Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2006;37:256-262
Published online before print December 8, 2005, doi: 10.1161/01.STR.0000196989.09900.f8
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
37/1/256    most recent
01.STR.0000196989.09900.f8v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steiner, T.
Right arrow Articles by Diringer, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steiner, T.
Right arrow Articles by Diringer, M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Related Collections
Right arrow Other Stroke Treatment - Medical
Right arrow Coumarins
Right arrow Acute Cerebral Hemorrhage

(Stroke. 2006;37:256.)
© 2006 American Heart Association, Inc.

Comments, Opinions, and Reviews

Intracerebral Hemorrhage Associated With Oral Anticoagulant Therapy

Current Practices and Unresolved Questions

Thorsten Steiner, MD, PhD; Jonathan Rosand, MD, MSc Michael Diringer, MD, FAHA

From the Department of Neurology, University of Heidelberg, Germany (T.S.); the Vascular and Critical Care Neurology, Massachusetts General Hospital, Boston, Mass (J.R.); and the Neurology/Neurosurgery Intensive Care Unit, Department of Neurology, Washington University, St Louis, Mo (M.D.).

Correspondence to Dr Thorsten Steiner, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. E-mail thorsten_steiner{at}med.uni-heidelberg.de


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowEpidemiology
 down arrowPathophysiology
 down arrowCurrent Treatment Strategies
 down arrowGuidelines for Reversal of...
 down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
Background and Purpose— Life-threatening intracranial hemorrhage, predominantly intracerebral hemorrhage (ICH), is the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. Early intervention focuses on rapid correction of coagulopathy in order to prevent continued bleeding.

Summary of Review— This article reviews the epidemiology of OAT-associated ICH (OAT-ICH), and current treatment options, with the aim of providing a framework for future studies of unresolved questions. A number of acute treatments are available, but all have a significant risk of inducing thrombosis and other side effects, and vary in their rapidity of effect: vitamin K (very slow response time), fresh frozen plasma (slow response time, large volume of fluid required, transfusion-related acute lung injury), prothrombin complex concentrates, and recombinant activated factor VII. Current practice is to administer a combination of vitamin K and either fresh frozen plasma or prothrombin complex concentrates; the occasional use of recombinant activated factor VII has been reported. No prospective study has addressed the efficacy of, or outcomes from, the use of these practices.

Conclusions— Current management of OAT-ICH is varied and not based on evidence from randomized controlled trials. Well-designed clinical trials are essential if we are to identify the effective acute treatments for OAT-ICH that are urgently needed.


Key Words: etiology • intracerebral hemorrhage • oral anticoagulant agents • therapy • warfarin


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowEpidemiology
 down arrowPathophysiology
 down arrowCurrent Treatment Strategies
 down arrowGuidelines for Reversal of...
 down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
Spontaneous intracerebral hemorrhage (SICH) is the deadliest form of stroke, with a mortality rate between 30% and 55%,1–3 increasing to as high as 67% in patients receiving oral anticoagulant therapy (OAT).3,4 The incidence of OAT-related-ICH (OAT-ICH) is expected to increase in the coming years as the result of an anticipated rise in the incidence of atrial fibrillation attributable to an aging population (Figure 1).5,6



View larger version (13K):
[in this window]
[in a new window]
  		Figure 1. Projected number of adults with atrial fibrillation in the United States between 1995 and 2050. (Reproduced from reference 6). Upper and lower curves represent the upper and lower scenarios based on sensitivity analyses.

Although there has been significant progress in our understanding of the pathophysiology, rate of hematoma expansion, treatment, and the critical time window for controlling the bleeding in SICH, our current understanding of OAT-ICH remains limited. Despite ICH being the most serious and frequently fatal complication of OAT, there are currently no universally accepted guidelines for treatment.

This article reviews the epidemiology of OAT-ICH, its pathophysiology, and treatment options, based on currently available data. Pressing questions concerning optimal treatment and the time window for controlling ongoing bleeding are also discussed.


*    Epidemiology
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Epidemiology
down arrowPathophysiology
 down arrowCurrent Treatment Strategies
 down arrowGuidelines for Reversal of...
 down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
Worldwide, the incidence of SICH ranges from 10 to 20 per 100 000 population/year.7,8 The reported incidence of OAT-ICH is 7- to 10-fold higher than in patients who are not receiving OAT, and is as high as 1.8% per year in stroke-prone patients.3,4,9–12 OAT-ICH comprise 70% of all OAT-related intracranial hemorrhages, with the remainder being subdural hemorrhages.10 In Sweden, a prospective registry of all patients with ICH during a 1-year period found that, of 466 cases of intracranial hemorrhage, 73.2% were SICH, 22.7% were attributable to subarachnoid hemorrhage (80% aneurysmal), and the remaining 4.2% were caused by arteriovenous malformations or tumors. Whereas SICH was associated with hypertension (37%), cerebrovascular disease (41%), or OAT (12%), there was no association between OAT and subarachnoid hemorrhage.13 In epidemiologic studies the incidence of all strokes range from 200 to 500 per 100 000. ICH accounts for 8% to 15% of strokes,14,15 and OAT-ICH accounts for 10% to 12% of all ICH.13 Thus, we estimate that OAT-ICH occurs at a rate 2 to 9 per 100 000 population/year.

