In an unpublished series of cases involving accusations or convictions of inflicted trauma in the form of “shaken/impact baby syndrome,” largely collected by attorney and jury counselor Toni Blake of San Diego, California (personal communication, 2000), the cases had the following features in common:
1) All occurred in fragile infants born from complicated pregnancies; problems included prematurity, low birth weights, drug/alcohol problems, maternal toxemia, diabetic mothers, or other maternal complications;
2) all infants were 6 months age or less;
3) onset of signs and symptoms occurred at about 2, 4, or 6 months of age, within 12 days of vaccines;
4) all infants had subdural hematomas;
5) some infants had multiple fractures. In the year 2000 the series included 25 cases, but I understand that it is now much larger.
Spontaneous Intracerebral Hemorrhage Due to Coagulation Disorders
Alfredo Quinones-Hinojosa, M.D.; Mittul Gulati, M.D.; Vineeta Singh, M.D.; Michael T. Lawton, M.D.
Neurosurg Focus 15(4), 2003. © 2003 American Association of Neurological Surgeons
Abstract and Introduction Abstract Although intracranial hemorrhage accounts for approximately 10 to 15% of all cases of stroke, it is associated with a high mortality rate. Bleeding disorders account for a small but significant risk factor associated with intracranial hemorrhage. In conditions such as hemophilia and acute leukemia associated with thrombocytopenia, massive intracranial hemorrhage is often the cause of death. The authors present a comprehensive review of both the physiology of hemostasis and the pathophysiology underlying spontaneous ICH due to coagulation disorders. These disorders are divided into acquired conditions, including iatrogenic and neoplastic coagulopathies, and congenital problems, including hemophilia and rarer diseases. The authors also discuss clinical features, diagnosis, and management of intracranial hemorrhage resulting from these bleeding disorders.
Introduction Each year, approximately 37,000 to 52,400 people in the US suffer an ICH. This entity accounts for 10 to 15% of all cases of stroke and is associated with a high mortality rate (only 38% of affected patients survive the 1st year). The cause of ICH is generally classified as primary or secondary. Primary ICH, due to spontaneous rupture of damaged small vessels or amyloid angiopathy, accounts for 78 to 88 % of cases. Secondary ICH, associated with vascular anomalies, tumors, or impaired coagulation, occurs only in a minority of patients.
Coagulation and/or bleeding disorders account only for a small but significant risk factor associated with ICH. In conditions such as hemophilia and acute leukemia associated with thrombocytopenia, massive intracranial hemorrhage is often the cause of death.[68,87] In this article, we present a comprehensive review of physiology of hemostasis as well as the current understanding of the origin and pathophysiology underlying spontaneous ICH due to coagulation disorders (Table 1).
Physiology of Hemostasis Blood coagulation and platelet-mediated hemostasis are the two important defense mechanisms against bleeding. The coagulation cascade is triggered as soon as blood contacts the injured endothelial lining. The responses of the coagulation cascade are ideally coordinated with the formation of the platelet plug that initially occludes a vascular lesion. Anticoagulant mechanisms ensure careful control of coagulation and, under normal conditions, prevail over the procoagulant forces. In the CNS, however, an imbalance between pro- and anticoagulant systems due to inherited or acquired factors may result in bleeding or thrombotic diseases. We begin with a review of platelet function, the coagulation cascade, and regulation of normal hemostasis and follow this with a description of various coagulopathies that are related to intracranial bleeding.
Platelet Function Platelets are involved in a sequence of events during the hemostatic process including the following: 1) adherence; 2) shape change; 3) secretion and activation of circulating platelets; and 4) binding/aggregation of additional platelets. During the first few minutes after endothelial cell disruption, an initial unstable platelet plug forms (adherence). Thromboxane A, a strong platelet aggregator, is released by platelets, which, along with catecholamines, serotonin, cations, clotting factor, and platelet-derived growth factor, activate platelets in the area, in turn leading to the additional aggregation to form a more stable platelet plug.
Platelets take part in hemostasis at three different levels. First, by sticking to endovascular collagen as well as to each other, they form a physical barrier to additional blood loss. Second, the platelet phospholipid surface provides a surface for activation of factors V and X, thereby facilitating the formation of fibrin mesh at the site of vascular injury. Third, some of the platelet granule constituents have a vasoconstrictive effect that further helps control bleeding.
At the end of the coagulation cascade (see CoagulationCascade) fibrinogen or vWF binds to specific platelet membrane receptors located in the glycoprotein IIb/IIIa integrin complex. The glycoprotein IIb/IIIa complex is the most abundant receptor on the platelet surface. Glycoprotein IIb/IIIa, as the final fibrinogen receptor, has in recent years become the target of a new class of antiplatelet medications, which will be discussed with other iatrogenic coagulopathies.
Coagulation Cascade The classic coagulation cascade is composed of two basic parts, an intrinsic pathway and an extrinsic pathway (Fig. 1). The intrinsic pathway occurs by physical chemical activation, whereas the extrinsic pathway is activated by tissue factor released from damaged cells. The physiological role of the intrinsic pathway is not fully understood because it is not thought to be important in trauma-initiated coagulation.
Figure 1. Diagrams showing intrinsic and extrinsic pathways of blood coagulation. The coagulation cascade is initiated via the extrinsic pathway as a result of tissue damage and the exposure of blood to tissue factor (TF). The two pathways converge when factor X is activated. The active forms of the serine proteases and of the two cofactors V and VIII are indicated by a lower case a; X denotes the zymogen factor X, and Xa the active enzyme factor Xa. The activation of factors V and VIII by thrombin and by factor Xa is denoted, as well as the initiation of the intrinsic pathway by thrombin-mediated activation of factor XI. Thrombin also activates factor XIII and protein C of the protein C anticoagulant system. PL = phospholipid.
Extrinsic Pathway. The extrinsic pathway is initiated by injury to the avascular wall or nonvascular tissue. Nonvascular tissue cells contain an integral membrane protein called tissue factor. Damage to the blood vessel wall exposes plasma to tissue factor. Factor VII is a circulating plasma protein that then binds to tissue factor, creating a complex. In doing so, factor VII is activated to factor VIIa. This complex, in the presence of Ca++ and phospholipids, activates factors IX and X to factors IXa and Xa.[70,82] Factors IXa and Xa may remain associated with the tissue factor–bearing cell, or they may diffuse into the blood and bind to the surface of nearby activated platelets that have already formed the primary platelet plug.
Factor Xa and its cofactor Va form a phospholipidbound complex called the prothrombinase complex, which is highly activated on the surface of platelets and, in the presence of Ca++, cleaves prothrombin (factor II) to thrombin (factor IIa). Thrombin cleaves fibrinogen (factor I) to fibrin (factor Ia), which is covalently cross-linked by factor XIIIa into fibrin strands.
Factor VIII greatly accelerates the activation of factor X. Factor VIII circulates bound to vWF, which is an adhesive protein important for generation of the initial platelet plug. After activation, factor VIIIa dissociates from vWF and forms a complex on the platelet surface, which also activates factor X to Xa.
Thrombin feedback is important to the entire aforedescribed system. There is a paradox in that activation of factors V and VIII require thrombin, yet conversion of prothrombin to thrombin requires factors Va and VIIIa. This paradox illustrates the delicate balance of hemostasis in which minute amounts of activated factors are normally circulating. The degree of activation of any given factor can be visualized on a continuum, rather than viewed as an on/off dichotomy. Thrombin, once generated, is a powerful procoagulant. It catalyzes the further conversion of factors V and VIII to their activated forms through a positive feedback mechanism and converts more prothrombin to thrombin. In this manner, thrombin is able to accelerate the entire cascade once generated, resulting in the formation of large amounts of fibrin. It is important to understand that when the cascade is activated, the amount of product formed in the individual reactions increases logarithmically as one moves down the cascade.
Intrinsic Pathway. The physiological role and the precise mechanism of activation of the intrinsic pathway is less well understood. This pathway most likely begins with trauma to the blood vessel or exposure of blood to collagen in a damaged vascular wall. In response to these stimuli, two events occur. First, factor XII (otherwise known as the Hageman factor) is converted from its inactive form (zymogen) to its active form (factor XIIa). Second, platelets are activated. Factor XIIa enzymatically activates factor XI to factor XIa, a reaction requiring the presence of high–molecular weight kininogen and prekallekrin. Factor XIa is also a protease, whose function is to convert factor IX to factor IXa, which in turn converts factor X to factor Xa. Once factor Xa is generated, the remainder of the pathway is similar to the extrinsic pathway.
