagulation system will be reviewed.

Topics: Blood Coagulation Factors; Cerebral Hemorrhage; Ethamsylate; Factor VIIa; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Plasma; Ultrasonography; Vitamin K

Preterm infants are at risk of periventricular haemorrhage. This can be a sign of brain damage that might lead to neurodevelopmental abnormalities, including cerebral palsy. It has been suggested that vitamin K might improve coagulation in preterm infants and thereby decrease the risk of periventricular haemorrhage.. The objective of this review was to assess the effects of vitamin K administered to women at risk of imminent very preterm birth to prevent periventricular haemorrhage and associated neurological injury in the infant.. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2008).. Randomised or quasi-randomised trials of vitamin K administered parenterally or orally to women at risk of imminent preterm birth. The primary outcomes were neonatal mortality, neonatal neurological morbidity, as measured by the presence of periventricular haemorrhage (PVH) on ultrasound during the first week of life, and long-term neurodevelopment. Secondary outcomes included other neonatal morbidity and any maternal side effects.. Two review authors independently assessed eligibility, trial quality and extracted data.. Seven trials were included, involving 607 women. The trials were of variable quality. Antenatal vitamin K was associated with a non-significant reduction in all grades of periventricular haemorrhage (risk ratio (RR) 0.76; 95% confidence interval (CI) 0.54 to 1.06) and a significant reduction in severe PVH (grades 3 and 4) (RR 0.58; 95% CI 0.37 to 0.91) for babies receiving prenatal vitamin K compared with control babies. When the two quasi-randomised trials were excluded, antenatal vitamin K was associated with a non-significant reduction in all grades of PVH (RR 0.87; 95% CI 0.60 to 1.26) and a non-significant reduction in severe PVH (RR 0.82; 95% CI 0.49 to 1.36).There was an unfavourable effect of vitamin K on development as measured by the Bayley Mental Development Index at two years of age, however these results are derived from one trial with many participants lost to follow up. No difference was found in the incidence of other neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given vitamin K and children not so exposed.. Vitamin K administered to women prior to very preterm birth has not been shown to significantly prevent periventricular haemorrhages in preterm infants or improve neurodevelopmental outcomes in childhood.

Topics: Antifibrinolytic Agents; Cerebral Hemorrhage; Cerebral Ventricles; Child; Developmental Disabilities; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Obstetric Labor, Premature; Pregnancy; Randomized Controlled Trials as Topic; Vitamin K

Warfarin is the most commonly used oral anticoagulant. Intracranial hemorrhage is the most serious complication of anticoagulation and the anticoagulant effect of warfarin has to be urgently reversed in this situation. Traditional methods of reversal of the anticoagulant effect of warfarin involving the use of vitamin K and fresh frozen plasma are slow and relatively ineffective and there is a need for alternative treatment approaches.. Agents such as prothrombin complex conjugates and recombinant activated factor VII are being increasingly used to emergently correct warfarin-associated coagulopathy. Over the last decade, several small case series have suggested that these agents may lead to more rapid correction of the INR, however, improved clinical outcome is yet to be proven. A recent small prospective trial has also demonstrated the safety of a prothrombin complex conjugate and its efficacy in rapidly correcting an elevated INR in these patients.. There is a need for well designed randomized clinical trials aimed at evaluating the efficacy of these agents in improving the outcome of patients with anticoagulant associated intracranial hemorrhage.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Factor VIIa; Humans; Plasma; Vitamin K; Vitamins; Warfarin

Anticoagulant-associated intracerebral hemorrhage (ICH) is a devastating disease, causing death in half of patients and permanent disability in the majority of survivors. The finding that patients often continue bleeding after hospital presentation offers the possibility that emergency warfarin reversal may improve outcomes. As no clinical trials have demonstrated the superiority of any one treatment strategy, various treatment options are available. Intravenous vitamin K is the definitive therapy; however, as monotherapy it can require many hours to take effect. Therefore, it is often considered an adjunct agent. Coagulation factors can be repleted with fresh frozen plasma (FFP), which is widely available and relatively low cost, but can require substantial time to deliver in real-world settings. A number of coagulation factor products collectively termed prothrombin complex concentrates (PCCs) are widely available that can rapidly provide many or all the vitamin K-dependent coagulation factors. Recombinant activated factor VII is used in many centers for this purpose, as it is thought to provide a procoagulant effect that may compensate for the lack of the other critical factors. Until clinical trials demonstrate the superiority of any one means of warfarin reversal, a number of expert guidelines from national organizations are available to help local providers guide therapy. At our institution, we have focused on improving the rapid and reliable delivery of a combination of intravenous vitamin K and FFP, with continued re-dosing until the desired INR lowering is achieved.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Drug Interactions; Humans; Plasma; Practice Guidelines as Topic; Vitamin K; Warfarin

Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are three families of anti-platelet agents with proven clinical efficacy: (1) cyclo-oxygenase inhibitors, such as aspirin; (2) adenosine diphosphate receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel; and (3) glycoprotein IIb/IIIa antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and thienopyridine compounds are used in the long-term prevention of cardiovascular and cerebrovascular events in patients at risk. Despite the good risk-to-benefit ratio of anti-platelet agents, the risk of severe bleeding complications, including cerebral haemorrhage, is slightly increased, albeit to a much lesser extent than that associated with the use of other antithrombotic drugs, such as anticoagulants or thromobolytic agents. In addition, it must be noted that the increased incidence of haemorrhagic stroke is usually outweighed by a significant decrease in the incidence of ischaemic strokes. The combination of aspirin and vitamin K antagonists may be associated with the heightened risk of cerebral haemorrhage, compared to treatment with either drug alone.

Topics: Acute Coronary Syndrome; Aspirin; Cerebral Hemorrhage; Clinical Trials as Topic; Humans; Intracranial Hemorrhages; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Vitamin K

Current understanding of oral anticoagulant treatment and related intracerebral haemorrhage remains rather limited as compared to that of spontaneous intracerebral haemorrhage. Although intracerebral haemorrhage is the most serious complication of oral anticoagulant treatment, standardized treatment guidelines are still lacking. The currently employed treatments are aimed at normalization of the iatrogenic coagulation impairment, and are not based on randomized controlled trials evidence. Since most patients with oral anticoagulant treatment-intracerebral haemorrhage are at high risk of cardio-embolism and often myocardial infarction, it is uncertain whether the use of procoagulant treatments for oral anticoagulant treatment-intracerebral haemorrhage may increase their risk of thrombotic complications. Patients who receive chronic oral anticoagulant treatment urgently require effective treatments for acute oral anticoagulant treatment-intracerebral haemorrhage, and therefore controlled clinical trials are needed.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Clinical Trials as Topic; Factor VIIa; Hematoma; Humans; Iatrogenic Disease; Plasma; Prothrombin; Recombinant Proteins; Risk; Risk Factors; Vitamin K

Life-threatening intracranial hemorrhage, predominantly intracerebral hemorrhage (ICH), is the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. Early intervention focuses on rapid correction of coagulopathy in order to prevent continued bleeding.. This article reviews the epidemiology of OAT-associated ICH (OAT-ICH), and current treatment options, with the aim of providing a framework for future studies of unresolved questions. A number of acute treatments are available, but all have a significant risk of inducing thrombosis and other side effects, and vary in their rapidity of effect: vitamin K (very slow response time), fresh frozen plasma (slow response time, large volume of fluid required, transfusion-related acute lung injury), prothrombin complex concentrates, and recombinant activated factor VII. Current practice is to administer a combination of vitamin K and either fresh frozen plasma or prothrombin complex concentrates; the occasional use of recombinant activated factor VII has been reported. No prospective study has addressed the efficacy of, or outcomes from, the use of these practices.. Current management of OAT-ICH is varied and not based on evidence from randomized controlled trials. Well-designed clinical trials are essential if we are to identify the effective acute treatments for OAT-ICH that are urgently needed.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Clinical Trials as Topic; Factor VIIa; Hemorrhage; Humans; Recombinant Proteins; Risk; Thrombosis; Vitamin K

To elucidate predisposing factors for enlargement of intracerebral hematoma (ICH) during warfarin therapy, we reviewed 47 patients on warfarin who developed acute ICH and determined relationships among ICH enlargement, INR reversal and clinical data. Among 36 patients treated to counteract the effects of warfarin within 24 h of onset, ICH increased in 10 patients (enlarged group), but remained unchanged in the remaining 26 (unchanged group), while ICH remained unchanged in another 11 patients in whom the effect of warfarin was reversed after 24 h. The international normalized ratio (INR) was counteracted immediately in 11 patients treated with prothrombin complex concentrate (PCC) but gradually in the other 36 treated by reducing the dose of warfarin, or by administering vitamin K or fresh frozen plasma. Multivariate analysis with a logistic regression model showed an INR value <2.0 at admission or for 24 h after immediate INR correction with PCC prevented ICH enlargement (OR 0.069, 95%CI 0.006-0.789, p = 0.031). An INR value of >2.0 within 24 h of ICH seems an important predisposing factor for ICH enlargement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Diabetes Mellitus; Disease Progression; Female; Humans; Hypercholesterolemia; Hypertension; International Normalized Ratio; Liver Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

Preterm infants are at risk of periventricular haemorrhage. This can be a sign of brain damage that might lead to neurodevelopmental abnormalities, including cerebral palsy. It has been suggested that vitamin K might improve coagulation in preterm infants.. The objective of this review was to assess the effects of vitamin K administered to women at risk of imminent very preterm birth to prevent periventricular haemorrhage and associated neurological injury in the infant.. We searched the Cochrane Pregnancy and Childbirth Group trials register, Cochrane Controlled Trials Register, and bibliographies up to September 2000.. Randomised or quasi-randomised trials of vitamin K administered parenterally or orally to women at risk of imminent preterm birth. The primary outcomes were neonatal mortality, neonatal neurological morbidity, as measured by the presence of periventricular haemorrhage (PVH) on ultrasound during the first week of life, and long term neurodevelopment. Secondary outcomes included other neonatal morbidity and any maternal side effects.. Eligibility, trial quality assessment and data extraction were done independently by two reviewers.. Five trials were included, involving more than 420 women. The trials were of variable quality. Antenatal vitamin K was associated with a non-significant trend to a reduction in all grades of periventricular haemorrhage (relative risk (RR) 0.82, 95% confidence interval (CI) 0.67-1.00) and in severe PVH (grades 3 and 4) (RR 0.75, 95% CI 0.45-1.25) for babies receiving prenatal vitamin K compared with control babies. This trend disappeared when poorer quality trials were excluded. Information on neurodevelopment was only given for a small sample of children in one trial with discrepancy in results given in the two reports.. Vitamin K administered to women prior to very preterm birth has not been shown to significantly prevent periventricular haemorrhages in preterm infants.

Topics: Antifibrinolytic Agents; Cerebral Hemorrhage; Cerebral Ventricles; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Obstetric Labor, Premature; Pregnancy; Randomized Controlled Trials as Topic; Vitamin K

Preterm infants are at risk of periventricular haemorrhage. This can damage the brain and lead to neurodevelopmental abnormalities, including cerebral palsy. It has been suggested that vitamin K might improve coagulation in preterm infants.. The objective of this review was to assess the effects of vitamin K administered to women at risk of imminent very preterm birth to prevent periventricular haemorrhage and associated neurological injury in the infant.. We searched the Cochrane Pregnancy and Childbirth Group trials register, Cochrane Controlled Trials Register, and bibliographies up to January 1999.. Randomised or quasi-randomised trials of vitamin K administered parenterally or orally to women at risk of imminent preterm birth. The primary outcomes were neonatal mortality, neonatal neurological morbidity, as measured by the presence of periventricular haemorrhage (PVH) on ultrasound during the first week of life, and long term neurodevelopment. Secondary outcomes included other neonatal morbidity and any maternal side effects.. Eligibility, trial quality assessment and data extraction were done independently by two reviewers.. Five trials were included, involving more than 420 women. The trials were of variable quality. Antenatal vitamin K was associated with a non-significant trend to a reduction in all grades of periventricular haemorrhage (relative risk (RR) 0.82, 95% confidence interval (CI) 0.67-1.00) and in severe PVH (grades 3 and 4) (RR 0.75, 95% CI 0.45-1.25) for babies receiving prenatal vitamin K compared with control babies. This trend disappeared when poorer quality trials were excluded. Information on neurodevelopment was given for a small sample of children in one trial and no differences were seen.. Vitamin K administered to women prior to very preterm birth does not appear to be able to significantly prevent periventricular haemorrhages in preterm infants.

Topics: Cerebral Hemorrhage; Cerebral Ventricles; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Obstetric Labor, Premature; Pregnancy; Vitamin K

In comparison with the incidence of cerebrovascular accident in the general population, atrial fibrillation increases the risk by a factor of five. Although age is without doubt the main risk factor for cerebrovascular accidents in patients with permanent of paroxysmal non-valvular atrial fibrillation, other independent risk factors have been identified: a previous history of hypertension, cerebrovascular accident, heart failure or diabetes. These factors enable identification of a population at risk in which oral anticoagulation may be recommended with an excellent efficacy/risk ratio. Six large scale randomised controlled multicenter trials of primary prevention have been published with a total of over 2,800 patients with non-valvular atrial fibrillation. The combined results of these trials show that treatment with vitamin K antagonist (INR 2-3) leads to a significant reduction in the risk of an ischaemic cerebrovascular accident of 64% (95% CI [51-74]; p < 0.001) and in the risk of death from all causes of 28% (95% CI [12-47]; p = 0.038) with a slight increase in the risk of cerebral haemorrhage (+ 2.7% NS). Although the benefits of aspirin therapy are not as impressive (reduction of the risk of an ischaemic cerebrovascular accident of 22%; 95% CI [0-39]; p = 0.053), this alternative may be proposed in patients under 75 years of age without the previously mentioned risk factors. The value of combined aspirin-oral anticoagulant therapy, especially in high risk patients, has not yet been established and is under evaluation.

Topics: Adult; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Middle Aged; Platelet Aggregation Inhibitors; Primary Prevention; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

Vitamin K is a fat-soluble vitamin crucial to the production of many proteins involved with the coagulation process. It is integral in the synthesis of coagulants (factors II, VII, IX and X) and anticoagulants (proteins C and S). It is generally recognised that routine administration of vitamin K (phytomenadione) shortly after birth will prevent major neonatal morbidity and mortality related to haemorrhage. Vitamin K supplementation during pregnancy is also recommended if mothers are on anticonvulsant therapy or prolonged treatment with certain antibiotics. These medications, if ingested by pregnant women, predispose the neonate to a bleeding tendency caused by vitamin K deficiency. Vitamin K treatment of pregnant mothers before premature delivery has also been suggested to reduce the incidence of severe intracranial haemorrhage (ICH) in premature neonates. Although further studies are pending, the data to date do not support using antenatal vitamin K for preventing ICH.

Topics: Anticonvulsants; Cerebral Hemorrhage; Epilepsy; Female; Hemorrhage; Humans; Infant, Newborn; Infant, Premature, Diseases; Leukemia; Placenta; Pregnancy; Pregnancy Complications; Vitamin K; Vitamin K Deficiency

Hemorrhage in the infant from vitamin K deficiency is still a concern in pediatrics. Vitamin K given intramuscularly will largely prevent hemorrhagic disease in the newborn, even in infants who are exclusively breast-fed and are thus at the greatest risk for bleeding. The vitamin K content of human milk is very low compared with standard infant formulas. Results with oral vitamin K prophylaxis, currently used in some countries following the association found in a single report between childhood cancer and intramuscular vitamin K, are far more controversial. Any role of vitamin K in the prevention of IVH in premature infants has not been sufficiently demonstrated. Ongoing developments in this field will lead to improved methods of detecting early vitamin K deficiency and perhaps suitable alternatives to intramuscular vitamin K prophylaxis in the newborn.

