Stroke. 2003;34:1826-1827
Published online before print July 3, 2003,
doi: 10.1161/01.STR.0000083533.81284.0B
(Stroke. 2003;34:1826.)
© 2003 American Heart Association, Inc.
Editorial Comment—Routine Thrombophilia Testing in Stroke Patients Is Unjustified
Graeme J. Hankey, MD, FRCP, FRACP, Guest Editor
John W. Eikelboom, MBBS, MSc, FRACP, FRCPA, Guest Editor
Stroke Unit, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
Thrombosis and Haemophilia Service, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
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Introduction
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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.
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What Are the Thrombophilias?
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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).
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How Common Are the Thrombophilias?
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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 al
3 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).
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What is the Likely Attributable Risk of Stroke for the Thrombophilias?
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The data of Jerrard-Dunne et al
3 and others
5–7 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 higher
9,10 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 ovale
11) or heart chambers (eg, atrial fibrillation).
12 Much larger studies than previously undertaken are required
to answer this question.
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What Are the Costs of the Laboratory Tests for Thrombophilias?
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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 $1014
13; 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
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What Is the Effectiveness of the Laboratory Tests in Optimizing Patient Management and Outcome?
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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.
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References
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- Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol. 2001; 114: 512–528.[CrossRef][Medline]
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- Martinelli I. Pros and cons of thrombophilia testing: pros. J Thromb Haemost. 2003; 1: 412–413.[CrossRef][Medline]
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- 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.[Abstract/Free Full Text]
- Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001; 344: 1222–1231.[Free Full Text]
- 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.[Abstract/Free Full Text]
- Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke. 2000; 31: 3067–3078.[Abstract/Free Full Text]
- 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.[Abstract/Free Full Text]
- 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.[Abstract/Free Full Text]
- 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.[Free Full Text]
- Weih M, Villringer A. Coagulopathies in ischemic stroke. Stroke. 2001; 32: 1234–1237.[Free Full Text]
- 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.[Abstract/Free Full Text]
- Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. 2001; 32: 803–808.[Free Full Text]
- 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.[Abstract/Free Full Text]
This article has been cited by other articles:
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R. K. Patel and R. Arya
Tests for Hereditary Thrombophilia Are of Limited Value in the Black Population
Stroke,
December 1, 2003;
34
(12):
e236 - e236.
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Introduction
What Are the Thrombophilias?