(Stroke. 1996;27:1719-1720.)
© 1996 American Heart Association, Inc.
Articles |
Cerebral Venous Thrombosis
Role of Activated Protein C Resistance and Factor V Gene Mutation
the University of Texas Health Science Center at San Antonio (R.L.B.) and the University of Arizona College of Medicine (Tucson) (B.M.C.).
Correspondence to Robin L. Brey, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284-7883.
Key Words: cerebral embolism and thrombosis • genetics • protein C • factor V
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Introduction |
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 Top Introduction References |
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The number of well-described familial and acquired conditions that are predisposing factors for thrombosis continues to increase. Although most are uncommon, in 1993 a new condition that has ultimately been recognized as activated protein C resistance (APC-R) was reported.1 This condition is present in approximately half of thrombosis-prone families and has an autosomal dominant inheritance pattern with variable penetrance.2 The genetic basis for APC-R is a point mutation in the coagulation factor V gene at the site where APC inactivates Va (Arg506).3 This common factor V gene mutation (Arg506Gln), also termed factor V Leiden, leads to thrombosis caused by the persistence of a degradation-resistant Va procoagulant in homozygous and heterozygous individuals. Factor V Leiden is seen in 90% of patients with venous thrombosis and APC-R, suggesting that there may be other genetic or functional defects responsible for APC-R in a minority of patients.4 The prevalence of the factor V mutation varies by geography and ethnicity, ranging from 2% to 15% in western societies.4 At present, it is considered to be the most common mutation in the European gene pool, leading Dahlback4 to speculate that it may convey a survival advantage.
The clinical significance of the factor V Leiden mutation in peripheral venous thrombosis has now become firmly established. APC-R is found in 20% to 60% of patients with deep venous thrombosis, depending on the selection criteria, the assay system for APC used, and the population studied (reviewed in Reference 4). Heterozygosity for the factor V gene mutation is associated with a 3.5- to 10-fold increased risk and homozygosity with a 50- to 100-fold increased risk of thrombosis.4 5 Interestingly, most individuals who are heterozygous for the factor V gene mutation, and many who are homozygous, will never experience a thrombotic event.
The risk for thrombosis in this condition is substantially influenced by the presence of additional familial or acquired thrombosis risk factors.4 5 For example, individuals with combinations of APC-R due to the factor V gene mutation and deficiencies in protein C or protein S have a higher thrombosis risk than those with APC-R alone. One recent study described both arterial and venous thromboses in consanguineous kindreds with the coexistence of hereditary homocystinuria and factor V Leiden.6 Likewise, prothrombotic conditions such as pregnancy, hormonal contraception, and surgery in individuals with the factor V gene mutation also substantially increase thrombosis risk.4 It is unclear whether individuals with APC-R that is not associated with the factor V Leiden mutation are at similar increased risk in the presence of acquired prothrombotic conditions. In this regard, Fisher and colleagues7 have presented a tantalizing study showing an almost 10% incidence of non–factor V Leiden–related APC-R in Hispanics with ischemic stroke.
In this issue of Stroke, three articles report on the association between APC-R and cerebral venous thrombosis (CVT).8 9 10 Taken together, these articles add 11 more cases of CVT associated with APC-R to the 7 cases in the existing literature.11 12 13 Five of these appear as isolated case reports,10 11 13 and the remainder are contained in three retrospective studies.8 9 12 In both studies, which used a case-control design, the prevalence of APC-R was approximately 20% in patients with CVT and 2% to 3% in normal control subjects.8 12 Martinelli and colleagues12 report that APC-R is associated with a ninefold increased risk for CVT. Although 2 of the patients with CVT reported had APC-R without the factor V gene mutation, the remainder (88% of patients) were heterozygous for the mutation. Thus, both the prevalence of APC-R and the proportion of patients with the factor V gene mutation in patients with CVT are similar to those in patients with deep venous thrombosis. Another important similarity is the frequency of other genetic and acquired thrombosis risk factors in patients with APC-R and CVT: hormonal contraceptives in 8, pregnancy/puerperium in 4, primary antiphospholipid antibody syndrome in 1, nephrotic syndrome in 1, treatment with high-dose intravenous steroids in 1, and immobilization in 1. In 1 of these patients, antithrombin III deficiency was present as well. Only 2 of 18 reported cases (11%) demonstrated no other thrombosis risk factors. As with APC-R associated with deep venous thrombosis, it appears that CVT in patients with APC-R may most commonly occur when the coagulation system balance is tipped toward thrombosis by the presence of multiple genetic or acquired risk factors acting in concert.
