Hypercoagulability as a cause of stroke in adults. (Featured CME Topic: Stroke).

Abstract: Arterial hypercoagulability can lead to cerebrovascular disease. Common causes of venous thromboembolism, including factor V Leiden, the prothrombin 20210 mutation, deficiencies of proteins C and S, and antithrombin deficiency are not likely to be associated with stroke. Rather, polymorphisms in fibrinogen, the factor XIII gene, and platelet glycoproteins are congenital abnormalities that have been associated with stroke. Similarly, the acquired conditions, lupus anticoagulants, and heparin-induced thrombocytopenia have a strong association with cerebrovascular disease. This article reviews arterial hypercoagulability as a cause of stroke in adults and identifies an appropriate hypercoagulability workup for patients with idiopathic stroke.

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The ability of blood to coagulate is essential for the survival of a species. In humans, when coagulation is too efficient, thrombosis becomes one of the most common causes of morbidity and mortality in developed countries. Specifically, coronary artery disease and stroke are among the leading causes of death and disability in the United States. Thrombosis can be divided anatomically into venous and arterial thrombosis. The pathophysiology of these two types of clotting is quite different. Clotting in the low-flow venous system is generally associated with deposition of fibrin, whereas arterial thrombosis is usually associated with platelet reactivity and vascular wall damage. Although not absolute, these distinctions suggest that the etiologic factors accounting for venous thrombosis are distinct from those accounting for arterial thrombosis (Table 1).

Inherited Hypercoagulable States Leading to Stroke

Polymorphisms of Coagulation Proteins

The most common congenital cause of venous thrombosis is activated protein C resistance, which is most often associated with a mutation causing substitution of arginine for glutamine at residue 506 of factor V (factor V Leiden). (1,2) Although a common cause of venous thrombosis in the low-flow venous system, activated protein C resistance is most likely not associated with stroke in adults. (3) Similarly, other relatively common causes of venous thrombosis including deficiencies of protein C, deficiencies of protein S, deficiencies of antithrombin, and the prothrombin 20210 G[right arrow] A mutation are likely not associated with stroke in adult patients. (4,5) Therefore, a typical "hypercoagulability workup" is most often of very low yield when applied to patients with stroke. (6)

Arterial thrombosis is the result of an atheromatous plaque that ruptures and causes platelet activation and aggregation resulting in an obstructive lesion that subsequently leads to tissue damage. In this model, plaque rupture leads to endothelial damage, promoting platelet adhesion by means of the platelet glycoprotein Ib/IX/V complex and the ligand von Willebrand Factor (vWF). This allows for the adherence of platelets to damaged endothelium. Platelet adherence alone is not sufficient for hemostasis. Platelet plug formation requires platelet-platelet binding by means of the platelet receptor, glycoprotein IIb/IIIa. On activation, glycoprotein IIb/IIIa is linked by its two potential ligands, fibrinogen and/or vWF. Finally, fibrinogen is converted to fibrin, resulting in a stable platelet plug.

Elevated levels of fibrinogen are a common and consistent finding in persons with stroke. (7) Fibrinogen is encoded by three different genes on chromosome 4, which code for the [alpha], [beta], and [gamma] chains, respectivity. (8) Serum fibrinogen levels are variable and can increase in response to infectious or inflammatory conditions as part of the acute-phase response. Because of the central role of fibrinogen in hemostasis, it is not surprising that polymorphisms within the fibrinogen gene have been associated with stroke. Specific examples include results from the Austrian Stroke Prevention Study, which showed an association between a polymorphism in the [beta] chain of fibrinogen at position -148 and carotid atherosclerosis. (9) Interestingly, fibrinogen levels were much more weakly associated with disease in this study. Similarly, a polymorphism in the [beta]-promoter region at position -455 has been associated with cerebrovascular disease in Japanese patients. (10) The results of these and similar s tudies suggest that, over time, additional polymorphisms are likely to be discovered in the fibrinogen gene that are related to stroke.

