The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis – a population-based case-control study

Abstract

In this population-based case-control study we explored the association of antiphospholipid antibodies with pregnancy-related venous thrombosis. From 1990 through 2003 615 pregnant women were identified at 18 hospitals in Norway with a diagnosis of first time VT. In 2006, 531 of 559 eligible cases and 1092 of 1229 eligible controls were invited for further investigations. The final study population comprised 313 cases and 353 controls, who completed a comprehensive questionnaire and donated a single blood sample, 3-16 years after index pregnancy. We report the results on lupus anticoagulant, anticardiolipin antibodies, and anti-ß₂ glycoprotein-1 antibodies alone, in combination, and with the contribution of the factor V Leiden and the prothrombin gene G20210A polymorphisms. Cut-off values for APAs were chosen according to current international consensus. 29 (9.3%) of the cases and 24 (6.8%) of the controls had at least one positive test for APAs (OR 1.4; 95% CI 0.8-2.5). Nine cases (2.8%) and no controls had more than one positive test (multi-positivity) for APAs. After excluding women with factor V Leiden or prothrombin polymorphisms, still 6 cases were multi-positive for APAs. We conclude that multi-positivity, but not single-positivity, for APAs was weakly associated with a history of ante- and postnatal VT.

Introduction

Pregnancy is associated with progressive activation of coagulation and inhibition of fibrinolysis [1], [2]. These physiologic changes reduce the risk of bleeding during delivery, but increase the risk of venous thrombosis (VT), which is one of the leading causes of maternal morbidity and death in developed countries [3], [4], [5], [6]. Both congenital and acquired thrombophilia increase the risk of VT [7], [8]. Antiphospholipid antibodies (APAs) comprise a heterogeneous group of autoantibodies, and are considered to be among the most commonly acquired thrombophilias [9], [10]. The antiphospholipid syndrome is defined by venous or arterial thrombosis and/or specific pregnancy complications in patients with persistently positive tests for APAs [11]. The laboratory criteria include repeated positive tests for lupus anticoagulants (LA), anticardiolipin (aCL) antibodies, and/or anti-ß₂ glycoprotein-1 (anti-ß₂GP1) antibodies [11].

The major autoantigen for APAs is ß₂GP1, which mediates the binding of APAs to target cells, such as endothelial cells, platelets, monocytes, and trophoblasts. APAs are thought to interfere with the procoagulant, anticoagulant, and fibrinolytic systems, to produce a prothrombotic environment and trigger thrombosis [12].

In patients with systemic lupus erythematosus and other autoimmune diseases APAs are established risk factors for VT [13], [14]. However, the role of APAs in the etiology of VT among healthy individuals and especially among healthy pregnant women has not yet been settled. Comparison of results across studies on the relationship between APAs and risk of VT is difficult because of different enrollment criteria, inconsistency in which type of APAs that are examined, different cut-offs for test positivity, and lack of assay standardization. The association of aCL antibodies, and especially the IgM isotype, to VT is uncertain, and there is an ongoing debate whether these antibodies should be included in the definition of APS [15], [16], [17], [18].

The aim of the present case-control study was to investigate the association of different APAs, either alone or in combination, to pregnancy-related first time VT, when considering the contribution of the factor V Leiden and/or the prothrombin gene G20210A polymorphisms (prothrombin polymorphism). Based on circumstantial evidence so far, our main hypothesis was that cases with a history of pregnancy-related VT had higher prevalence of APAs as compared with controls.