Hematologic Disorders and Stroke
Hematologic abnormalities lead to thrombosis in the cerebral vasculature, causing ischemic cerebrovascular events. However, the majority of patients with ischemic cerebrovascular events do not have a well-defined hematologic abnormality. Coagulation disorders that predispose to strokes remain poorly defined but have been implicated in venous strokes (cerebral venous thrombosis) rather than arterial strokes. Platelet function abnormality, inherited hemostatic abnormality, and vascular injury promote thrombosis.
The aim of this article is to highlight the significance of these factors in stroke, to assess their impact on long-term prognosis, and to outline an approach to the patient with stroke for evaluation of hemostatic abnormalities. The specific factors discussed in this article include factor V Leiden (ie, resistance to activated protein C [APC]  ), deficiencies of proteins C and S  and antithrombin III, sickle cell anemia, hyperhomocystinemia, antiphospholipid syndrome (APS), hereditary disorders of fibrinolysis, and certain acquired conditions leading to abnormal platelet function and hypercoagulable state.
Hematologic Risk Factors in Stroke
In general, patients with blood dyscrasias and stroke are prone to recurrent cerebrovascular events. These patients are usually younger than stroke patients in the general population and do not have the vascular risk factors. Known hematologic abnormalities are estimated to account for about 4% of all strokes, [3, 4] but this proportion may be higher in younger people.
APC resistance and factor V Leiden
The most common inherited defect leading to venous thrombosis is hereditary resistance to activated protein C (APC), which is caused by a mutation in factor V (factor V Leiden) and that renders activated factor V unable to be cleaved by APC. [5, 6] . This occurs in 5-7% of the normal population, 20% of patients with deep vein thrombosis (DVT), and 60% with recurrent DVT.
No study has established a relationship between factor V Leiden and arterial strokes, thus the incidence of this factor in patients with stroke is not known. In general, however, factor V Leiden correlates more with venous mechanisms of thrombosis than arterial ones. Factor V Leiden is suspected, therefore, to be associated with paradoxical emboli or with venous sinus thrombosis more than with arterial mechanisms of stroke. The heterozygous state, unlike the homozygous state, has not been shown to be a risk factor for recurrent venous thromboembolism.
Deficiency of thrombin antagonists
Protein C, protein S, and antithrombin III (ATIII) deficiencies are all extremely rare, with a frequency ranging from 1 per 1000 to 1 per 5000 in the general population. In a study by Martinez et al, 10 of 60 patients (17%) had an acute ischemic stroke that was attributed to deficiencies in protein C, protein S, or ATIII. 
Cerebral vein thrombosis is a more frequent presentation than arterial stroke. No clear-cut association has been found between protein C or ATIII deficiency and arterial strokes, although patients with low protein C levels at the time of acute stroke have poor outcomes. However, a prospective study did find free protein S deficiency in 23% of young patients with stroke of uncertain cause, but this finding could be associated with higher levels of C4b (an acute phase reactant that decreases free protein S levels).
Once a deficiency of protein C, protein S, or ATIII is identified, differentiating between congenital and acquired cases is important.
Prothrombin gene mutation
Reports indicate that a G-to-A transition at nucleotide position 20210 (G20210A) in the prothrombin gene is considered a risk factor for cerebral venous thrombosis.  The heterozygous state, unlike the homozygous state, has not been shown to be a risk factor for recurrent venous thromboembolism. This mutation has not been associated clearly with acute ischemic strokes.
Hereditary abnormalities of fibrinolysis
Dysplasminogenemia is caused by genetic mutations that produce fibrinogen molecules that form clots resistant to fibrinolysis or that bind with increased avidity to platelets to promote thrombosis. This results in hypofibrinolysis by various mechanisms, including a decreased level of circulating plasminogen, an abnormally functioning plasminogen, an increase in the concentration of plasminogen activator inhibitor, or a decrease in the level of plasminogen activator.
Although an association with stroke per se has yet to be described, these mutations thereby increase the risk of venous and arterial thrombotic episodes, including stroke, and should be considered in a young patient with stroke and a history of recurrent DVT.
