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Treatment of Warfarin-Associated Intracerebral Hemorrhage: Literature Review and Expert Opinion

      Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.
      FFP (fresh frozen plasma), ICH (intracerebral hemorrhage), INR (international normalized ratio), PCC (prothrombin complex concentrate), rFVIIa (recombinant factor VIIa)
      The frequent use of long-term oral anticoagulation in elderly patients, particularly to prevent stroke in individuals with atrial fibrillation, has resulted in an increase in warfarin-associated intracerebral hemorrhage (ICH).
      • Kucher N
      • Castellanos LR
      • Quiroz R
      • Koo S
      • Fanikos J
      • Goldhaber SZ
      Time trends in warfarin-associated hemorrhage.
      • Flaherty ML
      • Haverbusch M
      • Sekar P
      • et al.
      The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].
      Half of the patients with warfarin-associated ICH die within 30 days, and this uniformly high early mortality rate has remained stable over time
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Rosand J
      • Eckman MH
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      • Steiner T
      • Rosand J
      • Diringer M
      Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions.
      • Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group
      A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin.
      • Sjalander A
      • Engstrom G
      • Berntorp E
      • Svensson P
      Risk of haemorrhagic stroke in patients with oral anticoagulation compared with the general population.
      • Gage BF
      • Waterman AD
      • Shannon W
      • Boechler M
      • Rich MW
      • Radford MJ
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      (Table 1). Adequate treatment remains to be defined.
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      No consensus exists about the optimal short-term treatment of this lethal, iatrogenic form of stroke. Randomized trials meaningfully addressing treatment are not available, and current management is based largely on small clinical case series.
      • Steiner T
      • Rosand J
      • Diringer M
      Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions.
      TABLE 1Early Mortality in Anticoagulant-Associated Intracranial Hemorrhage
      ReferenceMethodNo. of central nervous bleeds% (No.) of 30-day mortality
      Hart et al,
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      1995
      Literature review, 15 studies, 1982-199445460 (272)
      Neau et al,
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      2001
      Case series7944 (35)
      Sjoblom et al,
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      2001
      Medical record review15154 (82)
      Rosand et al,
      • Rosand J
      • Eckman MH
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.
      2004
      Prospective case series10252
      Three-month mortality.
      (53)
      Berwaerts et al,
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      2000
      Case series4244 (35)
      SPIRIT trial,
      • Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group
      A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin.
      1997
      Randomized trial2743 (18)
      Sjalander et al,
      • Sjalander A
      • Engstrom G
      • Berntorp E
      • Svensson P
      Risk of haemorrhagic stroke in patients with oral anticoagulation compared with the general population.
      2003
      Case series4844 (21)
      Gage et al,
      • Gage BF
      • Waterman AD
      • Shannon W
      • Boechler M
      • Rich MW
      • Radford MJ
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      2001
      Medicare cohort∼20052 (104)
      Pooled data110353
      SD ± 7.
      (602)
      * Three-month mortality.
      SD ± 7.
      In the absence of well-designed clinical trials, treatment based on the opinions of experts in clinical stroke, neurologic intensive care, and hematology and coagulation is likely the best available evidence. In this article, current treatment options for warfarin-associated ICH and management recommendations solicited independently from 7 international experts are reviewed.

      METHODS

      A computerized search of the OVID database from January 1996 to January 2006 combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage was undertaken. The reference lists from recent review articles were also examined. From the elicited sources, 4 of the coauthors (R.G.H., C.S.K., M.I.A., and W.D.F.) drafted the narrative review of the recent literature. Because information about the practical clinical pharmacology of prothrombin complex concentrates (PCCs) is not readily accessible, 2 coauthors (B.J.H. and R.C.G.) prepared a structured pharmacological summary of these drugs (Appendix 1
      Factor IX complex (human). Lexi-Comp Drug Reference. Lexi-Comp Online.
      ).
      Seven experts in clinical stroke (B.N., T.S., and T.Y. or M.Y.), neurological intensive care (J.R., S.A.M., and E.F.M.W.), and hematology and coagulation (J.E.A.) were asked to independently address the following 3 questions:
      • 1.
        How should anticoagulation be reversed in a patient with acute (within 6 hours of symptom onset) warfarin-associated ICH with an international normalized ratio (INR) of 2.5? What are the roles of recombinant factor VIIa (rFVIIa) and PCCs?
      • When should anticoagulation (warfarin) be restarted in survivors of warfarin-associated ICH with mechanical prosthetic heart valves?
      • Under what circumstances (if any) should anticoagulation be resumed in a patient with chronic nonvalvular atrial fibrillation who experienced an ICH during warfarin therapy? Does it matter whether the INR was 1.8 or 3.5 at the time of the hemorrhage?
      An expert was defined as someone with involvement with one or more publications on the specific topic or who had personal experience treating warfarin-associated ICH. The selection of experts was also based on geographic location to reflect an international perspective (United States, Japan, Germany, and Sweden). No pharmaceutical company participated in the development of this article or in the selection of the experts.
      The experts were provided with the literature review, Appendix 1, and access to all sources cited in the reference list. Rather than attempting to reach a consensus, individual responses were collated and summarized (Table 2). Full answers provided by the experts are available online at www.mayoclinicproceedings.com linked to this article. Experts did not have access to each other's responses.
      TABLE 2Expert Recommendations for the Management of Warfarin-Associated ICH: Responses to 3 Specific Questions
      See text for complete statement of the questions. Complete responses available online at www.mayoclinicproceedings.com linked to this article. FFP = fresh frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCCs = prothrombin complex concentrates; rFVIIa = recombinant activated factor VIIa.
      QuestionExpert 1Expert 2Expert 3
      Expert has served as consultant for NovoNordisk.
      Expert 4
      Expert has served as consultant for NovoNordisk.
      Expert 5
      Expert has served as consultant for NovoNordisk.
      Expert 6Expert 7
      • 1.
        How can anticoagulation best be reversed (INR=2.5)?
      rFVIIa and vitamin KrFVIIa if deteriorating; FFP and vitamin K otherwiserFVIIa, FFP, and vitamin KFFP or PCCs and vitamin KPCCs and vitamin KPCCs and vitamin KPCCs and vitamin K
      • 2.
        When should anticoagulation with prosthetic cardiac valve be restarted?
      >7 d in most patients
      If patient was older than 80 years and if moderate to severe leukoaraiosis was absent.
      >7 d if computed tomogram stable5-10 dLow-dose heparin as early as 48 h10-14 d
      Low-dose heparin as early as 24 hours after normalization of INR (<1.5).
      1-3 d7 d
      • 3.
        Should warfarin therapy be restarted for atrial fibrillation?
      With reluctanceIf prior ischemic strokeProbably neverIf ICH is deep (ie, nonlobar)If ICH is deep (ie, nonlobar)If ICH is deep (ie, nonlobar)In secondary
      * See text for complete statement of the questions. Complete responses available online at www.mayoclinicproceedings.com linked to this article. FFP = fresh frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCCs = prothrombin complex concentrates; rFVIIa = recombinant activated factor VIIa.
      Expert has served as consultant for NovoNordisk.
      If patient was older than 80 years and if moderate to severe leukoaraiosis was absent.
      § Low-dose heparin as early as 24 hours after normalization of INR (<1.5).

