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Marburg I polymorphism of factor VII–activating protease is associated with idiopathic venous thromboembolism
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     the Institute of Transfusion Medicine, Campus Virchow-Klinikum, Charite—Universittsmedizin Berlin, Germany.

    Abstract

    The factor VII–activating protease (FSAP) variant Marburg I is known to attenuate the profibrinolytic system in vitro and was recently shown to be a significant predictor for the evolution and progression of carotid stenosis. The objective of this case-control study was to assess FSAP Marburg I's role in the occurrence of venous thromboembolism (VTE). The frequency of FSAP Marburg I was significantly increased in patients with a history of VTE (17 of 213 patients, 8.0%, P = .014) or idiopathic VTE (12 of 103 patients, 11.7%, P = .002) compared to healthy controls (5 of 213 controls, 2.3%). Logistic regression analysis confirmed FSAP Marburg I to be an independent risk factor for VTE (odds ratio, 3.5; 95% confidence interval [CI], 1.2-10.0) and idiopathic VTE (odds ratio, 6.2; 95% CI, 2.0-18.9).

    Introduction

    Factor VII–activating protease (FSAP) has 2 main functions in coagulation. It was first described as a tissue factor–independent activator of factor VII promoting early steps of the coagulation pathway1 and was later found to contribute to the fibrinolytic pathway by activating prourokinase.2 The Marburg I polymorphism (Gly511Glu) is a frequent variant of FSAP in which the activity toward prourokinase is diminished, while the capacity to activate factor VII is preserved.3 Due to the resulting hemostatic imbalance, it seems likely that FSAP Marburg I may promote the development of thromboembolic diseases. FSAP Marburg I was shown recently to be a significant predictor for the evolution and progression of carotid stenosis,4 but it is unknown whether it plays a role in the occurrence of venous thromboembolism (VTE).

    This case-control study was designed to determine whether FSAP Marburg I is associated with an increased risk of VTE.

    Study design

    Statistical analyses included univariate analysis (Fisher exact test) and logistic regression analysis with factor V Leiden, PT 20210G A, and FSAP Marburg I as independent variables. Statistical analyses were performed using SPSS statistics package V.11 (SPSS, Chicago, IL) and GraphPad Prism 4 (GraphPad Software, San Diego, CA).

    Results and discussion

    Significant hereditary thrombophilic risk factors other than FSAP Marburg I, for instance, factor V Leiden (n = 54), PT 20210G A (n = 13), factor V Leiden + PT 20210G A (n = 3), factor V Leiden + protein S deficiency (n = 2), protein S deficiency (n = 1), and antithrombin deficiency (n = 1) were found in 74 patients. A history of VTE in relatives of patients with FSAP Marburg I and no other significant hereditary thrombophilic risk factors was found in 4 of 10 cases. The frequencies of carriers of factor V Leiden and PT 20210G A in controls, patients with VTE, and idiopathic VTE (Table 2) are in agreement with previously published data,7-9 reflecting the comparable composition of our collectives.

    Based on our data FSAP Marburg I appears to be a candidate for hereditary thrombophilia. However, some details of our study should be discussed. We analyzed prevalent and not incident cases. Thus, there might be a tendency for inadequate recall of past events. This will not influence the accuracy of the detection of FSAP Marburg I and VTE, because both were based on objective findings. However, the recall of circumstances of VTE might be in some cases incomplete, although the majority of patients presented within 1 year after VTE.

    The association of FSAP Marburg I with VTE in prevalent cases could be due to a survival bias of this factor. Although this explanation does not seem likely, it cannot be completely ruled out. An additional potential source of bias is the used control group. Blood donors necessarily should have no known underlying diseases, for example, malignancies or autoimmune diseases. However, as these diseases are not likely to influence the genotype frequency of FSAP, our control group seems to be suitable for determining the frequency of FSAP Marburg I in our geographical area.

    FSAP Marburg I is a prevalent variant that exhibits an independent association with VTE. Similar to the prevalence of factor V Leiden and PT 20210G A,9 its frequency in the general population is about 2% to 4%.4 Its effect was especially pronounced in patients with idiopathic VTE, who are known to be prone for recurrence of disease.10 However, based on the presented data, no statement about the influence of FSAP Marburg I on the recurrence rate of VTE is possible. This should be the aim of further studies. The possible significance of FSAP Marburg I becomes obvious when one considers that many previously described thrombophilic risk factors were found to be associated with VTE only under certain circumstances, for example, in surgical patients11 or in combination with other thrombophilic risk factors.12-14

    Finally, our results might be helpful in understanding the findings of Prandoni et al,15 who described an association between atherosclerosis (carotid plaques) and idiopathic but not secondary VTE and who raised the question whether these 2 conditions might share common risk factors. Interestingly, FSAP Marburg I was initially described as a predictor for the evolution and progression of carotid stenosis,4 and in our study it could be demonstrated to be associated with idiopathic but not with secondary VTE (Table 2).

    Larger studies are needed to conclusively determine the importance of FSAP Marburg I in VTE.

    Acknowledgements

    This work is dedicated to my father, Prof Dr Immo Hoppe.

    We thank Gisela Diederich for excellent technical assistance.

    Footnotes

    Prepublished online as Blood First Edition Paper, October 14, 2004; DOI 10.1182/blood-2004-08-3328.

    The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.

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