Intracerebral Hemorrhage Associated With Oral Anticoagulant Therapy: Current Practices and Unresolved Questions

Background and Purpose— 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. Summary of Review— 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. Conclusions— 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.

[1]  S. Mayer,et al.  Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage , 2007, Stroke.

[2]  R. Rossaint,et al.  Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. , 2005, The Journal of trauma.

[3]  M. Rich,et al.  Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. , 2005, The American journal of medicine.

[4]  G. Mariani,et al.  Clinical phenotypes and factor VII genotype in congenital factor VII deficiency , 2005, Thrombosis and Haemostasis.

[5]  D. Brody,et al.  Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage , 2005, Neurocritical care.

[6]  B. Hunt,et al.  "Off-license" use of recombinant activated factor VII. , 2004, Blood reviews.

[7]  T. Brott,et al.  Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. , 2004, Mayo Clinic proceedings.

[8]  E. Wood,et al.  Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis , 2004, The Medical journal of Australia.

[9]  J. Hanley.  Warfarin reversal , 2004, Journal of Clinical Pathology.

[10]  S. Greenberg,et al.  Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage , 2004, Neurology.

[11]  C. Eby,et al.  Transfusion medicine service policies for recombinant factor VIIa administration , 2004, Transfusion.

[12]  A. Dávalos,et al.  Early neurologic deterioration in intracerebral hemorrhage , 2004, Neurology.

[13]  J. Duguid,et al.  Guidelines for the use of fresh‐frozen plasma, cryoprecipitate and cryosupernatant , 2004, British journal of haematology.

[14]  D. Singer,et al.  The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. , 2004, Archives of internal medicine.

[15]  M. Brophy,et al.  Anaphylactoid Reactions to Vitamin K , 2001, Journal of Thrombosis and Thrombolysis.

[16]  P. Park,et al.  The emerging role of recombinant-activated factor VII in neurocritical care , 2004, Neurocritical care.

[17]  G. Pomper,et al.  Risks of transfusion-transmitted infections: 2003. , 2003, Current opinion in hematology.

[18]  S. Imbesi,et al.  Intramedullary Spinal Cord Astrolipoma: Case Report , 2003, Neurosurgery.

[19]  J. C. Sørensen,et al.  Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects , 2003, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[20]  D. Singer,et al.  Can Patients Be Anticoagulated After Intracerebral Hemorrhage?: A Decision Analysis , 2003, Stroke.

[21]  W. Hacke,et al.  Stroke MRI in Intracerebral Hemorrhage: Is There a Perihemorrhagic Penumbra? , 2003, Stroke.

[22]  T. Lindahl,et al.  A Critical Evaluation of the Prothrombin Time for Monitoring Oral Anticoagulant Therapy , 2003, Pathophysiology of Haemostasis and Thrombosis.

[23]  G. Newman,et al.  Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment. , 2003, Journal of neurosurgery.

[24]  J. Ingerslev,et al.  Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation , 2003, Journal of thrombosis and haemostasis : JTH.

[25]  H. Naritomi,et al.  Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. , 2003, Thrombosis and haemostasis.

[26]  H. Diener,et al.  Management Patterns and Health Care Use after Intracerebral Hemorrhage , 2003, Cerebrovascular Diseases.

[27]  S. Mayer.  Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage , 2003, Stroke.

[28]  E. Seifried,et al.  Practical guidelines for the clinical use of plasma. , 2002, Thrombosis research.

[29]  G. Volcheck,et al.  The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. , 2002, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[30]  C. Bianco.  Choice of Human Plasma Preparations for Transfusion , 2002, Vox sanguinis.

[31]  Eric E. Smith,et al.  Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke , 2002, Neurology.

[32]  K. Minematsu,et al.  Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. , 2001, Internal medicine.

[33]  B. Norrving,et al.  Management and Prognostic Features of Intracerebral Hemorrhage During Anticoagulant Therapy: A Swedish Multicenter Study , 2001, Stroke.

[34]  M. Makris,et al.  The management of coumarin‐induced over‐anticoagulation , 2001 .

[35]  R. E. Adams,et al.  Hypoperfusion without Ischemia Surrounding Acute Intracerebral Hemorrhage , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  D. Singer,et al.  Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. , 2001, JAMA.

[37]  S. Borzak,et al.  How safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage? , 2001, Chest.

[38]  M. Makris,et al.  The management of coumarin-induced over-anticoagulation Annotation. , 2001, British journal of haematology.

[39]  J. Hirsh,et al.  Managing oral anticoagulant therapy. , 2001, Chest.

[40]  E. Wijdicks,et al.  Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. , 2000, Archives of neurology.

[41]  W. Hacke.  The dilemma of reinstituting anticoagulation for patients with cardioembolic sources and intracranial hemorrhage: how wide is the strait between Skylla and Karybdis? , 2000, Archives of neurology.

[42]  A. Lindgren,et al.  Incidence of intracerebral and subarachnoid haemorrhage in southern Sweden , 2000, Journal of neurology, neurosurgery, and psychiatry.

[43]  S. Greenberg,et al.  Warfarin-associated hemorrhage and cerebral amyloid angiopathy , 2000, Neurology.