      LITERATURE REVIEW

       Frequency of Warfarin-Associated ICH

      Warfarin-associated ICH is not rare at hospitals that serve large numbers of patients undergoing anticoagulation and appears to be increasing.
      • Flaherty ML
      • Haverbusch M
      • Sekar P
      • et al.
      The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].
      A survey of consecutive patients with supratentorial ICH admitted to the Massachusetts General Hospital between 1994 and 2001 found that 24% were taking warfarin, an average of 1 patient per month with warfarin-associated ICH admitted to this tertiary care hospital.
      • Eckman MH
      • Rosand J
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.
      Other studies of ICH in the middle to late 1990s reported that approximately 12% (range, 6%-16%) of patients with primary ICH were receiving oral vitamin Kantagonists.
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      • Nilsson OG
      • Lindgren A
      • Stahl N
      • Brandt L
      • Saveland H
      Incidence of intracerebral and subarachnoid haemorrhage in southern Sweden.
      • Woo D
      • Sauerbeck LR
      • Kissela BM
      • et al.
      Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study.
      In a large population-based survey conducted in 2002 to 2003, 18% of all ICHs occurred during anticoagulation.
      • Flaherty ML
      • Haverbusch M
      • Sekar P
      • et al.
      The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].
      Based on these figures, approximately 8000 to 10,000 cases of warfarin-associated ICH are estimated to occur annually in the United States.

       Correlations With Anticoagulation Intensity

      Anticoagulation with warfarin increases the risk of ICH 2 to 5 times, directly related to the intensity of anticoagulation
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      • Go AS
      • Hylek EM
      • Chang Y
      • et al.
      Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?.
      ; nevertheless, most warfarin-associated ICHs occur during anticoagulation intensities that are within the conventional therapeutic range (ie, INRs of 2.0-3.5).
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Eckman MH
      • Rosand J
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.
      • Hylek EM
      • Go AS
      • Chang Y
      • et al.
      Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.
      The degree of INR prolongation at the time of ICH seems to predict progressive hematoma enlargement after admission, functional outcome, and mortality,
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      • Eckman MH
      • Rosand J
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.
      • Yasaka M
      • Oomura M
      • Ikeno K
      • Naritomi H
      • Minematsu K
      Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose.
      although some have reported no correlation.
      • Flibotte JJ
      • Hagan N
      • O'Donnell J
      • Greenberg SM
      • Rosand J
      Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage.
      The outcome is fatal in two thirds of ICH patients with INRs greater than 3.0 at presentation.
      • Eckman MH
      • Rosand J
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.

       Clinical Presentation and Diagnosis

      The mean age of patients with warfarin-associated ICH is in the 70s, reflecting the age distribution of patients undergoing anticoagulation combined with the special propensity for ICH to affect elderly patients. Focal neurologic signs in a patient undergoing anticoagulation, particularly if associated with headache, nausea and vomiting, obtundation, and elevated blood pressure, warrant emergent evaluation for ICH. Symptom onset is usually sudden (ie, stroke-like). In nearly half of patients, the hematoma enlarges slowly during the initial 12 to 24 hours with attendant progression of neurologic deficits.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
      • Yasaka M
      • Oomura M
      • Ikeno K
      • Naritomi H
      • Minematsu K
      Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose.
      • Flibotte JJ
      • Hagan N
      • O'Donnell J
      • Greenberg SM
      • Rosand J
      Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage.
      • Yasaka M
      • Minematsu K
      • Naritomi H
      • Sakata T
      • Yamaguchi T
      Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin.
      Hematoma enlargement after 6 to 12 hours from onset is common in warfarin-related ICH, but this is rare in spontaneous ICH.
      • Flibotte JJ
      • Hagan N
      • O'Donnell J
      • Greenberg SM
      • Rosand J
      Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage.
      Involvement of the cerebellum in warfarin-associated ICH has been reported in several but not all studies.
      • Flaherty ML
      • Haverbusch M
      • Sekar P
      • et al.
      The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Kase CS
      • Robinson RK
      • Stein RW
      • et al.
      Anticoagulant-related intracerebral hemorrhage.
      The relative distribution of lobar vs deep white matter or basal ganglia locations appears to be similar in spontaneous vs warfarin-associated ICH.
      Intracerebral hemorrhage is visible immediately as a hyperdense area on computed tomograms; occasionally a dark rim, presumably representing unclotted blood, can be present in actively bleeding patients with excessively prolonged INRs.
      • Hart RG
      • Boop BS
      • Anderson DC
      Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
      • Ichikawa K
      • Yanagihara C
      Sedimentation level in acute intracerebral hematoma in a patient receiving anticoagulation therapy: an autopsy study.
      Magnetic resonance imaging with special gradientecho techniques is highly sensitive.
      • Kidwell CS
      • Chalela JA
      • Saver JL
      • et al.
      Comparison of MRI and CT for detection of acute intracerebral hemorrhage.
      Large hematoma volume (>50 mL), intraventricular extension, and shift of midline structures are associated with poorer outcome.
      • Neau JP
      • Couderq C
      • Ingrand P
      • Blanchon P
      • Gil R
      • VGP Study Group
      Intracranial hemorrhage and oral anticoagulant treatment.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Berwaerts J
      • Robb OJ
      • Jeffers TA
      • Webster J
      Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.