The most common long-term indication for OAT is the prevention of ischemic stroke in patients with atrial fibrillation, a common condition of the elderly. Unfortunately, OAT dramatically increases the risk for ICH (placebo versus warfarin, 0.1% versus 0.3% to 3.7%), worsens the severity of ICH, and significantly increases the likelihood of death when ICH occurs.5,17–19 Unfortunately, with the aging of the population, the impact of OAT-ICH is likely to increase as the numbers of patients with atrial fibrillation increase.


*    Pathophysiology
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 *Pathophysiology
down arrowCurrent Treatment Strategies
 down arrowGuidelines for Reversal of...
 down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
Current Concepts of OAT-ICH
Hart and colleagues hypothesize that the use of OAT merely unmasks intracerebral bleeding that would otherwise remain asymptomatic, especially in patients with underlying hypertension or cerebrovascular disease.20 A number of observations support this hypothesis. First, gradient-echo MRI indicates that microbleeds can be found even in neurologically normal individuals and are strongly associated with increased age and hypertension.21 Second, cerebral amyloid angiopathy is most commonly found in people over 65 years of age and is a major risk factor for SICH in the elderly. Both advancing age and cerebral amyloid angiopathy are also important contributory factors to lobar ICH in patients who are receiving OAT,22,23 suggesting that, in many cases, both SICH and OAT-ICH may have the same underlying cause. Third, data from the Stroke Prevention in Reversible Ischemia Trial (SPIRIT) and the European Atrial Fibrillation Trial (EAFT) indicate that patients with primary underlying cerebrovascular disease had a remarkably higher risk of OAT-ICH.24,25 Moreover, studies suggest that the presence of white matter lesions, so-called "leukoaraiosis," is an independent predictor of SICH.26 The underlying causes of SICH and OAT-ICH may therefore be the same, with OAT acting as an exacerbating factor. These considerations may also explain why the distribution of locations in the brain where OAT-ICH occurs is no different from that seen in patients with SICH.4,13

Although the majority of OAT-ICH cases occur when a prothrombin time-international normalized ratio (PT-INR) is within the therapeutic range, higher intensities of anticoagulation clearly increase the risk of OAT-ICH,4,5,17,27 suggesting that OAT may also directly cause ICH. Oral anticoagulants interfere with the synthesis of vitamin K-dependent clotting factors, resulting in low levels of factors VII, IX, X, and prothrombin (Figures 2 and 3Down). It is possible that adequate levels and functional forms of these clotting factors are essential to counteract the stress placed on blood vessels as part of normal daily activities and to prevent bleeding.28,29



View larger version (14K):
[in this window]
[in a new window]
  		Figure 2. A simplified coagulation process. Coagulation is initiated by the binding of factor VIIa to the exposed tissue factor (TF) on subendothelium at the site of vascular injury. TF-factor VIIa complex activates factor IX and factor X. Factor IXa also activates factor X. Factor Xa, in turn, rapidly converts prothrombin to thrombin, generating small amounts of thrombin. Thrombin activates factor V and factor VIII, accelerating the activation of prothrombin and factor X, respectively. Thrombin also activates factor XI to factor XIa, which, in turn, activates factor IX. The generation of large amounts of factor Xa by factor IXa and factor VIIIa ensures that sufficient amounts of thrombin are continuously generated to convert fibrinogen to fibrin. Thrombin activates factor XIII to factor XIIIa, which then cross-links the soluble fibrin monomers to form a stable fibrin clot.



View larger version (29K):
[in this window]
[in a new window]
  		Figure 3. Mechanism of action of vitamin K antagonists. In the liver, reduced vitamin K catalyzes the carboxylation converting an inactive form of prothrombin, factors VII, IX, and X, to an active form. In this process, reduced vitamin K is converted to oxidized vitamin K, which is converted back to vitamin K by the enzyme epoxide reductase. Vitamin K antagonists inhibit epoxide reductase; hence, oxidized vitamin K cannot be recycled back to vitamin K, resulting in a depletion of reduced vitamin K.