Although sickle cell disease itself does not alter hemostasis, it is believed to be a risk factor for stroke by vascular damage. The mechanism is a progressive, segmental narrowing of the distal internal carotid artery and portions of the circle of Willis and proximal branches of the major intracranial arteries. Sickle cell plugging of microcirculation and cerebral veins has also been noted.
The incidence of stroke in patients with hemoglobin SS is 10%; in those with hemoglobin SC, it is 2-5%. The incidence of brain infarction peaks around age 10 years.
Other erythrocyte disorders, such as polycythemia vera, cause hyperviscosity-related diminished cerebral blood flow.
Acquired disorders associated with abnormal platelet function
Most of the microvascular occlusions of thrombotic thrombocytopenic purpura (TTP) are secondary to multiple microvascular platelet-fibrin thrombi that involve small arteries and capillaries. Most studies of coagulation and fibrin degradation products are normal, but elevated plasma fibrinogen is often found.
Heparin-induced thrombocytopenia is a disorder in which patients develop antibodies against heparin that are directed toward platelets, causing activation. Two types have been identified: Type I develops 1-5 days after institution of heparin therapy and is a benign condition that results in platelet aggregation. Type II develops 6-10 days after institution of heparin therapy and is a risk factor for recurrent stroke.
Myeloproliferative disorders, particularly essential thrombocytosis and polycythemia vera, place patients at higher risk of thrombotic events, including stroke. Atherosclerosis and dysfunctional platelets, more than elevated platelet count, are believed to contribute to the cerebral thrombotic events.
Paroxysmal nocturnal hemoglobinuria also causes cerebrovascular thrombotic events, associated primarily with venous thrombosis.
Hyperhomocystinemia is associated with vasculopathy. Patients with stroke have homocysteine levels 1.5 times those of age- and sex-matched controls. Prospective and case-control studies have found that the incidence of stroke increases with increasing homocysteine levels. Thus, all young persons with unexplained stroke, especially those with atherosclerosis, should have homocysteine levels checked. Unlike most prothrombotic states, hyperhomocystinemia causes more arterial strokes than venous.
Individuals who are homozygous for cystathionine beta synthase deficiency develop premature atherosclerosis and often experience a stroke early in life. Homozygous patients clinically manifest a marfanoid habitus, lenticular dislocations, and other skeletal abnormalities, in addition to strokes. These patients excrete homocysteine in the urine and have 20-fold or greater elevations of homocysteine and related amino acids in the plasma. However, patients who are heterozygous for cystathionine beta synthase deficiency can develop a mild clinical picture.
A mutation in methylenetetrahydrofolate reductase (MTHFR) in the folate pathway has been correlated with an increase in plasma homocysteine and may be a cardiovascular disease risk factor. However, hyperhomocystinemia is more commonly acquired; the most common acquired cause of hyperhomocystinemia is dietary deficiency of folate and vitamin B-12. MTHFR C677T, homozygous TT, or A1298C are not risk factors for cerebral arterial or venous thrombosis.
The range for a normal serum homocysteine is controversial, but levels greater than 14 µmol/L, the highest quartile of homocysteine levels, significantly increase the risk of stroke. Folate and vitamin B-12 levels should be checked, as evidence that folate and B-12 deficiencies can lead to elevated homocysteine levels is definite.
Older age and renal insufficiency can lead to elevated homocysteine levels, as can the use of antiepileptic drugs such as phenytoin.
Antiphospholipid syndrome (APS) (ie, presence of antiphospholipid [aPL] antibodies or lupus anticoagulant [LA]) occurs in 10% of patients with acute ischemic stroke. This number is higher in younger patients. Recognizing aPL antibodies is important, as they are associated with a hypercoagulable state characterized by fetal loss, thrombocytopenia, and venous and arterial thrombosis.
The 3 major types of clinically relevant aPL antibodies are anticardiolipin (aCL) antibodies, LA, and anti–β2 -glycoprotein I (anti-β2 GPI) antibodies. In a patient with APS, the concordance of aCL and LA may be up to 70%. Up to 10% of patients with aPL antibodies are positive solely for anti-β2 GPI antibodies.
The mechanisms of thrombosis are heterogeneous and include cardiac valve lesions that embolize, hypercoagulable states, and cerebral vascular endotheliopathy. They tend to interfere in some way with normal endothelial cell functions via the protein C and protein S anticoagulant pathway.