       Reversing the Coagulation Defect

      Warfarin-associated ICH should prompt emergent correction of anticoagulation. Even small hematomas in patients who have undergone anticoagulation therapy can expand during the initial 24 to 48 hours, particularly if the INR is greater than 3.0, and anticoagulation should be reversed without delay. Several options exist for achieving this goal (Table 3). No randomized trials assessing clinical outcomes were found on treatment of warfarin-associated ICH. The existing literature consists mainly of small case series, often retrospective and potentially biased by selection. In the absence of meaningful evidence, the management of these patients varies widely.
      TABLE 3Reversing Anticoagulation in Warfarin-Associated Intracerebral Hemorrhage
      INR = international normalized ratio.
      Management optionTime to anticoagulation reversalComments and cautions
      Discontinuing warfarin therapy5-14 d
      Vitamin K
      A total of 10 mg intravenously by slow infusion throughout 10 minutes.
      6-24 h to correct the INR
      • Replacement of factors IX and X takes longer than 24 hours, risk of anaphylaxis with intravenous injection, warfarin resistance in higher doses up to 1 wk
      Fresh frozen plasma3-6 h for infusion, typically 12-32 h for reversalVolume (2-4 L to normalize INR) can be prohibitive
      Prothrombin complex concentrate15 min after 10-min to 1-h infusionLimited availability, cost, variable cofactor content based on manufacturer, potentially prothrombotic
      Factor VIIa concentrate15 min after bolus infusionShort half-life, cost, potentially prothrombotic, uncertain safety
      * INR = international normalized ratio.
      A total of 10 mg intravenously by slow infusion throughout 10 minutes.
      Vitamin K and fresh frozen plasma (FFP) are standard therapies to reverse warfarin anticoagulation, but neither agent is ideal for emergency anticoagulation reversal. Both vitamin K and FFP take several hours to reduce the INR and have a potential for adverse reactions.
      • Manno EM
      • Atkinson JLD
      • Fulgham JR
      • Wijdicks EFM
      Emerging medical and surgical management strategies in the evaluation and treatment of intracerebral hemorrhage.
      Administration of vitamin K (10 mg intravenously) does not normalize the INR for 6 to 24 hours. A dose of 5 to 10 mg may be repeated every 12 hours, up to a total dose of 25 mg.
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      • Ansell J
      • Hirsh J
      • Dalen J
      • et al.
      Managing oral anticoagulant therapy.
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      • Lacy CF
      • Armstrong LL
      • Goldman MP
      • Lance LL
      The infusion rate is 1 mg/min, and it can be diluted in dextrose 5% in water or dextrose 5% in normal saline.
      • Lacy CF
      • Armstrong LL
      • Goldman MP
      • Lance LL
      Subcutaneous administration may be safer, but the effect is even slower and less reliable.
      • Bianco C
      Choice of human plasma preparations for transfusion.
      • Fiore LD
      • Scola MA
      • Cantillon CE
      • Brophy MT
      Anaphylactoid reactions to vitamin K.

       Fresh Frozen Plasma

      The volume of FFP required to reverse fully the coagulation defect (often 2-4 L if the INR is greatly prolonged) is an important limiting factor in this critically ill population. A rapid infusion is also required to increase the plasma protein levels significantly, increasing the risk of circulatory overload.
      • Hellstern P
      • Muntean W
      • Schramm W
      • Seifried E
      • Solheim BG
      Practical guidelines for the clinical use of plasma.
      Calculation of the amount of FFP (in milliliters) required to reverse the effects of warfarin is based on the INR, body weight, and target INR after correction
      • Schulman S
      Care of patients receiving long-term anticoagulant therapy.
      • Yasaka M
      • Sakata T
      • Naritomi H
      • Minematsu K
      Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation.
      • Hart RG
      Management of warfarin-associated intracerebral hemorrhage. UpToDate Online 14.3.
      (Table 4).
      TABLE 4Conversion of the International Normalized Ratio (INR) to Prothrombin Complex Concentrates (PCCs) (Expressed as Percentage of Normal Plasma)
      Calculate needed milliliters of fresh frozen plasma using the following formula35: (target level % × present level %) × body weight37 in kilograms.
      • Schulman S
      Care of patients receiving long-term anticoagulant therapy.
      • Hart RG
      Management of warfarin-associated intracerebral hemorrhage. UpToDate Online 14.3.
      INRPCCs (%)
      >55
      4.0–4.910
      2.6–3.215
      2.2–2.520
      1.9–2.125
      1.7–1.830
      1.4–1.640
      1.0–1.3100
      * Calculate needed milliliters of fresh frozen plasma using the following formula
      • Schulman S
      Care of patients receiving long-term anticoagulant therapy.
      : (target level % × present level %) × body weight
      • Hart RG
      Management of warfarin-associated intracerebral hemorrhage. UpToDate Online 14.3.
      in kilograms.
      Time to treatment has been suggested as a main prognostic factor of anticoagulation reversal in this particular patient population. On multivariable analysis of retrospectively reviewed emergency department records of 69 patients in the Boston, Mass, area, the shorter the time to vitamin K and FFP treatment, the higher the likelihood of INR correction, but without an evident improvement in neurologic outcome.
      • Goldstein JN
      • Thomas SH
      • Frontiero V
      • et al.
      Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage.

       Prothrombin Complex Concentrates

      For more than a decade, PCCs (also known as factor IX concentrate) have been used to treat warfarin-associated ICH in Europe.
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      Use of PCCs normalizes the INR more rapidly than FFP infusion,
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      • Cartmill M
      • Dolan G
      • Byrne JL
      • Byrne PO
      Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies.
      but its effect on clinical outcomes is unproved.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      A single randomized trial that included only 5 patients with anticoagulation-associated ICH was confounded by concomitant infusion of FFP.
      • Boulis NM
      • Bobek MP
      • Schmaier A
      • Hoff JT
      Use of factor IX complex in warfarin-related intracranial hemorrhage.
      The PCC preparations vary in the ratio of their coagulation factor components, making even indirect comparisons tenuous
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      (Appendix 1).
      In 8 studies that included a total of 107 patients treated with PCCs for warfarin-associated ICH, thrombosis was reported in 4 (7%) of 57, and early mortality occurred in 15 (24%) of 64 (Table 5). Of 7 patients in these series identified as having subsequent enlargement of the ICH, worsening occurred in 4 patients 12 to 72 hours later in associationwith incomplete correction (INRs of 1.5, 1.9, 2.7, and 3.2), combined with the use of heparin in 3.
      • Yasaka M
      • Oomura M
      • Ikeno K
      • Naritomi H
      • Minematsu K
      Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose.
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      Many experts suggest monitoring the patient carefully to keep the INR normal for the initial 72 hours after ICH to minimize hematoma expansion.
      TABLE 5Prothrombin Complex Concentrates (PCCs) in Warfarin-Associated Intracerebral Hemorrhage (ICH)
      % (No.) of patients
      ReferenceNo. of patientsManufacturerCompositionMedian doseICH enlargementThrombosisEarly mortality (%)
      Early mortality ranged from 2 to 30 days.
      Sjoblom et al,
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.
      2001
      23Prothrompex-T/ImmunoFactors II, VII, IX, and XNot reportedNot reportedNot reported39
      Yasaka et al,
      • Yasaka M
      • Oomura M
      • Ikeno K
      • Naritomi H
      • Minematsu K
      Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose.
      2003
      11PPSB-HT Nichiyaku/Nihon20 IU of factors II, VII, IX, and X; 380 IU/mL of protein C12.5 IU/kg (∼900 IU)22 (2/9)
      Nine ICHs plus 1 each of subdural and epidural hematoma: 1 hematoma enlargement was associated with an international normalized ratio of 2.7, which occurred 24 hours after initial correction by PCC without coadministration of vitamin K.
      0 (0/11)9
      Fredriksson et al,
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      1992
      10Preconativ/KabiFactors II (50 IU/mL), IX (60 IU/mL), and X (50 IU/mL)26 IU/kg (1930 IU)Not reported10 (1/10)20
      Yasaka et al,
      • Yasaka M
      • Sakata T
      • Naritomi H
      • Minematsu K
      Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation.
      2005
      27PPSB-HT Nichiyaku/Nihon500 IU of factors II, VII, IX, and X; 380 IU of protein C10.85 IU/kg (2.6-26.8 IU/kg)7 (2/27)Not reportedNot reported
      Cartmill et al,
      • Cartmill M
      • Dolan G
      • Byrne JL
      • Byrne PO
      Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies.
      2000
      6IXA/BPLNot specified50 IU/kgNot reported0 (0/6)17
      Boulis et al,
      • Boulis NM
      • Bobek MP
      • Schmaier A
      • Hoff JT
      Use of factor IX complex in warfarin-related intracranial hemorrhage.
      1999
      3Konyne/BayerFactors II (38 IU), VII (4 IU), IX (25 IU), and X (38 IU)40-50 IU/kgNot reported0 (0/3)33
      Bertram et al,
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      2000
      11Not specifiedNot specifiedNot reported2727 (3/11)
      Enlargement of ICH occurred on days 2 and 3 associated with international normalized ratio of 1.5, 3.2, and 1.9 at the time of deterioration and receiving full-dose (n=2) or low-dose heparin. Of 7 patients with prosthetic valves given PCCs, 2 had middle cerebral artery ischemic strokes on treatment days 4 and 5.
      9
      Makris et al,
      • 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.
      1997
      16Prothrombin-T/Immuno or IXA/BPLFactors II, VII, IX, and X25-50 IU/kgNot reported0 (0/16)Not reported
      * Early mortality ranged from 2 to 30 days.
      Nine ICHs plus 1 each of subdural and epidural hematoma: 1 hematoma enlargement was associated with an international normalized ratio of 2.7, which occurred 24 hours after initial correction by PCC without coadministration of vitamin K.
      Enlargement of ICH occurred on days 2 and 3 associated with international normalized ratio of 1.5, 3.2, and 1.9 at the time of deterioration and receiving full-dose (n=2) or low-dose heparin. Of 7 patients with prosthetic valves given PCCs, 2 had middle cerebral artery ischemic strokes on treatment days 4 and 5.
      Thrombotic events have occasionally been reported to complicate infusion of PCC,
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      but the risk is difficult to quantify from available reports because of different preparations, dosages (correcting the INR to different levels), and patient populations. Thrombogenic effects may well vary with the specific PCC preparation,
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      • Hellstern P
      Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency.
      and whether current PCCs are associated with thrombosis has never been substantiated.
      • Levi M
      • Bijsterveld NR
      • Keller TT
      Recombinant factor VIIa as an antidote for anticoagulant treatment.
      Most of the available data (Table 5) suggest that use of PCC in warfarin-associated ICH is relatively safe.
      • Preston FE
      • Laidlaw ST
      • Sampson B
      • Kitchen S
      Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients.
      However, Bertram et al
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      reported large ischemic strokes occurring in 3 of 11 ICH patients treated with PCCs (including 2 of 7 with prosthetic cardiac valves) on days 2, 4, and 5, despite 2 patients being treated with low-dose heparin. This study did not report the dosages and composition of the PCC to allow comparison to other studies.