Regulatory Mechanisms of the Cascade The regulatory mechanisms of the coagulation cascade serve the following two main functions: to limit the amount of fibrin clot formed to avoid ischemia of tissues and to prevent widespread thrombosis. Regulators of hemostasis include tissue factor pathway inhibitor, antithrombin III, activated protein C and protein S, thrombomodulin, and the fibrinolytic system.
Tissue Factor Pathway Inhibitor. As previously described, coagulation is normally initiated when vessel or tissue injury exposes circulating factor VIIa to tissue factor. Through this interaction, a tissue factor–factor VIIa complex is formed and can subsequently activate small amounts of factors IX and X, eventually resulting in limited quantities of thrombin. Tissue factor pathway inhibitor is a protein that mediates the feedback inhibition of the tissue factor–factor VIIa complex, resulting in decreased activation of both factor IX and X. Small amounts of factor Xa are required for TFPI to achieve its inhibition of factor VIIa–tissue factor complex. Therefore, on initiation of the cascade tissue factor–VIIa complexes are formed and small amounts of factor Xa and thrombin are generated. The limited quantities of factor Xa will result in feedback inhibition of its own synthesis via TFPI.
Antithrombin III. Antithrombin III, a protein synthesized by liver and endothelial cells, binds and directly inactivates thrombin and the other serine proteases (factors IXa, Xa, and XIa). The uncatalyzed reaction between the serine proteases and antithrombin III is relatively slow. The serine proteases still have time to generate thrombin and fibrin before becoming inactivated. In the presence of heparin or similar sulfated glycosaminoglycans, however, the reaction between antithrombin III and the serine proteases is virtually instantaneous and results in the immediate blockage of fibrin formation. Normal endothelial cells express heparan sulfate (a sulfated glycosaminoglycan). Antithrombin III binds to the heparan sulfate and is then able to inactivate any nearby serine proteases, thus preventing the formation of fibrin clot in undamaged areas. This mechanism is the molecular basis for the use of heparin as a therapeutic anticoagulant.
Activated Protein C and Protein S. Proteins C and S are both vitamin K–dependent inhibitors of the procoagulant system. Together, they inactivate factors Va and VIIIa. Protein C circulates in the blood as a zymogen and is activated to a serine protease by the binding of thrombin to thrombomodulin. Protein S markedly enhances the activity of protein C. By inactivating factors Va and VIIa, proteins C and S significantly decrease the tempo of thrombin generation, thereby dampening the cascade.
Thrombomodulin. Thrombomodulin is an endothelial cell receptor that binds thrombin. When thrombodulin and thrombin form a complex, the conformation of the thrombin molecule is changed. This altered thrombin molecule then readily activates protein C and loses its platelet-activating and protease activities. Therefore, the binding of thrombomodulin to thrombin converts thrombin, from a tremendously potent procoagulant into an anticoagulant. This is important in the normal physiological state because normal endothelial cells produce thrombomodulin, which binds any circulating thrombin, thus preventing clot formation in undamaged vessels.
Fibrinolytic System. The continuous generation of cross-linked fibrin would create a clot capable of obstructing normal blood flow. The fibrinolytic system is present to keep clot formation in check by actually degrading the fibrin strands. Plasminogen is an inactive protein made in endothelial cells, liver cells, and eosinophils. It is activated to plasmin by an enzyme called plasminogen activator. Plasmin has this ability to degrade fibrin strands, preventing the buildup of excess clot.
Pathophysiology of Bleeding Disorders Coagulopathies leading to intracranial hemorrhage can be broadly divided into acquired and congenital disorders of hemostasis. The most prevalent category of acquired coagulopathies iatrogenically result from therapies such as aspirin, anticoagulants, and thrombolytic agents. Other acquired coagulopathies that cause ICH include bleeding dyscrasias secondary to the following: 1) neoplasms; 2) ITP; and 3) thrombocytopenia induced by alcohol, liver and kidney disease, and other drugs. Congenital disorders include hemophilia A, hemophilia B, and other rarer diseases. In the following section we review these causes.
Acquired Disorders: Iatrogenic Coagulopathies Causing ICH Antiplatelet Agents. A number of antiplatelet agents that have been introduced in recent years are reviewed at the end of this section. The most prevalent antiplatelet agent in the world, however, is aspirin by far. Aspirin works by irreversibly inactivating the enzyme cyclooxygenase, which results in decreased production of the natural platelet aggregant thromboxane A2. This inhibition makes aspirin an excellent antiplatelet agent in the clinical setting. In patients who have suffered an acute MI and those with prior occlusive cardiovascular disease, aspirin reduces the risks of nonfatal MI, nonfatal stroke, and vascular disease–related death. In primary prevention trials conducted in patients without these preexisting conditions, aspirin therapy has also been shown to reduce the risk of a first MI in men; limited data make it difficult to draw conclusions regarding its effect on stroke and total cardiovascular death. Randomized data from studies in women and other populations are lacking.
Incidence of ICH due to Aspirin. Although the proven benefits of aspirin in MI have resulted in millions of Americans taking it on a daily basis, concerns have been raised about its main side effect, which is a hemorrhagic complication. Aspirin-related bleeding in the upper GI tract has been studied in detail, as has aspirin-related ICH. The first suggestion that increased incidence of ICH might be a complication in aspirin users is found in the Physician's Health Study, which reported 23 hemorrhagic strokes among 11,037 individuals receiving low-dose aspirin (325 mg every other day) compared with 12 hemorrhagic strokes in 11,034 individuals receiving placebo. This finding was considered noteworthy but of borderline statistical significance (p = 0.06).
Subsequent Clinical Trials of Aspirin Use. In the 1991 Swedish Aspirin Low-Dose Trial investigators of patients with a history of TIA or minor stroke reported that the prevalence of intracranial hemorrhage was 1.5%. Finally, in 1997, the International Stroke Trial Collaborative Group concluded that administration of 300 mg aspirin daily compared with placebo following acute stroke prevented 1.2 ischemic strokes per 100 treated patients but caused in excess of 0.41 ICHs.
Investigations comparing antiplatelet with placebobased therapy are rarely undertaken at the present time, because it is now considered unethical to withhold antithrombotic therapy from patients at risk for ischemic stroke. In 1999, however, Boysen examined several large stroke-prevention trials to derive a benefit/risk ratio for antiplatelet drugs in the prevention of secondary stroke. The author found that in patients with prior TIA or stroke, aspirin prevented one to two vascular events (stroke, acute MI, or vascular death) per 100 treatmentyears with an excess risk of fatal and severe hemorrhage of 0.4 to 0.6 per 100 treatment-years. In the same study, Boysen found that the risk of aspirin-associated hemorrhage was greatest in the acute phase of stroke (several weeks after infarction) than in the stable phase after ischemic infarction. Even in this acute phase, however, there was a net benefit to aspirin administration, with prevention of approximately one death or nonfatal ischemic stroke per 100 treated patients. Overall, the data indicate that aspirin therapy for primary or secondary stroke prevention and primary MI prevention may slightly increase the low baseline risk of ICH but that the increased risk is usually outweighed by the benefits of aspirin.
Other Antiplatelet Agents. In addition to aspirin, other antiplatelet agents that have grown in popularity in recent years include clopidogrel (Plavix), abciximab (ReoPro), as well as aspirin combined with extended-release dipyridamole (Aggrenox). As discussed, the glycoprotein IIb/ IIIa complex is an integrin found abundantly on the platelet surface, which binds to fibrinogen and is important in platelet aggregation. Clopidogrel, abciximab, and dipyridamole all act as glycoprotein IIb/IIIa inhibitors in slightly different ways and have different indications. Abciximab is most often given as an adjunct to percutaneous coronary intervention performed for the prevention of cardiac ischemic complications. Aspirin combined with extended- release dipyridamole, on the other hand, can be administered to decrease the risk of stroke in patients who have suffered a prior TIA or complete ischemic stroke.
In a limited number of studies the authors have examined the risk of intracranial hemorrhage in patients receiving these newer antiplatelet agents. The most comprehensive data are derived from a metaanalysis conducted by Memon, et al., in which the authors evaluated 14 randomized trials of intravenous platelet glycoprotein IIb/IIIa receptor inhibitors. The authors compared the incidence of intracranial hemorrhage among 15,850 patients receiving glycoprotein IIb/IIIa inhibitors with that among 12,039 patients receiving placebo. They found that the incidence of intracranial hemorrhage with heparin combined with any glycoprotein IIb/IIIa inhibitor was similar to that in patients receiving placebo with heparin (0.12 and 0.09%, respectively; odds ratio 1.3; 95% confidence interval 0.6–3.1; p = 0.59). The incidence of ICH in those receiving glycoprotein IIb/IIIa drugs alone was similar to that in those receiving heparin alone (0.07 and 0.06%, respectively). They concluded that intravenous glycoprotein IIb/ IIIa receptor inhibitors alone or in combination with heparin do not cause a statistically significant excess of intracranial hemorrhage compared with heparin alone.