Hematoma Expansion in OAT-ICH
ICH is a dynamic process. In SICH, hematoma expansion is thought to result from persistent bleeding or rebleeding from a single site of arterial rupture or secondary bleeding in the perilesional tissue.30 Hematoma expansion occurs in nearly 40% of patients with SICH in the early hours following onset,1,31 and extravasation of contrast media within the hematoma, a possible indicator of ongoing bleeding, has been detected in 46% of SICH cases.32 Whether hematoma expansion occurs with similar frequency and time course in OAT-ICH remains unknown.

Although the incidence and dynamics of hematoma expansion in OAT-ICH remain to be established, hematoma expansion in OAT-ICH may be more common and occur over a longer time frame than in SICH, because of persistent coagulopathy. In a retrospective study of 47 patients with OAT-ICH, hematoma expansion was found in 28% of those evaluated within 24 hours of onset.33 However, in this study, apart from vitamin K, some patients also received fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC), and it is unclear as to which treatment(s) those patients with hematoma expansion had received. In another study, hematoma expansion up to day 7 was found in 16% (9/57) of patients who were not on OAT compared with 54% (7/13) in those on OAT.18

Presumably, a prolonged natural course of hematoma expansion in OAT-ICH would provide a longer time window for treatment with hemostatic therapy.

Perihematomal Edema in OAT-ICH
Although several studies in SICH suggest that the role of perihematomal ischemia is small at most,34,35 no similar measurements have been undertaken in OAT-ICH. It is possible that acute reversal of anticoagulation might paradoxically exacerbate perihematomal edema. Factors released from activated platelets at the site of bleeding, such as vascular endothelial growth factor, may interact with thrombin to increase vascular permeability and contribute to the development of edema.36 Although, in theory, a hemostatic drug that locally enhances the generation of thrombin, such as recombinant activated factor VIIa (rFVIIa), might increase brain edema, results from a recent clinical trial in SICH show that this was not the case.37


*    Current Treatment Strategies
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 *Current Treatment Strategies
down arrowGuidelines for Reversal of...
 down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
The primary aim of OAT-ICH management is reversal of the anticoagulant effect to limit ongoing bleeding and hematoma expansion. Treatment options include vitamin K, FFP, PCC, and rFVIIa.9,38–40 Different preparations of OAT have different half-lives (HLT): for example, 36 to 42 hours for warfarin and 7 days for coumarin,41 and therefore the treatment of OAT-ICH may have to be tailored to the particular type of oral anticoagulant used by the patient.

Vitamin K
It takes at least 2 to 6 hours, and often more than 24 hours, to achieve an effective response to vitamin K administration, although vitamin K alone is often inadequate to completely normalize the international normalized ratio in that time frame. Concomitant administration of coagulation factors is therefore required. Nevertheless, because of the short HLT of transfused coagulation factors (factor II: 48 to 60 hours; factor VII: 5 to 6 hours; factor IX: 20 to 24 hours; factor X: 24 to 48 hours), the administration of 5 to 20 mg of vitamin K is necessary to achieve a sustained reversal of anticoagulation.42–46 The effect of vitamin K is more rapid when given intravenously. Although there have been concerns regarding allergic and anaphylactic reactions to intravenous vitamin K, the risk of this complication appears to be quite low,47 with an incidence in one study of 3 per 10 000 doses (95% CI: 0.04 to 11 per 10 000 doses).48 Subcutaneous administration may be safer but does not correct the INR as rapidly or as reliably as intravenous use.49

Fresh Frozen Plasma
FFP contains all coagulation factors in a nonconcentrated form; hence, to achieve effective hemostasis a large volume (up to several liters) is required.9,50,51 In principle, 1 mL of FFP/kg body weight increases the levels of coagulation factors by 1 to 2 International Units (IU)/dL.52 The traditional dose of 10 to 15 mL of plasma/kg body weight may have to be exceeded in massive bleeding.53 However, the standard of an FFP unit is based on its factor VIII content; the actual levels of vitamin K-dependent coagulation factors are not specified and vary considerably.50,54 Our routine experience, and that of others, suggests that FFP volumes required to reduce the INR below 1.4 may vary considerably: for example, between 800 and 3500 mL.39,55

FFP requires compatibility testing and thawing before transfusion. Furthermore, the large volume required and a rapid transfusion rate can lead to circulatory overload. In cases of life-threatening bleeding such as ICH, or in patients with impaired cardiac function, FFP is therefore a less than ideal treatment option. In addition, FFP transfusion is associated with several potential adverse reactions, including transfusion-related acute lung injury, blood-borne infection, citrate toxicity, and allergic reactions.56,57

