Editorial Comment—Routine Thrombophilia Testing in Stroke Patients Is Unjustified
The whole area of laboratory screening for thrombophilias in stroke patients is shrouded in uncertainty as to which (if any) patients to screen, what laboratory tests to order, how to interpret the results, and when to change therapy. To answer these questions, it is important to define the conditions and to consider their prevalence in the community and in patients with venous thromboembolism (VTE) and stroke; the likely attributable risk of stroke for each, if any, of the thrombophilias; the costs of the laboratory tests for thrombophilias; and the effectiveness of the results of testing in optimizing patient management and outcome.
What Are the Thrombophilias?
There is no internationally accepted definition of thrombophilia, but the term is commonly used to describe disorders of the hemostatic mechanisms that are likely to predispose to thrombosis.1 Thrombophilia may be inherited (deficiency of protein C, protein S, or antithrombin; activated protein C resistance resulting from the factor V Leiden mutation; the prothrombin gene [20210 G/A] mutation; and dysfibrinogenemia), acquired (lupus anticoagulant [LA] and anticardiolipin [ACL] antibodies), or mixed or unknown (high levels of coagulation factor VIII, IX, or XI; high levels of thrombin activatable fibrinolysis inhibitor).
How Common Are the Thrombophilias?
At least 1 thrombophilic disorder is present in ≈10% to 15% of the white Western European population,2 and as highlighted in the study by Jerrard-Dunne et al3 in this issue of Stroke, the distribution of blood concentrations of coagulation proteins, and thus diagnostic criteria and prevalence of thrombophilias, varies among other well-defined ethnic groups such as black Caribbeans and black Africans.3 Similarly, the prevalences of factor V Leiden and the 20210 G/A prothrombin gene mutation are common among healthy whites but extremely rare among Asians and Africans.4
In contrast to community controls, a thrombophilic disorder is present in as many as 30% of unselected individuals with VTE and 50% to 70% of those with recurrent VTE.2,4 Thrombophilias are an established independent causal risk factor for VTE and may account for a substantial proportion of cases of recurrent VTE. However, there is a paucity of evidence regarding how, if at all, the clinical management of patients with thrombophilia and VTE differs from that of individuals with VTE who do not have thrombophilia. Both groups are usually treated with oral anticoagulation for a finite period of time—but arguable longer if they have a thrombophilia that predisposes to further episodes of VTE.
In contrast to cases of VTE, the prevalence of inherited thrombophilia in patients with ischemic stroke is not significantly different from that among the general community3,5–7; therefore, the role, if any, of inherited thrombophilia in the origin of ischemic stroke is uncertain. Using ethnic-specific reference ranges, Jerrard-Dunne et al3 found that 6.3% of community controls (8 of 130) and 8.5% of ischemic stroke cases (11 of 130) had a thrombophilia (odds ratio [OR], 1.4; 95% confidence interval [CI], 0.5 to 3.6). We obtained very similar results in a case-control study of 219 hospital cases with a first-ever ischemic stroke and 205 randomly selected community controls stratified by age, sex, and postal code.5 The prevalence of any thrombophilia was only 14.7% (95% CI, 9.9 to 19.5) among cases compared with the expected 11.7% (95% CI, 7.4 to 17.0) among controls (OR, 1.3; 95% CI, 0.7 to 2.3).5 Similar results have also been reported in a systematic review by Bushnell and Goldstein.6 These data suggest that inherited thrombophilias may account for anything from 0% to ≈10% of cases of ischemic stroke (ie, the attributable risk is low). However, the prevalence of acquired thrombophilias, LA and ACL, is significantly higher in arterial thrombosis compared with controls and appears to be an independent predictor of stroke.8
We did not find any significant difference in the prevalence of inherited thrombophilia among etiological subtypes of ischemic stroke, but there was a nonsignificant trend toward a higher prevalence of any thrombophilia in 8 of the 45 cases (20.5%; 95% CI, 8 to 32) of ischemic strokes caused by cardiogenic embolism.5 Although the estimates are very imprecise because of the small sample size, it is biologically plausible that thrombophilia may predispose to “red” fibrin thrombi in areas of relative stasis of blood such as veins and heart chambers compared with the predominant “white” platelet thrombi that occur in areas of high shear stress in arteries. Our study was underpowered to reliably identify or exclude a modest, but important, association between a particular inherited thrombophilic disorder (eg, protein C deficiency) and a particular etiological stroke subtype (eg, cardiogenic embolism).