Topics: Cerebral Hemorrhage; Humans; Infant, Newborn; Infant, Premature, Diseases; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Cerebral haemorrhage is the main life-threatening complication of oral anticoagulant therapy. In order to identify a means of prevention, the authors undertook a retrospective study of 68 consecutive cases of anticoagulant-related intracerebral haemorrhage. The mortality was 38.5%. The respective frequency of intracerebral haemorrhage, subarachnoid haemorrhage, acute and chronic subdural haematomas was 63.2, 16.2, 10.3 and 10.3%, respectively. On admission, nearly half the patients (53%) had prothrombin ratios inferior to 25%. A predisposing factor was found in 58% of cases: hypertension (30.6%), head injury (14.5%), alcoholism or drug interaction (11.2%), and one case of intracerebral aneurysm. A history of a transient ischaemic attack or of a cerebrovascular accident was found in 10.2% of cases and 11.7% had a previous anticoagulant related extracranial haemorrhage. The initial indications for oral anticoagulation were ischaemic heart disease (32%), atrial fibrillation (20.5%), secondary prevention of venous thromboembolic disease (17.6%) and primary prevention of venous thrombosis (11.7%). The duration of treatment for isolated ischaemic heart disease was over 6 months in all cases: the average duration of treatment was 12.4 months in phlebitis and pulmonary embolism. A critical review of the indications of treatment in the light of recent recommendations showed that if inappropriate indications were rare, the sometimes unnecessary prolongation of treatment was more common. Nearly half of these cases were receiving anticoagulants when the potential benefits were questionable at the time of the haemorrhagic complication. Clinical and biological follow-up is necessary for patients on anticoagulants; minor bleeding complications may be the prelude to major haemorrhage. Biological follow-up is based on control of the international normalised ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Hydroxycoumarins; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Indenes; Male; Middle Aged; Risk Factors; Vitamin K

More than ten years ago, vitamin E supplementation was proposed as a prophylaxies against a syndrome that might be caused by oxygen toxicity and/or membrane instability such as retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and periventricular/intraventricular hemorrhage (PVH/IVH). The results obtained from several studies to date does not support the usefulness of vitamin E supplements in the prevention of BPD. However, several reports have suggested the utility of vitamin E in the prevention and/or inhibition of progress of ROP, although the use of vitamin E in premature infants for the possible prevention of severe ROP should still be considered investigational. On the other hand, the aggregate of evidence to date support the efficacy of tocopherol in preventing IVH of extremely premature infants. It is postulated that oxidative damage to capillary endothelial membranes of the subependymal layer predisposed the premature infant to subependymal bleeding and that vitamin E might act as an antioxidant to prevent such damage, thereby reducing the risk of hemorrhage.

Topics: Cerebral Hemorrhage; Humans; Infant, Newborn; Infant, Premature, Diseases; Retinopathy of Prematurity; Vitamin E; Vitamin K

Based on a case history of fetal haemorrhage due to maternal antiepileptic treatment and a review of 40 previously described similar cases, it is recommended that epileptic mothers receive vitamin K tablets throughout the month before delivery and intravenously during labour. It is further recommended that phytomenadione should be administered intravenously to the infant immediately after birth. Cord blood specimens should be submitted for immediate clotting studies and if diminished vitamin K-dependent factors are found, fresh frozen plasma should be given at a dose of 20 ml/kg over a period of 1-2 h. Alternatively, the drug treatment of women with epilepsy during pregnancy could be changed from liver enzyme inducing drugs to clonazepam, which is a benzodiazepine without liver enzyme-inducing properties. Further, no malformations have been reported in connection with this drug.

Topics: Adult; Blood Coagulation Tests; Cerebral Hemorrhage; Epilepsy; Epilepsy, Complex Partial; Epilepsy, Generalized; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Vitamin K

Periventricular-intraventricular hemorrhage is an important problem, resulting in significant mortality and morbidity. Attempts to reduce this complication require an understanding of its pathogenesis. In this chapter a model was proposed, consisting of a series of events resulting in rapid changes of cerebral blood flow and intracranial pressure and leading to rupture of the unique fragile vessels of the germinal matrix and intraventricular regions. Understanding the beneficial physiologic changes induced by such agents such as phenobarbital and vitamin K and that such pharmacologic therapy must be started during the antenatal period has resulted in significant reductions of severe grades of IVH. Further prospective studies are needed to confirm these results using these two drugs alone and in combination. Other potentially beneficial drugs such as indomethacin should be investigated. Although the benefits of such therapy may improve perinatal outcome, the emphasis in our discipline should be the continued attempt to prevent the delivery of these VLBW infants.

Topics: Cerebral Hemorrhage; Female; Humans; Indomethacin; Infant, Newborn; Phenobarbital; Pregnancy; Prenatal Care; Risk Factors; Vitamin K

Topics: Antihypertensive Agents; Blood Coagulation Disorders; Cerebral Hemorrhage; Erythroblastosis, Fetal; Ethamsylate; Female; Humans; Hypertension; Immunoglobulins; Infant, Newborn; Phenobarbital; Plasmapheresis; Pregnancy; Rho(D) Immune Globulin; Vitamin K; Vitamin K Deficiency

Topics: Breast Feeding; Cerebral Hemorrhage; Child; Child, Preschool; Factor IX; Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Infant, Newborn, Diseases; Liver Function Tests; Prothrombin; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Angina Pectoris; Arteriosclerosis; Blood Coagulation; Cerebral Hemorrhage; Chemical Phenomena; Chemistry; Coumarins; Drug Antagonism; Drug Synergism; Female; Hemorrhage; Humans; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Myocardial Infarction; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Thrombophlebitis; Vitamin K

Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested.. The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62).. Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.

Topics: Aged; Atrial Fibrillation; Catheter Ablation; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Postoperative Hemorrhage; Pyridines; Stroke; Thiazoles; Vitamin K

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Germany; Humans; Male; Retrospective Studies; Vitamin K

Intracerebral hemorrhage (ICH) is a life-threatening complication of non-vitamin K antagonist oral anticoagulants (NOAC). Little is known about the effect of intensity of anticoagulation on NOAC-ICH. We describe the current use of coagulation testing in the emergency setting and explore associations with baseline size and expansion of hematoma as determined in a previous study.. Data from the prospective multicenter RASUNOA registry were analyzed. Patients with NOAC-ICH were enrolled between February 2012 and December 2014. Frequency of local test performance of specific (anti-factor Xa tests, diluted thrombin time) and non-specific tests (international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time) was analyzed. The association of anticoagulation intensity at admission with hematoma volume and hematoma expansion was explored.. In 61 NOAC-ICH patients enrolled at 21 centers, drug-specific coagulation testing was performed in 16 cases (26%), and only 29% of centers appeared to use drug-specific tests in NOAC-ICH at all. In some cases, INR and aPTT values were normal despite drug concentrations in the peak range. In patients with available drug-specific concentrations, 50% had drug levels in the peak range at admission. Higher intensity of anticoagulation was not associated with higher hematoma volume at admission or with subsequent hematoma expansion.. Drug-specific tests are only infrequently used in NOAC-ICH. Normal results in non-specific coagulation do not reliably rule out peak range concentrations. Anticoagulation intensity at admission does not predict baseline hematoma volume or subsequent hematoma expansion.

Topics: Aged; Aged, 80 and over; Antithrombins; Blood Coagulation Tests; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Registries; Stroke; Vitamin K

Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin.. The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding.. The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category.. Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Contraindications; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Factors; Stroke; Vitamin K; Warfarin

The objective of this paper is to determine if phenobarbital exposure during pregnancy affects developmental outcome at age 2 years. Between 1991 and 1994, 401 pregnant patients at risk for delivery prior to 34 weeks' gestation were invited to participate; 48 mothers declined entry. Before delivery, pharmacy randomized the pregnant women to receive phenobarbital and vitamin K or identically appearing placebo in a blinded fashion. Developmental follow-up at age 2 years was performed. Children from the treatment group scored significantly lower on the Bayley Mental Developmental Index (mean MDI +/- 1 SD) than children whose mothers were randomized to the placebo group [104 +/- 21 (n = 59) vs. 113 +/- 22 (n = 62), p = 0.023]. Of 36 independent variables, randomization group was one of five that individually contributed to the prediction of the Bayley MDI score (p < 0.05). It was concluded that perinatal phenobarbital therapy may impair developmental outcome.

Topics: Adult; Anticonvulsants; Central Nervous System Depressants; Cerebral Hemorrhage; Chi-Square Distribution; Child Development; Child, Preschool; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intelligence; Motor Skills; Phenobarbital; Placebos; Pregnancy; Prenatal Exposure Delayed Effects; Regression Analysis; Risk Factors; Vitamin K

ōk--q----_xD-xD whether maternal antenatal therapy with vitamin K and phenobarbital prevents intracranial hemorrhage in premature newborns.. Women at high risk for spontaneous or indicated premature delivery before 34 weeks' gestation were randomly assigned to receive either placebo or vitamin K and phenobarbital. All patients received betamethasone and antibiotics and were managed uniformly by a single perinatal group in one hospital. All newborns were managed uniformly in the same nursery by one neonatal group. Two independent interpretations of neonatal head ultrasound examinations were obtained.. The duration of gestation at study entry and at delivery were similar in the placebo (181 mothers) and treatment (191) groups. With the hospital radiology group (the primary interpreter), the incidence rates of severe intracranial hemorrhage (8 versus 7%) and mild intracranial hemorrhage (38 versus 32%) were similar for both groups. With the secondary interpreter (a single pediatric radiologist), the incidence rates of severe intracranial hemorrhage (9 versus 7%) and mild intracranial hemorrhage (27 versus 26%) were also similar. Neonatal mortality was equivalent in both the placebo and treatment groups (8 versus 10%).. Combined antenatal therapy with vitamin K and phenobarbital does not reduce the frequency or severity of intracranial hemorrhage in premature newborns.

Topics: Adolescent; Adult; Algorithms; Cerebral Hemorrhage; Double-Blind Method; Drug Therapy, Combination; Female; Gestational Age; Humans; Incidence; Infant, Newborn; Infant, Premature, Diseases; Phenobarbital; Pregnancy; Prenatal Care; Severity of Illness Index; Vitamin K

Topics: Cerebral Hemorrhage; Diseases in Twins; Double-Blind Method; Humans; Infant, Newborn; Infant, Premature, Diseases; Phenobarbital; Randomized Controlled Trials as Topic; Vitamin K

To determine whether antepartum phenobarbital and vitamin K reduce the risk of intraventricular hemorrhage in premature newborns.. Patients at imminent risk for spontaneous or indicated premature delivery between 24-34 weeks' gestation were randomized to receive either placebo or vitamin K and phenobarbital. All patients received betamethasone and antibiotics and were managed uniformly by a single perinatal group in one hospital. All newborns were managed uniformly in the same facility by a single neonatal group.. There was a nonsignificant reduction in all grades of intraventricular hemorrhage in the treatment group when compared to the placebo group (48.2 versus 38.3%; P > .05). Frequencies were reduced for severe intraventricular hemorrhage (grades 3 and 4) (6.0 versus 2.5%; P > .05) and mild intraventricular hemorrhage (grades 1 and 2) (42.2 versus 35.8%; P > .05).. Antepartum phenobarbital and vitamin K effected a nonsignificant reduction in both mild and severe intraventricular hemorrhage. The incidence of severe intraventricular hemorrhage in our control group was significantly less than that observed in previous studies.

Topics: Cerebral Hemorrhage; Double-Blind Method; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Phenobarbital; Pregnancy; Prenatal Care; Vitamin K

The purpose of our study was to determine whether maternal vitamin K1 administered antenatally improved global coagulation parameters and the levels of specific vitamin K-dependent proteins in low-birth-weight infants.. Thirty-three preterm mothers admitted in labor were assigned in a prospective, blinded fashion to receive either intramuscular vitamin K1 (17) or placebo (16). At delivery cord blood samples were tested for prothrombin time, activated partial thromboplastin time, factor II and protein C activity, and antigen levels. Statistical analysis was by Student t test.. No statistically significant differences could be demonstrated with regard to group mean values for global tests (prothrombin time, activated partial thromboplastin time) or specific vitamin K-dependent protein levels (factor II, protein C) in newborns whose mothers received antenatal vitamin K compared with those who did not.. These results would suggest that antenatal vitamin K1 therapy to mothers < 32 weeks' gestation has no significant effect on the level of vitamin K-dependent factors in the fetus.

Topics: Adolescent; Adult; Antigens; Blood Coagulation; Blood Coagulation Disorders; Cerebral Hemorrhage; Double-Blind Method; Female; Fetal Blood; Humans; Infant, Low Birth Weight; Infant, Newborn; Injections, Intramuscular; Maternal-Fetal Exchange; Obstetric Labor, Premature; Partial Thromboplastin Time; Pregnancy; Prospective Studies; Protein C; Prothrombin; Prothrombin Time; Vitamin K

The effect of maternal administration of vitamin K1 on cord blood prothrombin time, activated partial thromboplastin time, activity of factors II, VII, and X, and antigen levels of factors II and X in infants less than 35 weeks' gestation was evaluated. Pregnant women in preterm labor were randomly assigned to receive 10 mg of vitamin K1 intramuscularly or no injection. If delivery did not occur in 4 days, the dose of vitamin K1 was repeated. Women who continued their pregnancy 4 days beyond the second dose received 20 mg of vitamin K1 orally daily until the end of the 34th week of gestation. The birth weights of infants ranged from 370 to 2550 g and gestational age ranged from 22 to 34 weeks. The prothrombin time, activated partial thromboplastin time, factors II, VII, and X activity, and factors II and X antigen levels were not statistically different in either group of infants. Intraventricular hemorrhage occurred in 25 of 51 control infants and 25 of 47 vitamin K-treated infants. More control infants had grade III intraventricular hemorrhage on day 1 (P = .032), but on day 3 and 14 of life, the severity of intraventricular hemorrhage was comparable in both groups. Infants in whom an intraventricular hemorrhage developed were significantly smaller, younger, and more critically ill than infants without intraventricular hemorrhage. Administration of vitamin K1 to pregnant women at less than 35 weeks' gestation does not improve the hemostatic defects nor does it reduce the incidence or severity of intraventricular hemorrhage in their infants.

Topics: Blood Coagulation; Cerebral Hemorrhage; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Maternal-Fetal Exchange; Pregnancy; Prenatal Care; Prospective Studies; Random Allocation; Vitamin K

To establish the effect of antenatal vitamin K on the incidence and severity of intraventricular hemorrhage, 92 patients destined to deliver infants less than 32 weeks' gestation were, in a prospective fashion, randomly assigned to two groups. Group I received 10 mg of vitamin K1 intramuscularly every 5 days until delivery. Group II received no antenatal vitamin K1 therapy. There were 100 neonates less than 1500 gm, equally divided between groups I and II with respect to gestational age, birth weight, race, sex, presentation, route of delivery, duration of labor, Apgar scores, and arterial umbilical cord acid-base balance. The antenatal use of vitamin K resulted in significant reduction in the prothrombin time (12.7 versus 15.2 seconds) and partial thromboplastin time (42.6 versus 58.9 seconds; p less than 0.05). Furthermore, group I experienced a lower incidence of total (16% versus 36%) and severe (0% versus 11%) grades of intraventricular hemorrhage (p less than 0.05). This study suggests that the antenatal use of vitamin K may result in a reduction and severity of intraventricular hemorrhage in the neonate less than 1500 gm.