The results of the aforementioned metaanalysis, while suggesting that intravenous glycoprotein IIb/IIIa inhibitors did not increase the risk of intracranial hemorrhage in anticoagulant-treated patients, failed to provide information on the incidence of hemorrhagic stroke in patients receiving oral formulations of the medications alone. The authors also did compare glycoprotein IIb/IIIa inhibitors with a more commonly used antiplatelet agent—namely, aspirin. One study in which the authors addressed this question was the CAPRIE (that is, clopidogrel compared with aspirin in patients at risk of ischemic events) trial. This was a randomized, blinded, international trial designed to assess the relative efficacy and safety of oral clopidogrel (75 mg once daily) and aspirin (325 mg once daily). There were 19,185 patients, with more than 6300 in each clinical subgroup, recruited over 3 years, with a mean follow-up period of 1.91 years. There were no major differences in terms of safety. The incidence of ICH in the clopidogrel group was 0.33%, whereas it was 0.47% in the aspirin group. Analysis of current data suggests that the newer antiplatelet agents discussed thus seem to be associated with an ICH risk profile similar to that of aspirin.
Anticoagulation Therapy. Many Americans are undergoing anticoagulation therapy at any given time. Warfarin, heparin, and enoxaparin are currently the most commonly used anticoagulants. Warfarin is an oral anticoagulant that interferes with vitamin K metabolism in the liver and results in the synthesis of nonfunctional coagulation factors II, VII, IX, and X, as well as proteins C and S. Warfarin thus prolongs the PT and is monitored by assessing a standardized form of this test known as the INR. Heparin, on the other hand, is a parenterally administered anticoagulant agent that acts by potentiating the action of both antithrombin III and TFPI, thus prolonging the PTT. Enoxaparin (Lovenox) is the most commonly used member of a relatively new class of anticoagulants known as low–molecular weight heparins. It is obtained by alkaline degradation of heparin benzyl ester and is approximately one third the molecular size of standard heparin. The mechanism of action of enoxaparin is similar to that of heparin, although enoxaparin has a longer half-life (4.5 compared with 1.1 hours) and does not require PTT monitoring.[8,117]
Anticoagulation-related bleeding is clinically similar for each of the aforementioned drugs and accounts for 10 to 20% of all ICHs in different series.[62,92,134] Furthermore, ICH is the most dreaded and least treatable complication of anticoagulation therapy. In the second Stroke Prevention in Atrial Fibrillation study, investigators showed that the occurrence of ICH actually negated the reduction in ischemic stroke among older hypertensive patients receiving warfarin.
Location of ICH in Patients Receiving Anticoagulants. Approximately 70% of ICH episodes associated with anticoagulation consist of intraparenchymal (cerebral) hemorrhage, whereas most of the remainder are subdural hematomas. Although a tendency for intraparenchymal bleeding in the cerebellum has been reported, Hart, et al., in a review in which they examine aggregate data from 15 studies of anticoagulant-related ICH, found no particular predilection for the cerebellum, as well as a relative frequency of lobar ICH similar to that in patients not receiving anticoagulant agents.
Epidemiology of ICH in Patients Receiving Anticoagulants. In a 1995 review, Hart, et al., suggested that anticoagulation to a "therapeutic" INR of 2.5 to 4.5 increases annual risk of intracranial hemorrhage by seven- to 10- fold, to an absolute rate of nearly 1% for high-risk patient groups. Evaluation of individual large series shows great variation in the incidence of anticoagulation-treated patients in whom ICH is a complication, with annual incidences ranging from 0.1% in a 1974 study of 3862 patients to 2.2% in a 1993 study of 186 patients.
To address the question of ICH risk associated with different anticoagulants, several groups have also examined the risks and benefits of heparin compared with enoxaparin in the form of randomized clinical trials. The second trial of Heparin and Aspirin Reperfusion Therapy was a randomized comparison of enoxaparin with unfractionated heparin adjunctive to recombinant tPA thrombolysis and aspirin. Four hundred patients undergoing reperfusion therapy with tPA and aspirin were randomly assigned to undergo adjunctive therapy for at least 3 days with either enoxaparin or heparin. The authors found that although enoxaparin was at least as effective as heparin as an adjunct to thrombolysis, intracranial hemorrhage occurred with similar frequency in both treatment groups.
Another group comparing heparin and enoxaparin evaluated patients who had sustained a major trauma, a population at very high risk for developing venous thromboembolism in the absence of thromboprophylaxis. Enoxaparin was significantly better at reducing DVT risk than heparin, and the two groups again shared statistically similar rates of adverse outcomes including intracranial hemorrhage.
Presentation of ICH in Patients Receiving Anticoagulants. Anticoagulant-related ICH differs from that due to other causes in several ways (Fig. 2). Most significantly, ICH related to anticoagulation often develops gradually and insidiously, over many hours or even days. Anticoagulant- related ICHs often continue to enlarge after they are first seen on neuroimaging studies, a fact not well appreciated by treating physicians who may delay reversing anticoagulation therapy for hours while the patient continues to deteriorate. This becomes a difficult dilemma for high-risk patients receiving warfarin for the prevention of ischemic strokes. The mortality rate associated with anticoagulant-related ICH ranges from 46 to 68% in various studies, and the mean rate is 60%, which is much higher than that associated with infarctions.
Figure 2. Axial CT scans obtained in a 41-year-old woman with antiphospholipid syndrome and history of a left middle cerebral artery stroke 13 years before presentation, which resulted in rightsided weakness. She was placed on lifelong anticoagulation therapy with Coumadin and Lovenox for stroke prophylaxis. Two weeks before admission, the patient developed gradually worsening headaches and altered metal status. The day of admission she was found to have acute-onset new left-sided weakness and INR of 2.8. Axial CT scans revealing acute bilateral subdural hematomas. Coagulopathy was corrected using fresh-frozen plasma, platelets, and vitamin K, and she was taken to surgery for evacuation of the hematomas. She recovered to baseline status and was discharged home.
Risk Factors Predisposing ICH in Patients Receiving Anticoagulants. Risk factors have been identified that predispose an anticoagulation-treated patient to ICH. Hypertension has been implicated in several studies,[17,57,65,85,132] although other authors have failed to find a relationship between hypertension and ICH.[39,56] Increasing age and prior ischemic infarction[57,74,119] are other risks firmly linked to increased ICH in anticoagulation-treated patients. One major risk factor fairly unique to anticoagulation, and which physicians must be especially careful to monitor in groups of patients already susceptible to ICH, is the extent of anticoagulation. Several authors have linked increased ICH to abnormally prolonged PTs.[61,65,77,132] In 1994, Hylek and Singer suggested that the rate of ICH in this population is equal to an inherent baseline risk multiplied by the patient's intensity of anticoagulation, finding a doubling of risk with each 0.5 increase in PT.
Mechanism of ICH in Patients Receiving Anticoagulants. The precise mechanism by which anticoagulation increases the incidence of ICH is unclear. One idea is that the anticoagulation may cause subclinical brain hematomas to grow to clinical importance. Autopsy examination performed in elderly hypertensive individuals often reveals collections of hemosiderin, which may be related to small-vessel vasculopathies. Hemorrhages derived from these small vessels may usually be contained by normal hemostatic mechanisms, which fail when anticoagulants are present, allowing the hemorrhages to grow. Roob and Fazekas have suggested that findings of such smallvessel disease on MR images may be predictive of an anticoagulation-treated patient's risk for spontaneous bleeding.
Thrombolytic Agents. Thrombolytic agents are those that activate the body's fibrinolytic system by converting plasminogen to plasmin. Plasmin binds to fresh fibrin clots, dissolving them and generating fibrinogen degradation products. Their main clinical use has been in the treatment of acute MI and most studies of ICH related to thrombolytic therapy have been conducted in this population. The authors of several studies, however, have also evaluated ICH in patients who underwent thrombolytic therapy for ischemic stroke.
Commonly used fibrinolytic agents have included the exogenous substances streptokinase, urokinase, and the endogenous tPA. Initial studies in which investigators studied urokinase and streptokinase in the treatment of MI were limited by the fact that these substances activate both fibrin-bound plasminogen and circulating plasminogen, thus producing a systemic fibrinolytic state.[114,126] Although these agents were quite successful in dissolving coronary artery clots, bleeding complications necessitating transfusion occurred in 9% of patients and ICH in up to 1.6% of patients treated with urokinase and streptokinase.[1,116] Tissue plasminogen activator theoretically has a clinical advantage over urokinase and streptokinase in that it is relatively clot specific, activating fibrin-bound plasminogen preferentially over circulating plasminogen. Verstraete, et al., in a comparison study of tPA and streptokinase for acute MI, confirmed that tPA therapy resulted in a higher rate of coronary artery patency and a lower rate of bleeding complications. In most recent studies on ICH in thrombolytic therapy for acute MI, investigators have used tPA as the agent of choice.