What is the Likely Attributable Risk of Stroke for the Thrombophilias?
The data of Jerrard-Dunne et al3 and others5–7 suggest that the attributable risk of inherited thrombophilia for ischemic stroke is likely to be low overall and perhaps even nonexistent in some ethnic groups such as individuals of African and African-Caribbean descent.3 However, it may be higher9,10 and of clinical relevance for particular ethnic groups,3 particular types of thrombophilia (eg, the acquired thrombophilias, LA or ACL),8 and particular etiological subtypes of stroke such as thromboembolism from an area of stasis in the veins (via a right-to-left shunt, eg, patent foramen ovale11) or heart chambers (eg, atrial fibrillation).12 Much larger studies than previously undertaken are required to answer this question.
What Are the Costs of the Laboratory Tests for Thrombophilias?
The cost of a battery of tests to investigate inherited coagulation defects, activated protein C resistance, ACL, and LA in 1 patient at Duke Hospital (Durham, NC) is US $101413; inherited thrombophilia at University College Hospital (London, UK) is Euros 500 (US $500)2; and inherited or acquired thrombophilia at Royal Perth Hospital (Australia) is Aus $313.50 (US $200).5
What Is the Effectiveness of the Laboratory Tests in Optimizing Patient Management and Outcome?
At present, the finding of a positive test for ≥1 thrombophilic disorders using ethnic-specific reference ranges does not prove that it is relevant to the cause, because there is a 5% to 15% chance that the result is coincidental, as seen in community controls.3 Furthermore, there is no clear evidence to suggest the clinical circumstances under which a positive result is more likely to be causal (eg, unexplained stroke, young stroke, cardiogenic stroke). And even if larger studies do establish a causal association between ≥1 thrombophilias (eg, LA) and a subtype of ischemic stroke (eg, small-vessel disease), it is not certain how the finding of a positive test result (eg, LA positive) should change management; for example, there have been no randomized trials comparing anticoagulation with antiplatelet therapy in these patients.9 If our hypothesis proves correct and the acquired thrombophilias play a contributory role in a minority of patients with ischemic stroke caused by thromboembolism from the veins or cardiac chambers, many of the patients are likely to be anticoagulated long term anyway, regardless of the presence or absence of a thrombophilia.
We believe that outside a research setting, there is no justification for incurring the substantial costs of routine thrombophilia screening in patients with ischemic stroke in the absence of reliable data linking any or all of the thrombophilias to the origin of any subtype of ischemic stroke or to a favorable response to a particular intervention. Further research should focus on the possible role of acquired thrombophilias (LA, ACL) in the pathogenesis of specific etiological subtypes of ischemic stroke (embolism from or via the heart, perhaps small-vessel disease) and the response of etiologically relevant thrombophilias to different antithrombotic regimens. The article by Jerrard-Dunne et al highlights the importance of accounting for ethnic differences in the pursuit of answers to these questions.
Jerrard-Dunne P, Evans A, McGovern R, et al. Ethnic differences in markers of thrombophilia: implications for the investigation of ischemic stroke in multiethnic populations: the South London Ethnicity and Stroke Study. Stroke. 2003; 34: 1821–1827.
Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke. 2001; 32: 1793–1799.
Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke. 2000; 31: 3067–3078.
Austin H, Chimowitz MI, Hill HA, et al. Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women. Stroke. 2002; 33: 2762–2769.
Galli M, Luciano D, Bertolini G, et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003; 101: 1827–1832.
Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the stroke council of the American Heart Association. Circulation. 2001; 103: 163–182.
Weih M, Villringer A. Coagulopathies in ischemic stroke. Stroke. 2001; 32: 1234–1237.
Pezzini A, Del Zotto E, Magoni M, et al. Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke. 2003; 34: 28–33.
Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. 2001; 32: 803–808.
Bushnell C, Siddiqi Z, Morgenlander JC, Goldstein LB. Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke. Neurology. 2001; 56: 624–627.