eMedicine Specialties > Neurology > Neuro-vascular Diseases

Blood Dyscrasias and Stroke

Author: Anand Vaishnav, MD, Cerebrovascular Fellow, Senior Instructor, Department of Neurology, Oregon Stroke Center, Oregon Health Sciences University
Coauthor(s): Souvik Sen, MD, MS, FAHA, Associate Professor of Neurology, Founding Director of UNC Hospital Stroke Center, Department of Neurology, University of North Carolina at Chapel Hill
Contributor Information and Disclosures

Updated: Mar 29, 2006

Introduction

Background

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 hematological abnormality. Coagulation disorders that predispose to strokes remain poorly defined. 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; and antiphospholipid antibody (aPL) syndrome.

Pathophysiology

Hemostasis means prevention of blood loss. Hemostasis is provided by an interaction of normal vessel responses, platelet plug formation, and activation of the coagulation cascade. The coagulation cascade involves activation of blood coagulation factors with formation of prothrombin activator, which catalyzes the conversion of prothrombin to thrombin. Thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form a clot.

Counteracting hemostasis are normal vascular endothelial cells, which inhibit platelet adhesion and aggregation, and proteins such as thrombomodulin. Thrombomodulin activates protein C, which in turn activates protein S; together, the 2 factors play a role in inactivating factors V and VIII. Antithrombin III also plays a role in inactivating factor X and thrombin, thus inhibiting thrombosis. In this way, interactions among multiple plasma proteins, protein C, and protein S; resistance to APC; antithrombin III; and normal vascular endothelial cells form an important barrier to thrombosis.

Factors that accelerate the hemostatic mechanism or inhibit mechanisms that counteract hemostasis contribute to an increased state of thrombogenicity (ie, hypercoagulability) and thereby play an etiological role in strokes.

Frequency

United States

Known hematologic abnormalities are estimated to account for about 4% of all strokes. This proportion may be higher in younger people.

Factor V Leiden (ie, APC resistance) occurs in 5-7% of the normal population, 20% of patients with deep vein thrombosis (DVT), and 60% with recurrent DVT. The incidence of this factor in patients with stroke is not known; in general, however, this factor 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.

Protein C and S and antithrombin III deficiencies are all extremely rare. The frequency of occurrence ranges from 1 per 1000 to 1 per 5000 in the general population.

Sickle cell anemia is a significant etiologic factor in stroke. The incidence of stroke in patients with hemoglobin SS is 10%; in those with hemoglobin SC, 2-5%.

Hyperhomocystinemia is a factor in stroke. Patients with stroke have homocysteine levels 1.5 times those of age- and sex-matched controls.

aPL syndrome (ie, presence of aPL or lupus anticoagulant) occurs in 10% of patients with acute ischemic stroke. This number is higher in younger patients.

International

Incidence is not known.

Mortality/Morbidity

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.

Race

African American patients are at higher risk of sickle cell anemia. None of the other blood dyscrasias have strong racial associations.

Sex

Blood dyscrasias that commonly lead to stroke occur equally in men and women.

Age

Blood dyscrasias are suspected if a patient younger than 50 years suffers an unexplained stroke. However, older age does not preclude the presence of blood dyscrasias that may lead to stroke.

Clinical

History

• Blood dyscrasias or hypercoagulability should be suspected in patients with ischemic stroke who have the following characteristics:
  • Younger than 50 years with no obvious cause of stroke
  • History of multiple unexplained strokes
  • Prior history of venous thrombosis
  • Family history of thrombosis
  • Abnormalities on routine screening coagulation tests
• In addition, the aPL syndrome must be suspected in patients with history of multiple miscarriages, dementia, optic neuropathy, and thrombocytopenia, as well as lupuslike syndromes and "complicated migraine."

Physical

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 aPL syndrome. In patients diagnosed with blood dyscrasias, a search should be made for clinical findings of thrombosis elsewhere, including venous thrombosis. In a few instances, aPL syndrome is associated with Sneddon syndrome, which is manifested by livedo reticularis and cerebrovascular disease.