Location and Presentation of ICH in Patients Receiving Thrombolytics. The location of ICH related to thrombolytic therapy is lobar in 70 to 90% of cases and multiple in almost one third of patients.[46,63,64,129] These clinical features are similar to those seen in anticoagulant-related ICH, suggesting that the hemorrhages do not result from hypertension but from a coagulopathy induced by the treatment. The ICH usually occurs soon after treatment has begun. In the Thrombolysis in Myocardial Infarction study, Gore, et al., found that 40% of TPA-related ICH started during the infusion, with another 25% occurring within 24 hours of treatment.
Wijdicks and Jack examined clinical presentation in a series of eight patients with post–tPA ICH. They found that, compared with other types of ICH, patients in the tPA series tended to have fluid levels in the hematomas (suggesting continuing or repeated hemorrhages), multiple parenchymal hemorrhages, and blood in multiple compartments (intraventricular, subarachnoid, subdural, and parenchymal). Patients with post–tPA ICH also tended to suffer a catastrophic clinical course, with seven of eight patients dying or ending up in a persistent vegetative state within hours of hemorrhage onset.
Epidemiology of ICH in Patients Receiving Thrombolytics. The use of tPA is associated with hemorrhagic complications in 15 to 33% of patients,[21,104] with most of these bleeding episodes occurring at vascular catheterization sites. Intracranial hemorrhage is a rare complication of tPA therapy. Carlson, et al., examined pooled data obtained in greater than 5000 patients treated with tPA, including all US trials through May 1987 and five large European trials. They found a combined ICH incidence of 0.68%. Although the various trials involved different study designs, dose regimens, and selection criteria, the data suggested an increased incidence of ICH at higher tPA doses.
In contrast to this relatively low incidence of ICH in controlled clinical trials of tPA, higher frequencies of the complication have been reported in the community, ranging from 1.1 to 5%, with studies using Federal Drug Administration–approved doses and guidelines. These figures make it crucial to carefully assess a patient's presentation and risk profile before initiating tPA therapy for acute MI.
Risks Predisposing ICH. O'Connor, et al., analyzed the risk factor profile of tPA-related ICH. They found age older than 65 years, history of hypertension, and aspirin use to be risk factors for this complication. In the Thrombolysis in Myocardial Infarction study, Gore, et al., reported increased rates of ICH associated with higher tPA doses, increased patient age, history of hypertension, history of neurological disease (TIA or stroke), and use of Ca++-channel blockers. These risk factors are disputable. In a study by Kase, et al., examining 1700 patients treated with duteplase, the authors found no relationship between ICH and older age, sex, weight, history of hypertension, history of stroke, or aspirin/Ca++-channel blocker. Although these authors used a different thrombolytic agent from tPA, these conflicting results suggest that risk profiles for ICH have not yet been fully defined.
Heparinization is considered standard therapy in patients undergoing thrombolysis and is undertaken to prevent reocclusion of the coronary artery. This practicehas raised the question of whether combining thrombolytic with anticoagulant agents increases the risk of tPA-related ICH. In the 1988 results of the Anglo-Scandinavian Study of Early Thrombolysis, the authors reported an 0.08% incidence of hemorrhage in 2493 patients in the placeboplus- heparin arm and a 0.27% incidence in the tPA-plusheparin arm. Although this increase was not statistically significant, it did suggest a higher incidence of ICH when tPA and heparin are combined.
Mechanism of ICH in Patients Receiving Thrombolytics. Several ideas have been proposed regarding the mechanism by which tPA increases risk of ICH. Early systemic theories suggesting a fibrinolytic state or thrombocytopenia as integral components in tPA-related ICH have not been confirmed.[46,64] If such conditions were to explain tPA-related ICH, systemic bleeding would be expected as well.
A more likely theory proposed by several authors is the existence of cerebral amyloid angiopathy in those thrombolysis- treated patients in whom ICH develops.[99,129] It is possible that this angiopathy, which is highly prevalent in the elderly, is a contributing factor in tPA-related ICH.
Thrombolytics in Treatment of Acute Ischemic Stroke. Currently, the only thrombolytic therapy licensed for use in acute ischemic stroke is tPA, initiated within 3 hours of symptom onset and under strict limitations. This therapy is based on the data reported in five prospective randomized clinical trials of intravenous thrombolytic therapy.
In three of these trials (the Multicentre Acute Stroke Trial–Europe, Multicentre Acute Stroke Trial–Italy, and Australian Streptokinase trial), intravenous streptoknase was administered up to 6 hours after stroke. All three trials were terminated prematurely because of excessive early mortality and symptomatic hemorrhage, and no conclusions could be drawn. The incidence of ICH ranged from 6.7 to 17.5% in the treatment groups, whereas it was 0.3 to 0.7% in controls. In the fourth trial, the European Cooperative Acute Stroke Study, participants were randomized to receive tPA or placebo within 6 hours of stroke onset. Although the overall patient analysis showed no benefit associated with tPA over placebo, the investigators demonstrated that by retrospectively designating a target population of individuals (those without signs of major infarction on CT scans), they could demonstrate statistically significant benefit within the target population.
In the fifth trial, the NINDS stroke study, patients were randomly assigned to receive intravenous tPA or placebo within 3 hours of stroke onset. Hemorrhage detected on CT scanning was an exclusion criterion. There was an absolute increase in "good" outcomes of 11 to 13% in tPA-treated patients in the NINDS trial. Symptomatic ICH occurred in 6.4% of tPA-treated patients compared with 0.6% in those given placebo. There are several reasons why the NINDS trial showed positive results, whereas none were discussed in the other studies. In the NINDS study, there was a narrower treatment window—3 hours compared with 4 hours in Australian Streptokinase trial and 6 hours in the other trials listed. In the NINDS trial, investigators also used a smaller tPA dose (0.9 mg/kg) than in the other studies, as well as excluding anticoagulation- treated patients and enforcing more rigorous blood pressure control (pretreatment maximum of 185/110 mm Hg). The good outcome demonstrated in the NINDS trial is the basis for current guidelines on tPA administration following acute ischemic stroke.
Neoplastic Coagulopathies Causing ICH The leading cause of ICH in cancer patients is intratumoral hemorrhage, which is most commonly seen in patients with solid tumors including melanoma, germ cell tumors, and lung carcinoma. Coagulopathies are another major cause of ICH in cancer patients and are most often seen in those with leukemia. The largest study on CVD in cancer patients to date was published by Graus, et al., from Memorial Sloan–Kettering Cancer Center in 1985. In this excellent autopsy series the authors examined 4326 patients with systemic cancer, in 500 (14.6%) of whom CVD was present. Graus, et al., and subsequent authors have suggested that coagulopathy-related ICHs in leukemia have distinct causes when they occur in subgroups of patients with and without blastic crises, with a third mechanism explaining the high incidence of hemorrhages in APML. Other investigators of coagulopathic ICH in cancer patients have looked at the specific presentation of subdural hemorrhages and examined patients with thrombocythemia secondary to myeloproliferative disorders.
Before considering these specific studies, it is useful to describe the unique features that distinguish CVD in cancer patients from that in the general population. One difference is that cancer patients often present with encephalopathy rather than with acute focal neurological signs. Another is that the risk profile is unique in cancer patients. In the series reported by Graus, et al., factors such as direct tumor effect, coagulopathy, and infection were more significant causes of ICH than the hypertension commonly associated with hemorrhage.
Leukemia and ICH: Epidemiology of ICH in Leukemia. In the series by Graus, et al., 500 of 4326 patients were found to have some type of CVD. In 244 of these ICH was present and 88 cases were due to coagulopathy. Of the 88 cases of ICH due to coagulopathy, underlying leukemia was present in 69, carcinoma in 10, lymphoma in seven, and multiple myeloma in two. The authors compiled a subset of data on all leukemia patients in whom autopsy was performed, to show overall frequency of ICH in the disease. They found that of 453 total leukemia cases in their series, ICH was present in 69 (15.2%) at autopsy. Remarkably, each case involving a leukemia patient with ICH was retrospectively shown to have a coagulopathy at the time of death, to which the authors attributed the CNS hemorrhage.