Topics: Blood Coagulation; Cerebral Hemorrhage; Female; Humans; Infant, Newborn; Pregnancy; Prenatal Care; Prospective Studies; Random Allocation; Respiratory Distress Syndrome, Newborn; Vitamin K

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Female; Gastrointestinal Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Thromboembolism; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Anticoagulant treatment increases the risk of intracerebral hemorrhage (ICH), but whether the treatment, more specifically non-vitamin K oral anticoagulants (NOACs), increases the risk of cerebral microbleeds (CMBs) remains uncertain. We performed this study to investigate the development of new CMBs due to NOACs or warfarin treatment in patients with atrial fibrillation (AF).We prospectively recruited AF patients before anticoagulation from June 2016 to June 2018. We performed susceptibility-weighted imaging (SWI) examinations on all enrolled AF patients and re-examined SWI 1 year later. We compared demographic features and new CMBs between the NOACs group and the warfarin group. Univariate analysis of clinical factors was performed according to the development of new CMBs; and age, a HAS-B(L)ED score, warfarin use, and the presence of baseline CMBs were then selected for inclusion in the multivariate logistic regression model.A total of 72 AF patients were recruited, 29 of whom were assigned to the NOACs group and 43 to the warfarin group. Finally, 1 patient in the NOACs group (3.4%) and 9 patients (20.9%) in the warfarin group developed new CMBs after 1 year follow-up (P = .08). Univariate analysis showed that age, a HAS-B(L)ED score ≥4, the presence of baseline CMBs were associated with the development of new CMBs (P < .05). And multivariate regression analysis showed baseline CMBs (P = .03, odds ratio = 6.37, 95% confidence interval 1.15-35.36) was independently related to the increase in new CMBs.AF patients treated with NOACs may have a decreased trend in the development of new CMBs compared with those treated with warfarin. Baseline CMBs increased the frequency of new CMBs during anticoagulant treatment. The development of new CMBs in AF patients with anticoagulation requires further longitudinal studies with longer follow-up in larger samples.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Follow-Up Studies; Humans; Vitamin K; Warfarin

This study aimed to determine the impact of the approval of prothrombin complex concentrates on the treatment of vitamin K antagonist-related intracerebral hemorrhage.. We retrospectively studied all patients with vitamin K antagonist-related intracerebral hemorrhage treated with prothrombin complex concentrate at our institutes between January 2010 and June 2021. Before approval, prothrombin complex concentrate was administered as either 500 or 1000 IU at the physician's discretion (previous dose group). After approval, we adopted the manufacturer's recommended regimen (recommended dose group). The primary outcome was post-administration international normalized ratio. Secondary outcomes were the amount of prothrombin complex concentrate administered and proportion of post-administration international normalized ratio <1.5, hematoma expansion, thrombotic events within 30 days, modified Rankin scale 0-3 at discharge, and in-hospital mortality.. Thirty-two and 19 patients in the previous and recommended dose groups, respectively, were included. The post-administration international normalized ratio significantly differed between groups. The prothrombin complex concentrate dose and proportion of patients achieving post-administration international normalized ratio <1.5 were significantly higher in the recommended dose group than in the previous dose group (1500 IU vs. 500 IU, p<0.001 and 100% vs. 68%, p = 0.008). The proportions of hematoma expansion, thromboembolic events, modified Rankin scale 0-3, and mortality did not differ between groups.. After prothrombin complex concentrate approval, prothrombin time-international normalized ratio correction was more effective with a significant increase in the prothrombin complex concentrates dose for vitamin K antagonist-associated intracerebral hemorrhage; however, there was no apparent difference in clinical outcomes.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Fibrinolytic Agents; Hematoma; Humans; International Normalized Ratio; Prothrombin; Retrospective Studies; Vitamin K

This study determined the influence of age on bleeding characteristics and clinical outcomes in primary spontaneous (non-OAC), vitamin K antagonist-related (VKA-) and non-vitamin K antagonist oral anticoagulant-related (NOAC-) ICH.. Pooled individual patient data of multicenter cohort studies were analyzed by logistic regression modelling and propensity-score-matching (PSM) to explore the influence of advanced age on clinical outcomes among non-OAC-, VKA-, and NOAC-ICH. Primary outcome measure was functional outcome at three months assessed by the modified Rankin Scale, dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6) functional outcome. Secondary outcome measures included mortality, hematoma characteristics, and frequency of invasive interventions.. In VKA-ICH 33.5% (670/2001), in NOAC-ICH 44.2% (69/156) and in non-OAC-ICH 25.2% (254/1009) of the patients were ≥80 years. After adjustment for treatment interventions and relevant parameters, elderly ICH patients comprised worse functional outcome at three months (adjusted odds ratio (aOR) in VKA-ICH: 1.49 (1.21-1.84); p < 0.001; NOAC-ICH: 2.01 (0.95-4.26); p = 0.069; non-OAC-ICH: 3.54 (2.50-5.03); p < 0.001). Anticoagulation was significantly associated with worse functional outcome below the age of 70 years, (aOR: 2.38 (1.78-3.16); p < 0.001), but not in patients of ≥70 years (aOR: 1.21 (0.89-1.65); p = 0.217). The differences in initial ICH volume and extent of ICH enlargement between OAC-ICH and non-OAC-ICH gradually decreased with increasing patient age.. As compared to elderly ICH-patients, in patients <70 years OAC-ICH showed worse clinical outcomes compared to non-OAC-ICH because of larger baseline ICH-volumes and extent of hematoma enlargement. Treatment strategies aiming at neutralizing altered coagulation should be aware of these findings.

Topics: Administration, Oral; Aged; Anticoagulants; Cerebral Hemorrhage; Hematoma; Humans; Stroke; Vitamin K

The impact of platelets on hematoma enlargement (HE) of intracerebral hemorrhage (ICH) is not yet sufficiently elucidated. Especially the role of reduced platelet counts on HE and clinical outcomes is still poorly understood. This study investigated the influence of thrombocytopenia on HE, functional outcome, and mortality in patients with ICH with or without prior antiplatelet therapy (APT).. Our study implies that thrombocytopenia does not affect rates of HE and functional outcome among ICH patients, neither in patients with nor without APT. In light of increased mortality, the significance of platelet transfusions for ICH patients with thrombocytopenia and previous APT should be explored in future studies.

Topics: Aged; Aged, 80 and over; Cerebral Hemorrhage; Cohort Studies; Female; Germany; Humans; Male; Platelet Aggregation Inhibitors; Platelet Count; Propensity Score; Retrospective Studies; Thrombocytopenia; Treatment Outcome; Vitamin K

Management of warfarin-associated intracerebral hemorrhage (ICH) necessitates rapid reversal of anticoagulation. Guideline-based management of warfarin-associated ICH includes timely administration of prothrombin complex concentrate (PCC) and intravenous (IV) vitamin K. In 2017, our hospital implemented an order set for warfarin reversal to facilitate computerized provider order entry (CPOE), and the pharmacy department began prospective verification and dispensing of all PCC orders for anticoagulant reversal. We sought to compare the proportion of patients who received timely, guideline-based therapy for warfarin-associated ICH before and after these changes. We conducted a single-center, retrospective cohort study of all warfarin-associated ICH patients who had an order for PCC. A total of 66 patients were included; 32 patients (pre-intervention cohort) were evaluated in the 2 year period prior to the process improvement changes, while 34 patients (post-intervention cohort) were evaluated in the 2 year period following these changes. Baseline characteristics were similar between groups. The proportion of patients receiving timely guideline-based therapy was significantly higher in the post-intervention cohort compared to the pre-intervention cohort (76.5% vs 34.4%, p < 0.001), primarily driven by increased ordering of vitamin K 10 mg IV in conjunction with PCC in the post-intervention cohort. Our results indicate that implementation of an order set to assist with CPOE, in addition to prospective pharmacist verification of PCC orders, leads to increased adherence to guideline-based management of warfarin-associated ICH.

Topics: Anticoagulants; Anticoagulation Reversal; Blood Coagulation Factors; Cerebral Hemorrhage; Humans; International Normalized Ratio; Pharmacists; Prospective Studies; Retrospective Studies; Vitamin K; Warfarin

Spontaneous intracerebral haemorrhage associated with oral anticoagulants (ICH-OAC) has a high mortality rate. The emergence of new anticoagulant drugs and reversal protocols increases interest in this entity.. The main objective is to determine the mortality rate in patients with ICH-OAC (early, in-hospital, global) in our health area and to analyse the main variables related to it. The secondary objective is to determine the efficacy of anticoagulation reversal therapies (ART) as reflected by radiological expansion of the haematoma and the functional prognosis.. A prospective observational study that introduced a protocol aimed at the management of patients with ICH-OAC. It included general measures and neuromonitoring, individualised administration of ART, cranial tomography and a six-month follow-up. Data on the drugs prescribed in the area during this period, mortality and functional prognosis were collected. A bivariate and logistic regression study was designed to investigate mortality-related variables.. Forty-nine patients were included over three years; of these, 71.4% received ART. Mortality was 16.3% (first 24 hours), 53.1% (admission) and 61.2% (180 days). Lower survival was observed among patients with higher baseline scores on the National Institutes of Health Stroke Scale (NIHSS) (p < 0.0001), creatinine value (p = 0.02), International Normalised Index (p = 0.048), bleeding volume (p = 0.008), hydrocephalus (p = 0.015) and acenocoumarol intake (p = 0.030). Patients who did not receive ART had a greater rate of early mortality (p = 0.003). The only variable independently related to overall mortality was the baseline NIHSS score (odds ratio = 1.282; 95% confidence interval: 1.023-1.608; p = 0.031).. ICH-OAC has a high mortality rate, related to the use of acenocoumarol and regardless of the initial clinical situation. A lower rate of early mortality was found among patients who received ART.. Mortalidad en pacientes con hemorragia intracerebral asociada a anticoagulación oral. Eficacia de un protocolo de reversión y seguimiento clínico (proyecto HIC-ACO).. Introducción. La hemorragia intracerebral espontánea asociada a anticoagulantes orales (HIC-ACO) presenta una elevada mortalidad. La aparición de nuevos fármacos anticoagulantes y protocolos de reversión aumenta el interés por esta entidad. Objetivos. El objetivo principal es determinar la tasa de mortalidad en pacientes con HIC-ACO (precoz, hospitalaria, global) en nuestra área sanitaria y analizar las principales variables relacionadas. El objetivo secundario es determinar la eficacia de las terapias de reversión de la anticoagulación (TRA), reflejada por la expansión radiológica del hematoma y el pronóstico funcional. Pacientes y métodos. Estudio prospectivo observacional que introdujo un protocolo dirigido al manejo de pacientes con HIC-ACO. Incluyó medidas generales y neuromonitorización, administración individualizada de TRA, tomografía craneal y seguimiento durante seis meses. Se recogieron los fármacos prescritos en el área durante este período, mortalidad y pronóstico funcional. Se diseñó un estudio bivariante y regresión logística para investigar variables relacionadas con la mortalidad. Resultados. Se incluyó a 49 pacientes durante tres años; de ellos, un 71,4% recibió TRA. La mortalidad fue del 16,3% (primeras 24 horas), el 53,1% (ingreso) y el 61,2% (180 días). Se observó una menor supervivencia entre pacientes con puntuaciones basales mayores en la National Institutes of Healt Stroke Scale (NIHSS) (p lower than 0,0001), valor de creatinina (p = 0,02), índice internacional normalizado (p = 0,048), volumen hemorrágico (p = 0,008), hidrocefalia (p = 0,015) y toma de acenocumarol (p = 0,030). Los pacientes que no recibieron TRA tuvieron una mayor mortalidad precoz (p = 0,003). La única variable relacionada con la mortalidad global de forma independiente fue la puntuación en la NIHSS basal (odds ratio = 1,282; intervalo de confianza al 95%: 1,023-1,608; p = 0,031). Conclusiones. La HIC-ACO presenta una elevada mortalidad, relacionada con la toma de acenocumarol y de forma independiente con la situación clínica inicial. Se comprobó una menor tasa de mortalidad precoz entre pacientes que recibieron TRA.

Topics: Aged; Aged, 80 and over; Anticoagulants; Anticoagulation Reversal; Antidotes; Cerebral Hemorrhage; Clinical Protocols; Factor Xa Inhibitors; Female; Follow-Up Studies; Hospital Mortality; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neuroimaging; Prospective Studies; Severity of Illness Index; Tertiary Care Centers; Thromboembolism; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.

Topics: Aged; Anticoagulants; Antifibrinolytic Agents; Aortic Valve; Aspirin; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Heart Valve Prosthesis; Hematoma, Subdural; Humans; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Mitral Valve; Plasma; Platelet Aggregation Inhibitors; Pregnancy; Retrospective Studies; Subarachnoid Hemorrhage; Subarachnoid Hemorrhage, Traumatic; Thromboembolism; Vitamin K; Warfarin

Although intracerebral hemorrhage (ICH) score is used to provide an estimate on the probability of mortality following spontaneous ICH of any cause, its utility has not been exclusively tested in ICH patients with history of treatment with vitamin K antagonists (VKAs) or non-vitamin K oral anticoagulants (NOACs). The aim of the present report is to investigate the utility of ICH score for mortality prognostication of VKA-ICH and NOAC-ICH patients. We used receiver operating characteristic curve analyses to estimate the accuracy parameters for the different values of ICH score in the prognosis of mortality within 30-days after the onset of NOAC-ICH or VKA-ICH. We analyzed data from 108 NOAC-ICH and 241 VKA-ICH patients (median age 76 years, 58% males, median NIHSS score 11 points, median ICH-score 2 points). ICH score of 4 points was uncovered to be the most favorable threshold for the prediction of 30-day mortality both after NOAC-ICH (sensitivity: 57.7%, specificity: 98.8%) or VKA-ICH (sensitivity: 42.1%, specificity: 92.6%). However, comparison of the areas under the curve (AUC) suggested a cumulatively higher (p = .001) predictive value of ICH-score in the prognostication of 30-day mortality after ICH related to the use of NOACs (AUC: 0.92, 95%CI: 0.86-0.98) compared to the ICH related to the use of VKAs (AUC: 0.77, 95%CI: 0.70-0.83). In conclusion, ICH score seems to have an adequate predictive utility in the prognostication of 30-day mortality following an ICH related to the use of oral anticoagulants, with better yield in ICH cases associated with the use of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Humans; Internationality; Male; Mortality; Prognosis; Prospective Studies; Vitamin K

Four-factor prothrombin complex concentrate is the first-line treatment in vitamin K antagonist-related intracerebral haemorrhage. Early administration is associated with improved patient outcomes. A quality improvement project investigated delays in prothrombin complex concentrate administration in vitamin K antagonist-related intracerebral haemorrhage in order to reduce the time from computed tomography scan confirming intracerebral haemorrhage to prothrombin complex concentrate administration (scan-to-needle time).. Twenty patients were identified by retrospective audit over a 3-year period. The median scan-to-needle time for prothrombin complex concentrate was 156 minutes. Several points of delay were identified, including contacting both haematology and transfusion departments for prothrombin complex concentrate dosing and dispensing. Following this audit, interventions were brought in which included the introduction of a protocol with a prothrombin complex concentrate dosing algorithm, negating the need to contact haematology before administration. A dedicated supply of prothrombin complex concentrate was given to the stroke unit avoiding the need to contact the transfusion service.. A re-audit showed a 68% reduction in median scan-to-needle time from 156 minutes to 49 minutes. Prospective data collection is ongoing.

Topics: Aged; Aged, 80 and over; Algorithms; Blood Coagulation Factors; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Female; Humans; Male; Quality Improvement; Retrospective Studies; Time Factors; Tomography, X-Ray Computed; Vitamin K

Hematoma enlargement (HE) is associated with clinical outcomes after supratentorial intracerebral hemorrhage (ICH). This study evaluates whether HE characteristics and association with functional outcome differ in deep versus lobar ICH.. Pooled analysis of individual patient data between January 2006 and December 2015 from a German-wide cohort study (RETRACE, I + II) investigating ICH related to oral anticoagulants (OAC) at 22 participating centers, and from one single-center registry (UKER-ICH) investigating non-OAC-ICH patients. Altogether, 1954 supratentorial ICH patients were eligible for outcome analyses, which were separately conducted or controlled for OAC, that is, vitamin-K-antagonists (VKA, n = 1186) and non-vitamin-K-antagonist-oral-anticoagulants (NOAC, n = 107). Confounding was addressed using propensity score matching, cox regression modeling and multivariate modeling. Main outcomes were occurrence, extent, and timing of HE (>33%/>6 mL) and its association with 3-month functional outcome.. Occurrence of HE was not different after deep versus lobar ICH in patients with non-OAC-ICH (39/356 [11.0%] vs. 36/305 [11.8%], P = 0.73), VKA-ICH (249/681 [36.6%] vs. 183/505 [36.2%], P = 0.91), and NOAC-ICH (21/69 [30.4%] vs. 12/38 [31.6%], P = 0.90). HE extent did not differ after non-OAC-ICH (deep:+59% [40-122] vs. lobar:+74% [37-124], P = 0.65), but both patients with VKA-ICH and NOAC-ICH showed greater HE extent after deep ICH [VKA-ICH, deep: +94% [54-199] vs. lobar: +56% [35-116], P < 0.001; NOAC-ICH, deep: +74% [56-123] vs. lobar: +40% [21-49], P = 0.001). Deep compared to lobar ICH patients had higher HE hazard during first 13.5 h after onset (Hazard ratio [HR]: 1.85 [1.03-3.31], P = 0.04), followed by lower hazard (13.5-26.5 h, HR: 0.46 [0.23-0.89], P = 0.02), and equal hazard thereafter (HR: 0.96 [0.56-1.65], P = 0.89). Odds ratio for unfavorable outcome was higher after HE in deep (4.31 [2.71-6.86], P < 0.001) versus lobar ICH (2.82 [1.71-4.66], P < 0.001), and only significant after small-medium (1st volume-quarter, deep: 3.09 [1.52-6.29], P < 0.01; lobar: 3.86 [1.35-11.04], P = 0.01) as opposed to large-sized ICH (4th volume-quarter, deep: 1.09 [0.13-9.20], P = 0.94; lobar: 2.24 [0.72-7.04], P = 0.17).. HE occurrence does not differ among deep and lobar ICH. However, compared to lobar ICH, HE after deep ICH is of greater extent in OAC-ICH, occurs earlier and may be of greater clinical relevance. Overall, clinical significance is more apparent after small-medium compared to large-sized bleedings.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cerebral Intraventricular Hemorrhage; Cerebrum; Clinical Trials as Topic; Cohort Studies; Female; Germany; Hematoma; Humans; Male; Middle Aged; Registries; Single-Blind Method; Vitamin K