In 2006, the Sapporo Criteria for APS were updated.  Clinical criteria include vascular thrombosis and pregnancy morbidity. The laboratory criteria on 2 or more occasions more than 12 weeks apart include the following:
ACL antibodies (immunoglobulin [Ig] G or IgM; medium or high titer of >40 GPL/MPL or >99th percentile, where GPL is IgG phospholipid units and MPL is IgM phospholipid units)
Anti–β 2 -glycoprotein I antibodies (IgG or IgM, >99th percentile)
There is evidence that at least one lipoprotein, lipoprotein(a) (Lp(a)), is elevated in selected populations with cerebrovascular disease. Many studies have shown elevated Lp(a) to be a potent risk factor for stroke, especially in young individuals. However, a clear role for the treatment of elevated Lp(a) in preventing strokes has yet to be established.
Evaluation of Patients With Blood Dyscrasias and Stroke
Patient characteristics and physical findings
Blood dyscrasias or hypercoagulability should be suspected in patients with ischemic stroke who have the following characteristics:
Younger than 55 years with no obvious cause of stroke
History of multiple unexplained strokes
Previous history of venous thrombosis
Family history of thrombosis
Abnormalities on routine screening coagulation tests
In addition, antiphospholipid syndrome (APS) must be suspected in patients with history of multiple miscarriages, dementia, optic neuropathy, and thrombocytopenia, as well as lupuslike syndromes and "complicated migraine." Although strokes of all sorts are noted, involvement of the cerebral cortex and subadjacent white matter by platelet-fibrin microthrombi is most commonplace.
Few physical findings point toward the diagnosis of blood dyscrasias in stroke. Blood dyscrasias more commonly predispose to thrombosis in the large arteries. Uncommonly, blood dyscrasias may lead to lacunar stroke or cardioembolic stroke, as seen in APS.
In patients diagnosed with blood dyscrasias, a search should be made for clinical findings of thrombosis elsewhere, including venous thrombosis. In a few instances, antiphospholipid syndrome (APS) is associated with Sneddon syndrome, which is manifested by livedo reticularis and cerebrovascular disease.
Other conditions that should be considered when evaluating blood dyscrasias and stroke include cardioembolic stroke; dissection syndromes; fibromuscular dysplasia; lacunar syndromes; anterior circulation stroke; cerebral venous thrombosis; cerebellar, intracranial, and subarachnoid hemorrhage; epidural and subdural hematomas; seizures and epilepsy; atherosclerotic disease of the carotid artery; and transient ischemic attack.
Metabolic diseases have also been associated with stroke, including hyperglycemia/hypoglycemia; syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS); methylmalonic acidemia; and propionic acidemia.
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are recommended tests for all patients in whom a hypercoagulable state is suspected.
PT is used to diagnose deficiencies or inhibitors of factors I, II, V, VII, and X. It also is used to monitor warfarin therapy and screen for vitamin K deficiency. PT results are usually expressed in terms of a standardized international normalized ratio (INR).
APTT is used to diagnose deficiencies or inhibitors of factors VIII, IX, XI, and XII, as well as to diagnose deficiency of von Willebrand factor. This study is also used to monitor heparin therapy and as a screening test for lupus anticoagulant (LA).
Tests for Hypercoagulability
Additional testing is aimed at specific hypercoagulable states that may be suspected on the basis of patient history and findings (see Evaluation of Patients With Blood Dyscrasia and Stroke). 
Thrombin time is used to diagnose fibrinogen deficiencies, to detect heparin resistance, and to monitor fibrinolytic therapy.
Antiphospholipid antibodies and lipoprotein(a) levels
Antiphospholipid antibodies of the immunoglobulin (Ig) G class and lupus anticoagulant (LA) are tested in patients with or without clinical systemic lupus in whom hypercoagulability is suspected. These patients include those with stroke who have a history of thrombocytopenia, fetal loss, dementia, optic change, and recurrent venous thrombosis.
High levels of Lp(a) have been correlated with atherosclerosis of the cerebral and other vasculature.