Graus, et al., analyzed their 69 leukemia cases by cancer subtype. They found that of 129 acute lymphoblastic leukemia patients, nine (7%) suffered ICH, whereas among 192 patients with AML 43 (22.4%) experienced similar complications. The higher incidence of ICH in AML can be partly explained by the natural history of one AML subtype, APML, which is discussed below.
Graus, et al., further subdivided the 69 patients with leukemia who suffered coagulopathic ICH into two groups. In the larger group of 50 patients (72.5%), there was no intracerebral leukostasis, parenchymal leukemic nodules, or perivascular leukemic infiltration; patients in this group usually presented with sepsis and had multiple coagulopathies including DIC, leukopenia, and thrombocytopenia. The mean platelet count was 13,500/mm3, and the mean WBC count was 8000/mm3.
In the smaller group of 19 (27.5%), the patients suffered ICH associated with CNS leukemic infiltration. Thirteen of these patients exhibited severe intracerebral leukostasis, with milder thrombocytopenia (mean platelet count 35,000/mm3), and a grossly elevated WBC count (70,000–731,000/mm3). The authors' autopsy findings and the work of subsequent authors provide insight into possible mechanisms by which the aforementioned subtypes of ICH arose.
Mechanisms of ICH in Leukemia: Leukostasis. In 13 of 19 patients in the smaller subgroup of coagulopathic leukemia cases in the study reported by Graus, et al., leukostasis (plugging of thin-walled cerebral vessels by leukemic blasts) and parenchymal leukemic nodules were demonstrated, with leukocytosis as their primary coagulopathy. Other coagulation disorders such as thrombocytopenia may have contributed to hemorrhage in these patients, but were not severe enough to cause hemorrhage alone. In a different study Fritz, et al., confirmed the importance of leukocytosis as a risk factor for ICH. These authors evaluated 81 patients with acute leukemia who died, 18 of ICH. Of these 81 patients, the WBC count was greater than 300,000/mm3 in 13 cases, and this group included nine (69%) who died of ICH. On the other hand, of the remaining 68 patients in whom the WBC count was less than 300,000/mm3, only nine (13%) died of ICH. This was a highly significant difference (p < 0.001), and the two groups were well matched for degree of thrombocytopenia. 38 Intracerebral hemorrhage associated with leukocytosis is most commonly seen in AML, and the bleeding often occurs at the time that leukemia is diagnosed (as in five of the 13 cases of ICHs in the series by Graus, et al.). Hemorrhages associated with hyperleukocytosis are usually multiple and intraparenchymal.
The mechanism of hemorrhage in leukostasis is likely a combination of two events: 1) direct infiltration and rupture of vessels by leukemic nodules and; 2) damage to the walls of small vessels by hypoxic vasodilation and hyperviscosity secondary to the leukostasis. A morphological study performed by Azzarelli and Roessmann showed that nondeformable myeloblastic cells are capable of blocking the lumen of capillaries, leading to the events described.
Emergency radiotherapy has been proven effective in preventing ICH due to leukostasis. In a 1983 review by Hug, et al., the authors studied 46 patients with AML and pretreatment leukocytosis (WBC > 100,000/mm3) and found that antimetabolites (which rapidly arrest leukemic cell proliferation) and leukapheresis (which prevents further leukostatic plug formation) are other promising means of preventing ICH in patients at risk for leukostasis.
Multiple Systemic Coagulopathies in the Absence of Leukostasis Within the larger leukemia subgroup of 50 patients (72.5%) in the study by Graus, et. al., there was no intracerebral leukostasis, parenchymal leukemic nodules, or perivascular leukemic infiltration. The origin of ICH in these patients was coagulopathic, but the coagulopathy was very different from that in patients with leukostasis. Patients in this larger subgroup usually presented with sepsis and had multiple blood dyscrasias including neutropenia, leukopenia, and thrombocytopenia. Simply put, ICH in this subgroup is a late complication and the pathogenesis is likely multifactorial.
Cases involving these multiple coagulopathies would be expected to have a high incidence of systemic bleeding rather than isolated ICH. The series published by Groch, et al., in 1960 confirmed this expectation. Thirty-nine (85%) of 46 patients with ICH sustained hemorrhages elsewhere, whereas in only 20 (43%) of 47 patients without ICH at autopsy was there evidence of systemic bleeding. Rather than presenting with ICH at diagnosis like many of the patients with leukostasis and CNS leukemic infiltration, those with multiple systemic coagulopathies usually sustained hemorrhage when their condition relapsed or treatment destroyed much of their bone marrow but had failed to induce a complete remission.
Acute promyelocytic leukemia is a unique subtype of acute nonlymphoblastic leukemia. It is unusual in that more than 60% of patients with this type of leukemia die of ICH. Like patients with leukostasis and CNS leukemic infiltration, patients with APML often present with ICH at diagnosis. In patients with APML, however, the mechanism of hemorrhage is DIC. In APML, malignant promyelocytes release nuclear and granular fractions that contain both procoagulant and fibrinolytic activity.[45,47] These granules trigger the destructive cascade of DIC and help account for the much higher rate of ICH seen in AML than in acute lymphoblastic leukemia.
Subdural Hemorrhage in Cancer Patients. Subdural hemorrhages most frequently result from dural metastasis of leukemia and are also seen in lymphoma and carcinoma. In the study reported by Graus, et al., each of 27 patients with carcinoma and a subdural hematoma also exhibited tumor infiltration of the dura at autopsy. The mechanism of hemorrhage in these cases was believed to begin with tumor obstructing vessels of the external dural layer, which resulted in dilation and rupture of capillaries of the inner layer. The autopsy results led the authors to conclude that subdural hematomas are rarely associated with bleeding disorders.
Minette and Kimmel found very different results in a 1989 review of patients with systemic cancer and subdural hematomas. They stratified their patients into several groups, one of which involved cases of malignant hematological lesions (primarily leukemia). In this group, the authors found that coagulopathies were present in 24 (85%), whereas dural metastases were present in only six (21%). They qualified their results, however, as possibly underestimating the group with metastases, given that microscopic inspection of the dura had not been conducted in all patients. Although the clinical presentation of subdural hematomas in the coagulopathy population did not differ from that in the general population, mortality rates were far higher in the group with abnormal coagulation profiles.
Primary Thrombocythemia Causing ICH. Primary (essential) thrombocythemia is a neoplastic condition in which platelets are oveproduced without a recognizable cause. The disease is characterized by extremely high platelet counts, splenomegaly, leukocytosis, and anemia. Common manifestations include bleeding from the GI, respiratory, or urinary tract, or the skin. Although ICH is a rare complication of this syndrome, it has been recorded in association with head trauma. Kase, et al., also reported on a case of lobar ICH in an 82-year-old man with thrombocythemia and platelet count of 1,000,000/mm3.
Idiopathic Thrombocytopenic Purpura Immune thrombocytopenic purpura is typically a benign, self-limiting disorder occurring in young, previously healthy children. In ITP, autoantibodies are made to platelets, resulting in accelerated platelet destruction. Immune thrombocytopenic purpura presents very variably, and petechiae, mucous membrane bleeding, and GI/CNS hemorrhages have all been reported as presentations of the disease. More than 80% of such patients with ITP experience a complete sustained remission within a few weeks to a few months of initial presentation, irrespective of any therapy given. The major concern is the small but finite (0.1–0.9%) risk of intracranial hemorrhage, which occurs in patients with very low platelet counts (< 20,000/mm3).
In a recent metaanalysis, Lee and Kim examined 31 patients with ITP complicated by ICH, including seven from the authors' own series and 24 patients reported on in the literature. In 24 patients there was an intraparenchymal or SAH, and a subdural hemorrhage was present in seven. Mean age of the patients with ICH was significantly lower than that in those with subdural hematoma. The mortality rate associated with ICH in ITP those was similar to that in those with spontaneous ICH.
In a 1997 study in Japan, investigators evaluated infants born to mothers with ITP. The authors evaluated findings in 93 pregnancies (one resulting in twins) in 31 hospitals between 1985 and 1994. Forty-nine (52%) of the neonates had thrombocytopenia (< 150,000 platelets/mm3). In 19 neonates (20%) a bleeding tendency was shown but was generally mild. In only one neonate (1%) (a case of asymptomatic intracranial hemorrhage), deep bleeding occurred secondary to thrombocytopenia. The lowest platelet count of neonates after birth occurred on Day 4, not on Day 0. There was no correlation between maternal and neonatal platelet counts. There was, however, an apparent correlation between the neonatal platelet count on Day 0 and the lowest platelet count after birth. Treatment of the mothers with intravenous high-dose γ- globulin and prednisolone did not prevent risk of neonatal thrombocytopenia significantly. The results of this study suggest that monitoring platelet counts in children born to mothers with ITP for approximately 1 week after birth and that correction of platelet count as necessary may help prevent ICH and other bleeding episodes in this population.