Causes

• Factor V Leiden
  • The most common inherited defect leading to venous thrombosis is hereditary resistance to APC, which is caused by a mutation in factor V (factor V Leiden) that renders activated factor V unable to be cleaved by APC.
  • No study has established a relationship between factor V Leiden and arterial strokes. Factor V Leiden has been associated primarily with venous events.
  • Clinical assays for factor V Leiden are available. More than 95% of patients with resistance to APC have the Arg506Gln mutation defect, which is readily identifiable by DNA amplification and analysis (Quest Diagnostics).
• Protein C, protein S, and antithrombin III deficiencies
  • Cerebral vein thrombosis is a more frequent presentation than arterial stroke. No clear-cut association has been found between protein C or antithrombin III deficiency and arterial strokes, though patients with low protein C levels at the time of acute stroke have had poor outcomes.
  • 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 antithrombin III is identified, differentiating between congenital and acquired cases is important.
• Hereditary abnormalities of fibrinolysis
  • Dysplasminogenemia 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 abnormalities should be considered in a young patient with stroke and a history of recurrent DVT.
  • Dysfibrinogenemia 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. These mutations thereby increase the risk of venous and arterial thrombotic episodes, including stroke.
  • Most strokes result from cerebral venous occlusion, but large arterial thrombotic strokes also are described in relatively young individuals and in those without other recognized risk factors.
• Sickle cell disease
  • Sickle cell disease causes a vasculopathy that, along with stasis in small arteries, is a principal mechanism by which it causes strokes. 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 also is noted.
  • The incidence of brain infarction peaks around age 10 years.
  • Erythrocyte disorders besides sickle cell anemia, such as polycythemia vera, cause hyperviscosity-related diminished cerebral blood flow.
  • Essential thrombocythemia and paroxysmal nocturnal hematuria also cause cerebrovascular thrombotic events. Paroxysmal nocturnal hematuria has been associated primarily with venous thrombosis.
• Hyperhomocystinemia
  • Hyperhomocystinemia is associated with vasculopathy. Unlike most prothrombotic states, it causes more arterial strokes than venous.
  • Elevated levels of homocysteine and related disulfide compounds are clear risk factors for stroke.
  • 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.
  • Patients who are heterozygous for cystathionine beta synthase deficiency can develop a mild clinical picture.
  • Recently, 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 more commonly is acquired; the most common acquired cause of hyperhomocystinemia is dietary deficiencies of folate and vitamin B-12.
  • 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.
  • The range for a normal serum homocysteine is controversial, but levels above 14 µmol/L, the highest quartile of homocysteine levels, significantly increase the risk of stroke.
  • Folate and vitamin B-12 levels should be checked, since 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 antibody syndrome
  • aPLs are polyclonal and polyclass antibodies that bind to anionic and neutral phospholipid-containing moieties.
  • Recognizing aPLs is important, as they are associated with a hypercoagulable state characterized by fetal loss, thrombocytopenia, and venous and arterial thrombosis.
  • Initially associated with systemic lupus erythematosus (SLE), these antibodies now are known to be found also in patients without SLE; patients without SLE who have these antibodies are diagnosed as having the "primary antiphospholipid antibody syndrome" (aPS).
  • The two major types of clinically relevant aPLs are anticardiolipin antibodies (aCLs), which require the presence of serum cofactor beta-2 glycoprotein for binding, and lupus anticoagulant (LA), which may not require the presence of beta-2 glycoprotein. In a patient with aPS, the concordance of aCL and LA may be up to 70%.
  • About 10% of all patients with ischemic stroke harbor aPL, and the figure is much higher in younger patients.
  • Cerebrovascular symptoms associated with aPS include amaurosis fugax, occlusion of retinal arteries and veins, transient ischemic events of the brain, thrombosis of cerebral arteries and veins, and dementia. Although strokes of all sorts are noted, involvement of the cerebral cortex and subadjacent white matter by platelet-fibrin microthrombi is most commonplace.
  • The mechanisms of thrombosis are heterogenous 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.
• Disorders associated with abnormal platelet function
  • Thrombotic thrombocytopenic purpura (TTP) is a thrombotic illness of obscure origin, more common in women, causing stroke with associated fever, Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Most of the microvascular occlusions 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 levels of fibrinogen often are found. The disorder is caused by large aggregates of von Willebrand factor and platelets. An antibody prevents normal cleavage of these complexes. The treatment usually involves plasmapheresis, which is often life saving.
  • 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 resultsin platelet aggregation. Type II develops 6-10 days after institution of heparin therapy and is a risk factor for recurrent stroke. The incidence of heparin-induced thrombocytopenia may be reduced by using low-molecular-weight (LMW) heparin, such as enoxaparin (Lovenox). However, if a patient has heparin-induced thrombocytopenia, the antibodies to heparin cross-react with LMW heparin. After the onset of heparin-induced thrombocytopenia, danaparoid may be used as an alternative. However, the role of danaparoid in stroke prevention is not known.
  • 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. Antiplatelet therapy, usually aspirin, is advocated. Additional pharmacological measures, such as lowering of platelet counts with hydroxyurea or anagrelide, also have been reported to benefit patients. These treatments are better accomplished in conjunction with hematologic consultation.
• Lipoprotein (a) elevation
  • Recent evidence identifies at least one lipoprotein, lipoprotein (a) [Lp(a)], whose levels are elevated in selected populations with cerebrovascular disease. Many studies have shown elevated levels to be a potent risk factor for stroke, especially in young individuals.
  • A clear role for the treatment of elevated levels of Lp(a) in preventing strokes still is not established.
• Prothrombin gene mutation: Recent 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. This mutation has not been associated clearly with acute ischemic strokes.

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