The application of non-vitamin K antagonist oral anticoagulant (NOAC) reduces the risk of intracerebral hemorrhage (ICH) in comparison with vitamin K antagonist (VKA). However, the features and outcomes of NOAC-associated ICH are still unclear, especially for Asian populations.. We retrospectively analyzed 49 consecutive patients who had spontaneous ICH while using NOAC or VKA. We compared the clinical characteristics, ICH volume, 7-day and 3-month mortality, and functional outcomes at discharge and 3 months post-stroke using the modified Rankin Scale (mRS) between NOAC- and VKA-associated ICH. The clinical features, ICH volume, ICH location, and/or treatment methods were statistically adjusted.. Among the 49 ICH patients, 15 (30.6%) were using NOAC and 34 (69.4%) were taking VKA. There were no significant differences in the initial ICH volume between groups (mean volume 34.2 ± 43.8 vs. 59.4 ± 46.5 mL, p = 0.061). The percentage of early mortality (within 7 days post-ICH) was significantly lower in the NOAC group (13.3% vs. 44.1%; p = 0.047), but the 3-month mortality was similar (33.3% vs. 47.1%; p = 0.294). The functional outcome was equally poor in both groups at discharge (p = 0.670) and 3 months post-ICH (mean mRS score 4.7 ± 1.3 vs. 4.6 ± 1.7, p = 0.766).. There were no significant differences in initial ICH volume, 90-day mortality, or functional outcomes between NOAC and VKA-associated ICH in Asians.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Registries; Retrospective Studies; Survival Analysis; Taiwan; Time Factors; Vitamin K

Topics: Anticoagulants; Cerebral Hemorrhage; Humans; Prognosis; Registries; Vitamin K

Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation-related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA-ICH, 48% in NOAC-ICH). NOAC-ICH patients had lower median CMB count [2(IQR:1-3) vs. 7(4-11); P < 0.001]; ≥5 CMBs were less prevalent in NOAC-ICH (4% vs. 31%, P = 0.006). This inverse association between NOAC exposure and high CMB count persisted in multivariable logistic regression models adjusting for potential confounders (OR 0.10, 95%CI: 0.01-0.83; P = 0.034).

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Humans; Male; Middle Aged; Prevalence; Retrospective Studies; Stroke; Vitamin K

The incidence of intracerebral hemorrhage (ICH) in patients using oral anticoagulation (OAC) will continue to increase with the demographic change of an aging population. As compared to primary spontaneous ICH, OAC-ICH is characterized by larger hematoma volumes, more frequent hematoma enlargement and intraventricular hemorrhage resulting in an even worse prognosis. Specific treatment should focus on immediate reversal of anticoagulation in addition to the basic acute management of ICH. In ICH patients using vitamin K antagonists (VKA), complete anticoagulant reversal with an international normalized ratio (INR) <1.3 should be achieved as quickly as possible using prothrombin complex concentrate (PCC) with additional substitution of vitamin K. Patients with ICH under dabigatran treatment should receive idarucizumab. In ICH patients using factor-Xa inhibitors, andexanet should be administered as soon as approved in Europe or within clinical studies and if unavailable alternatively high-dose PCC administration. Regarding OAC resumption, results from randomized trials are pending. In comprehensive observational studies and meta-analyses ICH patients resuming OAC showed a reduced incidence of thromboembolic events and mortality without significantly increased rates of hemorrhagic complications. Non-vitamin K dependent oral anticoagulants (NOAC) might further increase the safety of OAC resumption, which should be initiated after 4-8 weeks for patients with atrial fibrillation. In contrast, VKA resumption in patients with mechanical heart valves should not take place earlier than 1 week after ICH. Generally, safety of OAC resumption appears to be affected by ICH localization along with the presence of cerebral microbleeding, cortical superficial siderosis and cortical/convexity subarachnoid hemorrhage, making it crucial to weigh up the individual patient risk with respect to thromboembolic versus hemorrhagic events.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Europe; Humans; Randomized Controlled Trials as Topic; Vitamin K

Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3-3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5-14) h vs. 10 (IQR 7-16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6-14) h vs. 12 (8-19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Component Transfusion; Cerebral Hemorrhage; Chi-Square Distribution; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Massachusetts; Middle Aged; Plasma; Retrospective Studies; Statistics, Nonparametric; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K; Warfarin

Although non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH).. To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH.. Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines-Stroke hospitals.. Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival.. In-hospital mortality.. Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, -5.7% [97.5% CI, -7.3% to -4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, -15.0% [95.5% CI, -26.3% to -3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, -5.0% [97.5% CI, -6.8% to -3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant.. Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Confounding Factors, Epidemiologic; Female; Hospital Mortality; Humans; Male; Platelet Aggregation Inhibitors; Registries; Retrospective Studies; Risk; Vitamin K; Warfarin

Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH.. We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03).. Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Drug Administration Schedule; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Thromboembolism; Treatment Outcome; Vitamin K

Topics: Cerebral Hemorrhage; Emigrants and Immigrants; Germany; Humans; Infant Welfare; Infant, Newborn; Male; Psychomotor Agitation; Vitamin K; Vitamin K Deficiency; Vomiting

Background and Purpose- The aim of this study was to prospectively validate our prior findings of smaller hematoma volume and lesser neurological deficit in nonvitamin K oral anticoagulant (NOAC) compared with Vitamin K antagonist (VKA)-related intracerebral hemorrhage (ICH). Methods- Prospective 12-month observational study in 15 tertiary stroke centers in the United States, Europe, and Asia. Consecutive patients with premorbid modified Rankin Scale score of <2 with acute nontraumatic anticoagulant-related ICH divided into 2 groups according to the type of anticoagulant: NOAC versus VKA. We recorded baseline ICH volume, significant hematoma expansion (absolute [12.5 mL] or relative [>33%] increase), neurological severity measured by National Institutes of Health Stroke Scale score, 90-day mortality, and functional status (modified Rankin Scale score). Results- Our cohort comprised 196 patients, 62 NOAC related (mean age, 75.0±11.4 years; 54.8% men) and 134 VKA related (mean age, 72.3±10.5; 73.1% men). There were no differences in vascular comorbidities, antiplatelet, and statin use; NOAC-related ICH patients had lower median baseline hematoma volume (13.8 [2.5-37.6] versus 19.5 [6.6-52.0] mL; P=0.026) and were less likely to have severe neurological deficits (National Institutes of Health Stroke Scale score of >10 points) on admission (37% versus 55.3%, P=0.025). VKA-ICH were more likely to have significant hematoma expansion (37.4% versus 17%, P=0.008). NOAC pretreatment was independently associated with smaller baseline hematoma volume (standardized linear regression coefficient:-0.415 [95% CI, -0.780 to -0.051]) resulting in lower likelihood of severe neurological deficit (odds ratio, 0.44; 95% CI, 0.22-0.85) in multivariable-adjusted models. Conclusions- Patients with NOAC-related ICH have smaller baseline hematoma volumes and lower odds of severe neurological deficit compared with VKA-related ICH. These findings are important for practicing clinicians making anticoagulation choices.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hematoma; Humans; Male; Middle Aged; Neuroimaging; Prospective Studies; Treatment Outcome; Vitamin K; Warfarin

Background and Purpose- This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), vitamin K antagonist (VKA)- and non-VKA oral anticoagulant-associated ICH. Methods- Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume. Results- A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non-VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0-3; APT, 48/202 [23.8%] versus no APT, 187/587 [31.9%]; P=0.030) and higher mortality (APT, 103/202 [51.0%] versus no APT, 237/587 [40.4%]; P=0.009), whereas no significant differences were present in primary spontaneous ICH and non-VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 [7.4-61.4] versus 15.7 [5.7-44.5] mL; P=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 [1.20-2.70]; P=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients. Conclusions- APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Platelet Aggregation Inhibitors; Prognosis; Propensity Score; Severity of Illness Index; Tomography, X-Ray Computed; Vitamin K

Intracranial haemorrhages (ICH) represent a severe and frequently lethal complication in patients treated with vitamin K antagonists (VKA). The purpose of our study is to describe the factors and clinical features associated with mortality in these patients.. We conducted an observational, retrospective, multi-centre study based on prospective stroke registries in Spain. We included all patients admitted to neurology departments during a one-year period who met the following inclusion criteria: being 18 or older, having a diagnosis of ICH, and receiving VKA. Clinical and radiological parameters and 3-month outcomes were analysed.. A total of 235 patients from 21 hospitals were included. Mortality rate at 90 days was 42.6%. Bivariate analysis showed a significant association between death and the following factors: median NIHSS score at admission (5 [IQR = 9] vs 17 [IQR = 14] points, P<.01) and presence of an extensive hemispheric haemorrhage (4.9% vs 35%, P < .01; χ. ICH in patients treated with VKA is associated with high mortality rates; mortality in these patients is mainly and independently associated with the clinical situation at stroke onset.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cause of Death; Cerebral Hemorrhage; Female; Humans; Middle Aged; Prognosis; Registries; Retrospective Studies; Spain; Stroke; Vitamin K; Young Adult

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Consensus; Coronary Artery Disease; Drug Substitution; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Risk Factors; Stents; Thrombosis; Vitamin K

The aim of this study was to assess effectiveness and safety of antithrombotics for stroke prevention in non-valvular atrial fibrillation in real-use conditions.. We used a population-based retrospective cohort study. Information emerges from SIDIAP, a database containing anonymized information from electronic health records from 274 primary healthcare centres of the Catalan Health Institute, Catalonia (Spain), with a reference population of 5 835 000 people. Population includes all adults with a new diagnosis of non-valvular atrial fibrillation registered in SIDIAP from 2007 to 2012. The main outcome of antithrombotics' effectiveness was stroke. The main outcomes of safety were cerebral and gastrointestinal haemorrhages. We also estimated all-cause mortality. We used multivariable Cox proportional hazard models to examine association between antithrombotic treatment and main outcomes.. We included 22 205 subjects with non-valvular atrial fibrillation; 40.8% initiated on vitamin K antagonists (VKA), 33.4% on antiplatelets and 25.8% untreated. We found stroke-risk reduction with VKA, hazard ratio (HR) 0.72 (95% confidence interval (CI), 0.58-0.91), also seen in patients with CHADS. This study found a stroke-risk reduction associated with VKA and an increased risk of gastrointestinal bleeding associated with platelet-aggregation inhibitors in comparison with untreated patients. Both antithrombotic groups showed a reduction in all-cause mortality. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Databases, Factual; Electronic Health Records; Female; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Primary Health Care; Proportional Hazards Models; Retrospective Studies; Spain; Stroke; Treatment Outcome; Vitamin K

Clinical outcome and mortality in intracerebral haemorrhage (ICH) associated with anticoagulant treatment is poor. Novel direct oral anticoagulant drugs (NOACs) are increasingly prescribed. Management of NOAC-associated ICH might be more challenging. The aim of this study was to compare the clinical and radiological course of ICH patients being treated with different forms of oral anticoagulant drugs.. The study is a retrospective observational study. Haemorrhage in other intracranial compartments except the ventricular system were explicitly excluded. Four groups were categorised and compared with regard to their clinical and radiological course (NOACs, vitamin K antagonists [VKAs], platelet inhibitors and patients without anticoagulant/antiplatelet drugs). Clinical as well as radiological parameters were analysed.. Overall, 182 patients were included (2011 to early 2016). Twenty-five patients with NOAC-associated ICH were included (47 with VKAs, 50 with platelet inhibitors and 60 patients without anticoagulant/antiplatelet drugs). The frequency of NOAC-associated ICH increased over the years. Diabetes was found significantly more often in the NOAC patients (p = 0.05). The clinical and radiological courses in the three different patient groups with impaired coagulation were similar. Mortality was significantly higher in patient groups with impaired coagulation (p = 0.04) compared to those without anticoagulant/antiplatelet drugs. Multivariate analysis revealed the Glasgow Coma Scale (GCS) score as a strong predictor for worse outcome and mortality.. The frequency of NOAC-associated ICH increased in the last 5 years. Diabetes might be a risk factor for ICH when receiving NOACs. Clinical outcome in NOAC-associated ICH is poor and mortality is as high as in patients with other oral anticoagulant/antiplatelet drugs.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Retrospective Studies; Vitamin K

Background There is a lower reported incidence of intracranial hemorrhage with non-vitamin K antagonist oral anticoagulants compared with vitamin K antagonist. However, the functional outcome and mortality of intracranial hemorrhage patients were not assessed. Aims To compare the outcome of vitamin K antagonists- and non-vitamin K antagonist oral anticoagulants-related intracranial hemorrhage. Methods We included consecutive patients with acute non-traumatic intracranial hemorrhage on oral anticoagulation therapy admitted between January 2013 and June 2015 at four university hospitals. Clinical and demographic data were obtained from individual medical records. Intracranial hemorrhage was classified as intracerebral, extra-axial, or multifocal using brain computed tomography. Three-month functional outcome was assessed using the modified Rankin Scale. Results Among 246 patients included, 24 (9.8%) were anticoagulated with a non-vitamin K antagonist oral anticoagulants and 222 (90.2%) with a vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants patients were older (81.5 vs. 76 years, p = 0.048) and had intracerebral hemorrhage more often (83.3% vs. 63.1%, p = 0.048). We detected a non-significant trend for larger intracerebral hemorrhage volumes in vitamin K antagonists patients ( p = 0.368). Survival analysis adjusted for age, CHA

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Male; Stroke; Treatment Outcome; Vitamin K

To analyze the effect of previous antiplatelet (AP) and vitamin K antagonist (VKA) treatments on outcome in patients with primary intracerebral hemorrhage (ICH).. In this prospective observational study, we analyzed 529 patients according to antithrombotic pretreatment: none, AP, or VKA. Very-early (24-hour) death, 3-month mortality, and functional independence were analyzed.. Of 236 (44.6%) pretreated patients, 147 (27.8%) patients were taking AP and 89 (16.8%) VKA. Very-early death was observed in 13.4% and was increased in pretreated patients: 19.0% for AP and 27.0% for VKA treatment, compared to 6.5% in non-pretreated patients,. A high percentage of patients with ICH preventively treated with VKA or AP died during the first 24 hours after admission. Both treatments were predictors of very-early mortality. The final effect of antithrombotics on 3-month mortality remains significant through its strong effect on very-early mortality. Safety concerns about starting chronic antithrombotic treatment should be considered not only when VKA treatment is planned but also for AP treatment.

