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Original Article

Iatrogenic causes of an ICH: OAT therapy

Iorio, A.a

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European Journal of Anaesthesiology: February 2008 - Volume 25 - Issue - p 8-11
doi: 10.1017/S0265021507003171
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Intracerebral haemorrhage (ICH) is less common than ischaemic stroke: ranging from 20 to 60 vs. 183 to 349 per 100 000 people per year for ICH and ischaemic stroke, respectively. However, ICH is associated with the highest reported death rate (up to 50% of cases), which ranges approximately between 0.2 and 0.4 cases per 1000 population per year [1-3]. Haematoma volume is the critical determinant of death as well as of functional outcome after ICH [4], and it appears to be the result of a dynamic process, with continuous bleeding or re-bleeding over several hours [4,5]. About 30% of ICH occurs in patients on antithrombotic treatment, but it has not been clearly demonstrated yet as to whether oral anticoagulant treatment (OAT) or antiplatelet treatment (APT) negatively affects the natural history of ICH, possibly leading to larger haematomas and more disabling strokes [6,7]. The relevance of this issue is evident when the increasing number of patients on antithrombotic treatment is compared with the rate of intracranial bleeding [8,9]. Therefore, the use of OAT or APT for the prevention of thromboembolic events [10,11] should take into account the outcome of possible haemorrhagic side-effects, particularly in elderly subjects [12-15].


It is possible that the use of OAT simply unmasks intracerebral bleeding that would otherwise remain asymptomatic [16]. Actually, magnetic resonance imaging (MRI) studies indicate that micro-haemorrhages can be found even in normal individuals [18]. Advancing age and cerebral amyloid angiopathy are important co-causal agents to lobar ICH in patients who receive OAT or not [18,19], suggesting that spontaneous intracerebral haemorrhage (SICH) and OAT-ICH may have the same underlying cause. Furthermore, the distribution of the cerebral locations where OAT-ICH occurs is similar to that of SICH [20,21]. Although most OAT-ICH cases occur when the prothrombin time-international normalized ratio (PT-INR) is within the therapeutic range, higher intensities of anticoagulation clearly increase the risk of OAT-ICH [20,22-24], suggesting that OAT may also directly cause ICH.

Haematoma growth

Although the incidence and dynamics of haematoma expansion in OAT-ICH still need to be established, it may be more common and occurs over a longer time frame than in SICH, because of persistent coagulopathy. Haematoma expansion up to day 7 was found in 16% (9/57) of patients who were not on OAT compared to 54% (7/13) of patients who were on OAT [25]. Probably, in OAT-ICH the natural course of haematoma expansion is more prolonged, perhaps up to 24 or 48 h [25-27], raising the possibility that patients presenting within 24 h may benefit from effective haemostatic treatment.


The primary aim of OAT-ICH management is reversal of the anticoagulant effect to limit ongoing bleeding and haematoma expansion. Treatment options include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCC) and activated recombinant factor VII (rFVIIa) [28-31]. There are currently no standardized guidelines for reversal of the anticoagulant effect in patients with OAT-ICH. UK guidelines issued by the British Committee for Standards in Haematology recommend 5 mg of intravenous (i.v.) or oral vitamin K, and 50 U kg−1 of PCC or 15 mL kg−1 of FFP [32]. The American Thoracic Society recommend 10 mg of i.v. vitamin K and PCC, without specifying the dose of PCC [33]. In particular, no guidelines are given about resuming OAT after ICH. Considerations concerning whether and when to resume therapeutic anticoagulation in patients who have experienced OAT-ICH include whether intracranial bleeding has been fully arrested, the estimated ongoing risk of thromboembolism and the presumed pathophysiology of the ICH, which will determine the risk of haemorrhage recurrence [28,34-39].

Vitamin K.

Even if it takes at least 2-6 h for vitamin K to achieve an effective response and hence vitamin K alone is often inadequate to quickly normalize the PT-INR, the i.v. administration of 5-20 mg of vitamin K is necessary to achieve a sustained reversal of anticoagulation, because of the relatively short half-life of other procoagulant factors as compared to coumarin derivatives [32,33,40-42].


FFP contains all coagulation factors in a non-concentrated form; hence, to achieve effective haemostasis a large volume (up to 3500 mL) is required [28,43,44]. One mL of FFP per kg increases the plasma levels of coagulation factors by 1-2 IU dL−1 [45]. Traditionally, 10-15 mL of plasma per kg body weight are administered, but they may have to be exceeded in massive bleeding [46]. The large volume required and the rapid transfusion rate can lead to circulatory overload, particularly in cardiopathic patients. Moreover, FFP transfusion is associated with several adverse reactions, mainly transfusion-related acute lung injury and allergic reactions [47,48].