Other Causes of Thrombocytopenia Associated With ICH Any condition that results in a low platelet count theoretically predisposes a patient to bleeding disorders, including ICH (Fig. 3). Thrombocytopenia has multiple causes, and one common classification scheme is as follows: 1) decreased platelet production, as seen in certain congenital disorders and cases of bone marrow damage (due to radiation, drugs); 2) increased platelet destruction, as in ITP, and other diseases including thrombotic thrombocytopenic purpura, posttransfusion purpura, and DIC; 3) abnormal sequestration, usually in the spleen, as in cirrhosis; and 4) multiple causes, as commonly seen in alcoholics. Cases of thrombocytopenia-induced ICH have been linked to use of certain medications, as well as to uremia, alcohol use, and liver transplants.
Figure 3. Axial CT scan obtained in a 87-year-old man with a history of hypertension who was admitted with acute-onset nausea, vomiting, and aphasia. He was febrile, his platelet count was 58/mm3 and coagulation profile was moderately prolonged. The CT scans revealed focal hematoma in the midline cerebellum, as well as SAH and intraventricular hemorrhage. The patient was admitted for palliative care, with the diagnosis of ICH secondary to DIC and thrombocytopenia. Mass effect led to cerebellar herniation and death.
Drug-Induced Thrombocytopenia Resulting in ICH. Numerous have been associated with thrombocytopenia, including certain cytotoxic drugs, antimalarial agents, antiepileptic medications, furosemide, digoxin, and estrogens. Any of these drugs could theoretically cause thrombocytopenia that could in turn contribute to ICH in a patient, especially one with other risk factors. In 1985, Kikta, et al., described two patients in whom intracranial hemorrhage developed after ingestion of diet pills containing phenylpropanolamine in combination with caffeine. The first patient sustained bilateral simultaneous cerebral hemorrhages, and the second sustained an SAH. A case of quinidine resulting in ICH was reported by Glass, et al., in 1989, who described patients receiving digoxin, verapamil, and quinidine who developed epistaxis and a frontotemporal ICH. Thrombocytopenia (4000 platelets/ mm3) was demonstrated on admission to the hospital, but PT and PTT were normal. The patient died despite drug discontinuation and initiation of steroid therapy, platelet transfusions, immunoglobulins, and evacuation of the hematoma.
Uremia and ICH. Uremia is largely seen in adults with kidney disease who develop a platelet defect that tends to parallel the patient's increases in blood urea nitrogen and creatinine. In addition to a decreased number of platelets, bleeding also reflects a functional deficit of platelet coagulant activity. The incidence of serious bleeding complications in uremia is decreasing, largely due to the efficacy of dialysis in correcting blood dyscrasias.
Although bleeding disorders secondary to chronic uremia are on the decline, a more acute entity called HUS has been reported as a cause of ICH. This syndrome usually affects children younger than 10 years of age and is characterized by destruction of red blood cells, damage to the lining of blood vessel walls, and, in severe cases, kidney failure. Most cases of HUS occur after an infection in the digestive system caused by Escherichia coli. Patients with HUS present with GI symptoms such as abdominal pain, vomiting, and bloody diarrhea. In 2000, Manton, et al., described the case of a 4-year-old girl who died of ICH while being treated for HUS-related renal failure. Examination of urine and feces cultures showed verocytotoxin producing E. coli. The authors emphasized the importance of postmortem culture analysis of tissues and fluids in establishing a diagnosis in this case, because their histological evaluation was compromised by profound sepsis and tissue putrefaction.
Alcohol and ICH. A number of abnormalities of hemostasis are demonstrated in alcoholic patients. Thrombocytopenia in these patients is due to associated folate deficiency, splenic sequestration, and direct toxic effects of alcohol on the bone marrow. Numerous functional deficits have also been described in the platelets of alcoholics, which are associated with disturbances in ultrastructural morphology.
The largest study to date on alcohol use and ICH was conducted by the Honolulu Heart Program, which between 1965 and 1977 followed 8006 men in a prospective study of CVD. Of those individuals free of stroke at the time of study entry, 2916 were classified as nondrinkers of alcohol and 4962 as drinkers. In the 12-year follow-up period, 197 drinkers and 93 nondrinkers experienced a stroke. No significant relationships were noted between alcohol and thromboembolic stroke. The risk of hemorrhagic stroke, however, more than doubled for light drinkers and nearly tripled for those considered to be heavy drinkers. These findings were statistically significant and independent of hypertensive status and other risk factors. Results further indicated that alcohol had a greater effect on hemorrhagic strokes that were subarachnoid in origin, conferring a three- to fourfold increased risk for moderate and heavy drinkers compared with nondrinkers. In a 1995 case-control study, Juvela, et al., compared patients who had a recently sustained an ICH with peers who had not, and they found that recent moderate and heavy alcohol intake (< 24 hours before onset of ICH symptoms) was a significant independent risk for hemorrhage.
Intracerebral Hemorrhage in Liver Transplant Patients. Neurological complications including central pontine myelinosis, seizures, and ICH have been reported in patients who have undergone liver transplant procedures. In a 1991 series, Estol, et al., examined 55 autopsy cases of 1357 patients who had undergone liver transplantation at the University of Pittsburgh, and they found that 13 (23.6%) of these patients had sustained an ICH and five (9%) had experienced cerebral infarctions. Of the 13 patients with ICH, five had bleeding at multiple sites, with a total of eight intraparenchymal hemorrhages, seven SAHs, and four subdural hematomas. Some degree of coagulopathy was shown in all patients, with either thrombocytopenia, a prolonged PT, or both. Although fungal infections caused by Aspergillus sp. were seen in three of the patients, the authors concluded that coagulopathy was the significant risk underlying the bleeding propensity in all of their patients.
In a 1995 case-control study, Wijdicks, et al., analyzed possible causative mechanisms for ICH after orthotopic liver transplantation. They identified a group of eight patients with ICH demonstrated after orthotopic liver transplantation and a control series of 207 patients who had undergone liver transplantation but had not sustained an intracranial hemorrhage. In their analysis they found that bacteremia or fungemia was present in five of the eight patients with ICHs (62%) but in only 11% of the control group (p = 0.03, Fisher exact test). They concluded that both infections and thrombocytopenia play a role in ICH after liver transplantation.
Congenital Disorders Hemophilia. Hemophilia A and B are rare conditions with a combined incidence of approximately 1 in 10,000 individuals. They are caused by a deficiency of coagulation factors VIII (hemophilia A) and IX (hemophilia B). Both are x-linked congenital disorders and are thus far more prevalent in males than in females. Hemophilia can be graded according to its severity as mild, moderate, or severe. In mild hemophilia, 5 to 30% of normal factor level is present, and abnormal bleeding is usually associated with obvious trauma, tooth extraction, or surgery. In moderate hemophilia, the factor level is 1 to 3%, and the symptoms are usually intermediate between those of patients with mild and severe disease. In severe hemophilia, the factor level is 0 to 1% of average normal levels, and patients suffer numerous hemorrhages from an early age, as well as spontaneous bleeding into muscles and joints. Intracerebral hemorrhage is the most feared complication of hemophilia and the leading cause of death in patients with the disease.
Incidence of ICH in Hemophilia. In a 1960 review and case series Silverstein provided one of the first comprehensive looks at ICH in hemophilia. Silverstein reviewed the literature dating back to 1819 and found that the incidence of ICH in hemophilia was between 2.2 and 7.8% in recent series. Silverstein also examined data obtained in hemophiliacs admitted to his institution (Mt. Sinai Hospital in New York) and reported the incidence of ICH to be 6.3% (six documented and five likely episodes of bleeding in 174 patients admitted). In a series of Australian patients published several years later, Kerr found that 15 (13.8%) of 109 hemophiliacs sustained 19 episodes CNS bleeding among them. In the largest series to date, Eyster, et al., sent a mail survey to 12 US institutions; they reported a total of 71 CNS bleeding episodes among a population of approximately 2500 hemophiliacs (2.8%). In a recent series, de Tezanos Pinto, et al., followed 1410 hemophiliacs, 106 (7.5%) of whom suffered a total of 156 episodes of ICH. Findings in these latter series suggest that the incidence range that Silverstein proposed four decades earlier remains valid.