Factor XIII serves to cross-link fibrin to render it more resistant to shear forces. A polymorphism causing substitution of valine for leucine at residue 34 of the factor XIII gene has been associated with protection from venous thrombosis. (11) A study looking at over 600 patients with stroke showed an increase in this genotype in patients with intracerebral hemorrhage. (12) There were no relationships between this polymorphism and thrombotic stroke in this study.

Polymorphisms of Platelet Proteins

As mentioned, platelets are important in promoting clot in situations of high shear stress such as in arterial flow systems. Platelets work by means of adhesion and aggregation. Glycoprotein IIb/IIIa is an integrin class molecule found on the platelet surface that is responsible for platelet aggregation by binding to vWF or fibrinogen. (13) A common point mutation in glycoprotein IIIa, termed PLA2, leads to a substitution of proline for leucine at position 33. PLA2 has been suggested as a risk factor for coronary artery disease. (14) Although potentially associated with coronary artery disease, several published studies have suggested that this polymorphism is unlikely to be associated with stroke. (15-17) The glycoprotein Ib/IX/V complex is a platelet protein responsible for platelet adhesion using vWF as the ligand. A polymorphism in the region of the glycoprotein Lb gene responsible for keeping the ligand-binding region distal to the platelet surface leads to a variable number (one, two, three, or four) o f tandem repeats. There appears to be an association of repeat number genotype with cerebrovascular disease. (18)

Other Polymorphisms

Elevated levels of homocysteine have been associated with arterial thrombosis. (19) A point mutation in the methylene tetrahydrofolate reductase gene (C677T) has been associated with elevated levels of homocysteine in homozygotes. A large meta-analysis failed to show a positive link between this mutation and arterial disease, including stroke. (20)

Acquired Hypercoagulable States Leading to Stroke

Lupus Anticoagulants. Lupus anticoagulants are antibodies that prolong phospholipid-dependent clotting tests such as the activated partial thromboplastin time. The term "lupus anticoagulant" is misleading in that these antibodies are found in disorders other than lupus, and the presence of these antibodies is not associated with bleeding but rather may be associated with thrombosis in both venous and arterial systems. In fact, up to one third of patients harboring lupus anticoagulants will have a thrombotic event. (21) Most commonly, these antibodies, which function as nonspecific inhibitors of coagulation reactions involving phospholipid surfaces, are discovered clinically by a prolongation of the activated partial thromboplastin time. However, other coagulation tests such as the prothrombin time or the dilute Russell viper venom time may also be prolonged. These antibodies are sometimes called antiphospholipid antibodies or, more specifically, anticardiolipin antibodies. Although some of these antibodies r eact with phospholipids, most require a cofactor, [[beta].sub.2]-glycoprotein 1, to bind to cardiolipin. (22) To further complicate this issue, not all patients with lupus anticoagulants have demonstrable antibodies to phospholipids or cardiolipin, and vice versa. (23,24) In addition, antibody levels can fluctuate such that a negative antibody titer does not rule out the presence of antibodies. This is particularly problematic during acute thrombotic episodes, when the titer can decline to normal. (25) Furthermore, not all patients with detectable antibodies have thrombotic events. When patients have both demonstrable antibodies and clinical thrombosis, this is termed the "antiphospholipid antibody syndrome." The mechanism of thrombosis in patients with lupus anticoagulants is not firmly established but may be related to platelet activation, impaired fibrinolysis, endothelial cell damage, monocyte activation, or endothelial displacement of annexin V, a potent naturally occurring anticoagulant.