Topics: Aged; Aged, 80 and over; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Regression Analysis; Risk Factors; Severity of Illness Index; Survival Analysis; Time Factors; Vitamin K

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; Male; Plasma; Registries; Vitamin K

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; Male; Plasma; Registries; Vitamin K

Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin K antagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited.. Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being 'related', 'probably related', 'possibly related', 'unlikely related' or 'not related' to treatment with PCC. To identify factors associated with TEs, log-rank analyses were applied.. Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2-3.8) before and 1.3 (IQR 1.2-1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000-2,500) was administered. Nineteen TEs were observed (9.3%); none were classified 'related' but 9 were classified as 'possibly' or 'probably related' to PCC infusion (4.4%). One allergic reaction (0.5%), 'unlikely related' to PCC, was observed. In the whole cohort, PCC doses >2,000-3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively).. Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Databases, Factual; Disability Evaluation; Drug Hypersensitivity; Female; Germany; Humans; International Normalized Ratio; Kaplan-Meier Estimate; Length of Stay; Male; Predictive Value of Tests; Retrospective Studies; Risk Factors; Thromboembolism; Time Factors; Treatment Outcome; Vitamin K

There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies.. We pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all-cause 30-day case fatality using Cox regression.. We included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784-3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934-1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014-2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874-1.323, p = 0.492); 4-factor PCC (n = 441) was associated with higher case fatality compared to 3-factor PCC (n = 144, HR = 1.441, 95% CI = 1.041-1.995, p = 0.027).. The combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA-ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; Male; Plasma; Proportional Hazards Models; Registries; Retrospective Studies; Treatment Outcome; Vitamin K

We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC).. This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8-22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1-1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences.. IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Incidence; Male; Middle Aged; Pilot Projects; Thrombolytic Therapy; Treatment Outcome; Vitamin K

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Hemorrhage; Humans; Risk Factors; Vitamin K

Prothrombin complex concentrates (PCC) can rapidly normalise prolonged prothrombin time, induced by vitamin K antagonists (VKA). We conducted a multicentre retrospective study to investigate whether reversal of VKA coagulopathy with 4-factor PCC improves the survival of patients with VKA-related intracerebral haemorrhage as compared to plasma.We included 135 consecutive patients with VKA-related intracerebral haemorrhage treated either with plasma (mainly in Canada) or 4-factor PCC (The Netherlands and Sweden) for the reversal of VKA. Data on characteristics of the patients and the haemorrhage were collected. The volume of intracerebral haematoma was calculated from the first computed tomography (CT) scan. The unadjusted and adjusted odds ratio (OR) for 30-day all-cause mortality in both treatment groups was compared using logistic regression. Patients who received plasma (n=35, median 4 units) more often had diabetes, antiplatelet therapy, and intraventricular haemorrhage on the initial CT scans than patients who received PCC (n=100, median 22.5 IU/kg [interquartile range 20-26 IU], median of total dose 1,700 IU). The volume of intracerebral haematoma was larger in the plasma-treated group compared to the PCC-treated group (haematoma, mean 64.5 vs 36.0 cm³; p=0.021). The unadjusted OR for all-cause 30-day mortality in the PCC group was 0.40 (95% confidence interval, 0.18-0.87; p=0.021) compared to the plasma group. After adjusting for the haematoma volume, bleeding localisation and age, the effect of PCC on mortality became non-significant. In conclusion, treatment with 4-factor PCC for VKA reversal in patients with intracerebral haemorrhage does not seem to reduce the 30-day all-cause mortality compared to plasma.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Component Transfusion; Cerebral Hemorrhage; Chi-Square Distribution; Coagulants; Female; Humans; International Normalized Ratio; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Netherlands; Odds Ratio; Ontario; Plasma; Prothrombin Time; Retrospective Studies; Risk Factors; Sweden; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage.. Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist-associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth>12.5 cm3 or relative growth>33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan-Meier analysis was used for survival.. EHG occurred in 25.8%, ENW in 19.3%, and mortality was 31.8% at 30 days. Thirty-day mortality was significantly higher in patients with ENW (hazard ratio, 3.21; 95% confidence interval, 2.00-5.17; P<0.0001) and in patients with EHG (hazard ratio, 2.13; 95% confidence interval, 1.42-3.18; P<0.0001, log-rank test). Median CRP was 12 mg/L (interquartile range, 10-17) in the EHG group and 7 mg/L (interquartile range, 4-12.1) in those without EHG (P<0.0001). In multivariable analyses, plasma CRP>10 mg/L independently predicted EHG (odds ratio, 4.71; 95% confidence interval, 2.75-8.06; P<0.0001) and ENW (odds ratio, 2.70; 95% confidence interval, 1.50-4.84; P=0.0009).. CRP>10 mg/L is independently predictive of EHG and ENW, both of which are associated with increased mortality. Inflammation may be important in contributing to EHG and warrants further investigation.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Biomarkers; C-Reactive Protein; Cerebral Hemorrhage; Disease Progression; Female; Glasgow Coma Scale; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Prognosis; Prospective Studies; Registries; Regression Analysis; ROC Curve; Survival Analysis; Treatment Outcome; Vitamin K

The efficacy and safety of anticoagulation with use of vitamin K antagonists (VKAs) is highly dependent on the quality of anticoagulation control as reflected by the average time in a therapeutic range of 2.0 to 3.0. A clinical dilemma is trying to predict which anticoagulation-naive patients with atrial fibrillation (AF) would do well on a VKA (with a time in therapeutic range > 70%) and which are less likely to do well on a VKA but could be managed with novel oral anticoagulants.. The cohort comprised 8,120 patients, among whom 4,637 patients were receiving VKA. We investigated whether the SAMe-TT₂R₂ (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]) score could discriminate among patients with AF who were likely to have a labile international normalized ratio (INR) during follow-up as well as stroke/thromboembolism (TE), clinically relevant bleeding (defined as severe bleeding and as Bleeding Academic Research Consortium [BARC]-defined major bleeding), and death while being treated with a VKA.. During a mean follow-up of 1,016 ± 1,108 days, there was a significant increase in risk of severe bleeding events (risk ratio [RR], 1.38; 95% CI, 1.12-2.68; P = .002) and a significant increase in risk of major BARC bleeding (RR, 1.77; 95% CI, 1.29-2.44; P = .0005) in patients with AF with a high SAMe-TT₂R₂ score (> 2). Increasing SAMe-TT₂R₂ score was associated with an increasing risk of labile INR (P = .004), stroke/TE (P = .007), severe bleeding (P < .0001), major BARC bleeding (P < .0001), and death (P = .002) at follow-up. Among the patients taking VKAs, the SAMe-TT₂R₂ score was predictive of labile INR (C statistic approximately 0.58) as well as of stroke/TE, severe bleeding, major BARC bleeding, and death (C statistic, 0.54-0.57 for events), reflecting the suboptimal time in therapeutic range in such patients. This was not the case for patients who were not taking VKAs.. We demonstrate that the SAMe-TT₂R₂ score was predictive for an increasing risk of stroke/TE, severe bleeding, major BARC bleeding, and death, reflecting poor anticoagulation control (and labile INRs) among patients with AF given VKAs.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Comorbidity; Drug Interactions; Female; Follow-Up Studies; Humans; International Normalized Ratio; Male; Middle Aged; Predictive Value of Tests; Racial Groups; Risk Assessment; Sex Factors; Stroke; Survival Rate; Tobacco Use; Treatment Outcome; Vitamin K

Intracerebral hemorrhage (ICH) is the most devastating complication of oral anticoagulation (OAC). As the number of patients on long-term OAC is expected to rise, the proportion of intracerebral hemorrhage related to OAC (OAC-ICH) in relation to spontaneous ICH (spont-ICH) is expected to increase as well. We determined the proportion of OAC-ICH in consecutive stroke patients and explored differences between OAC-ICH and spont-ICH regarding initial volume, hematoma expansion and outcome. Our prospective study consecutively enrolled patients with supra- and infratentorial ICH. The National Institute of Health Stroke Scale Score and the modified Rankin Scale (mRS) score at baseline and after 3 months, medical history and demographic variables were recorded. All admission and follow-up CTs/MRIs were analysed regarding ICH volume using the ABC/2-method. Intraventricular hemorrhage (IVH) was quantified using the Graeb score. Within 19 months, 2,282 patients were admitted to our ER. 206 ICH patients were included. Overall, 24.8 % of all ICH were related to OAC. Compared to patients with spont-ICH, OAC-ICH patients were older (p = 0.001), more frequently had initial extension of ICH into the ventricles (p = 0.05) or isolated primary IVH (p = 0.03) and a higher Graeb score upon admission (p = 0.01). In contrast, initial ICH volume (p = 0.16) and ICH expansion (p = 0.9) in those receiving follow-up imaging (n = 152) did not differ between the two groups. After correction for age, there was a trend towards poorer outcome in OAC-ICH (p = 0.08). One-fourth of all ICH are related to OAC. Initial extension of ICH into the ventricles and primary IVH are more frequent in OAC-ICH. The rate of hematoma expansion in OAC-ICH patients is similar to non-anticoagulated ICH patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Data Interpretation, Statistical; Disease Progression; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Neurologic Examination; Prospective Studies; Stroke; Treatment Outcome; Vitamin K; Warfarin

Reversal of anticoagulation is recommended to correct the international normalised ratio (INR) for patients with intracranial haemorrhage (ICH) associated with vitamin K antagonists (VKA). However, the validity of such treatment is debated. We sought to identify, prospectively, the prognostic effect of VKA-ICH treatment in a cohort of patients (n=71; median age 78 years, range 20-89; 52% males). Data collated were: baseline characteristics, treatments, baseline and post-treatment INR, haematoma volume, and haematoma enlargement. Treatment effects and prognostic factor assessment were in relation to mortality and functional outcomes. On admission, the patients had a median score of 9 [p25; p75 of 5; 20] on the National Institute of Health Stroke Scale (NIHSS) and a mean INR of 2.7 (range: 0.9 - 10.8). Haematoma volume (34.6 cm³; SD: 24.9) correlated with NIHSS (r = 0.55; p<0.001) but not with INR. Anticoagulation reversal treatment was administered in 83% of patients. INR <1.5 was achieved in 60.7% of cases. Death or dependency at three months was 76%. Neither baseline INR, anticoagulation reversal nor haematoma enlargement were related to mortality or functional outcome. The only independent prognostic factor was clinical severity on admission. Baseline NIHSS predicted mortality (OR: 1.18; 95%CI: 1.09-1.27), independence (OR: 0.83; 95%CI: 0.74-0.94) and neurological recovery (NIHSS 0-1) (OR: 0.83; 95%CI: 0.73-0.95). The data indicate that VKA-ICH had a poor prognosis. Treatment and INR correction did not appear to affect outcomes.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Hematoma; Humans; International Normalized Ratio; Male; Middle Aged; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome; Vitamin K; Young Adult

To prevent major hemorrhage during anticoagulation, it is quite important to manage controllable risk factors such as hypertension, diabetes mellitus, smoking habit, and too much alcohol intake. It is also important to avoid dual antithrombotic therapy as long as possible, which increases severe bleeding events. For patients with major bleeding during anticoagulation, we should stop oral medication, stop bleeding by mechanical compression or surgical interventions, and maintain circulation blood volume and blood pressure by appropriate intravenous drip infusion. When intracranial hemorrhage happens, adequate treatment to suppress blood pressure should be provided. Administration of prothrombin complex concentrate (PCC) and vitamin K is effective for urgent reversal of anticoagulation by warfarin. The PCC may be also useful for that by novel oral anticoagulants.

Topics: Administration, Oral; Alcohol Drinking; Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Diabetes Mellitus; Drug Therapy, Combination; Factor IX; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension; Risk Assessment; Risk Factors; Smoking; Vitamin K; Warfarin

The high prevalence of atrial fibrillation in aging populations leads to an increasing incidence of vitamin K antagonists-associated intracerebral hemorrhages (VKAs-ICH). It remains unclear whether VKAs are causes or risk factors for ICH. We aimed at identifying the specificities of VKAs-ICH.. We compared baseline characteristics of 545 consecutive patients receiving or not receiving VKAs before admission for spontaneous ICH. To determine whether the influence of VKAs depends on the underlying vasculopathy, that is, cerebral amyloid angiopathy in lobar, and deep perforating arteries vasculopathy in deep ICH, we compared characteristics of ICH (including volume) according to the anatomic distribution of ICH in multiple linear regression.. VKAs-ICH accounted for 83 patients, that is, 15% (95% confidence intervals, 12-18) of ICH in our cohort. The use of VKAs did not influence anatomic distribution of ICH. The impact of VKAs on ICH volume differed according to ICH location: in nonlobar ICH, VKAs use was associated with significant larger ICH volumes (median volume 25 mL vs 12 mL; P=0.002). In lobar ICH, VKAs use did not influence the volume (median 26 mL vs 30 mL; P=0.507).. A similar anatomic distribution of ICH in patients with or without VKAs suggests that VKAs should not be considered as a cause of ICH because both locations are usually due to different vasculopathies (deep perforating arteries vasculopathy in deep and cerebral amyloid angiopathy in lobar). The different impact of VKAs on ICH volumes according to location suggests a different susceptibility of these vasculopathies to VKAs. This finding may lead to specific therapeutic strategies.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Risk Factors; Vitamin K

The management of antithrombotic therapy after intracerebral hemorrhage (ICH) in anticoagulated patients is not well defined. We analyzed the risks and benefits of antiplatelet therapy (AG) against the resumption of anticoagulation with vitamin K antagonists (AVK) in a series of patients.. Retrospective study of ICH in anticoagulated patients. We registered demographic data, history of hypertension (HT), time of follow-up and new cerebral vascular events (ICH, stroke [IC]).. We evaluated 88 patients, mean age 69±9 years, 50% men, 73% hypertensive. During the acute phase 18 patients died and the follow-up was lost in 31. Of the remaining (n=39), AVKs were resumed in 25 and changed to AG in 14. Comparing the characteristics of both groups, the anticoagulated group was younger (P=.005) and the embolic sources were more often of higher risk (P=.003). After an average follow-up of 54±31 months, the distribution of events was: IC (AVKs 8%, AG 14.3%, P=.6), ICH (AVKs 24%, AG 7.1%, P=.38), IC or ICH (AVKs 32%, AG 21.4%, P=.48) and death (AVKs 29%, AG 7.1%, P=.21). This trend of increased risk of new events in patients with AVKs was confirmed by Kaplan-Meier curves, although without statistical differences.. Restarting AVK treatment after ICH in anticoagulated patients could increase the risk of new bleeding events and mortality. Prospective studies are needed to define a better and appropriate antithrombotic therapy after ICH related with anticoagulation.

Topics: Aged; Anticoagulants; Aspirin; Cerebral Hemorrhage; Clopidogrel; Female; Follow-Up Studies; Humans; Intracranial Embolism; Ischemic Attack, Transient; Male; Middle Aged; Platelet Aggregation Inhibitors; Recurrence; Retrospective Studies; Risk; Risk Factors; Stroke; Ticlopidine; Vitamin K

Intracerebral hemorrhage (ICH) is the most serious bleeding complication of vitamin K antagonist (VKA) therapy, carrying a high mortality. Rapid reversal of VKA in ICH is critical. Plasma therapy, the standard of care in the US, is not optimal. The ideal prothrombin complex concentrate (PCC) containing all vitamin K-dependent factors (VKDFs) is not available in the US. Therefore, the authors developed a Trauma Coumadin Protocol (TCP) consisting of a 3-factor PCC available in the US (which contains insufficient factor VII [FVII]) with a low-dose recombinant FVIIa to rapidly reverse VKA.. Forty-six patients treated with the TCP were retrospectively analyzed. Fourteen patients had pre- and post-TCP plasma samples collected to assess their VKDF increment. Eleven patients had measurable intraparenchymal hematomas, which were evaluated for expansion.. The mean pre- and post-TCP international normalized ratios (INRs) were 3.4 (median 2.9) and 1.0 (median 0.9), respectively. Once corrected, INR was maintained at < 1.3 during a patient's hospital stay. The pre-TCP median values of FII, FVII, FIX, and FX were 28%, 21%, 45%, and 20%, respectively; post-TCP median values increased to 144%, 417%, 102%, and 143%, respectively. Four of the 11 patients with measurable intraparenchymal hemorrhage had expansion at 24 hours after TCP. One patient probably (8 hours post-TCP) and 1 patient possibly (3 days post-TCP) had thrombotic complications.. The TCP was very effective in rapidly reversing VKA-associated coagulopathy; however, this protocol should be used cautiously in patients at high risk for thrombosis.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Clinical Protocols; Drug Combinations; Factor VIIa; Female; Hematoma; Humans; International Normalized Ratio; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Vitamin K; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Factor VIIa; Hemostatic Techniques; Hemostatics; Humans; International Normalized Ratio; Plasma; Prothrombin; Vitamin K

The incidence of vitamin K deficiency in infancy has decreased markedly, due to prophylactic administration of vitamin K during the neonatal period. However, vitamin K deficiency bleeding may occur during or after the neonatal period despite prophylactic administration in Japan. Two cases are reported of intracranial hemorrhage associated with coagulopathy in full-term infants who had received prophylactic administration of vitamin K. More reliable methods for prophylactic administration should be established.

Topics: Blood Coagulation Disorders; Cerebral Hemorrhage; Humans; Infant; Infant, Newborn; Male; Treatment Failure; Vitamin K; Vitamin K Deficiency Bleeding

Cerebral venous thrombosis is an uncommon disease characterized by expansive cerebral edema, venous infarction and massive intracerebral hemorrhage. Magnetic resonance imaging and angiography are useful for diagnosis of cerebral venous thrombosis. A 54-year-old man was admitted with headache, vomiting and right hemiparesis. Computed tomography (CT) revealed subcortical hematoma in the left parietal lobe. Digital subtraction angiography (DSA) demonstrated occlusion of the left Labbé vein with dilation of cortical veins and deep cerebral veins. He also suffered from pulmonary embolization and deep vein thrombosis in the lower extremities. Anticoagulant and thrombolytic agents were administered, then respiratory condition and hemiparesis were improved. However, his condition deteriolated 7 months after the initial attack. CT revealed huge subcortical hematoma in the same site. He underwent craniotomy and intracerebral hematoma was evacuated during treatment with vitamin K. His symptom gradually improved and he was discharged with moderate disability 2 months after operation. Dicision of surgical treatment is difficult because there is a risk of rebleeding due to thrombolytic therapy and progressive venous congestion. Since anticoagulant and thrombolytic therapy are inevitable, surgical indication for refractory intracerebral hemorrhage associated with cerebral venous thrombosis should be considered carefully.