Risk Factors for ICH in Hemophilia. Hemophiliacs who are young, have suffered recent head trauma, and harbor more severe baseline disease are at increased risk for ICH. The age demographics were noted by Silverstein who examined 31 cases of proven ICH (25 already reported on in the literature and six from his own series) and found that 15 (48%) of these patients were younger than age 10 years, whereas 27 (87%) of 31 were younger than 20 years of age. In the larger series reported by Eyster, et al., they demonstrated similar results, with 38 (54%) bleeding episodes in patients younger than 10 years of age, and 51 (72%) of 71 patients younger than 18 years of age. Finally, in the recent series by de Tezanos Pinto, et al., the mean age of patients with hemophilia A and ICH was 14.8 years and that of those with hemophilia B was 9 years of age. In their series, 46% of overall ICH episodes occurred in patients before age 10 years and 72% in those younger than 20 years of age.
Head trauma has been suspected as a risk factor for ICH since 1840, when the authors of an article in Lancet described two hemophiliacs who died in 1819 after falls "in which they received blows on the head not sufficiently severe to have produced much mischief in a sound state of the system, but which in them was followed by extravasation of blood within the cranium." Silverstein found that recent head trauma had occurred in 14 (45.2%) of the 31 definite cases of ICH he described in hemophiliacs. Kerr reported that five (26%) of 19 patients in his series suffered head trauma, with one only sustaining minor trauma in a pillow fight with his hemophiliac brother. In the series by Eyster, et al., 38 (54%) of the 71 ICHs were preceded by head trauma, whereas in the series reported by de Tezano Pinto, et al., 62 (40%) of 156 bleeding episodes occurred in patients with such a history.
Several authors have noted that severe hemophilia poses an increased risk for ICH over milder forms of the disease. In his series, Kerr found that patients with severe hemophilia presented with ICH at a mean age of 16 years, whereas those with mild hemophilia presented at a mean age of 46 years. Eyster, et al., reported that 59 (83%) of their 71 patients with ICHs also suffered from a severe form of hemophilia. Similar results were reported by de Tezanos Pinto, et al., in whose series approximately 74% of patients with ICH had severe hemophilia.
Presentation of Posttraumatic ICH in Hemophiliacs. The presentation of ICH following head trauma in patients with hemophilia differs from that in the general population (Fig. 4). In general, with the exception of subdural hematomas, the majority of patients with posttraumatic ICH exhibit obvious signs and symptoms within the first 24 hours. Eyster, et al., found that the mean symptomfree interval following head trauma in hemophiliacs was 4 ± 2.2 days. In a study in which they followed all registered hemophiliacs living in Israel, Martinowitz, et al., found that seven (2.4%) of 288 patients suffered a total of eight episodes of ICH, with four of these eight episodes secondary to head trauma. The mean symptom-free interval ranged from 6 hours to 10 days. This difference between hemophiliacs and nonhemophiliacs emphasizes the slow, indolent nature of hemorrhage in the former category after even trivial trauma.
Figure 4. Computerized tomography scan demonstrating a supratentorial subdural hematoma with small left SAH secondary to hemophilia, obtained in a 34-year-old man with a history of mental retardation, hemophilia A with multiple inhibitors, and possible childhood seizures. He had a several-day history of nausea and four convulsions on the day of admission. The CT scanning studies revealed a supratentorial subdural hematoma and small left SAH (shown). The patient received specialized treatment with human recombinant factor VIIa as well as Autoplex (an antiinhibitor coagulant complex), and the coagulopathy was corrected. The patient recovered to baseline status and was discharged home on hospital Day 19.
Outcome of ICH in Hemophiliacs. In 1960, Silverstein found that 22 (71%) of the 31 hemophiliac patients in his series and the literature he reviewed had died of ICH. He correctly predicted that cryoprecipitate treatments, widely introduced in the early 1960s, would cause a sharp decline in this mortality rate. A few years later, Kerr reported that five (33%) of his 15 patients died of ICH. Eyster, etal., similarly reported a mortality rate of 34%, although they noted that the mortality rate was 67% in cases in which the hemorrhage was intraparenchymal; it was much lower for other types of ICH (10% for subdural hemorrhage and 18% for SAH).
Martinowitz, et al., commenting on the results published by Eyster, et al., stated that the reduction in mortality rates since 1960 was due to improved treatment of subdural hematoma and SAH rather than to better management of coagulopathies with cryoprecipitate infusion. They cited the high mortality rate in their own series (four [57%] deaths in seven cases) to support their point. They claimed that poor results "despite adequate replacement and supportive therapy, were probably due to the conservative and hesitant approach of the neurosurgeons."
Rare Congenital Disorders Resulting in ICH. Although hemophilia A and B are the most prevalent congenital bleeding disorders, other rarer congenital coagulopathic states have been linked to ICH, usually in case reports or very small series. These relatively rare causes of ICH include vWF deficiency,[2,91] congenital afibrinogenemia, and deficiencies in certain coagulation factors including factors V, VII, and XIII. Even less frequently, genetically hypercoagulable states such as antiphospholipid syndrome, prothrombin mutation, and factor V Leyden deficiency have been associated with ICH through mechanism of superior sagittal sinus (or other venous) thrombosis transforming into venous hemorrhage.[95,100,101] These genetically hypercoagulable states are especially dangerous when risks are compounded, as in pregnant women or those receiving oral contraceptives (Figs. 5–7).
Figure 5. A T1-weighted MR image obtained in a 26-year-old woman who, 2 days after an uncomplicated cesarean-section birth, presented with headaches, seizures, aphasia, and a right hemiparesis. She was found to have a superior sagittal sinus thrombosis and a left parietal hemorrhage secondary to genetically hypercoagulable state, a heterozygote for the prothrombin G to A mutation. Anticoagulation therapy consisted of heparin and followed by Coumadin, and she was transferred to rehabilitation services on hospital Day 15 after partial recovery of her speech, cognitive status, and right-sided motor function. The rest of her workup, including homocysteine levels, anticardiolipin antibody, protein S, antithrombin 3, and factor V Leyden, indicated normal findings.
Figure 6. Imaging studies acquired in a previously healthy 51- year-old woman, who had been receiving hormone replacement therapy for 30 months and who developed severe right-sided headache, nausea, vomiting, altered mental status, aphasia, and a generalized seizure. A: An MR venogram revealing an occluded superior sagittal sinus. B: An MR image demonstrating a left frontal intraparenchymal hematoma. The patient underwent anticoagulation therapy and made a good recovery. Hypercoagulability workup showed that the patient was heterozygous for a mutation in a newly described prothrombin gene, which is associated with increased risk of thrombosis in women taking estrogen supplementation.
Figure 7. Imaging studies obtained in a 21-year-old woman who was admitted with focal seizures involving her right arm and speech impairment 4 weeks after an uncomplicated delivery. A: An MR venogram demonstrating left transverse and sigmoid sinus thrombosis and left jugular vein thrombosis. B: Axial CT scan revealing hemorrhagic venous infarction in the left superior temporal lobe with thrombosis of the vein of Labbé.
Clinical Features and Diagnosis Patients with large ICHs present with a decreased level of consciousness due to increased ICP and/or direct compression or distortion of the thalamic and brainstem reticular activating system.[4,92] Approximately 25% of patients with ICH who are originally alert will experience secondary deterioration in the level of consciousness within 24 hours.[86,102] The risk of deterioration can be exacerbated by the presence of intraventricular blood, expanding hematoma, and worsening cerebral edema.
Presentation can be classified according to the location of the hematoma (Table 2). For instance, if the lesion is in higher cortical areas, patients may present with aphasia, neglect, gaze deviation, and hemianopia. Patients with supratentorial ICH around the putamen, caudate, and thalamus will most likely present with contralateral sensorimotor deficits due to internal capsule involvement. Patients with infratentorial ICH may exhibit signs of brainstem dysfunction including cranial nerve abnormalities, gaze abnormalities, and contralateral motor deficits. If the cerebellum is involved, the patient may present with ataxia, nystagmus, and ipsilateral dysmetria. Patients with ICH involving a ventricular component may experience nonspecific symptoms including headache and vomiting.[88,92]
Seizures are common with intracranial hemorrhage. Faught and colleagues followed 123 patients with primary ICH for a mean of 4.6 years to determine the incidence, prevalence, and type of epileptic seizures. They found that 25% of patients experienced seizures and in half of these patients, the seizures began within 24 hours of the hemorrhage. Seizure incidence was high in cases involving bleeding into lobar cortical structures (54%), low in cases involving basal ganglionic hemorrhages (19%), and absent in cases involving thalamic hemorrhages. In this series, the prevalence of chronic epilepsy was much lower: 13% in 30-day to 2-year survivors and 6.5% in 2- to 5-year survivors. The efficacy of antiepileptic drugs in intracranial hemorrhage remains uncertain.