[44]  R. Hart.  What causes intracerebral hemorrhage during warfarin therapy? , 2000, Neurology.

[45]  W. Hacke,et al.  Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation , 2000, Journal of Neurology.

[46]  R. Kumar,et al.  Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. , 1999, Archives of internal medicine.

[47]  A. Schmaier,et al.  Use of factor IX complex in warfarin-related intracranial hemorrhage. , 1999, Neurosurgery.

[48]  Edward Groth,et al.  Facts and hypotheses , 1999, Nature Biotechnology.

[49]  J. Gorter,et al.  Major bleeding during anticoagulation after cerebral ischemia , 1999, Neurology.

[50]  A. Baxter,et al.  Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. , 1999, Stroke.

[51]  P. Hellstern,et al.  Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. , 1999, Thrombosis research.

[52]  C. Ludlam,et al.  Thrombosis and disseminated intravascular coagulation following treatment with the prothrombin complex concentrate, DEFIX. , 1999, Thrombosis and haemostasis.

[53]  P Kapeller,et al.  MRI evidence of past cerebral microbleeds in a healthy elderly population , 1999, Neurology.

[54]  B. Krischek,et al.  The overdosed patient and bleedings with oral anticoagulation. , 1999, Seminars in thrombosis and hemostasis.

[55]  P. Heuschmann,et al.  A prospective community-based study of stroke in Germany--the Erlangen Stroke Project (ESPro): incidence and case fatality at 1, 3, and 12 months. , 1998, Stroke.

[56]  J. Boissel,et al.  The effect of recombinant factor VIIa (NovoSeven™) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0 , 1998, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[57]  P. Uberfuhr,et al.  Thromboembolic Complications Associated with the Use of Prothrombin Complex and Factor IX Concentrates , 1998, Thrombosis and Haemostasis.

[58]  E. Wijdicks,et al.  Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. , 1998, Mayo Clinic proceedings.

[59]  Guidelines on oral anticoagulation: third edition , 1998 .

[60]  Ewing,et al.  VENOUS INFARCTION OF A TESTICLE FOLLOWING FACTOR IX CONCENTRATE (DEFIX) , 1998, British journal of haematology.

[61]  R. Tait,et al.  Management of oral anticoagulant-induced intracranial haemorrhage. , 1998, Blood reviews.

[62]  P. Hellstern,et al.  In Vitro Characterization of Solvent/Detergent‐Treated Human Plasma and of Quarantine Fresh Frozen Plasma , 1998, Vox sanguinis.

[63]  F. Verheugt,et al.  A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin , 1997, Annals of neurology.

[64]  P. Hellstern,et al.  Measurement of factor VII and of activated factor VII in healthy individuals and in prothrombin complex concentrates. , 1997, Thrombosis research.

[65]  F. Rosendaal,et al.  Emergency Oral Anticoagulant Reversal: The Relative Efficacy of Infusions of Fresh Frozen Plasma and Clotting Factor Concentrate on Correction of the Coagulopathy , 1997, Thrombosis and Haemostasis.

[66]  C. Sudlow,et al.  Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. , 1997, Stroke.

[67]  J. Broderick,et al.  Early hemorrhage growth in patients with intracerebral hemorrhage. , 1997, Stroke.

[68]  Takenoriyamaguchi,et al.  Enlargement of Spontaneous Intracerebral Hemorrhage , 1996 .

[69]  Haruko Yamamoto,et al.  Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. , 1996, Stroke.

[70]  W. J. Hamilton,et al.  Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial , 1996, The Lancet.

[71]  David C. Anderson,et al.  Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. , 1996, Archives of internal medicine.

[72]  S. Juvela.  Risk factors for impaired outcome after spontaneous intracerebral hemorrhage. , 1995, Archives of neurology.

[73]  R. Hart,et al.  Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. , 1995, Stroke.

[74]  H. Katayama,et al.  Contrast sonography for detection of vesicoureteral reflux , 1994, The Lancet.

[75]  S. Connolly,et al.  Stroke Prevention in Atrial Fibrillation II Study , 1994, The Lancet.

[76]  E. Hylek,et al.  Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin , 1994, Annals of Internal Medicine.

[77]  Stroke Investigators.  Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study , 1994, The Lancet.

[78]  H. White,et al.  Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation : stroke prevention in atrial fibrillation II study. Commentary , 1994 .

[79]  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. , 1994, Archives of internal medicine.

[80]  B. Norrving,et al.  Emergency Reversal of Anticoagulation After Intracerebral Hemorrhage , 1992, Stroke.

[81]  J. Broderick,et al.  The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. , 1992, The New England journal of medicine.

[82]  J. V. van Swieten,et al.  Intracerebral hematomas during anticoagulant treatment. , 1990, Stroke.

[83]  S. Rose,et al.  [Quality control of prothrombin complex preparations: in vivo and in vitro findings]. , 1990, Beitrage zur Infusionstherapie = Contributions to infusion therapy.

[84]  R. O'Reilly,et al.  Warfarin metabolism and drug-drug interactions. , 1987, Advances in experimental medicine and biology.