Topics: Cerebral Hemorrhage; Diagnostic Imaging; Fibrinolytic Agents; Humans; Male; Middle Aged; Perioperative Care; Venous Thrombosis; Vitamin K

Use of vitamin K antagonists (VKAs) for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) necessitates frequent monitoring of the international normalized ratio (INR) to avoid the increased risk of hemorrhage associated with excess anticoagulation, or ischemic stroke due to insufficient anticoagulation. We therefore developed a model to estimate the excess morbidity attributable to inadequate INR control in NVAF populations.. Equations expressing the risk of cerebrovascular events as a function of INR were generated using published data. Additional functions were developed to estimate the excess risk attributable to inferior INR control, using the clinical trial setting as the reference.. The derived risk functions were applied to French NVAF patients receiving anticoagulation in routine medical practice. This population achieved a time in therapeutic range (INR 2.0-3.0) of 59%, compared with 68% time in therapeutic range (TTR) in the SPORTIF III and V clinical trials. However, there was considerable variation in the TTR among patients in routine care, of whom 36% were in range for less than 50% of the time. Among this latter group, the relative risk, compared with the clinical trial setting, was 1.47 for ischemic stroke and 2.68 for intracranial hemorrhage. Conversely, for patients achieving a TTR greater than 50%, the relative risks for ischemic stroke and intracranial hemorrhage were 0.99 and 1.16, respectively.. This model permits estimation of the excess risk attributable to inferior INR control in NVAF populations receiving VKA anticoagulation, and has implications for public health planning and management.

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Brain Ischemia; Cerebral Hemorrhage; France; Humans; International Normalized Ratio; Models, Statistical; Morbidity; Public Health; Quality of Health Care; Risk Factors; Stroke; Vitamin K

Vitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational gamma-glutamyl carboxylation resulting in biological active so called vitamin K-dependent proteins. In turn, K>O is reduced by the enzyme VKORC1 (vitamin K epoxide reductase complex component 1) to complete the vitamin K cycle. To investigate the biological role of VKORC1 in vivo, we generated VKORC1 knockout mice. Homozygous VKORC1-deficient mice developed normally until birth. Within 2-20 days after birth, the knockout mice died due to extensive, predominantly intracerebral haemorrhage. Bleeding resulted from a severe deficiency of gamma-carboxylated clotting factors. This lethal phenotype could be rescued by oral administration of vitamin K. Additionally, morphometric analysis of the limbs in VKORC1-deficient animals revealed reduced length of bone calcification relative to wild-type control mice. The observed phenotype of VKORC1 knockout mice excludes the existence of other enzymes with VKOR activity that can substitute to supply vitamin K hydroquinone required for maturation of blood clotting factors. Thus, our study underscores the essential role of VKORC1 in vitamin K-dependent gamma-glutamyl carboxylation.

Topics: Animals; Animals, Newborn; Blood Coagulation Factors; Bone and Bones; Calcification, Physiologic; Carbon Dioxide; Cells, Cultured; Cerebral Hemorrhage; Embryonic Stem Cells; Extremities; Mice; Mice, Inbred C57BL; Mice, Knockout; Mixed Function Oxygenases; Vitamin K; Vitamin K Epoxide Reductases

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Humans; Intracranial Thrombosis; Phenotype; Risk Assessment; Stroke; Vitamin K

Unexpectedly elevated INR values are commonly encountered in clinical practice. In the absence of bleeding, such values may be treated with either simple warfarin withdrawal or the administration of low doses of oral vitamin K. Oral vitamin K will more rapidly return the INR to the therapeutic reference interval; however, its impact on bleeding is unknown. If the INR is in excess of 10, most experts would recommend the administration of vitamin K and, in the case of active bleeding, additional administration of coagulation factors either in the form of fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC). Coagulation factor replacement is required given the need to urgently correct the INR; however, vitamin K should not be forgotten since it is required to antagonize the effect of warfarin, preventing "rebound" anticoagulation after transfused coagulation factors are consumed. This paper will review the evidence supporting various treatment modalities and will provide suggestions for treatment. Future advances in this area will likely focus on evaluations of the relative merits of FFP and PCCs.

Topics: Anticoagulants; Blood Coagulation; Cerebral Hemorrhage; Factor VIIa; Humans; International Normalized Ratio; Recombinant Proteins; Vitamin K

The objective of this study is to show the effectiveness of Factor IX complex concentrate (FIXCC) for rapid reversal of an elevated International Normalized Ratio (INR) in patients with anticoagulation-associated intracerebral hemorrhage (AAICH).. We, retrospectively, analyzed the clinical data of 19 patients with the diagnosis of AAICH from January 2005 to May 2006. A comparison was made among patients treated with FFP and Vit.K [FFP-group (n = 9)] and patients treated with FIXCC in addition to FFP and Vit.K [FIXCC-group (n = 10)]. INR of 1.4 or less was taken as target.. Mean INR on admission for FFP and FIXCC group was 1.84 +/- 0.31 and 2.44 +/- 1.48, respectively (P = 0.315). After administration of therapy, the INR was reduced from 1.84 +/- 0.31 to 1.34 +/- 0.08 (P < 0.05) in FFP group and 2.44 +/- 1.48 to 1.34 +/- 0.07 (P < 0.005) in FIXCC group. Three patients in FFP group (33%) and 8 patients in FIXCC group (80%) reached their target INR in 3-4 h after initiation of therapy (P = 0.012). Mean time taken by both FFP and FIXCC groups to reach the target INR was 8.52 +/- 5.60 h and 4.25 +/- 2.12 h, respectively (P < 0.05). The mean rate of INR correction was 0.06 +/- 0.03 and 0.27 +/- 0.25 per hour for the FFP and FIXCC group, respectively (P < 0.005). There was one death in FIX group and two in FFP group and no thrombotic complications.. Our data suggests that FIXCC in combination with FFP and Vit.K may result in decreased time required when compared to FFP and Vit.K alone for correction of warfarin associated coagulopathy in neurosurgical emergencies.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Cerebral Hemorrhage; Drug Interactions; Drug Therapy, Combination; Factor IX; Female; Humans; International Normalized Ratio; Male; Middle Aged; Plasma; Retrospective Studies; Treatment Outcome; Vitamin K; Vitamins; Warfarin

Goals of hemorrhage management involve promoting coagulation and reducing fibrinolysis to enhance clot formation and stability, and minimizing hemorrhagic expansion to reduce the likelihood of adverse outcomes. The optimal hemostatic regimen to obtain these goals will differ according to the clinical scenario. Two hypothetical cases of patients with hemorrhage are presented that are typical of those encountered by clinical pharmacists who practice in centers that treat trauma or surgical patients or patients in need of emergency or critical care because of serious bleeding. To maximize therapy, the clinician must be aware of how best to clinically apply hemostatic agents, their comparative benefits and disadvantages, and the optimal methods for monitoring their effectiveness and toxicities.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Critical Care; Emergency Service, Hospital; Evidence-Based Medicine; Factor VII; Factor VIIa; Female; Fibrinolysis; Hemorrhage; Hemostasis; Hemostatics; Humans; Intraoperative Complications; Male; Middle Aged; Pharmacists; Plasma; Recombinant Proteins; Vitamin K; Warfarin

In this study, clinical and demographic features of 16 cases with late vitamin K deficiency bleeding are presented. Ages of infants were between 30 and 130 days. Their delivery histories were uneventful, and family histories for bleeding disorders were negative. All parents except one were unaware of whether their children received vitamin K at birth or not. All cases did not have any underlying illness to explain the abnormal coagulation profile. The common presenting finding was pallor (62.5%). Intracranial haemorrhage was the most common bleeding site (37.5%), and two patients (12.5%) died because of it. Late vitamin K deficiency bleeding is still an important handicap in infants. Parents and healthcare providers should be informed about the importance of vitamin K prophylaxis to prevent vitamin K deficiency in infants.

Topics: Blood Coagulation Tests; Cerebral Hemorrhage; Female; Humans; Infant; Male; Pallor; Retrospective Studies; Turkey; Vitamin K; Vitamin K Deficiency; Vitamins

Anticoagulation-related intracerebral hemorrhage (ICH) is often fatal, and rapid reversal of anticoagulation is the most appealing strategy currently available for treatment. We sought to determine whether particular emergency department (ED) interventions are effective in reversing coagulopathy and improving outcome.. Consecutive patients with warfarin-related ICH presenting to an urban tertiary care hospital from 1998 to 2004 were prospectively captured in a database. ED records were retrospectively reviewed for dose and timing of fresh-frozen plasma (FFP) and vitamin K, as well as serial coagulation measures. After excluding patients with incomplete ED records, do-not-resuscitate orders established in the ED, initial international normalized ratio (INR) < or =1.4, and for whom no repeat INR was performed, 69 patients were available for analysis. The primary outcome was a documented INR < or =1.4 within 24 hours of ED presentation.. Patients whose INR was successfully reversed within 24 hours had a shorter median time from diagnosis to first dose of FFP (90 minutes versus 210 minutes; P=0.02). In multivariable analysis, shorter time to vitamin K, as well as FFP, predicted INR correction. Every 30 minutes of delay in the first dose of FFP was associated with a 20% decreased odds of INR reversal within 24 hours (odds ratio, 0.8; 95% CI, 0.63 to 0.99). Dosing of FFP and vitamin K had no effect. No ED intervention was associated with improved clinical outcome.. Time to treatment is the most important determinant of 24-hour anticoagulation reversal. Although additional study is required to determine the clinical benefit of rapid reversal of anticoagulation, minimizing delays in FFP administration is a prudent first step in emergency management of warfarin-related ICH.

Topics: Aged; Anticoagulants; Blood Transfusion; Cerebral Hemorrhage; Emergency Medicine; Female; Hospitals; Humans; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Plasma; Prospective Studies; Retrospective Studies; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Intracerebral hemorrhage (ICH) is the most serious and potentially fatal complication of oral anticoagulant therapy (OAT). Still, there are no universally accepted treatment regimens for patients with OAT-ICH, and randomized controlled trials do not exist. The aim of the present study was to compare the acute treatment strategies of OAT-associated ICH using vitamin K (VAK), fresh frozen plasma (FFP), and prothrombin complex concentrates (PCCs) with regard to hematoma growth and outcome.. In this retrospective study, a total of 55 treated patients were analyzed. Three groups were compared by reviewing the clinical, laboratory, and neuroradiological parameters: (1) patients who received PCCs alone or in combination with FFP or VAK (n=31), (2) patients treated with FFP alone or in combination with VAK (n=18), and (3) patients who received VAK as a monotherapy (n=6). The end points of early hematoma growth and outcome after 12 months were analyzed including multivariate analysis.. Hematoma growth within 24 hours occurred in 27% of patients. Incidence and extent of hematoma growth were significantly lower in patients receiving PCCs (19%/44%) compared with FFP (33%/54%) and VAK (50%/59%). However, this effect was no longer seen between PCC- and FFP-treated patients if international normalized ratio (INR) was completely reversed within 2 hours after admission. The overall outcome was poor (modified Rankin scale 4 to 6 in 77%). Predictors for hematoma growth were an increased INR after 2 hours, whereas administration of PCCs was significantly protective in multivariate analyses. Predictors for a poor outcome were age, baseline hematoma volume, and occurrence of hematoma growth.. Overall, PCC was associated with a reduced incidence and extent of hematoma growth compared with FFP and VAK. This effect seems to be related to a more rapid INR reversal. Randomized controlled trials are needed to identify the most effective acute treatment regimen for lasting INR reversal because increased levels of INR were predisposing for hematoma enlargement.

Topics: Administration, Oral; Aged; Anticoagulants; Blood Coagulation Factors; Blood Component Transfusion; Cerebral Hemorrhage; Critical Care; Female; Hematoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Plasma; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

In infants, intracerebral hemorrhage (ICH) is most likely the result of trauma or disturbances of coagulation function. Routine and standard care of the newborn includes the administration of vitamin K to prevent hemorrhagic disease of the newborn. We present two infants, the products of home deliveries, who did not receive vitamin K at birth. Both infants developed ICH at 5 weeks of age and presented with signs and symptoms of increased IC pressure. In both cases, recombinant factor VIIa was administered to correct coagulation function and allow immediate surgical intervention which included craniotomy and hematoma evacuation in one patient and placement of a ventriculostomy in the other to treat increased IC pressure. Despite this therapy, both infants were left with severe neurologic sequelae. These two cases illustrate that hemorrhagic disease of the newborn can occur when prophylactic vitamin K is not administered and that it can have devastating consequences. Given these issues, the routine administration of vitamin K to all infants is mandatory and should not be considered optional.

Topics: Antifibrinolytic Agents; Cerebral Hemorrhage; Factor VII; Factor VIIa; Fatal Outcome; Humans; Infant; Infant, Newborn; Male; Recombinant Proteins; Tomography, X-Ray Computed; Vitamin K; Vitamin K Deficiency Bleeding

Intracerebral hemorrhage (ICH) is associated with high mortality in patients on oral anticoagulant treatment. The normalization of hemostatic balance usually requires slow-acting or risky treatments, such as vitamin K, fresh frozen plasma or prothrombin complex concentrates, which have narrow therapeutic windows particularly in cardiopathic patients like those with mechanical heart valves. Recombinant activated factor VII (rFVIIa) seems useful in patients with normal or pathologic coagulation who have an ICH. We report of a patient on acenocumarol for mitro-aortic valve replacement, referred for headache and found at computerized tomography scanning to have a parietal hemorrhage with ventricular invasion. International normalized ratio was 3.22. The patient was treated with vitamin K and with a bolus of 80 mug/kg of rFVIIa, with correction of the international normalized ratio within 15 min. Sequential computerized tomographies showed progressive reduction of the hematoma and normalization of ventricular spaces and the patient fully recovered. No valvular dysfunctions or cardiac thrombi were found at sequential echocardiograms. Neurological examination at 3 months follow-up visit was completely normal. To our knowledge, this is the first report of the safe and successful use of rFVIIa to treat ICH in a patient on oral anticoagulants for prosthetic heart valves.

Topics: Cerebral Hemorrhage; Factor VII; Factor VIIa; Female; Heart Valve Prosthesis; Humans; Middle Aged; Recombinant Proteins; Recovery of Function; Stress, Mechanical; Tomography Scanners, X-Ray Computed; Treatment Outcome; Vitamin K

According to their code of professional conduct, German physicians are obliged to report suspected cases of adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (AkdA). On the basis of an agreement between the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) a common pharmacovigilance database within the German spontaneous reporting system was created. A user-friendly application program developed in-house enables the user to conduct searches about reported ADRs covering a wide variety of questions within a short period of time. ADRs caused by anticoagulants and by antiplatelet drugs still belong to the most reported adverse events. The most frequently reported suspected drugs are heparins, followed by ticlopidine, phenprocoumon, acetylsalicylic acid, and clopidogrel. Bleeding complications are the most often described ADR symptoms of any anticoagulation therapy, especially of phenprocoumon and acetylsalicylic acid. Another serious ADR is heparin-induced thrombocytopenia or changes in blood counts (CBC) due to ticlopidine and clopidogrel. During the past few years a reduction in severe reactions, such as cerebral hemorrhage, especially with fatal outcome was detectable because of better clinical management of oral anticoagulant therapy and of adverse events concerning heparin.

Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Anticoagulants; Aspirin; Association; Blood Cell Count; Cerebral Hemorrhage; Clopidogrel; Databases, Factual; Drug Information Services; Germany; Hemorrhage; Heparin; Humans; Phenprocoumon; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Thrombocytopenia; Ticlopidine; Time Factors; Treatment Outcome; Vitamin K

Levels of oxidative defenses and blood-clotting factors are normally reduced in newborns, increasing the risk of injury to developing brain structures around the time of birth. This early neonatal vulnerability corresponds to a timeframe in which the development of reward-related limbic structures is particularly active. Taking advantage of a serendipitous event in the history of treating newborns, we tested the hypothesis that vitamin K supplementation, administered to facilitate the synthesis of blood-clotting proteins within this critical timeframe, might also reduce the development of alcohol dependence later in life.. Subjects were approximately full-term male infants, selected from a large Danish birth cohort. Two thirds of the original 330 subjects in this study were high-risk sons of alcoholic fathers; 241 of the total completed the 30-year follow-up. Of subjects reported on for this article (N = 238), 44 received vitamin K supplementation at birth; 161 were considered high risk, and 66 were categorized as having lower birth weight (<6 lbs). A comprehensive series of measures was obtained on each subject before, during and shortly after birth as well as at 1 year of age. The Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, diagnosis of alcohol dependence and a measure of lifetime problem drinking served as the 30-year outcome variables.. Vitamin K treatment, inherited risk and low birth weight each independently predicted alcohol dependence and problem drinking at age 30. Vitamin K treatment was associated with significantly lower rates of alcohol dependence and fewer symptoms of problem drinking.. Vitamin K treatment at birth might protect against the development of alcoholism in adults by reducing early postnatal hemorrhage and oxidative brain damage.

Topics: Adolescent; Adult; Alcoholism; Blood Coagulation Factors; Brain Damage, Chronic; Cerebral Hemorrhage; Child; Child of Impaired Parents; Child, Preschool; Cohort Studies; Denmark; Follow-Up Studies; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Limbic System; Male; Oxidative Stress; Reward; Risk; Vitamin K

An 11-week-old male infant presented with intracerebral hemorrhage associated with coagulopathy manifesting as left hemiparesis, lethargy, and vomiting. Computed tomography demonstrated extensive right frontoparietal intracerebral hemorrhage extending into the ventricular system. Liver function tests revealed abnormal values of transaminases and bilirubin. Blood coagulation studies showed prolonged prothrombin time (PT) and activated partial thromboplastin time (APPT). PT and APTT immediately normalized after the administration of vitamin K and fresh frozen plasma. Right parietal craniotomy and evacuation of the hematoma were performed because of the deterioration in consciousness and left hemiparesis. No vascular abnormality was observed in the hematoma cavity. After surgery, he became alert and the left hemiparesis improved. There is a risk of intracerebral hemorrhage due to vitamin K deficiency even if prophylactic administration of vitamin K was given. Surgical treatment should be considered for the treatment of infantile spontaneous intracerebral hemorrhage, especially if neurological deterioration is present.

Topics: Antifibrinolytic Agents; Blood Coagulation Disorders; Cerebral Hemorrhage; Humans; Infant; Male; Preoperative Care; Vitamin K

Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA). Suggested regimens for control of highly elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma (FFP) or a prothrombin complex concentrate (PCC). In contrast, this communication present the first report on the efficacious use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system (CNS) bleeding emergencies. Pre-treatment INRs ranged from 1.7 to 6.6, and 10 min after a single dose of rFVIIa (10-40 microg/kg) all INRs were

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Cerebral Hemorrhage; Computer Systems; Drug Evaluation; Factor VII; Factor VIIa; Female; Hematoma; Hemostatics; Humans; International Normalized Ratio; Male; Middle Aged; Recombinant Proteins; Thrombelastography; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Topics: Anticoagulants; Apolipoproteins E; Biomarkers; Brain; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Genotype; Humans; International Normalized Ratio; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

We report a male infant with congenital tuberculosis who developed cerebral hemorrhage associated with vitamin K deficiency during treatment with isoniazid and rifampin. Despite an absence of risk factors for vitamin K deficiency, the severe hemorrhagic disorder occurred at 4 months of age. We speculate that vitamin K deficiency in the present case may have resulted from a synergic effect of antituberculosis agents and immaturity of vitamin K metabolism and/or its absorption.

Topics: Cerebral Hemorrhage; Humans; Infant; Infectious Disease Transmission, Vertical; Isoniazid; Male; Rifampin; Streptomycin; Tuberculosis; Vitamin K; Vitamin K Deficiency

We investigated the effect of prothrombin complex concentrate (PCC, median 500 IU) and vitamin K (10-20 mg) or either on blood coagulation and clinical findings in 17 patients with major hemorrhagic complication during warfarin treatment. Their international normalized ratio (INR) at admission was median 2.7 (2.0-above 10.0). In 11 patients treated with PCC and vitamin K, INR decreased to median 1.13 (0.91-1.36) 10 min after the administration with elevation of plasma levels of coagulant factors II, VII, IX, X and protein C.INR decreased abruptly after the administration of PCC without vitamin K in two patients but it increased again 12-24 h after, with decrease of coagulant factors levels. In one of them, a hematoma of the brain enlarged with INR re-increase 12-24 h after the administration. In four patients treated with vitamin K alone, INR decreased slowly from 2.69 (1.03-3.35) to 1.28 (1.25-1.44) 12-24 h after the administration in parallel with gradual increase of the coagulant factors.PCC administration with or without vitamin K seems to be more effective in rapidly correcting increased INR levels than vitamin K treatment without PCC. PCC without vitamin K may result in re-increase of INR and clinical deterioration.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Brain; Cerebral Hemorrhage; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Tomography, X-Ray Computed; Vitamin K; Warfarin

The incidence of spontaneous intracranial haemorrhage has increased markedly in line with the increased use of oral anticoagulant agents. Recent guidelines for reversal of this acquired coagulation defect in an emergency have been established, but they are not adhered to in all centres. Our unit is referred between 20 and 60 patients per year (1994-1999) who are anticoagulated and require urgent neurosurgical intervention. In order to investigate this, we performed a prospective study using prothrombin complex concentrate (PCC). PCC was given to the first six patients with intracranial haemorrhage admitted to the neurosurgical unit requiring urgent correction of anticoagulation (Group 1) and compared with patients receiving standard treatment with fresh frozen plasma and vitamin K (Group 2). Mean International Normalised Ratios of Group 1 were 4.86 pretreatment and 1.32 posttreatment, and of Group 2 were 5.32 and 2.30, respectively. Results for complete reversal and reversal time were significant for PCC with p < 0.001. We recommend PCC for rapid and effective reversal of warfarin in life-threatening neurosurgical emergencies.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Emergencies; Female; Hematoma, Subdural; Humans; International Normalized Ratio; Male; Middle Aged; Pilot Projects; Preoperative Care; Prospective Studies; Subarachnoid Hemorrhage; Vitamin K; Warfarin

Topics: Cerebral Hemorrhage; Continuity of Patient Care; Evidence-Based Medicine; Female; Health Knowledge, Attitudes, Practice; Humans; Infant Food; Infant, Newborn; Midwifery; Milk, Human; Pregnancy; Reference Values; Unnecessary Procedures; Vitamin K; Vitamin K Deficiency

A 3-month-old male infant with intracranial hemorrhage attributable to a vitamin K deficiency is reported. Vitamin K2 was administered orally at birth and then at 5 days and I month of age. Oral antibiotics were also given 2 days before the onset of bleeding. Although the incidence of intracranial hemorrhage resulting from vitamin K deficiency has decreased since the introduction of vitamin K2 prophylaxis, spontaneous intracranial hemorrhages are still being reported in infants. We suggest that vitamin K prophylaxis is needed especially for breast-fed infants and for those undergoing antibiotic therapy.

Topics: Cerebral Hemorrhage; Drug Administration Schedule; Humans; Infant; Male; Risk Factors; Vitamin K; Vitamin K Deficiency

Topics: Adult; Bile Ducts, Intrahepatic; Cerebral Hemorrhage; Fatal Outcome; Female; Humans; Infant; Male; Vitamin K; Vitamin K Deficiency

To determine the prevalence of vitamin K deficiency bleeding in the Netherlands, in order to evaluate the efficacy of recommendations on vitamin K prophylaxis.. Descriptive.. University Hospital Nijmegen, the Netherlands.. Active surveillance of vitamin K deficiency bleeding (VKDB) by the Dutch Paediatric Surveillance Unit from October 1, 1992 to December 31, 1994.. Of the 19 reported cases 5 could be validated as late vitamin K deficiency bleeding: 2 idiopathic cases, and 3 secondary cases due to liver disorders. One case had intracranial bleeding and died. None of the cases had received exactly the recommended prophylaxis. The incidence of late VKDB was calculated to be 1.1/100,000 live births. Before vitamin K prophylaxis was recommended the incidence was estimated to be 7/100,000.. The present Dutch recommendations for prevention of vitamin K deficiency bleeding-1 mg vitamin K at birth and thereafter for breastfed infants daily 25 micrograms from 2 to 13 weeks-appear effective.

Topics: Cerebral Hemorrhage; Epistaxis; Hematemesis; Humans; Infant; Infant, Newborn; Vitamin K; Vitamin K Deficiency

A 7-week old, male infant died from an intracerebral haemorrhage due to vitamin K deficiency. He had been exclusively breast-fed. Directly after birth no vitamin K was administered. From day 10 a daily dose of 25 microgram vitamin K was given orally. At post mortem a mild cholestasis was found which may have been an additional factor contributing to late vitamin K deficiency.

Topics: Breast Feeding; Cerebral Hemorrhage; Fatal Outcome; Humans; Infant; Male; Vitamin K; Vitamin K Deficiency

To compare three methods of vitamin K prophylaxis for neonatal vitamin K deficient intracranial haemorrhage.. We designed three strategies for vitamin K prophylaxis: 1. therapeutic administration of vitamin K in a mass screening system using the hepaplastin test; 2. routine oral administration of vitamin K to newborn infants; and 3. administration of vitamin K to lactating mothers during the late neonatal period in addition to the routine method. We evaluated the efficacy of these methods by determining hepaplastin test values at the first month of age.. 66,076 full term healthy newborn infants without any complications.. Of 55,513 infants in the mass screening system, 3068 infants received vitamin K therapeutically. At the first month of age, in the group where vitamin K was administered therapeutically, 56 infants (1.83%) exhibited low hepaplastin test values (< 40%) despite vitamin K administration. But extremely low values (< 20%), indicating a very high risk of neonatal intracranial haemorrhage, were observed in 34 (0.06%) of 52,445 infants who did not receive vitamin K. In the routine administration system, oral administration of vitamin K twice within the first week of life showed a lower incidence (0.19%) of low level cases than a single administration (1.56%). An additional administration of vitamin K to lactating mothers throughout the late neonatal period showed an effective result.

Topics: Administration, Oral; Cerebral Hemorrhage; Clinical Protocols; Female; Humans; Infant; Infant, Newborn; Japan; Mass Screening; Neonatal Screening; Perinatal Care; Pregnancy; Prenatal Care; Treatment Outcome; Vitamin K; Vitamin K Deficiency

Topics: Biliary Atresia; Blood Coagulation Disorders; Breast Feeding; Cerebral Hemorrhage; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Vitamin K; Vitamin K Deficiency

Healthy term infants born at the University of Missouri have received vitamin K prophylaxis as a single oral dose since 1967. A retrospective study was undertaken to determine whether either hemorrhagic disease of the newborn or any unexplained intracranial hemorrhage occurred in an infant who received orally administered vitamin K, but none could be found in three separate databases. We conclude that we have met our duty of providing appropriate care.

Topics: Administration, Oral; Cerebral Hemorrhage; Databases, Factual; Death Certificates; Humans; Incidence; Infant, Newborn; Injections, Intramuscular; Intubation, Gastrointestinal; Medical Records; Outcome and Process Assessment, Health Care; Retrospective Studies; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Cerebral Hemorrhage; Fatal Outcome; Female; Hepatitis; Humans; Infant, Newborn; Vitamin K

Topics: Blood Coagulation; Cerebral Hemorrhage; Female; Fetal Blood; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Maternal-Fetal Exchange; Pregnancy; Prenatal Care; Vitamin K

New York State's infant deaths and hospitalizations attributed to hemorrhagic disease of the newborn and other neonatal hemorrhagic conditions were reviewed. In 65% of 34 deaths reviewed, vitamin K was not documented as given or was given only after the onset of hemorrhage. Vitamin K was not included in standing orders in any of 22 hospitals contacted. As a result of this review, vitamin K prophylaxis was made a mandatory newborn care procedure in the State Public Health Code.

Topics: Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Infant Care; Infant, Newborn; New York; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Cerebral Hemorrhage; Humans; Infant, Newborn; Infant, Newborn, Diseases; Vitamin K

Topics: Cerebral Hemorrhage; Female; Humans; Infant, Newborn; Time Factors; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

During recent years, we have observed two cases of haemorrhage due to vitamin K deficiency which developed late in the neonatal period. One patient was a female infant aged six weeks with severe intracranial bleeding and the other was a female infant aged three weeks with marked haemorrhage from the umbilicus. Both of these infants were entirely breast-fed and had received vitamin K (1 mg fytomenadion) orally at birth. Both infants had unrecognized alfa-1-antitrypsin deficiency with liver involvement. In other European countries, many cases of late haemorrhagic disease of the newborn due to vitamin K deficiency have been registered in infants who had received oral vitamin K prophylaxis. On the basis of these observations and investigations which suggest that oral vitamin K prophylaxis is not so effective as intramuscular administration, it is suggested that the present oral vitamin K prophylaxis should be altered.

Topics: Administration, Oral; Cerebral Hemorrhage; Female; Humans; Infant; Infant, Newborn; Radiography; Umbilicus; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Although intracerebral hemorrhage is one of the most serious complications during oral anticoagulant therapy, there are no guidelines on emergency treatment with respect to reversal of anticoagulation effect in these patients.. We retrospectively compared laboratory data and clinical features in 17 cases of anticoagulant-related intracerebral hemorrhage treated with prothrombin complex concentrate (n = 10) or fresh-frozen plasma (n = 7).. In the group of patients treated with prothrombin complex concentrate, the mean prothrombin time decreased from 2.83 to 1.22 International Normalized Ratio within 4.8 hours, compared with a decrease from 2.97 to 1.74 within 7.3 hours in those given fresh-frozen plasma (i.e., four to five times more rapidly after treatment with prothrombin complex concentrate) (p less than 0.001). Symptoms and signs of intracerebral hemorrhage, measured on an eight-graded Reaction Level Scale, progressed on average 0.2 grades in patients given prothrombin complex concentrate compared with 1.9 grades in those given fresh-frozen plasma (p less than 0.05). In patients with prothrombin values above 1.46, clinical progression within 12 hours occurred in five of six cases.. Treatment with prothrombin complex concentrate reverses anticoagulation more rapidly than fresh-frozen plasma, which might be of importance for the prevention of further bleeding.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Blood Transfusion; Cerebral Hemorrhage; Emergency Medical Services; Humans; Infusions, Intravenous; Male; Middle Aged; Retrospective Studies; Tomography, X-Ray Computed; Vitamin K

Topics: Administration, Oral; Age Factors; Biliary Tract Diseases; Cerebral Hemorrhage; Ecchymosis; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hemothorax; Humans; Infant; Infant, Newborn; Liver Diseases; Male; Sweden; Time Factors; Vitamin K; Vitamin K Deficiency

Topics: Aged; Antithrombin III Deficiency; Cerebral Hemorrhage; Heparin; Humans; Male; Thromboembolism; Vitamin K

The Committee on Infant Nutrition of the Dutch National Cross Association and the Education Bureau on Food and Nutrition, and the Dutch Paediatric Association recommend the administration of a single oral dose of 1 mg vitamin K1 at birth to all healthy infants in order to prevent haemorrhagic disease of the newborn (HDN). Parenteral administration of vitamin K1 at birth is recommended for newborn especially at risk. For infants who are wholly or largely breastfed a daily dose of 25 micrograms vitamin K1 orally is recommended for the first three months, to be increased to 50 micrograms per day in case of additional risk factors. Literature on causes of vitamin K deficiency, incidence of HDN and trends in prophylaxis is summarized and issues which require further clarification are indicated.