PCC
PCC contain coagulation factors VII, IX, X, and prothrombin as well as proteins C, S, and Z in a concentrated form, and, unlike FFP, can be given without waiting for compatibility testing and thawing. The potency of PCC is expressed as factor IX content in IU, varying between preparations,58 and a dose consists of {approx}50 to 150 mL of reconstituted product. Based on data obtained from patients with hemophilia B, a dose of 1 IU of factor IX/kg body weight increases the level of plasma factor IX by 1 IU/dL.59

Studies of small numbers of patients suggest that PCC corrects a prolonged INR more rapidly than FFP.38,50,60 However, a retrospective study comparing vitamin K, FFP, PCC, and no treatment in 151 patients with OAT-ICH, found no difference in 90-day mortality.61 The main concerns with PCC-use focus on the potential to induce thrombosis and disseminated intravascular coagulation.62–66

rFVIIa
rFVIIa is approved for the treatment of bleeding in patients with hemophilia. A recent clinical trial in acute SICH without coagulopathy demonstrated that rFVIIa, despite causing an increased incidence of thromboembolic events, reduced hematoma growth, reduced mortality, and improved 90-day functional outcome.37 In patients with blunt trauma, rFVIIa significantly reduced red blood cell transfusions.67 Furthermore, rFVIIa has been used off-label in patients with uncontrolled bleedings attributable to hemostatic abnormalities resulting from trauma or massive blood loss, thrombocytopenia, inherited or acquired platelet dysfunction, liver dysfunction, in cardiac surgery, and for the prevention of perioperative bleedings.68,69 There are limited data regarding the use of rFVIIa in OAT-ICH. A study by Erhardtsen et al in healthy individuals receiving OAT demonstrated that administration of rFVIIa in doses ranging from 5 to 320 µg/kg successfully normalized the INR, and that the effect lasted longer with higher doses.70 Sørensen et al reported 6 patients who had been on OAT and were treated with rFVIIa for central nervous system bleeding.71 The doses used ranged from 10 to 40 µg/kg and the pretreatment INRs, which ranged from 1.7 to 6.6, were normalized to ≤1.5 within 10 minutes after rFVIIa administration. No adverse events, in particular thromboembolic events, were seen in the reported patients. In 2 retrospective studies including patients with OAT-ICH, rFVIIa was given alone (n=7) or in combination with FFP (n=12) in doses ranging from 15 to 120 µg/kg.39,55 The authors concluded that treatment with rFVIIa may have lead to a faster correction of INR or decreased FFP requirements. In these studies application of rFVIIa appeared to be safe.

Several features make rFVIIa a promising candidate for OAT-ICH treatment. These include rapid action localized to the site of vascular injury, low volume required for administration, and good efficacy and safety profiles.37,40 Nevertheless, patients on OAT have an increased risk for thromboembolism, and it is possible that the safety profile in patients with OAT-ICH could be different from that in SICH.


*    Guidelines for Reversal of Anticoagulant Effect
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 up arrowCurrent Treatment Strategies
 *Guidelines for Reversal of...
down arrowUnresolved Issues on Treatment
 down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
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 Hematology recommend 5 mg of intravenous or oral vitamin K, and 50 U/kg of PCC or 15 mL/kg of FFP.43 Another UK guideline, issued by the Northern Region Hematologists’ Group, reduce the recommended dose of PCC to 30 U/kg.45 The American Thoracic Society recommend 10 mg of intravenous vitamin K and PCC, without specifying the dose of PCC.44 The Australasian Society of Thrombosis and Hemostasis recommends 5 to 10 mg of intravenous vitamin K, 25 to 50 IU/kg of PCC, and 150 to 300 mL FFP.72 The recommendation for the concomitant use of PCC and FFP is because the PCC preparation licensed in Australia and New Zealand at the time the guidelines were published in 2004 did not contain factor VII.

We recommend administering 10 mg vitamin K with every treatment to support the supply of prothrombin-dependent clotting factors. Currently, PCC appears to be a logical treatment for immediate reversal of the anticoagulant effect. However, concerns regarding thromboembolic side effects persist. Although FFP is widely available, its efficacy is difficult to predict because of the variable contents of coagulation factors in each unit. Furthermore, the large volumes required limit its use in patients with impaired cardiac function. Treatment should be continued until the INR is normalized.

Costs of these treatments are difficult to predict for medical (interindividual variability of effect, variability of product), economic, and political reasons. Given a patient with 70 kg with an INR of 3 on admission, the costs to decrease the INR to 1.4 or lower may be {euro}330 to 550 for FFP (2000 to 3500 mL), {euro}400 to 900 for PCC ({approx}2000 U), and {euro}3500 to 5000 for rFVIIa (single 80 µg/kg dose). However, it is important to realize that the efficacy of a treatment should ultimately determine the clinical decision to use it, and, currently, no treatment has been prospectively shown to be effective.