       Dosing of PCC

      The PCC dosage is calculated according to body weight, degree of INR prolongation, and desired level of correction (Appendix 1); typical dosages are 25 to 50 IU/kg. The dose is based on the factor IX content of the preparation. After initial infusion of 500 to 1000 IU at a rate of 100 IU/min, subsequent infusion should be at 25 IU/min or less. Some have safely infused higher doses (3500 IU) during 10 minutes.
      • Preston FE
      • Laidlaw ST
      • Sampson B
      • Kitchen S
      Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients.
      The dose of PCC required to reverse warfarin anticoagulation is generally less than that for other causes of comparably prolonged INRs. For patients with warfarin-associated ICH, aiming for an INR of 1.2 or less is recommended.
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      The INR should be checked 30 minutes after the initial infusion to be certain that it is normal; if not, infusion of additional PCC should be considered.
      Alternatively, Yasaka et al
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      and Hellstern et al
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      reported successful treatment of 9 Japanese patients with warfarin-associated ICH using relatively low doses of PCC: 500 or 1000 IU was given depending on prolongation of the INR of less than 4.5 vs 4.5 or greater, respectively, with additional administration of 500 IU based on a subsequent INR obtained after the initial infusion (Table 5). Correction of INR occurred within 10 minutes of completion of the infusion. The median dosage (12.5 IU/kg) resulted in rapid correction of INR to normal, hematoma enlargement in 2 of 9 patients, and no thromboembolic episodes (including 4 patients with prosthetic cardiac valves). These same investigators prospectively treated 42 patients (median age, 70 years) with warfarin-related bleeding complications with a PCC with or without vitamin K. Of these 42 patients, 27 had ICH, 7 had epidural hematomas, and 1 had acute subdural hemorrhage. Initial infusion of 500 IU rapidly normalized the INR unless the initial INR was greater than 5.
      Vitamin K, 10 mg intravenously, should be given concomitantly with a PCC.
      • Fredriksson K
      • Norrving B
      • Stromblad LG
      Emergency reversal of anticoagulation after intracerebral hemorrhage.
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      • Yasaka M
      • Sakata T
      • Naritomi H
      • Minematsu K
      Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation.
      Some authors recommend low-dose heparin or low-dose low-molecular-weight heparin with PCC infusion to minimize the risk of thrombotic complications.
      • Hellstern P
      • Halbmayer WM
      • Kohler M
      • Seitz R
      • Muller-Berghaus G
      Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary.
      If the INR is corrected to normal using a PCC, many experts suggest beginning low-dose subcutaneous heparin or low-dose low-molecular-weight heparin 48 hours after ICH onset in patients with prosthetic cardiac valves and to restart warfarin therapy 7 to 14 days after ICH onset.
      • Cannegieter SC
      • Rosendaal FR
      • Briet E
      Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses.
      • 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?.
      For ICH survivors with a lower inherent risk of thromboembolism who will not resume anticoagulation, pneumatic compression stockings should be used for prevention of venous thromboembolism.
      • Lacut K
      • Bressollette L
      • Le Gal G
      • VICTORIAh (Venous Intermittent Compression and Thrombosis Occurrence Related to Intra-cerebral Acute hemorrhage) Investigators
      • et al.
      Prevention of venous thrombosis in patients with acute intracerebral hemorrhage.