Anticardiolipin antibodies are an independent risk factor for ischemic stroke, imparting a relative risk of 3 to 5. (26) In addition, patients whose sera demonstrate such antibodies appear to have a higher mortality after a stroke. (27) Similarly, antibodies directed specifically against [[beta].sub.2]-glycoprotein 1 are associated with a relative risk of stroke of 2 to 3. (28,29)

Heparin-Induced Thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is defined as a reduction in platelet count of 50% or a decrease in count to less than 150 X [10.sup.9] cells/L after the initiation of heparin therapy and occurs in approximately 3% of patients receiving unfractionated heparin. It occurs much less frequently in patients receiving low-molecular-weight heparin, especially if they have not been previously exposed to unfractionated heparin. HIT is caused by antibodies to the heparin-platelet factor 4 complex. These antibodies bind to the platelet Fc receptor and cause platelet activation. (30) Platelet activation can lead to arterial or venous thrombosis and has been associated with stroke. (31) Because of the profound thrombotic risk for patients with HIT, it is important to stop all heparin, including low-molecular-weight heparin, in patients who develop HIT. Warfarin should not be begun in patients with HIT until the patient is adequately anticoagulated with hirudin or other inhibitors of thrombin, because worsening of the thrombotic process can result. (32)

Elevated Levels of Homocysteine. Arterial disease has been associated with severely elevated levels of homocysteine since the late 1960s. (33) Moderate hyperhomocysteinemia is now recognized as a risk factor for arterial disease, including carotid artery stenosis (34) and stroke. (35) The pathogenesis of homocysteine-induced arterial disease is not well elucidated. However, it is theorized that homocysteine can induce endothelial cell dysfunction and stimulate low-density lipoprotein oxidation. (36) Supplemental folate, and to a lesser extent vitamin [B.sub.6] and vitamin [B.sub.12], can lower serum homocysteine levels, and vitamin supplementation is currently being investigated as a preventive treatment for patients with elevated homocysteine levels who are at risk for arterial disease.

Conclusions

The risk factors for venous thrombosis are distinct from those for arterial thrombosis and ischemic stroke. Routine evaluation for hypercoagulability such as assays for deficiencies of coagulation inhibitors, or genetic analysis for factor V Leiden or prothrombin 20210, are not helpful in identifying risk factors for adult patients with stroke. New genetic polymorphisms continue to be discovered and evaluated as risk factors for stroke. Currently, assays for most of the polymorphisms mentioned in this article are not commercially available. At this time, in assessing a young patient with stroke, assaying for the presence of lupus anticoagulants and anticardiolipin antibodies initially and in follow-up is helpful in determining future risk for stroke and in designing plans for secondary prevention. In addition, patients with acute thrombotic stroke who are taking heparin should be assayed for the presence of heparin autoantibodies. Heparin should be stopped in these patients and administration of other thromb in inhibitors should be substituted if anticoagulation is necessary. Because elevated homocysteine levels are responsive to vitamin therapy, and because of the association of hyperhomocysteinemia with arterial disease, measuring levels of total homocysteine in patients with stroke is reasonable. Because of the unclear association between elevated homocysteine levels and the presence of the methylenetetrahydrofolate reductase polymorphism, it is probably not helpful to assay for this polymorphism in patients with stroke. As we continue to identify risk factors for stroke and arterial thrombosis, it is hoped that we will someday be able to effectively target primary and secondary prevention strategies.

Table 1

Identified risk factors for arterial thrombosis associated with stroke
in adult patients

Fibrinogen polymorphisms
Factor XIII val34leu (possibly protective)
Glycoprotein IIIa pro33leu (PLA2)
Glycoprotein lb polymorphisms
Lupus anticoagulant
Heparin induced thrombocytopenia
Hyperhomocysteinemia

Accepted November 7, 2002.

References

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RELATED ARTICLE: Key Points

* Arterial and venous thrombosis have a different pathophysiologic basis and therefore have different causes.

* Common causes of venous thrombosis are not likely to be associated with stroke, necessitating a hypercoagulable state workup for stroke patients that is distinct from that of patients with a venous clot.

* The presence of a lupus anticoagulant, heparin antibodies, and elevated levels of homocysteine are the most common hypercoagulable states associated with stroke.

From the Section of Hematology/Medical Oncology, Department of Medicine, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA.

Reprint requests to Marc J. Kahn, MD, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL63, New Orleans, LA 70112. Email: [e-mail]

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