Protein C, protein S, and ATIII activity
Protein C activity is used to screen for protein C deficiency or to diagnose protein C deficiency secondary to dysproteinemia. To confirm protein C deficiency and to differentiate it from dysproteinemia, the protein C antigen is measured. Protein C deficiency is noted in liver disease, disseminated intravascular coagulation (DIC), vitamin K deficiency, and warfarin therapy.
Protein S activity is used to screen for protein S deficiency or to diagnose the presence of a dysfunctional protein. To confirm protein S deficiency and to differentiate it from dysproteinemia, the protein S antigen is measured. Protein S deficiency is noted following acute thrombotic events; in liver disease, DIC, vitamin K deficiency, warfarin therapy, l-asparaginase therapy, and pregnancy; and with oral contraceptive use.
Antithrombin III (ATIII) activity is used to screen for ATIII deficiency or to diagnose dysfunctional ATIII. To confirm antithrombin III deficiency and to differentiate it from dysproteinemia, the ATIII antigen is measured. Antithrombin III deficiency is noted following acute thrombotic events or surgery; in liver disease, nephrotic syndrome, DIC, heparin therapy, l-asparaginase therapy, and pregnancy; and with oral contraceptive use.
APC resistance and factor V Leiden assays
Resistance to activated protein C (APC) is the most common inherited risk factor for thrombosis and may be tested on plasma from patients on heparin or warfarin. A value < 2.2 indicates a high likelihood of APC resistance, and DNA-based testing for factor V Leiden should be then performed.
More than 95% of patients with resistance to APC have the Arg506Gln mutation defect, which is readily identifiable by DNA amplification and analysis. Testing for factor V Leiden is not confirmation that APC resistance is expressed.
Fasting homocysteine level is measured most commonly by high-performance liquid chromatography (HPLC) with fluorescence detection. Hyperhomocystinemia is associated with arterial and venous thrombosis and is to be distinguished from autosomal recessive homocystinuria. Elevated homocysteine levels are encountered in the elderly; in patients with nutritional deficiency of vitamin B-6, B-12, or folate; and in renal insufficiency and other disorders.
Hemoglobin electrophoresis enables detection of hemoglobin SS and SC. The test should be ordered in black individuals and others whose ethnicity puts them at particular risk of sickle cell anemia.
Magnetic Resonance Studies
Magnetic resonance imaging (MRI) of the brain (T1-, T2-, and diffusion-weighted images [DWIs]) may be helpful in assessing suspected stroke or stroke risk. Magnetic resonance venography may be useful if cerebral venous thrombosis is suspected.
Obtain a cerebral angiogram if noninvasive tests yield inconclusive results. Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) may be helpful in cases of arterial stroke.
Transcranial Doppler ultrasonography is used to assess stroke risk in patients with sickle cell anemia. [9, 10] This imaging modality is most useful in children, as it allows detection of increases in mean blood velocities within the circle of Willis and middle cerebral artery as the arteriopathy of sickle cell disease develops. Transcranial Doppler ultrasonography is also helpful in the assessment of intracranial arterial stenosis or occlusion.
Consider carotid ultrasonography if extracranial stenosis or occlusion is suspected.
Medical Treatment of Blood Dyscrasias
Treatment of blood dyscrasias that may cause stroke remains controversial. The risks and benefits of treatment must be considered in the context of the number of episodes of thrombosis. In patients who are not treated with anticoagulants, prophylaxis should be considered during times of high risk, such as pregnancy, immobilization, or the postoperative period.
General, evidence-based recommendations
The recent evidence-based guidelines have made recommendations on topics that are relevant to stroke/transient ischemic attack (TIA) patients with hypercoagulable state, as follows  :
Patients with arterial ischemic stroke or TIA with an established inherited thrombophilia should be evaluated for deep vein thrombosis (DVT), which is an indication for short- or long-term anticoagulant therapy depending on the clinical and hematologic circumstances (Class I; level of Evidence A).
Patients should be fully evaluated for alternative mechanisms of stroke. In the absence of venous thrombosis in patients with arterial stroke or TIA and a proven thrombophilia, either anticoagulant or antiplatelet therapy is reasonable (Class IIa; level of Evidence C).