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 hemorrhage recurrence.9,73–78


*    Unresolved Issues on Treatment
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 up arrowCurrent Treatment Strategies
 up arrowGuidelines for Reversal of...
 *Unresolved Issues on Treatment
down arrowConsiderations for Clinical...
 down arrowConclusions
 down arrowReferences
 
Time Window for Treatment
In SICH, evidence suggests that significant hematoma expansion tends to occur during the first 4 hours after onset, and this is likely to be the critical time window for a hemostatic treatment.30,37 In OAT-ICH, the natural course of hematoma expansion is probably more prolonged, perhaps up to 24 or 48 hours,1,18,79 raising the possibility that patients presenting as late as 24 hours (or even later) may benefit from effective hemostatic treatment.

Dose Regimen
Administration of an effective hemostatic agent at an early stage of SICH appears to accelerate the formation of a fibrin clot, which stops the bleeding.37 In this case, it seems that a single dose is sufficient. However, in OAT-ICH, the underlying coagulopathy may require a higher dose or repeated dosing.

Monitoring Hemostasis During the Reversal of Anticoagulant Effect
PT-INR is routinely used for regulating OAT as well as monitoring the reversal of its anticoagulant effect. The test is sensitive to decreased levels of factor VII and factor X, and prothrombin, but not to decreased levels of factor IX.50,53,80,51,75 Because FFP contains variable amounts of factor IX, the correction of the INR with FFP may not be accompanied by a correction of factor IX levels.50 For example, Makris et al found that administration of 800 mL FFP decreased the mean INR from 6.73 to 2.38, whereas the mean factor IX levels were essentially unchanged (from 26.45 IU/dL to 27.36 IU/dL).50 Thus, the INR may be normalized but the patient remains at risk of further bleeding.

The use of the INR for monitoring patients treated with rFVIIa is also problematic. Pharmacological doses of rFVIIa will always lower the INR regardless of the levels of other coagulation factors. Hence, when monitoring the reversal of anticoagulant effect, INR values should be interpreted with caution as they might not reflect the actual status of all vitamin K-dependent coagulation factors.53,51

Thromboelastography may provide a more meaningful measure of coagulation status. This system records a profile of clot formation in whole blood, providing an overall picture of hemostatic function.81,76 Based on 7 patients with central nervous system bleeding during OAT who were treated with rFVIIa, Sørensen and colleagues showed that it may be feasible to use thromboelastography to monitor hemostatic status.71 Nevertheless, more data are needed to prove the clinical utility of the measure.


*    Considerations for Clinical Trials in OAT-ICH
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 up arrowCurrent Treatment Strategies
 up arrowGuidelines for Reversal of...
 up arrowUnresolved Issues on Treatment
 *Considerations for Clinical...
down arrowConclusions
 down arrowReferences
 
The design of future trials will have to address choice and dose of agent, the timing of its administration, and the risk of adverse effects ranging from thromboembolism to the possibility of exacerbated neurologic injury. For ethical reasons, all patients will of necessity require some form of treatment (for example, vitamin K, FFP, PCC, rFVIIa). Dose and dosing frequency are relevant because normalization of coagulation may occur at different doses of the intervention, and the long HLT of the anticoagulation treatment may make it necessary to repeat the respective intervention. The appropriate time window for treatment is likely to be different from that of SICH,37 as the time course for ongoing bleeding and hematoma expansion in OAT-ICH appears to be prolonged. Patients with OAT-ICH also differ from most patients with SICH in that they are, by definition, at elevated risk for thromboembolism, which could complicate both acute treatment and the duration selected for maintaining a normal INR following the acute event. Finally, it will be important to select an ideal test for monitoring the therapeutic response to reversal of anticoagulation, because some individuals may respond more slowly to treatment than others. Ultimately, whether such acute interventions prove cost-effective will require further study, but given the high mortality of OAT-ICH and the enormous burden of disability among survivors, the opportunity for an effective treatment to prove cost-effective, even if considered costly in the short-term, is great.


*    Conclusions
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 up arrowCurrent Treatment Strategies
 up arrowGuidelines for Reversal of...
 up arrowUnresolved Issues on Treatment
 up arrowConsiderations for Clinical...
 *Conclusions
down arrowReferences
 
Current understanding of OAT-ICH remains limited and far behind that of SICH. Although ICH is the most serious complication of OAT, standardized treatment guidelines are still lacking. Current treatments focus on normalization of the iatrogenic coagulation disorder, and are not based on evidence from randomized controlled trials. Although most patients with OAT-ICH are at high risk of thromboembolism, and may be at high risk for myocardial infarction, the risks of these events in association with the various treatment strategies available for the management of OAT-ICH are unknown.