Death due to spontaneous ICH in the first 6 months ranges from 23 to 58%.[13,79,123] Three factors have been consistently associated with high mortality rate: low score on the GCS, large-volume hematoma, and intraventricular blood demonstrated on the initial CT scan.[13,79,123]
Using three categories of parenchymal hemorrhage volume (0–29 cm3, 30–60 cm3, and >/= 61 cm3) and two categories of the GCS score (>/= 9 or </= 8), Broderick and colleagues found that the 30-day mortality rate was predicted correctly with a sensitivity and specificity of 96 and 98%, respectively. Patients in whom initial CT scanning revealed a parenchymal hemorrhage volume of greater than or equal to 60 cm3 and in whom the GCS score was less than or equal to 8 the predicted 30-day mortality rate was 91%, whereas patients in whom the volume was less than 30 cm3 and the GCS score greater than or equal to 9 the predicted 30-day mortality rate was 19%. The authors also developed and validated a manual method by which measure hematoma volume on CT scans. This consists of half the product of A, B, and C, where A is the greatest diameter of the hemorrhage on the CT scan, B is the diameter perpendicular to A, and C is the number of slices demonstrating hematoma multiplied by the slice thickness.
Rapid onset of neurological abnormalities and decreased level of alertness are of paramount importance in suggesting ICH. After obtaining a history and performing a physical examination, the diagnosis of ICH requires cranial neuroimaging. Computerized tomography scanning has revolutionized the management of brain hemorrhage by demonstrating these lesions with detail and resolution. It helps to localize precisely the hematoma and outline the degree of brain edema and mass effect. The CT scanning study can be repeated rapidly and as needed to evaluate the subsequent clinical course.
With the advent of MR imaging, it is increasingly common to see clinical syndromes of lacunar infarction produced by small hemorrhages. This modality is very sensitive in detecting ICH but the findings depend on when it is performed after hemorrhage (Table 3). In the first few hours, MR imaging reveals minimal hypointensisty on T1-weighted sequences and minimal hyperintensity on T2-weighted sequences. One week after bleeding, both T1- and T2-weighted MR images demonstrate high signal. Macrophages ingest blood and produce hemosiderin, which shows as a chronic black rim around the margin of the hematoma that is now resorbing.
A lumbar puncture procedure is of no use in intracranial hemorrhage and it may be dangerous in the presence of mass effect, especially with cerebellar lesions.
Determining laboratory values is essential in establishing the origin of the intracranial hemorrhage in the acute setting (Table 4). Hematocrit, platelet count, and coagulation parameters (PT, PTT, and INR) should be obtained as soon as the patient arrives to the emergency department. A bleeding time is recommended in patients known to have been taking aspirin.
Management Practices Nonsurgical Management The management of the patient with ICH ranges from observation to hematoma evacuation in the operating room. The decision of when to intubate a patient with ICH presents a major challenge. Delayed intubation can lead to aspiration, hypoxemia, and/or hypercapnia, all of which can worsen the outcome. A neurosurgical consultation should be obtained rapidly if the patient exhibits signs of rapid deterioration in the mental status, herniation, and/or hydrocephalus. If the patient presents any of these signs, mannitol and hyperventilation therapy should be immediately implemented and an intraventricular catheter should be placed for drainage of cerebrospinal fluid.
Initial medical management should control blood pressure, correct coagulopathic disorders, control edema, and prevent seizures. Excessive reduction of mean arterial blood pressure should be avoided because autoregulation is impaired in the area surrounding the hemorrhage and decreased perfusion may lead to ischemia. Edema is treated with mannitol. The initial coagulation disorders should be addressed immediately. Fresh-frozen plasma, vitamin K, protamine, and platelet transfusions are used as needed depending on the patient's coagulation deficit. Patients receiving aspirin should undergo a platelet transfusion if they continue to bleed and if the bleeding time is prolonged. In patients with hemophilia at least 20% of their deficient factor should be maintained. If ICH is due to streptokinase, urokinase, or tPA, we recommend a combination of protamine and epsilon-aminocaproic acid.
Surgical Management Although no strict guidelines for the surgical evacuation of intracranial hematomas exist, the goals of evacuation are clear: reduce the mass effect, block the release of neuropathic products from the hematoma, and prevent prolonged interaction between the hematoma and normal tissue to avoid causing further tissue damage. Intracerebral blood can be removed via craniotomy, but the walls of the hematoma should be left intact to avoid precipitating recurrent hemorrhage.
Deep supratentorial hemorrhages (basal ganglia, thalamus, and pons) do not benefit from surgical evacuation, because most damage in these cases is caused by the initial hemorrhage and the sites are difficult to access surgically. Hankey and Hon conducted a metaanalysis of three randomized controlled trials of supratentorial hemorrhage involving 123 patients who underwent hematoma evacuation via open craniotomy and 126 patients who did not undergo surgery. In patients who underwent evacuation, the 6-month rate of death or dependency was higher (83 and 70%, respectively).
The morbidity and mortality associated with cerebellar hematomas are due to brainstem compression and surgery can relieve this pathological process. Cerebellar hematomas can be easily reached via midline or lateral suboccipital craniotomies. Patients with GCS scores less than or equal to 14 and hematomas at least 40 mm or 15 ml in volume appear to benefit the most from surgery, in contrast to those with GCS scores of at least 14 and hematomas less than or equal to 40 mm or 15 ml in volume in whom the likelihood of recovery is good.
Early stereotactic and endoscopic evacuation of hematoma is an alternative approach that might minimize damage to overlying normal tissue.[6,135] Auer and colleagues conducted a controlled randomized study in which they compared endoscopic evacuation and medical treatment in 100 patients with spontaneous supratentorial intracerebral (subcortical, putaminal, and thalamic) hematomas, excluding patients with aneurysms, arteriovenous malformations, brain tumors, or head injuries. Six months after hemorrhage, they found that in surgery-treated patients with subcortical hematomas the mortality rate was significantly lower (30%) than those treated medically (70%) (p < 0.05). Furthermore, 40% of surgically-treated patients experienced a good outcome with no or only a minimal deficit compared with 25% in the medically treated group; the difference was statistically significant for surgically-treated patients with no postoperative deficit (p < 0.01). This effect related to surgery was limited to patients in a preoperatively alert or somnolent state; stuporous or comatose patients experienced no better outcome after surgery. Outcome in surgically treated patients with putaminal or thalamic hemorrhage was no better than that in those treated medically; however, there was a trend toward better quality of survival and chance of survival in the surgery-based group.
Conclusions and Future Directions Spontaneous intracranial hemorrhage is fatal in approximately 50% of cases and accounts for approximately 10% of all strokes. Prompt diagnosis is imperative because delaying treatment can lead to secondary brain tissue damage. The goal of surgery in these patients is rapid evacuation of maximal volume of hematoma while causing minimal brain injury due to surgery itself.
Future interventions are focused on understanding the underlying mechanisms of ICH-related brain injury and improving methods of early hematoma evacuation. Xi and colleagues have postulated that thrombin is an important mediator of perihematoma edema in a pig model of lobar ICH and suggested that antithrombin therapies may have a role in ICH management. There is no question that new treatments need to be developed to prevent the secondary insult to normal brain tissue after intracranial hemorrhage. We need to develop techniques to study the genetic factors involved in the predisposition to develop intracranial hemorrhage and further develop techniques to reduce the deleterious effect of cerebral edema.
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Address reprint requests to: Alfredo Quinones-Hinojosa, M.D., Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, M-780, San Francisco, California 94143-0112. email: Quinones@neurosurg.ucsf.edu.
AML, acute myelocytic leukemia; APML, acute promyelocytic leukemia; CNS, central nervous system; CT, computerized tomography; CVD, cerebrovascular disease; DIC, disseminated intravascular coagulation; GCS, Glasgow Coma Scale; GI, gastrointestinal; HUS, hemolytic uremic syndrome; ICH, intracerebral hemorrhage; INR, international normalized ratio; ITP, idiopathic thrombocytopenic purpura; MI, myocardial infarction; MR, magnetic resonance; NINDS, National Institutes of Neurological Disorders and Stroke; PT, prothrombin time; PTT, partial thromboplastin time; SAH, subarachnoid hemorrhage; TFPI, tissue factor pathway inhibitor; TIA, transient ischemic attack; tPA, tissue plasminogen activator; vWF, von Willebrand factor; WBC, white blood cell
Alfredo Quinones-Hinojosa, M.D., Mittul Gulati, M.D., Vineeta Singh, M.D., and Michael T. Lawton, M.D., Departments of Neurological Surgery and Neurology, University of California San Francisco School of Medicine, San Francisco, California