For patients with spontaneous cerebral venous thrombosis and/or a history of recurrent thrombotic events and an inherited thrombophilia, long-term anticoagulation is probably indicated (Class IIa; level of Evidence C)
For patients with cryptogenic ischemic stroke or TIA in whom an APL antibody is detected, antiplatelet therapy is reasonable (Class IIa; level of Evidence B).
For patients with ischemic stroke or TIA who meet the criteria for the APL antibody syndrome, oral anticoagulation with a target international normalized ration (INR) of 2-3 is reasonable (Class IIa; level of Evidence B).
For adults with sickle cell disease and ischemic stroke or TIA, the general treatment recommendations cited above are reasonable with regard to control of risk factors and the use of antiplatelet agents (Class IIa; level of Evidence B).
Additional therapies that may be considered to prevent recurrent cerebral ischemic events in patients with sickle cell disease include regular blood transfusions to reduce hemoglobin S to less than 30-50% of total hemoglobin, hydroxyurea, or bypass surgery in cases of advanced occlusive disease (Class IIb; level of Evidence C).
Although folate supplementation reduces levels of homocysteine and may be considered for patients with ischemic stroke and hyperhomocysteinemia (Class IIb;level of Evidence B), no evidence suggests that reducing homocysteine levels prevents stroke recurrence.
Anticoagulation is probably effective for patients with acute central venous thrombosis (Class IIa; level of Evidence B).
In the absence of trial data to define the optimal duration of anticoagulation for acute central venous thrombosis, it is reasonable to administer anticoagulation for at least 3 months, followed by antiplatelet therapy (Class IIa; level of Evidence C).
For pregnant women with ischemic stroke or TIA and high-risk thromboembolic conditions such as hypercoagulable state, the following options may be considered: adjusted-dose unfractionated heparin (UFH) throughout pregnancy, for example, a subcutaneous dose every 12 hours with monitoring of activated partial thromboplastin time; adjusted-dose low molecular weight heparin (LMWH) with monitoring of anti-factor Xa throughout pregnancy; or UFH or LMWH until week 13, followed by warfarin until the middle of the third trimester and reinstatement of UFH or LMWH until delivery (Class IIa; level of Evidence C).
For women who have had ischemic stroke or TIA, postmenopausal hormone therapy (with estrogen with or without a progestin) is not recommended (Class III; level of Evidence A).
Hematologic consultation may be requested when the clinical diagnosis is uncertain, when abnormal test results require clarification, and when recommendations on the management of the blood dyscrasia is needed.
Patients with hypercoagulable states such as activated protein C (APC) resistance; protein C, protein S, or antithrombin III (ATIII) deficiencies; or antiphospholipid syndrome (APS) are treated with anticoagulants for stroke prophylaxis, especially if deep vein thrombosis (DVT) is present or recurrent thrombotic events have occurred. The anticoagulation regimen usually is started with intravenous (IV) heparin, maintaining the activated partial thromboplastin time (aPTT) at 2-3 times normal, until an oral anticoagulant (ie, warfarin) is able to achieve a therapeutic prothrombin time (PT) (international normalized ratio [INR]).
In protein C and S deficiencies, starting heparin before warfarin is imperative to avoid warfarin-induced skin necrosis. The level of anticoagulation in terms of PT (INR) required for stroke prophylaxis is uncertain. In the treatment of APS, a retrospective study reported that an INR of 3.0-3.5 was more effective than the routinely used INR of 2.0-3.0  ; however, 2 prospective studies showed that an INR of 2.0-3.0 is sufficient in APS. [13, 14] A sizable fraction of neurologists avoid treating patients with stroke with a heparin bolus, as this is thought to increase the risk of intracranial bleed.
Results of the Antiphospholipid Antibodies in Stroke Study (APASS) demonstrated that there was no difference between aspirin and warfarin for treatment of patients with anticardiolipin (aCL) antibodies or lupus anticoagulant (LA).  It is important to emphasize that APASS did not look specifically at APS. However, it was noted that the risk of recurrent thrombosis was increased in patients who had both aCL antibodies and LA. In addition, patients enrolled in APASS had low aCL antibody titers and a low INR, and the study was criticized for these limitations.