       Recombinant Factor VIIa

      Recombinant factor VIIa, a procoagulant agent approved for bleeding complications in patients with hemophilia, has been used to treat warfarin-associated ICH
      • Deveras RA
      • Kessler CM
      Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate.
      • Sorensen B
      • Johansen P
      • Nielsen GL
      • Sorensen JC
      • Ingerslev J
      Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
      • Veshchev I
      • Elran H
      • Salame K
      Recombinant coagulation factor VIIa for rapid preoperative correction of warfarin-related coagulopathy in patients with acute subdural hematoma.
      • Freeman WD
      • Brott TG
      • Barrett KM
      • et al.
      Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage.
      • Brody DL
      • Aiyagari V
      • Shackleford AM
      • Diringer MN
      Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage.
      (Table 6). Rapid correction of the INR was demonstrated in 2 small series that included 7 patients with ICH during anticoagulation treated with rFVIIa, FFP, and vitamin K.
      • Sorensen B
      • Johansen P
      • Nielsen GL
      • Sorensen JC
      • Ingerslev J
      Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
      • Freeman WD
      • Brott TG
      • Barrett KM
      • et al.
      Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage.
      In a clinical case series, Sorensen et al
      • Sorensen B
      • Johansen P
      • Nielsen GL
      • Sorensen JC
      • Ingerslev J
      Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
      evaluated the efficacy of rFVIIa in addition to vitamin K and FFP in 7 patients with warfarin-related central nervous system bleeding. Pretreatment INRs ranged from 1.7 to 6.6. Within minutes after a single bolus dose of rFVIIa (10-40 μg/kg), all INRs were 1.5 or less. Six patients underwent drainage of the hematoma, and all patients survived. The mean Glasgow Outcome Scale score at discharge was 2 (SD ± 1). No signs of thrombosis were reported.
      TABLE 6Recombinant Factor VIIa in Warfarin-Associated ICH
      ICH = intracerebral hemorrhage; IP = intraparenchymal; IV = intraventricular; SAH = subarachnoid hemorrhage; SDH = subdural hematoma.
      ReferenceNo. of patientsType of bleedAverage dose% (No.) of patients with ICH enlargementNo. of patients with thrombosis% (No.) of early mortality
      Sorensen et al,
      • Sorensen B
      • Johansen P
      • Nielsen GL
      • Sorensen JC
      • Ingerslev J
      Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
      2003
      7
      Only 6 patients had bleeds; 1 patient was at high risk of bleeding because of an international normalized ratio greater than 7.0 and spinal stenosis.
      3 IP, 1 SAH, 1 SDH, 1 spine trauma25 ∝g/kgNot reportedNone0 (0)
      Veshchev et al, 52 20021SDH120 ∝g/kgNot reportedNot reported100 (1/1)
      Freeman et al, 53 200473 IP, 1 IP and IV, 2 IV, 1 IP and SAH52.5 ∝g/kg12-28 (3/7)None28 (2/7)
      Brody et al, 54 2005
      All received vitamin K and fresh frozen plasma in addition to recombinant factor VIIa.
      124 ICH, 4 SDH, 4 others4.8 mg (range, 2.4-9.6 mg)Not reported142 (12/28)
      * ICH = intracerebral hemorrhage; IP = intraparenchymal; IV = intraventricular; SAH = subarachnoid hemorrhage; SDH = subdural hematoma.
      Only 6 patients had bleeds; 1 patient was at high risk of bleeding because of an international normalized ratio greater than 7.0 and spinal stenosis.
      All received vitamin K and fresh frozen plasma in addition to recombinant factor VIIa.
      Doses of 10 to 50 μg/kg have been used, a dose generally lower than that required to reverse coagulation deficits associated with factor inhibitors (100 μg/kg every 2-3 hours until bleeding stops). It should be reconstituted with sterile water for injection and used within 3 hours of reconstitution.
      • Lacy CF
      • Armstrong LL
      • Goldman MP
      • Lance LL
      It is unclear how accurately the INR reflects coagulation status after rFVIIa infusion.
      • Levi M
      • Bijsterveld NR
      • Keller TT
      Recombinant factor VIIa as an antidote for anticoagulant treatment.
      • Makris M
      • Watson HG
      Reversal of coumarin-induced over-anticoagulation [letter reply].
      There is concern that rFVIIa transiently corrects the warfarin-induced deficiency of factor VII, but it does not replace the other factor deficiencies associated with oral vitamin K antagonist therapy. The elimination half-life is short (2.5 hours). Repeat infusion is necessary unless standard therapies of vitamin K and FFP are used concomitantly. No studies have compared rFVIIa infusion with PCC in warfarin-associated ICH. Those who advocate rFVIIa for reversal of warfarin-induced coagulation defects note that its short half-life makes induction of a thrombogenic state less likely compared with infusion of a PCC
      • Sorensen B
      • Johansen P
      • Nielsen GL
      • Sorensen JC
      • Ingerslev J
      Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
      (Table 6).
      Mayer et al
      • Mayer SA
      • Brun NC
      • Begtrup K
      • Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators
      • et al.
      Recombinant activated factor VII for acute intracerebral hemorrhage.
      reported in 2005 a double-blind, placebo-controlled trial evaluating the efficacy of rFVIIa in acute spontaneous ICH (not associated with warfarin). In this study, 399 participants with acute spontaneous ICH verified by computed tomography were assigned to receive either placebo or 1 of 3 dosages (40, 80, or 160 μg/kg) of rFVIIa within 4 hours of symptom onset. The primary outcome was hematoma growth at 24 hours. Mortality (38%; P=.02) and the combined outcome of death or severe disability (P<.05 for all 3 dosages) were reduced in patients given rFVIIa. Arterial thrombosis (ischemic stroke and myocardial infarction) occurred in 5% of those assigned to rFVIIa vs none assigned to placebo.

       Recommendations for Reversing Anticoagulation in Warfarin-Associated ICH

      Few guidelines or consensus recommendations have been published regarding reversal of anticoagulation in this setting. A PCC administered with vitamin K is advocated by one recent guideline for patients with life-threatening bleeding undergoing anticoagulation (with rFVIIa as an alternative) but provides no specific recommendations regarding warfarin-associated ICH.
      • Ansell J
      • Hirsh J
      • Dalen J
      • et al.
      Managing oral anticoagulant therapy.
      A review by Steiner et al
      • Steiner T
      • Rosand J
      • Diringer M
      Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions.
      in early 2006 recommended a PCC coupled with 10 mg of vitamin K.
      However, PCCs are not readily available at most US hospitals. When available, their use is often restricted to hematology specialists. Despite its increasing use, rFVIIa currently does not have Food and Drug Administration label indication for spontaneous ICH or warfarin-associated ICH, its use may be complicated by thrombosis,
      • O'Connell KA
      • Wood JJ
      • Wise RP
      • Lozier JN
      • Braun MM
      Thromboembolic adverse events after use of recombinant human coagulation factor VIIa.
      and it is expensive.

       Surgical evacuation and blood pressure control

      The role of neurosurgical evacuation of ganglionic and lobar ICH during anticoagulation is not well defined, and most neurosurgeons are reluctant to operate in a setting of impaired hemostasis. However, given the high mortality accompanying warfarin-associated ICH, surgical treatment after reversing anticoagulation may be appropriate in select patients,
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      especially if the coagulopathy can be rapidly corrected. The International Surgical Trial in Intracerebral Haemorrhage
      • Mendelow AD
      • Gregson BA
      • Fernandes HM
      • STICH Investigators
      • et al.
      Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial.
      included only those with spontaneous supratentorial ICH.
      Blood pressure is often elevated in patients with ICH at admission. Treatment guidelines for acute, spontaneous ICH recommend treatment of hypertension with the aim of achieving a mean arterial pressure of less than 130 mm Hg.
      • Broderick JP
      • Adams Jr, HP
      • Barsan W
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association.
      Considerable controversy remains regarding whether high blood pressure contributes to continuing bleeding after ICH onset and if lowering of blood pressure can cause perihematomal ischemia or hematoma enlargement.
      • Powers WJ
      • Zazulia AR
      • Videen TO
      • et al.
      Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage.
      Despite the debate, some authors recommend that the systolic blood pressure be maintained below 180 mm Hg during the acute phase.
      • Broderick JP
      • Adams Jr, HP
      • Barsan W
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association.
      However, in 151 patients with anticoagulant-related ICH, acute blood pressure was not predictive of 1-month or 6-month mortality.
      • Sjoblom L
      • Hardemark HG
      • Lindgren A
      • et al.
      Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.