Patients who receive chronic OAT urgently require better treatments for acute OAT-ICH, and identification of these treatments can only come from rigorous and controlled clinical trials. Furthermore, successful clinical trials could offer hope, not only to those individuals who currently receive OAT, but also for those additional millions of patients for whom OAT is deemed too risky despite a clear indication. Reducing the morbidity and mortality of OAT-ICH could alter the risk-benefit analysis of chronic anticoagulation, with the potential for a "domino effect" reduction on the incidence of thromboembolism worldwide.


*    Acknowledgments
 
We thank Dr Inge Scharrer, Department of Internal Medicine-Hematology, Johann-Wolfgang-Goethe-University, Frankfurt, Germany for reviewing the manuscript, and Pranee Krailadsiri and Randa Grob-Zakhary, Novo Nordisk Health Care AG, and Paul Littlebury for assisting in the preparation of the manuscript.

Conflict of interest: T.S. has worked as a consultant for Novo Nordisk A/S and lectured at symposia organized by the company. J.R. has received educational grants from Novo Nordisk A/S and research support from the National Institutes of Health (K23 NS42695, R01 NS042147). M.D. has worked as a consultant for Astellas Pharma and Novo Nordisk A/S, lectured at symposia organized by the companies, and received funding from the National Institutes of Health (PPG N535966).

Received June 23, 2005; accepted October 19, 2005.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowEpidemiology
 up arrowPathophysiology
 up arrowCurrent Treatment Strategies
 up arrowGuidelines for Reversal of...
 up arrowUnresolved Issues on Treatment
 up arrowConsiderations for Clinical...
 up arrowConclusions
 *References
 