Although the studies reported in this issue serve to emphasize the importance of APC-R in CVT, the role of APC-R in cerebrovascular arterial occlusions is much less certain. In patients with arterial thrombosis, the frequency of APC-R is much lower.5 14 Sporadic cases have been reported with both stroke or myocardial infarction and APC-R. However, several large controlled studies have not supported an association between arterial thrombosis and APC-R.5 14 15 In selected individuals the factor V Leiden mutation in combination with additional prothrombotic states such as hyperhomocyst(e)inemia, or non–factor V Leiden APC-R in certain ethnic populations, may be important contributors to arterial strokes.6 7
Additional studies with larger numbers of patients will be necessary to establish the true incidence of APC-R in CVT. Taken together with previous reports, the articles in this issue suggest that APC-R may account for proportions of CVT cases similar to those of peripheral deep venous thromboses. Clearly, a careful laboratory examination to rule out APC-R is indicated for patients with unexplained CVTs. Such studies should not be considered routine in patients with ischemic stroke but are indicated for selected cases such as young individuals or those with migraine-related ischemic events.15 Deschiens and colleagues9 provide a reasonable algorithm for such an evaluation. To this paradigm, we would add determination of plasma homocyst(e)ine levels.6 16
Many issues regarding treatment, both acute and chronic, in patients with APC-R remain unresolved. Even acute thrombolytic therapies may be problematic. For example, in patients with APC-R who develop a pulmonary embolism, the thrombosis may be more resistant to dissolution.2 Furthermore, it is not clear whether treatment strategies should differ in patients with APC-R associated with the factor V gene mutation compared with those who do not have the mutation. It is also not clear whether an asymptomatic individual with APC-R should be treated prophylactically. It seems reasonable to treat prophylactically in situations of known increased thrombosis risk such as surgery, pregnancy, or immobilization. It also seems reasonable to suggest that women with APC-R abstain from taking hormonal contraceptives. The appropriate duration of anticoagulant treatment in patients with CVT and APC-R is not well delineated. In patients with one episode of CVT, particularly if an acquired prothrombotic condition present at the time of CVT has resolved, short-term anticoagulation may suffice. In patients with APC-R who suffer multiple thrombotic episodes, however, lifelong anticoagulation may be required.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004-1008.
2. Dahlback B, Hillarp A, Rosen S, Zoller B. Resistance to activated protein C, the FV:Q506 allele, and venous thrombosis. Ann Hematol. 1996;72:166-176.[Medline] [Order article via Infotrieve]
3. Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet. 1994;343:1536-1538.[Medline] [Order article via Infotrieve]
4. Dahlback B. Resistance to activated protein C, the Arg506 to Gln mutation in the factor V gene and venous thrombosis. Thromb Haemost. 1995;73:739-742.[Medline] [Order article via Infotrieve]
5.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995;332:912-917.
6.
Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Engl J Med. 1996;334:763-768.
7.
Fisher M, Fernandez JA, Ameriso SF, Xie D, Gruber A, Paganini-Hill A, Griffin JH. Activated protein C resistance in ischemic stroke not due to factor V arginine506
glutamine mutation. Stroke. 1996;27:1163-1166.
8.
Zuber M, Toulon P, Marnet L, Mas J-L. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996;27:1721-1723.
9.
Deschiens M-A, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, Samama MM, Bousser M-G. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996;27:1724-1730.
10.
Dulli DA, Luzzio CC, Williams EC, Schutta HS. Cerebral venous thrombosis and activated protein C resistance. Stroke. 1996;27:1731-1733.
11. Bridey F, Wolf M, Laissy JP, Morin V, Lefebvre M, de Prost S. Fatal cerebral venous thrombosis associated with the factor V Leiden mutation and the use of oral contraceptives. Thromb Haemost. 1995;74:1379. Letter.[Medline] [Order article via Infotrieve]
12. Martinelli I, Landi G, Merati G, Cella R, Tosetto A, Mannucci PM. Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost. 1996;75:393-394.[Medline] [Order article via Infotrieve]
13. Vuillier F, Moulin T, Tatu L, Rumbach L, Bertrand MA. Isolated cortical vein thrombosis and activated protein C resistance. Stroke. 1996;27:1440-1441.
14.
Press RD, Liu XY, Beamer N, Coull BM. Ischemic stroke in the elderly: role of the common factor V mutation causing resistance to activated protein C. Stroke. 1996;27:44-48.
15. Kontula K, Ylikorkala A, Miettinen H, Vuorio A, Kauppinen-Makelin R, Hamalainen L, Palomaki H, Kaste M. Arg506Gln factor V mutation (factor V Leiden) in patients with ischemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost. 1995;73:558-560.[Medline] [Order article via Infotrieve]
16. Cochran FB, Packman S. Homocystinuria presenting as sagittal sinus thrombosis. Eur Neurol. 1992;32:1-3.[Medline] [Order article via Infotrieve]
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