       Which Patients Should Receive Long-term Anticoagulation After Warfarin-Associated ICH?

      The indication for restarting oral anticoagulation should be carefully reassessed in the wake of a warfarin-associated ICH. No studies provide an accurate estimation of the risk of recurrent ICH in survivors of warfarin-associated ICH who are subsequently undergoing anticoagulation. In 5 small case series that included 14 patients with prosthetic heart valves who had warfarin-associated ICH and later underwent additional anticoagulation therapy, the aggregate risk appeared low, 3% per year (Table 7). However, the absolute risk of recurrent ICH in these younger patients with prosthetic heart valves during anticoagulation is likely lower than in older patients with atrial fibrillation. The presence of lacunar strokes,
      • de Jong G
      • Kessels F
      • Lodder J
      Two types of lacunar infarcts: further arguments from a study on prognosis.
      the burden of white matter disease,
      • Smith EE
      • Gurol ME
      • Eng JA
      • et al.
      White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage.
      • Smith EE
      • Rosand J
      • Knudsen KA
      • Hylek EM
      • Greenberg SM
      Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke.
      and the existence of clinically silent microhemorrhages (detected by magnetic resonance imaging gradient-echo techniques)
      • Roob G
      • Lechner A
      • Schmidt R
      • Flooh E
      • Hartung HP
      • Fazekas F
      Frequency and location of microbleeds in patients with primary intracerebral hemorrhage.
      • Jeerakathil T
      • Wolf PA
      • Beiser A
      • et al.
      Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study.
      • Fan YH
      • Zhang L
      • Lam WW
      • Mok VC
      • Wong KS
      Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke.
      • Kato H
      • Izumiyama M
      • Izumiyama K
      • Takahashi A
      • Itoyama Y
      Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis.
      • Nighoghossian N
      • Hermier M
      • Adeleine P
      • et al.
      Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: a gradientecho T2*-weighted brain MRI study.
      • Koennecke HC
      Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications.
      • Viswanathan A
      • Chabriat H
      Cerebral microhemorrhage.
      may help predict the recurrence of ICH. Currently, this information provides no method for riskstratification in predicting initial or recurrent ICH in clinical situations.
      TABLE 7Long-term Anticoagulation in Survivors of Warfarin-Associated ICH
      ICH = intracerebral hemorrhage; INR = international normalized ratio.
      ReferenceNo. of patientsMean age (y)IndicationTarget INR
      No information is available about achieved INRs during follow-up.
      Mean follow-up (mo)Outcome
      Punthakee et al,
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      2002
      6∼64Prosthetic valvesNot reported34No ICH
      Butler & Tait,
      • Butler AC
      • Tait RC
      Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up.
      1998
      4∼57Prosthetic valves2-3, 2.5-3, 3-3.5, 3-4.522No ICH
      Nakagawa et al,
      • Nakagawa T
      • Kubota T
      • Handa Y
      • Kawano H
      • Sato K
      Intracranial hemorrhage due to long-term anticoagulant therapy in patients with prosthetic heart valves—four case reports.
      1995
      Surgical evacuation performed for index ICH.
      111Prosthetic valveNot reported36
      Nagano et al,
      • Nagano N
      • Tabata H
      • Hashimoto K
      Anticoagulant-related intracerebral hemorrhage in patients with prosthetic heart valves—report of two cases.
      1991
      Surgical evacuation performed for index ICH.
      239Prosthetic valvesNot reported5
      Lau et al,
      • Lau CP
      • Chang CM
      • Lau GK
      • Wong CK
      • Fong PC
      • Yu YL
      Cerebral haemorrhage in anticoagulated patients with non-septic mechanical valvular prosthesis.
      1991
      165Prosthetic valve1.8-2.536No ICH
      Aggregate data14∼55Prosthetic valves271 ICH
      (3% per year)
      * ICH = intracerebral hemorrhage; INR = international normalized ratio.
      No information is available about achieved INRs during follow-up.
      Surgical evacuation performed for index ICH.
      For primary prevention of ischemic stroke in elderly patients with nonvalvular atrial fibrillation, the long-term risk of recurrent ICH during anticoagulation may outweigh its benefit.
      • Eckman MH
      • Rosand J
      • Knudsen KA
      • Singer DE
      • Greenberg SM
      Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.
      • Wani M
      • Nga E
      • Navaratnasingham R
      Should a patient with primary intracerebral haemorrhage receive antiplatelet or anticoagulant therapy?.
      Patient preferences are important to consider in this difficult discussion. In those with prosthetic cardiac valves or for secondary prevention in atrial fibrillation, the risks of thromboembolism in the absence of anticoagulation are much higher, and the risk-benefit assessment favors reinitiation of anticoagulation.
      The use of aspirin or other antiplatelet agents in combination with warfarin is likely to increase the risk of recurrent ICH, and this combination should not be used routinely.
      • Hart RG
      • Benavente O
      • Pearce LA
      Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis.
      • Shireman TI
      • Howard PA
      • Kresowik TF
      • Ellerbeck EF
      Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients.
      • Gasse C
      • Hollowell J
      • Meier CR
      • Haefeli WE
      Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.
      Targeting the lowest efficacious INR (eg, 1.8-2.5 for patients with atrial fibrillation) should be coupled with especially vigilant INR monitoring to minimize excessive anticoagulation. Control of blood pressure is critical; lowering systolic blood pressure by 10 mm Hg will reduce the risk of recurrent ICH by half.
      • Chapman N
      • Huxley R
      • Anderson C
      • et al.
      Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial.

       If Indicated, When Should Anticoagulation Be Restarted?