  1. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, Spilker J, Duldner J, Khoury J. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997; 28: 1–5.[Medline] [Order article via Infotrieve]
  2. Juvela S. Risk factors for impaired outcome after spontaneous intracerebral hemorrhage. Arch Neurol. 1995; 52: 1193–1200.[Abstract]
  3. Franke CL, de Jonge J, van Swieten JC, Op de Coul AA, van Gijn J. Intracerebral hematomas during anticoagulant treatment. Stroke. 1990; 21: 726–730.[Abstract]
  4. 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.[Abstract/Free Full Text]
  5. 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.[Abstract]
  6. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001; 285: 2370–2375.[Abstract/Free Full Text]
  7. Weimar C, Weber C, Wagner M, Busse O, Haberl RL, Lauterbach KW, Diener HC. Management patterns and health care use after intracerebral hemorrhage. A cost-of-illness study from a societal perspective in Germany. Cerebrovasc Dis. 2003; 15: 29–36.[Medline] [Order article via Infotrieve]
  8. Broderick JP, Brott T, Tomsick T, Huster G, Miller R. The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med. 1992; 326: 733–736.[Abstract]
  9. Butler AC, Tait RC. Management of oral anticoagulant-induced intracranial haemorrhage. Blood Rev. 1998; 12: 35–44.[CrossRef][Medline] [Order article via Infotrieve]
  10. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke. 1995; 26: 1471–1477.[Abstract/Free Full Text]
  11. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996; 348: 633–638.[CrossRef][Medline] [Order article via Infotrieve]
  12. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994; 343: 687–691.[CrossRef][Medline] [Order article via Infotrieve]
  13. 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.[Abstract/Free Full Text]
  14. 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.[Abstract/Free Full Text]
  15. Kolominsky-Rabas PL, Sarti C, Heuschmann PU, Graf C, Siemonsen S, Neundoerfer B, Katalinic A, Lang E, Gassmann KG, von Stockert TR. A prospective community-based study of stroke in Germany-the Erlangen Stroke Project (ESPro): incidence and case fatality at 1, 3, and 12 months. Stroke. 1998; 29: 2501–2506.[Abstract/Free Full Text]
  16. Deleted in proof.
  17. Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med. 1996; 156: 409–416.[Abstract]
  18. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004; 63: 1059–1064.[Abstract/Free Full Text]
  19. Gage BF, Birman-Deych E, Kerzner R, Radford MJ, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med. 2005; 118: 612–617.[CrossRef][Medline] [Order article via Infotrieve]
  20. Hart RG. What causes intracerebral hemorrhage during warfarin therapy? Neurology. 2000; 55: 907–908.[Free Full Text]
  21. 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.[Abstract/Free Full Text]
  22. 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.[Abstract/Free Full Text]
  23. 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.[Medline] [Order article via Infotrieve]
  24. Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology. 1999; 53: 1319–1327.[Abstract/Free Full Text]
  25. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Annals of Neurology. 1997; 42: 857–865.[CrossRef][Medline] [Order article via Infotrieve]
  26. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology. 2002; 59: 193–197.[Abstract/Free Full Text]
  27. Hylek E, Singer DE. Risk factor for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994; 120: 897–902.[Abstract/Free Full Text]
  28. Perry DJ. Factor VII Deficiency. Br J Haematol. 2002; 118: 689–700.[CrossRef][Medline] [Order article via Infotrieve]
  29. Mariani G, Herrmann FH, Dolce A, Batorova A, Etro D, Peyvandi F, Wulff K, Schved JF, Auerswald G, Ingerslev J, Bernardi F. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. Thromb Haemost. 2005; 93: 481–487.[Medline] [Order article via Infotrieve]
  30. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003; 34: 224–229.[Abstract/Free Full Text]
  31. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996; 27: 1783–1787.[Abstract/Free Full Text]
  32. Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen WA. Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. Stroke. 1999; 30: 2025–2032.[Abstract/Free Full Text]
  33. Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost. 2003; 89: 278–283.[Medline] [Order article via Infotrieve]
  34. Zazulia AR, Diringer MN, Videen TO, Adams RE, Yundt K, Aiyagari V, Grubb RL Jr, Powers WJ. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001; 21: 804–810.[CrossRef][Medline] [Order article via Infotrieve]
  35. Schellinger PD, Fiebach JB, Hoffmann K, Becker K, Orakcioglu B, Kollmar R, Juttler E, Schramm P, Schwab S, Sartor K, Hacke W. Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra? Stroke. 2003; 34: 1674–1679.[Abstract/Free Full Text]
  36. Sansing LH, Kaznatcheeva EA, Perkins CJ, Komaroff E, Gutman FB, Newman GC. Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment. J Neurosurg. 2003; 98: 985–992.[CrossRef][Medline] [Order article via Infotrieve]
  37. Mayer S, Brun N, Broderick J, Davis S, Diringer M, Skolnick B, Steiner T; for the Europe/Australasia NovoSeven ICH Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005; 352: 777–785.[Abstract/Free Full Text]
  38. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999; 45: 1113–1118; discussion 1118–1119.[CrossRef][Medline] [Order article via Infotrieve]
  39. Freeman WD, Brott TG, Barrett KM, Castillo PR, Deen HG Jr, Czervionke LF, Meschia JF. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004; 79: 1495–1500.[Medline] [Order article via Infotrieve]
  40. Fewel ME, Park P. The emerging role of recombinant-activated factor VII in neurocritical care. Neurocritical Care. 2004; 1: 19–30.[Medline] [Order article via Infotrieve]
  41. O’Reilly RA. Warfarin metabolism and drug-drug interaction. In: Wessler S, Becker CG, Y N, eds. Advances in experimental medicine and biology. New York: Plenum; 1986: 205–212.
  42. Beeck H, Hellstern P. In vitro characterization of solvent/detergent-treated human plasma and of quarantine fresh frozen plasma. Vox Sang. 1998; 74 (Suppl 1): 219–223.[Medline] [Order article via Infotrieve]
  43. Guidelines on oral anticoagulation: third edition. Br J Haematol. 1998; 101: 374–387.[CrossRef][Medline] [Order article via Infotrieve]