Thus, in deciding whether patients need to be treated with warfarin, their LA status and high-titer aCL antibodies should also be borne in mind, and high-intensity anticoagulation (target INR > 3.0) should be considered in appropriate patients. A clinical trial with defined APS and high titers of aCL antibodies and LA with high-intensity regimen of warfarin would probably answer the issue.
Currently, 3 new oral anticoagulants are available: Dabigatran (oral thrombin inhibitor), rivaroxaban (factor X inhibitor), and apixaban (factor X inhibitor). These agents are FDA approved to prevent thromboembolic events, including stroke/TIA in patients with atrial fibrillation. Their role in the prevention of stroke/TIA in patients with hypercoagulable state is yet to be determined.
Use of Antiplatelet Agents, Blood Transfusions, and Hydroxyurea
Patients with sickle cell anemia and stroke are treated with antiplatelet agents such as aspirin. The roles of other antiplatelet agents, such as ticlopidine (Ticlid) and clopidogrel (Plavix), or combination therapy with aspirin and dipyridamole (Persantine), specifically in prevention of strokes that result from blood dyscrasias, have not been evaluated.
Hyperhomocystinemia is treated with vitamin supplementation, usually folic acid and sometimes pyridoxine (vitamin B-6) and vitamin B-12, as well. Although the Vitamin in Stroke Prevention (VISP) trial results did not show any significant benefit of treatment with high doses of folic acid, pyridoxine, and vitamin B-12 in reducing adverse vascular outcomes in patients with nondisabling strokes and elevated homocysteine (relative to low doses of these vitamins), it did show that there was a persistent and graded association between total homocysteine and outcomes, irrespective of the treatment group.  A larger study with high baseline homocysteine levels and longer follow-up may help resolve the issue.
Hyperhomocystinemia has been attributed to dietary deficiency of vitamin B-6, vitamin B-12, or folic acid, especially in older patients with poor nutritional intake.
Patients with hypercoagulable states that may cause stroke typically take the oral anticoagulant warfarin. For these patients, monitoring vitamin K in the diet is important, as it may alter the efficacy of warfarin.
Patients being treated with an oral anticoagulant must be monitored with outpatient blood testing for prothrombin time (PT) (international normalized ratio [INR]). Initially, PT (INR) should be tested frequently to determine the maintenance dose (ie, daily to twice a week); once a regular maintenance dose is determined, PT (INR) may be checked monthly.
Supratherapeutic oral anticoagulation without monitoring can lead to intracranial and extracranial hemorrhage. Common reasons for such a state include overdosage, interaction with other drugs, and variation in dietary vitamin K. Subtherapeutic anticoagulation can lead to ischemic stroke. These potential pitfalls need to be discussed with the patient before initiating anticoagulation.
Another pitfall is starting a patient with a known history of a life-threatening bleeding disorder and a hypercoagulable state on either an antiplatelet agent or an anticoagulant. Treatment must be individualized for each patient, and the benefits of any treatment must outweigh the risks.
During an acute thrombotic event, certain coagulation parameters may display acquired deficiencies (protein S and antithrombin III [ATIII]). In addition, patients on warfarin can have low protein C and protein S values, whereas patients on heparin have low ATIII values. Other conditions known to affect coagulation parameters are liver disease (proteins C and S and ATIII), estrogens, pregnancy, and inflammatory disease (protein S).
Because each hereditary coagulation factor deficiency encompasses more than 100 mutations, genetic testing typically is not indicated in clinical practice.
Patients with cerebral amyloid angiopathy are at increased risk of intracranial hemorrhage while on warfarin, even when levels are within the normal therapeutic range. Caution is advised in considering warfarin for these patients. Magnetic resonance imaging (MRI) sequences such as gradient echo (GRE) are useful tools to detect multiple bleeds, a feature suggestive of amyloid angiopathy.
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- Hematologic Disorders and Stroke
- Hematologic Risk Factors in Stroke
- Evaluation of Patients With Blood Dyscrasias and Stroke
- Coagulation Studies
- Tests for Hypercoagulability
- Magnetic Resonance Studies
- Medical Treatment of Blood Dyscrasias
- Use of Antiplatelet Agents, Blood Transfusions, and Hydroxyurea
- Vitamin Supplementation
- Dietary Issues
- Outpatient Monitoring
- Special Considerations
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