      No large prospective trials have addressed the issue of when to restart anticoagulation after warfarin-associated ICH. The literature ranges from withholding warfarin anticoagulation for 4 to 6 weeks
      • Crawley F
      • Bevan D
      • Wren D
      Management of intracranial bleeding associated with anticoagulation: balancing the risk of further bleeding against thromboembolism from prosthetic heart valves.
      to withholding it for 1 to 2 weeks
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      • Phan TG
      • Koh M
      • Wijdicks EF
      Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk.
      • Wijdicks EF
      • Schievink WI
      • Brown RD
      • Mullany CJ
      The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves.
      to the use of intravenous heparin immediately after the INR is corrected to normal.
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      • Leker RR
      • Abramsky O
      Early anticoagulation in patients with prosthetic heart valves and intracerebral hematoma.
      Overall, the data (8 studies involving 132 patients, Table 8) suggest a low risk of thromboembolic complications between 7 and 14 days after anticoagulation reversal in patients with warfarin-associated ICH and prosthetic valves.
      TABLE 8Timing of Additional Anticoagulation in Patients With Warfarin-Associated ICH
      Reports and/or cases with surgical evacuation are excluded.30,31 ICH = intracerebral hemorrhage; INR = international normalized ratio.
      ReferenceNo. of patientsInitiation of anticoagulation and outcomes
      Punthakee et al,
      • Punthakee X
      • Doobay J
      • Anand SS
      Oral-anticoagulant-related intracerebral hemorrhage.
      2002
      7Warfarin therapy started a mean of 14 d (9-15 d in 4 patients); no ICH enlargement or thrombotic events
      Bertram et al,
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      2000
      13Full-dose intravenous heparin on days 1 and 2 in 7 patients, with hematoma enlargement in 2; of 6 patients given low-dose heparin, 3 had ischemic strokes on days 2, 4, and 5 (all previously treated with prothrombin complex concentrates)
      Butler & Tait,
      • Butler AC
      • Tait RC
      Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up.
      1998
      4Heparin on day 3 (range, 1-6) and warfarin on day 7 (range, 3-19) in 10 patients with ICHs (n=4) or subdural hematomas (n=6); no ICH enlargement or thrombotic events
      Phan et al,
      • Phan TG
      • Koh M
      • Wijdicks EF
      Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk.
      2000
      87Anticoagulation withheld for mean of 10 d, acute treatment to reverse anticoagulation not reported, and 1 ischemic stroke; the 30-d thromboembolism rate estimated as 3% for those with prosthetic cardiac valves
      Leker & Abramsky,
      • Leker RR
      • Abramsky O
      Early anticoagulation in patients with prosthetic heart valves and intracerebral hematoma.
      1998
      4Four patients given intravenous heparin 24-36 h as soon as INR was <1.5 after vitamin K and plasma infusion; no worsening
      Kawamata et al,
      • Kawamata T
      • Takeshita M
      • Kubo O
      • Izawa M
      • Kagawa M
      • Takakura K
      Management of intracranial hemorrhage associated with anticoagulant therapy.
      1995
      13Six patients underwent surgery; of 20 patients with intracranial hemorrhages and prosthetic valves, 1 thromboembolism in a setting of early postoperative heparin
      Babikian et al,
      • Babikian VL
      • Kase CS
      • Pessin MS
      • Caplan LR
      • Gorelick PB
      Resumption of anticoagulation after intracranial bleeding in patients with prosthetic heart valves [letter].
      1988
      3Of 6 patients with prosthetic cardiac valves (3 with ICHs and 3 with subdurals), warfarin therapy interrupted for a mean of 19 d without thromboembolism
      Gomez et al,
      • Gomez CR
      • Sandhu J
      • Mehta P
      Resumption of anticoagulation during hypertensive cerebral hemorrhage with prosthetic heart valve [letter].
      1988
      1Heparin on day 10 without hemorrhagic worsening in 1 patient
      * Reports and/or cases with surgical evacuation are excluded.
      • Yasaka M
      • Sakata T
      • Minematsu K
      • Naritomi H
      Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
      • Lacy CF
      • Armstrong LL
      • Goldman MP
      • Lance LL
      ICH = intracerebral hemorrhage; INR = international normalized ratio.
      In a study of 141 patients with warfarin-associated ICH, Phan et al
      • Phan TG
      • Koh M
      • Wijdicks EF
      Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk.
      reported anticoagulation interruption for a mean of 10 days. Only 3 patients (2%) experienced thromboembolic events (1 patient with a prosthetic cardiac valve); all 3 events occurred within 5 days from discontinuation of anticoagulation therapy. The authors concluded that the risk of thromboembolism is low if warfarin therapy is discontinued for 1 to 2 weeks. No information was reported about reversal of anticoagulation and whether INRs were corrected to normal in most patients (a previous report describing part of this patient cohort reported routine use of FFP and vitamin K).
      • Wijdicks EF
      • Schievink WI
      • Brown RD
      • Mullany CJ
      The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves.
      In contrast, Bertram et al
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      reported 2 large ischemic strokes in 7 ICH patients with prosthetic cardiac valves treated with PCCs despite concomitant treatment with low-dose heparin. The authors advocated the use of full-dose intravenous heparin on the day after treatment with PCCs. A possible explanation for the apparent difference in observed rates of thromboembolism after reversal of anticoagulation in these 2 studies is a prothrombotic state caused by infusion of high-dose PCCs in the series by Bertram et al,
      • Bertram M
      • Bonsanto M
      • Hacke W
      • Schwab S
      Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.
      although play of chance and/or publication bias could be operative.
      If the INR is corrected to normal using PCCs, it may be sensible to begin treatment with low-dose subcutaneous heparin or low-dose low-molecular-weight heparin 48 hours after ICH onset. For patients who will resume anticoagulation, it appears that warfarin therapy can be safely restarted 7 to 14 days after ICH.

      DISCUSSION

      Warfarin-associated ICH is a devastating iatrogenic problem whose frequency is increasing because more elderly people are receiving anticoagulation. It is a tragic irony that anticoagulation given to prevent ischemic stroke can be complicated by severe, usually lethal, hemorrhagic stroke as its most dreaded complication. In the absence of randomized trials, management is based on a combination of anecdotal experience, pathophysiologic constructs, and expert opinion. Not surprisingly, the management recommendations by 7 experts from 3 continents vary widely.
      All agree that anticoagulation should be urgently reversed, but how to achieve this varies from traditionalinfusion of FFP to use of PCCs and rFVIIa (all with vitamin K administration). The delay to reversal and volume overload with FFP has been acknowledged. Proponents of rFVIIa point to its rapid reversal of the INR and lack of volume overload, but other experts express concern that its safety among patients taking warfarin to prevent thrombosis is not established.
      All experts favored resumption of warfarin therapy within 5 to 10 days of ICH in stable patients (Table 2). No general consensus occurred regarding additional anticoagulation for patients with atrial fibrillation who experience ICH during warfarin therapy: the risk of thromboembolism (ie, prior ischemic stroke) and the risk of recurrent ICH (ie, lobar vs deep location of the initial ICH) were the key factors considered. We do not make specific treatment recommendations but rather define the range of management used by experts in the absence of solid clinical evidence.
      Is a randomized trial of short-term treatment of warfarin-associated ICH feasible? Some estimate that there are 10,000 cases annually in the United States alone.
      • Flaherty ML
      • Haverbusch M
      • Sekar P
      • et al.
      The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].
      The time window for effective intervention is probably longer than for spontaneous ICH and for ischemic stroke. In addition to direct benefits to those with warfarin-associated ICH, an efficacious intervention proven by randomized trials might well allay fears that cause anticoagulation to be withheld from many who would benefit. On the other hand, such a trial would be difficult to organize and expensive, require large numbers of participants (depending on the selected treatment arms), and be challenging to design, given the lack of a generally accepted standard treatment. Furthermore, some speculate that warfarin will be replaced by other oral anticoagulants in the future, but this remains speculative.