Topics: Bottle Feeding; Breast Feeding; Cerebral Hemorrhage; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Risk Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Administration, Oral; Cerebral Hemorrhage; Female; Humans; Infant; Infant, Newborn; Sweden; Vitamin K; Vitamin K Deficiency Bleeding

In order to evaluate the effect of vitamin K prophylaxis on the incidence of intracranial hemorrhage (ICH) in infants aged from 1 week to 12 months, a prospective surveillance study, from 1974 to 1988, was performed on the well-defined population of Nagasaki Prefecture, Japan. The incidence of ICH in infancy markedly decreased, from 34.3/100,000 to 10.1/100,000 live births, with the oral administration of vitamin K2 at both birth and 1 week, or with additional supplementation at 1 month of age. The diminished incidence was attributed to the decreased occurrence of acute ICH due to late hemorrhagic disease (LHD), a late onset form of vitamin K deficiency, and chronic subdural hematoma. On comparing the possible etiological factors, and clinical and laboratory findings between these 2 groups, it became apparent that chronic subdural hematoma shared some etiological factors (such as breast-feeding, liver dysfunction and no supplementation of vitamin K) with LHD. Furthermore, chronic subdural hematoma developed in some patients who had previously had acute ICH due to LHD. These findings suggest that coagulopathy due to vitamin K deficiency, including LHD, is causally related in the majority of, if not all, cases of chronic subdural hematoma without any history of trauma or central nervous system infections.

Topics: Cerebral Hemorrhage; Female; Follow-Up Studies; Hematoma, Subdural; Humans; Infant; Infant, Newborn; Male; Vitamin K

The paper describes 8 cases of delayed haemorrhagic disease caused by vitamin K deficiency, occurring from 16 days to 3 months after birth and observed in 1982-87. All these infants were breast fed and had received no vitamin K prophylaxis. On the basis of these findings, the preventive role of vitamin K in breast fed infants is emphasised.

Topics: Age Factors; Breast Feeding; Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Infant; Infant, Newborn; Male; Vitamin K; Vitamin K Deficiency

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Netherlands; Retrospective Studies; Vitamin K

Topics: Breast Feeding; Cerebral Hemorrhage; Humans; Infant; Infant, Newborn; Vitamin K; Vitamin K Deficiency

Haemorrhagic disease of the newborn is preventable by the routine administration of vitamin K to newborn babies. Despite this, prophylactic administration of Vitamin K1 remains controversial and haemorrhagic disease of the newborn continues to cause significant morbidity and mortality. We present two cases of this disease occurring recently in this region of New Zealand; one resulting in an infant's death, the other baby suffering from an intraventricular haemorrhage and secondary hydrocephalus. These cases prompted us to survey major New Zealand hospitals to assess their policy as regards routine vitamin K administration to newborn infants. The results of this survey suggest that there is now a uniform policy in New Zealand hospitals of giving intramuscular vitamin K. However, intramuscular vitamin K administration may still be objected to by some parents and lead to further cases of this preventable disease. Evidence now available shows that vitamin K1 given orally in a dose of 1 mg is effective in preventing haemorrhagic disease of the newborn.

Topics: Cerebral Hemorrhage; Cerebral Ventricles; Humans; Hydrocephalus; Infant, Newborn; Injections, Intravenous; Male; Vitamin K; Vitamin K Deficiency Bleeding

Infants weighing 1500 g or less at birth are susceptible to intraventricular hemorrhage. This may be due in part to low concentrations of vitamin K-dependent clotting factors. Women in labor between 24-34 weeks' gestation were selected, according to their hospital registration number, to receive 10 mg vitamin K1 intramuscularly at least four hours before delivery. Control women received no vitamin K. The study included only infants born of mothers who were in hospital more than four hours before delivery, who weighed 1500 g or less at birth, and were less than 34 weeks' gestation. Twenty vitamin K1 and 33 control infants qualified for the study. Infants in both groups received routine postnatal vitamin K1. On admission, the infant's prothrombin activity and partial thromboplastin time (PTT) were measured. A head ultrasound was done between days 2 and 4 of life. Results demonstrated significantly improved prothrombin activity, a nonsignificant trend toward improved PTT, and a significantly decreased frequency of intraventricular hemorrhage in infants whose mothers had received vitamin K1. The effect of antenatal vitamin K1 on prothrombin activity and PTT appeared to be more pronounced in female infants.

Topics: Blood Coagulation; Cerebral Hemorrhage; Cerebral Ventricles; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Maternal-Fetal Exchange; Partial Thromboplastin Time; Pregnancy; Prothrombin; Sex Factors; Vitamin K

4 infants (2 males, 2 females) with acute bleedings due to vitamin K-deficiency beyond the neonatal period are reported. Two infants had intracranial haemorrhage and died. All infants were born appropriate for date and became no vitamin K-prophylaxis. All were breast-fed. This report is a further prove for the existence of the late onset haemorrhagic disease of the newborn. The importance of general vitamin K-prophylaxis is outlined.

Topics: Blood Coagulation Tests; Breast Feeding; Cerebral Hemorrhage; Female; Hemorrhage; Humans; Infant; Infant, Newborn; Male; Vitamin K; Vitamin K Deficiency

To determine the most effective way of preventing intracranial hemorrhage due to vitamin K deficiency in infants, we first performed a comparative study using Normotest on the effects of several regimens for the oral administration of vitamin K2. Based on the results, we gave vitamin K2 orally, 2 mg, at birth, and then, 4 mg, at 1 week of age (on discharge from the newborn nursery) to all infants except premature and low-birth-weight infants born in Nagasaki Prefecture, Japan. Since then, as the number of infants with vitamin K2 prophylaxis increased, patients with intracranial hemorrhage due to vitamin K deficiency decreased in number, and no patient was found in 1984. The incidence of this disease in infants with vitamin K prophylaxis was 1/68,500, which was one-twentieth of that (1/3,500 live births) before the period when most neonates received vitamin K prophylaxis. From the results, we concluded that the oral administration of vitamin K2 at birth and 1 week of age prevents this disease.

Topics: Administration, Oral; Breast Feeding; Cerebral Hemorrhage; Humans; Infant, Newborn; Vitamin K; Vitamin K Deficiency

A Saudi Arabian infant with severe factor X deficiency who had had two intracranial haemorrhages is described. Attempts to raise his factor X level and improve his prothrombin time (PT) and partial thromboplastin time (PTT) by using vitamin K, oestradiol and danazol have failed. New therapeutic trials are necessary for patients with severe forms of this rare disorder.

Topics: Blood Transfusion; Cerebral Hemorrhage; Child, Preschool; Danazol; Estradiol; Factor X Deficiency; Humans; Hypoprothrombinemias; Male; Partial Thromboplastin Time; Prothrombin Time; Vitamin K

Topics: Biomarkers; Blood Coagulation Disorders; Blood Coagulation Factors; Cerebral Hemorrhage; Humans; Infant; Infant, Newborn; Male; Protein Precursors; Prothrombin; Vitamin K; Vitamin K Deficiency

This paper describes a case of late neonatal convulsions due to intracranial haemorrhage in a newborn with cholestatic hepatopathy due to PiZZ homozygote alpha-1-antitrypsin deficiency. The deficiency of vitamin K dependent clotting factors, responsible for the haemorrhage, seems to be due to the cholestasis and might have been aggravated by the non-administration of vitamin K at birth and by breast feeding. The response to vitamin K therapy was good.

Topics: alpha 1-Antitrypsin Deficiency; Cerebral Hemorrhage; Humans; Infant, Newborn; Male; Phenotype; Spasms, Infantile; Vitamin K

Topics: Cerebral Hemorrhage; Female; Humans; Infant; Ultrasonography; Vitamin K; Vitamin K Deficiency

Topics: Breast Feeding; Cerebral Hemorrhage; Female; Humans; Infant; Infant, Newborn; Male; Milk, Human; Vitamin K; Vitamin K Deficiency

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Emergencies; Female; Hematoma, Epidural, Cranial; Hematoma, Subdural; Hemorrhage; Heparin; Humans; Male; Middle Aged; Protamines; Spinal Diseases; Vitamin K

A 4-week-old, breast-fed female infant appeared healthy until signs and symptoms of CNS deterioration suddenly occurred. At presentation the infant was found to have a left-sided parietal intracerebral hematoma, markedly prolonged prothrombin time, and partial thromboplastin time, normal platelet count, and jaundice with a total and direct serum bilirubin level of 5.4 mg/dL and 2.6 mg/dL, respectively. Vitamin K1 and fresh frozen plasma returned the prothrombin time and partial thromboplastin time to normal values within 18 hours, suggesting that the infant had severe vitamin K deficiency complicated by intracerebral hemorrhage. Evaluation of the infant's direct hyperbilirubinemia led to the diagnosis of homozygous (pi-type ZZ [PiZZ] ) alpha-1-antitrypsin deficiency. The clinical circumstances predisposing to vitamin K deficiency in newborns and infants are discussed. Based on our observations in this case, we suggest that cholestatic liver disease should be suspected when unexplained vitamin K deficiency occurs in early infancy. The role of vitamin K in hemostasis and the laboratory diagnosis of vitamin K deficiency are discussed as they apply to the evaluation of hemorrhage in newborns and infants.

Topics: alpha 1-Antitrypsin Deficiency; Cerebral Hemorrhage; Cholestasis, Intrahepatic; Female; Humans; Infant, Newborn; Risk; Vitamin K; Vitamin K Deficiency

Topics: Cerebral Hemorrhage; Gastrointestinal Hemorrhage; Humans; Infant, Newborn; Vitamin K; Vitamin K Deficiency Bleeding

Two breast fed infants had late manifestations of Vitamin K deficiency. No underlying disease was found in the first case. The second patient was found to have alpha 1-Antitrypsin deficiency (Pi type ZZ). The latter patient initially responded well to a single dose of vitamin K administered orally (3 mg). However, three weeks later, he was admitted to our hospital with severe intracranial hemorrhage due to severe vitamin K deficiency. Vitamin K requirements in infants and clinical characteristics of vitamin K deficiency in infants older than 1 week are discussed.

Topics: Blood Coagulation Tests; Breast Feeding; Cerebral Hemorrhage; Female; Hemorrhagic Disorders; Humans; Infant; Infant, Newborn; Male; Vitamin K; Vitamin K Deficiency

Haemorrhages were observed in four wholly breastfed infants beyond the neonatal period. These infants were observed within a period of 8 weeks and showed the following characteristics: 1. Onset of bleedings was unexpected and without prior indication. 2. They were of a serious nature and involved the CNS in two children. 3. In all cases infants between 4 and 6 weeks of life were affected. 4. All infants had been wholly breastfed. 5. All were male. 6. There was a prompt improvement after administration of vitamin K or after blood or blood derivatives. Although preliminary own investigations do not indicate general lowering of vitamin-K-dependent coagulation factors in wholly breastfed infants in the postneonatal period, these 4 cases observed within a short time confirm the necessity to consider vitamin K deficiency in haemorrhages in infants in the postneonatal period. Diagnostic steps have to be initiated immediately.

Topics: Blood Transfusion; Breast Feeding; Cerebral Hemorrhage; Hemorrhage; Humans; Infant; Infant, Newborn; Male; Vitamin K; Vitamin K Deficiency

A bleeding syndrome due to severe prothrombin complex deficiency is reported in 93 infants. Most were breast fed (98 per cent), aged 2 weeks to 1 year and there were no serious preceding or associated diseases. Hemorrhagic diathesis, pallor and mild hepatomegaly were the major manifestations. The incidence of intracr anial bleeding was strikingly high (63 per cent) particularly with subdural and subarachnoid hemorrhage. Acute onset, short course and rapid clinical and laboratory improvement after vitamin K therapy were observed. Mortality rate was 35 per cent but has been reduced to 17 per cent since 1969. The location of bleeding, prompt diagnosis and early treatment are the major factors affecting prognosis. Severe prothrombin complex deficiency due to vitamin K deficiency accounted for the pathogenesis of bleeding. Possible causes of vitamin K deficiency were discussed but definite conclusions could not be drawn.

Topics: Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Male; Subarachnoid Hemorrhage; Syndrome; Vitamin K; Vitamin K Deficiency

Topics: Asphyxia Neonatorum; Autoantibodies; Blood Coagulation Tests; Blood Platelets; Blood Transfusion; Capillary Fragility; Capillary Permeability; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Exchange Transfusion, Whole Blood; Female; Hemophilia A; Hemorrhage; Hemorrhagic Disorders; Heparin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lung; Maternal-Fetal Exchange; Pregnancy; Thrombocytopenia; Vitamin K; Vitamin K Deficiency; von Willebrand Diseases

A total of 240 cases of a bleeding syndrome in infants due to prothrombin complex deficiency of unknown aetiology were reviewed. The majority of patients were breast fed, aged 1-2 months and the syndrome was more prevalent in males. Clinical manifestations consisted of bleeding, pallor and mild hepatomegaly in the majority of cases. Mild fever, diarrhoea, jaundice, and upper respiratory tract infection were associated in a few patients. Acute onset, short course and a high rate of intracranial bleeding (65%), particularly subdural and subarachnoid, were observed. The haemostatic defects appeared to be a marked reduction in factor II, VII, IX, and X. Complete blood counts remained relatively normal, with the exception of some changes (anaemia, leukocytosis), in response to the acute bleeding. Liver chemistry was normal or slightly impaired. No specific pathological changes were noted at autopsy, there were mild changes of liver cells, such as rare focal necrosis of liver cells, the proliferation of Kupffer cells, extramedullary haemopoeisis and mild cholestasis. Clinical improvement and correction of hemostatic defects were noted after vitamin K therapy alone or with fresh blood transfusion. Mortality rates were high in infants with intracranial bleeding (40-55%), while the overall mortality rate was 25%. The pathogenesis and the possibility of prevention of the syndrome were discussed.

Topics: Blood Coagulation; Blood Coagulation Factors; Breast Feeding; Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Liver; Male; Purpura; Thailand; Vitamin K

Topics: Alanine Transaminase; Anemia; Aspartate Aminotransferases; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Transfusion; Cerebral Hemorrhage; Ecchymosis; Female; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Prognosis; Prothrombin; Prothrombin Time; Seizures; Spinal Puncture; Subarachnoid Hemorrhage; Thrombin; Thromboplastin; Vitamin K

Topics: Asphyxia Neonatorum; Birth Weight; Blood Coagulation Tests; Blood Preservation; Cerebral Hemorrhage; Freezing; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infusions, Parenteral; Plasma; Prothrombin Time; Vitamin K

Topics: Blood Coagulation Tests; Cerebral Hemorrhage; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Infant, Premature, Diseases; Prothrombin Time; Time Factors; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Blood Coagulation Disorders; Blood Specimen Collection; Blood Transfusion; Cerebral Hemorrhage; Female; Fetal Diseases; Foreign Bodies; Hematocrit; Hemorrhage; Humans; Infant, Newborn; Labor, Obstetric; Male; Medical History Taking; Pregnancy; Scalp; Vitamin K

Topics: Acute Disease; Age Factors; Ascorbic Acid; Calcium; Cerebral Hemorrhage; Cortisone; Diet Therapy; Glomerulonephritis; Gluconates; Humans; Male; Middle Aged; Purpura; Rheumatic Diseases; Rutin; Vitamin K

Topics: Anemia; Angiography; Animals; Cats; Cerebral Hemorrhage; Dogs; Ecchymosis; Embolism; Fever; Gastrointestinal Hemorrhage; Hematoma; Hematuria; Hemorrhage; Hemothorax; Heparin; Humans; Hypotension; Ischemia; Leukocytosis; Shivering; Streptokinase; Thrombosis; Vitamin K

Nine out of 232 infants on whom the vacuum extractor was employed developed subaponeurotic haemorrhage and two of these infants died. In a further 78 infants born by vacuum extraction, all of whom received intramuscular vitamin K(1), four sustained subaponeurotic haemorrhage and one died. This type of haemorrhage was not encountered in over 12,000 infants born by other methods. Its relationship to vacuum extraction was found to be significantly more frequent when the thrombotest level was 10% or below of normal adult activity. It is suggested that infants born by vacuum extraction and with a thrombotest level of 10% or below might be protected from subaponeurotic haemorrhage by the transfusion of fresh frozen plasma.

Topics: Blood Coagulation Tests; Blood Transfusion; Cerebral Hemorrhage; Extraction, Obstetrical; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Injections, Intramuscular; Pregnancy; Statistics as Topic; Vitamin K

Topics: Birth Weight; Blood Coagulation Disorders; Blood Coagulation Tests; Cerebral Hemorrhage; Gestational Age; Humans; Infant Mortality; Infant, Newborn; Infant, Newborn, Diseases; Vitamin K

Topics: Adrenal Cortex Hormones; Cerebral Hemorrhage; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Intracranial Hemorrhages; Pathology; Prednisone; Vitamin K

Topics: Cerebral Hemorrhage; Child; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Vitamin K

Topics: Antifibrinolytic Agents; Cerebral Hemorrhage; Child; Hemostatics; Humans; Infant; Infant, Newborn; Intracranial Hemorrhages; Prothrombin Time; Vitamin K