  44. Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L, Jacobson A, Deykin D, Matchar D. Managing oral anticoagulant therapy. Chest. 2001; 119: 22S–38S[CrossRef][Medline] [Order article via Infotrieve]
  45. Hanley JP. Warfarin reversal. J Clin Pathol. 2004; 57: 1132–1139.[Abstract/Free Full Text]
  46. Bianco C. Choice of human plasma preparations for transfusion. Transfus Med Rev. 1999; 13: 84–88.[Medline] [Order article via Infotrieve]
  47. Fiore LD, Scola MA, Cantillon CE, Brophy MT. Anaphylactoid reactions to vitamin K. J Thromb Thrombolysis. 2001; 11: 175–183.[CrossRef][Medline] [Order article via Infotrieve]
  48. Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol. 2002; 89: 400–406.[Medline] [Order article via Infotrieve]
  49. Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999; 159: 2721–2724.[Abstract/Free Full Text]
  50. 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.[Medline] [Order article via Infotrieve]
  51. 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.[Medline] [Order article via Infotrieve]
  52. Hellstern P, Muntean W, Schramm W, Seifried E, Solheim BG. Practical guidelines for the clinical use of plasma. Thromb Res. 2002; 107 (Suppl 1): S53–S57.[Medline] [Order article via Infotrieve]
  53. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, Williamson LM. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004; 126: 11–28.[CrossRef][Medline] [Order article via Infotrieve]
  54. Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol. 2001; 114: 271–280.[CrossRef][Medline] [Order article via Infotrieve]
  55. Brody DL, Aiyagari V, Shakleford AM, Diringer MN. Use of recombinannt factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocritical Care. 2005; 2: 263–267.[Medline] [Order article via Infotrieve]
  56. Gilstad CW. Anaphylactic transfusion reactions. Curr Opin Hematol. 2003; 10: 419–423.[Medline] [Order article via Infotrieve]
  57. Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol. 2003; 10: 412–418.[CrossRef][Medline] [Order article via Infotrieve]
  58. Hellstern P, Beeck H, Fellhauer A, Fischer A, Faller-Stockl B. Measurement of factor VII and of activated factor VII in healthy individuals and in prothrombin complex concentrates. Thromb Res. 1997; 86: 493–504.[CrossRef][Medline] [Order article via Infotrieve]
  59. Arun B, Kessler CM. Clinical manifestation and therapy of hemophilias. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and thrombosis. London: Lippincott Williams & Wilkins; 2000: 815–824.
  60. Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke. 1992; 23: 972–977.[Abstract]
  61. Sjöblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, Stigendal L, Stockelberg D, Taghavi A, Wallrup L, Wallvik J. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001; 32: 2567–2574.[Abstract/Free Full Text]
  62. McNeill SA, Ewing JC, Wallace WA, Stewart LH. Venous infarction of a testicle following factor IX concentrate (DEFIX). Br J Haematol. 1998; 101: 210.[Medline] [Order article via Infotrieve]
  63. 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.[Medline] [Order article via Infotrieve]
  64. 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.[Medline] [Order article via Infotrieve]
  65. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999 (supp); 95: S7–S12.[Medline] [Order article via Infotrieve]
  66. Kohler M, Habauer G, Miyashita C, Braun B, Morsdorf S, Pindur G, Heiden M, Rose S, Ernert P. [Quality control of prothrombin complex preparations: in vivo and in vitro findings]. Beitr Infusionsther. 1990; 26: 186–189.[Medline] [Order article via Infotrieve]
  67. Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R, Axelsen M, Kluger Y. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005; 59: 8–18.[Medline] [Order article via Infotrieve]
  68. Ghorashian S, Hunt BJ. "Off-license" use of recombinant activated factor VII. Blood Rev. 2004; 18: 245–259.[CrossRef][Medline] [Order article via Infotrieve]
  69. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion. 2004; 44: 1325–1331.[CrossRef][Medline] [Order article via Infotrieve]
  70. Erhardtsen E, Nony P, Dechavanne M, French P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ration above 2.0. Blood Coagul Fibrinolysis. 1998; 9: 741–748.[Medline] [Order article via Infotrieve]
  71. 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. Blood Coagul Fibrinolysis. 2003; 14: 469–477.[CrossRef][Medline] [Order article via Infotrieve]
  72. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thromb Haemost. Med J Aust. 2004; 181: 492–497.[Medline] [Order article via Infotrieve]
  73. 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.[Abstract/Free Full Text]
  74. 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.[CrossRef][Medline] [Order article via Infotrieve]
  75. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol. 2000; 247: 209–214.[CrossRef][Medline] [Order article via Infotrieve]
  76. 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.
  77. 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.[Abstract/Free Full Text]
  78. 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.[Medline] [Order article via Infotrieve]
  79. Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, Castillo J. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology. 2004; 63: 461–467.[Abstract/Free Full Text]
  80. Jackson CM, Esnouf MP, Lindahl TL. A critical evaluation of the prothrombin time for monitoring oral anticoagulant therapy. Pathophysiol Haemost Thromb. 2003; 33: 43–51.[Medline] [Order article via Infotrieve]
  81. Sorensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost. 2003; 1: 551–558.[Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 CirculationHome page
J. Broderick, S. Connolly, E. Feldmann, D. Hanley, C. Kase, D. Krieger, M. Mayberg, L. Morgenstern, C. S. Ogilvy, P. Vespa, et al.
REPRINT: Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.
Circulation, October 16, 2007; 116(16): e391 - e413.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
H C Hanger, T J Wilkinson, N Fayez-Iskander, and R Sainsbury
The risk of recurrent stroke after intracerebral haemorrhage
J. Neurol. Neurosurg. Psychiatry, August 1, 2007; 78(8): 836 - 840.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
J. Broderick, S. Connolly, E. Feldmann, D. Hanley, C. Kase, D. Krieger, M. Mayberg, L. Morgenstern, C. S. Ogilvy, P. Vespa, et al.
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.
Stroke, June 1, 2007; 38(6): 2001 - 2023.
[Abstract] [Full Text] [PDF]