      CONCLUSION

      Reasonable management of warfarin-associated ICH includes a range of treatments in the absence of adequate data, as defined by the expert opinions delineated herein. Time to reversal of anticoagulation is crucial, and whatever treatment strategy is endorsed should be planned in advance in collaboration with local emergency medicine physicians and be used expeditiously. Randomized trials that address the management of warfarin-associated ICH are needed.

      APPENDIX 1. Prothrombin Complex Concentrates (PCCs) (Also Known as Factor IX Complex [Human]) for Reversal of Warfarin-Induced Bleeding

      Factor IX Complex (Human) Drug Information
      Factor IX complex (human). Lexi-Comp Drug Reference. Lexi-Comp Online.
      US BRAND NAMES: Bebulin; Profilnine HT; Proplex T; Konyne 80
      Tabled 1Prothrombin Complex Concentrate (PCC) Content of Factors II, VII, IX, and X
      Factors measured in units per 100 U of factor IX (ratios).
      ProductManufacturer
      Grifols Biologicals Inc, Los Angeles, Calif; Bayer Corp, West Haven, Conn; Baxter Biopharmaceuticals, Deerfield, Ill.
      Factor IIFactor VIIFactor IXFactor XCost per unit of factor VII
      Example cost calculation: Proplex T vial containing 600 U total (ratios as above), cost = $0.42 · 400 = $168.
      15 ($)
      Profilnine HT (500 U/vial)Grifols14811100640.75
      Konyne 80 (500 U/vial)Bayer100201001400.50
      Proplex T (30 mL)Baxter50400100500.42
      Bebulin (size not available)Baxter120131001390.75
      * Factors measured in units per 100 U of factor IX (ratios).
      Grifols Biologicals Inc, Los Angeles, Calif; Bayer Corp, West Haven, Conn; Baxter Biopharmaceuticals, Deerfield, Ill.
      Example cost calculation: Proplex T vial containing 600 U total (ratios as above), cost = $0.42 · 400 = $168.
      PHARMACOLOGICAL CATEGORY: Antihemophilic agent, blood product derivative.
      MECHANISM OF ACTION: Replaces deficient clotting factor, including factor X. Factor IX is a vitamin K-dependent coagulation factor that is synthesized in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway. Activated factor IX (IXa), in combination with factor VII:C, activates factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous factor IX to replace the deficiency present in hemophilia B temporarily restores hemostasis.
      CONTRAINDICATIONS: Liver disease with signs of intravascular coagulation or fibrinolysis, not for use in factor VII deficiencies (except Proplex T), patients undergoing elective surgery.
      WARNINGS/PRECAUTIONS: Use with caution in patients with liver dysfunction; prepared from pooled human plasma—the risk of viral transmission is not totally eradicated; monitor patients who receive repeated doses twice daily with partial thromboplastin time (PTT) and prothrombin time (PT) and level of factor being replaced (eg, usually VII or IX); if PT is less than 10 seconds, this may indicate risk of hypercoagulable complication.
      MONITORING PARAMETERS: Levels of factors being replaced (eg, VII or IX), PT, PTT.
      PHARMACODYNAMICS/KINETICS: Half-life elimination:
      • VII component: initial, 4-6 hours; terminal, 22.5 hours
      • IX component: 24 hours
      DOSING: ADULTS = Emergency correction of warfarin-induced coagulopathy; bleeding in factor IX deficiency: intravenous (only):
      • Note: dosage is expressed in units of factor IX activity and must be individualized.
      • Formula for units required to raise blood level percentage:
        Total blood volume (milliliters of blood per kilogram) = 70 mL/kg
        Plasma volume = total blood volume (milliliters) × [1 − hematocrit (in decimals)]
        For example, for a 70-kg adult with a hematocrit of 40%: plasma volume = [70 kg × 70 mL/kg] × [1 − 0.4] = 2940 mL
      • To calculate number of units needed to increase level to desired range (highly individualized and dependent on patient's condition):
        Number of units = desired level increase [desired level − actual level] × plasma volume (in milliliters)
        For example, for a 100% level in the above patient who has an actual level of 20%:
        Number of units needed = [1 (for a 100% level) − 0.2] × 2940 mL = 2352 U
      • As a general rule, the level of factor IX required for treatment of anticoagulant overdosage = 15 U/kg intravenously Sample calculation:
        70-kg patient × 15 U/kg of factor IX = 1050 U of factor IX needed
        Proplex T (rounded to next 100 U): 1100 U of factor IX needed
        Ratio=400 U of factor VII100 U of factor IX×?1100 U of factor IX=4400 U of factor VII needed


        Cost = 4400 U of factor VII × $0.42/U = $1848
      DOSAGE FORMS: Injection, powder for reconstitution (single-dose vials).
      ADMINISTRATION: Solution should be infused at room temperature. Intravenous administration only; should be infused slowly. Start infusion at a rate of 2 to 3 mL/min. If headache, flushing, or changes in pulse rate or blood pressure appear, the infusion rate should be decreased. Initially, stop the infusion until the symptoms disappear, then resume the infusion at a slower rate. Infuse at a rate not exceeding 3 mL/min.
      SIGNIFICANT ADVERSE REACTIONS
      • • 1% to 10%:
        Central nervous system: fever, headache, chills
        Neuromuscular and skeletal: tingling
        Miscellaneous: following rapid administration, transient fever
      • • <1% (limited to important or life-threatening): disseminated intravascular coagulation, flushing, nausea, somnolence, thrombosis following high dosages because of presence of activated clotting factors, tightness in chest, tightness in neck, urticaria, vomiting
      DRUG INTERACTIONS: Increased toxicity; do not coadminister with aminocaproic acid because it may increase risk of thrombosis.
      PRODUCT RESTRICTIONS/ORDERING INFORMATION: Per telephone communication with a representative from Baxter Bioscience (Jennifer Randolph, 1-800-423-2090 ext 5983), because of limited product availability, distribution of these products is restricted to prevent or control bleeding in patients with factor IX deficiency, especially hemophilia B and Christmas disease, factor VII deficiency (Proplex T only), and hemophilia. Average shelf-life of ordered vials is typically 6 to 12 months.

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        Mayo Clinic ProceedingsVol. 82Issue 3
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          Incorrect mathematical symbol: In the article by Aguilar et al entitled “Treatment of Warfarin-Associated Intracerebral Hemorrhage: Literature Review and Expert Opinion,” published in the January 2007 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2007;82:82-92), an incorrect mathematical symbol, a times sign rather than a minus sign, appeared in the equation in the footnote to Table 4 on page 85. The equation should read as follows: …(target level %-present level %) × body weight37 in kilograms.
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