PCC contain coagulation factors VII, IX, X and prothrombin, and can be quickly given without compatibility testing and time for thawing. Small studies suggest that PCC correct a prolonged PT-INR more rapidly than FFP [43,49,50], but a retrospective study comparing vitamin K, FFP, PCC and no treatment in 151 patients with OAT-ICH found no difference in 90-day mortality [51]. The main concern with PCC use focuses on the potential to induce thrombosis and disseminated intravascular coagulation [52-56].


rFVIIa administration is an appealing alternative to conventional factor replacement to reverse OAT anticoagulation. Almost any i.v. dose of rFVIIa can normalize the INR in an OAT patient within minutes [57], but the duration of INR normalization is short lasting and a function of the given amount. Doses of 5-20 μg kg−1 normalize the INR (<1.5) for 6-9 h, doses of 40-80 normalize the INR for 9-12 h and doses ≥120 μg kg−1 normalize the INR for 12-24 h [57]. Published series indicate that a wide range of rFVIIa doses can rapidly normalize elevated INR values in patients with oral anticoagulant-related ICH [57,58]. In the majority of patients rFVIIa was given in addition to conventional therapy with FFP and vitamin K, and in these reports the dose of rFVIIa generally ranged from 60 to 90 μg kg−1. No thrombotic complications occurred, even in patients at very high risk [59].

Current clinical trials in OAT-ICH

An open, prospective, multicentre randomized pilot trial to evaluate efficacy and safety of rFVIIa against standard therapy is currently running in Italy. Totally, 32 patients have to be enrolled in Italian Emergency Departments and Stroke Units. To date, six patients have been randomized, and the trial is still recruiting participating centres. rFVIIa is administered as a single bolus of 80 μg kg−1 within 24 h from symptom onset and within 1 h from the diagnostic computed tomography (CT). The primary efficacy end-point is the change of the ICH volume as measured by CT head scans from prior to rFVIIa administration to 24 h after. The secondary efficacy end-points is the difference between groups on the modified Rankin Scale, the Barthel Index, the Extended Glasgow Scale and the National Institute of Health's Stroke Scale over the duration of the trial. Additional details about the trial are available at (NCT00222625 - rFVIIa in ICH in Patients Treated With Anticoagulants or Anti-Platelets - Phase II trial: Sponsored by the University of Perugia. Contact [email protected]).

Conflict of interest: None.


1. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 1997; 28: 491-499.
2. Carolei A, Marini C, Di Napoli M et al.. High stroke incidence in the prospective community-based l'Aquila registry (1994-1998): first year's result. Stroke 1997; 28: 2500-2506.
3. Baldi G, Altomonte F, Altomonte M, Ghirarduzzi A, Brusasco C, Iorio RCA. Intracranial haemorrhage in patients on antithrombotics: clinical presentation and determinants of outcome in a prospective multicentric study in Italian emergency departments. Cerebrovasc Dis 2006; 22: 286-293.
4. Dennis MS. Outcome after brain haemorrhage. Cerebrovasc Dis 2003; 16: 9-13.
5. Kothari RU, Brott T, Broderick JP et al.. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996; 27: 1304-1305.
6. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypothesis. Stroke 1995; 26: 1471-1477.
7. Landerfeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-328.
8. Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002; 325: 1073-1075.
9. Mattle H, Kohler S, Huber P, Rohner M, Steinsiepe KF. Anticoagulation related intracranial extracerebral hemorrhage. J Neurol Neurosurg Psychiatry 1989; 52: 829-837.
10. Hankey GJ, Eikelboom JW. Antiplatelet drugs. Med J Aust 2003; 178: 568-574.
11. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. Chest 2004; 126: 204S-233S.
12. The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) Study Group. Oral anticoagulation in patients after cerebral ischaemia of arterial origin and risk of intracranial hemorrhage. Stroke 2003; 34: e45-e47.
13. Abbott RD, Curb JD, Rodriguez BL et al.. Age-related changes in risk factor effects on the incidence of thromboembolic and hemorrhagic stroke. J Clin Epidemiol 2003; 56: 479-486.
14. Palareti G, Leali N, Coccheri S et al.. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428.
15. Nicolini A, Ghirarduzzi A, Iorio A, Silingardi M, Malferrari G, Baldi G. Intracranial bleeding: epidemiology and relationships with antithrombotic treatment in 241 cerebral hemorrhages in Reggio Emilia. Haematologica 2002; 87: 948-956.
16. Hart RG. What causes intracerebral hemorrhage during warfarin therapy? Neurology 2000; 55: 907-908.
17. Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F. MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 1999; 52: 991-994.
    18. Rosand J, Hylek EM, O'Donnell HC, Greenberg SM. Warfarin associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 2000; 55: 947-951.
    19. Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. Intern Med 2001; 40: 1183-1188.
    20. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164: 880-884.
    21. Nilsson OG, Lindgren A, Stahl N, Brandt L, Saveland H. Incidence of intracerebral and subarachnoid haemorrhage in southern Sweden. J Neurol Neurosurg Psychiatry 2000; 69: 601-607.
    22. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation, Analysis of pooled data from five randomized controlled trials. Arch Intern Med, 1994; 154: 1449-1457.
    23. Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996; 156: 409-416.
    24. Hylek E, Singer DE. Risk factor for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
    25. Flibotte JJ, Hagan N, O'Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63: 1059-1064.
    26. Brott T, Broderick J, Kothari R et al.. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28: 1-5.
    27. Leira R, Davalos A, Silva Y et al.. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology 2004; 63: 461-467.
    28. Butler AC, Tait RC. Management of oral anticoagulant-induced intracranial haemorrhage. Blood Rev 1998; 12: 35-44.
    29. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45: 1113-1118.
    30. Freeman WD, Brott TG, Barrett KM et al.. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79: 1495-1500.
    31. Fewel ME, Park P. The emerging role of recombinant-activated factor VII in neurocritical care. Neurocritical Care 2004; 1: 19-30.
    32. Baglin TP, Rose PE, Walker ID et al.. Guidelines on oral anticoagulation: third edition. Br J Haemato 1998; 101: 374-387.
    33. Ansell J, Hirsh J, Dalen J et al.. Managing oral anticoagulant therapy. Chest 2001; 119: 22S-38S.
    34. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 2000; 57: 1710-1713.
    35. Ananthasubramaniam K, Beattie JN, Rosman HS, Jayam V, Borzak S. How safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage? Chest 2001; 119: 478-484.
    36. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neuro 2000; 247: 209-214.
    37. Hacke W. The dilemma of anticoagulation for patients with intracranial hemorrhage or how wide is the strait between Skylla and Karybdis? (Editorial). Neurology 2000; 57: 1682-1684.
    38. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 2003; 34: 1710-1716.
    39. Wijdicks EF, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clin Proc 1998; 73: 829-836.
    40. Beeck H, Hellstern P. In vitro characterization of solvent/detergent treated human plasma and of quarantine fresh frozen plasma. Vox Sang 1998; 74: 219-223.
    41. Hanley JP. Warfarin reversal. J Clin Pathol 2004; 57: 1132-1139.
    42. Bianco C. Choice of human plasma preparations for transfusion. Transfus Med Rev 1999; 13: 84-88.
    43. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77: 477-480.
    44. Pindur G, Morsdorf S, Schenk JF, Krischek B, Heinrich W, Wenzel E. The overdosed patient and bleedings with oral anticoagulation. Semin Thromb Hemost 1999; 25: 85-88.
    45. Hellstern P, Muntean W, Schramm W, Seifried E, Solheim BG. Practical guidelines for the clinical use of plasma. Thromb Res 2002; 107: S53-S57.
    46. O'Shaughnessy DF, Atterbury C, Bolton Maggs P et al.. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126: 11-28.
    47. Gilstad CW. Anaphylactic transfusion reactions. Curr Opin Hematol 2003; 10: 419-423.
    48. Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol 2003; 10: 412-418.
    49. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45: 1113-1118.
    50. Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23: 972-977.
    51. Sjoblom L, Hardemark HG, Lindgren A et al.. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32: 2567-2574.
    52. McNeill SA, Ewing JC, Wallace WA, Stewart LH. Venous infarction of a testicle following factor IX concentrate (DEFIX). Br J Haematol 1998; 101: 210.
    53. Roddie PH, Stirling C, Mayne EE, Ludlam CA. Thrombosis and disseminated intravascular coagulation following treatment with the prothrombin complex concentrate, DEFIX. Thromb Haemost 1999; 81: 667.
    54. Kohler M, Hellstern P, Lechler E, Uberfuhr P, Muller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998; 80: 399-402.
    55. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res 1999; 95: S7-S12.
    56. Kohler M, Habauer G, Miyashita C et al.. Quality control of prothrombin complex preparations: in vivo and in vitro findings. Beitr Infusionsther 1990; 26: 186-189.
    57. Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9: 741-748.
    58. Freeman WD, Brott TG, Barrett KM et al.. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79: 1495-1500.
    59. Conti S, La Torre D, Gambelunghe G, Ciorba E, Iorio A. Successful treatment with rFVIIa of spontaneous intracerebral hemorrhage in a patient with mechanical prosthetic heart valves. Clin Lab Haem 2005; 27: 283-285.


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