Thrombosis risk in purely obstetric APS

In this issue of Blood, Gris and colleagues show that the risks of venous thromboembolism and cerebrovascular symptoms are higher in women with purely obstetric antiphospholipid syndrome (APS) than in women without it.¹ 

Antiphospholipid syndrome is an autoimmune disorder presenting with venous and arterial thrombosis and/or obstetric complications in the presence of persistent antiphospholipid antibodies (aPLs), such as lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and/or anti–β₂-glycoprotein I antibodies. In the absence of other associated autoimmune disorders, such as systemic lupus erythematosus, the disease is classified as primary APS (PAPS). It is widely known that patients with APS may exhibit severe pregnancy morbidity, including unexplained recurrent fetal deaths at or beyond 10 weeks' gestation; recurrent spontaneous abortions before the 10th week of gestation; or severe pre-eclampsia, eclampsia, or placenta insufficiency resulting in premature births of morphologically normal neonates before 34 weeks of gestation.²  Patients with APS may develop 1 or more clinical episodes of arterial, venous, or microvascular thrombosis occurring in any tissue or organ, and these episodes can develop during pregnancy or outside pregnancy, both spontaneously or associated with other risk factors for thrombosis.²  Despite numerous potential complications during pregnancy, optimal management makes it possible to achieve a high live birth rate, up to 80% or 90%. Women with purely obstetric APS are those with no history of vascular thrombosis and who present APS during pregnancy However, the risk of thrombosis in women with purely obstetric APS is still unclear, although annual prevalence values between 7% and < 1% have been reported.^3-5  The variation in the estimated risk of thrombosis in purely obstetric APS has led to uncertainty in the management of these patients and to different approaches in prescribing prophylactic antithrombotic treatment for such women. In the large, clinical observational Nimes Obstetricians and Hematologists Antiphospholipid Syndrome (NOH-APS) study published in this issue,¹  Gris et al prospectively evaluated the rate of thrombotic events in women with purely obstetric APS and compared it with the rate in carriers of inherited (constitutional) thrombophilia because of the presence of factor V Leiden (F5 6025 polymorphism) and prothrombin G20210A (F2 rs1799963 polymorphism) mutations and in nonthrombophilic females. Primary prophylaxis of thrombosis for the patients with purely obstetric antiphospholipid syndromes consisted of low dose aspirin (LDA; 100 mg/d). Women with inherited thrombophilia and nonthrombophilic females were not taking any prophylaxis for thrombosis. During new pregnancies, antithrombotics were administered according to published guidelines, namely, low-molecular-weight heparin (LMWH; enoxaparin, 4000 IU/d) plus LDA (100 mg/d) were prescribed for all pregnant aPL women after the positive pregnancy test to delivery.^6,7  Women with inherited thrombophilia received the enoxaparin prophylaxis, 4000 IU/d, during the 6-week postpartum period. In cases with previous fetal loss, enoxaparin was also prescribed during pregnancy. Nonthrombophilic women received no prophylaxis during or after pregnancy. Elastic compression stockings were systematically prescribed for all participants.

The main results of this large prospective observational study reported here by Gris et al can be summarized as follows. First, the risks of venous thromboembolism and of cerebrovascular manifestations are higher in women with purely obstetric APS than in women without APS. The adjusted rate of VTE events is almost twice as high in APS women than in patients without APS. The overall cerebrovascular risk is nearly doubled in APS women compared with those without APS, even though only a few events are observed. Indeed, a higher risk of thrombosis is present in women with purely obstetric APS despite the use of LDA primary prophylaxis. Second, women carrying heterozygous factor V Leiden or prothrombin G20210A mutations who are asymptomatic for thrombosis and have experienced fetal deaths or recurrent abortions are not at increased risk of subsequent thrombosis compared with nonthrombophilic women. The incidence of thrombosis found in this cohort of inherited thrombophilic women does not differ from that found in the general population. This may be due to the selection of patients or to other factors, including intervention during pregnancies. However, these findings cannot be applied to those asymptomatic women belonging to thrombophilic families with the same polymorphisms who may have an increased risk of developing provoked or unprovoked VTE regardless of a previous history of pregnancy complications.⁸  Factor V Leiden polymorphism is shown to be an independent risk factor for transient ischemic attacks in APS. An interactive effect may indeed exist between aPLs and factor V Leiden polymorphism. Third, among all aPLAs, LAC is the only independent risk factor for venous thrombotic disease, including proximal unprovoked deep vein thrombosis, distal unprovoked deep vein thrombosis, and superficial vein thrombosis. Interestingly enough, a dose-effect relationship between LA intensity and the clinical outcome is observed. LAC is considered the most powerful predictor of thrombosis, as previously reported.⁹  Surprisingly, no single aPL is an independent risk factor for cerebrovascular events. Whether this can be related to an effect of the use of LDA prophylaxis or to other determinants (estro-progestative oral contraceptive use, smoking, other) is unclear.

In contrast with previous observations on triple aPLs positivity as a highly predictive factor for both venous and arterial thrombosis risk in male asymptomatic patients,¹⁰  in this cohort of women with purely obstetric APS high LA activity is associated with the highest risk of thrombosis after multivariate analysis. Interestingly, more venous than arterial events are seen in this cohort, possibly reflecting an effect of LDA.

What are the clinical implications of this study? Physicians badly need information on this type of patient for clinical management. The epidemiologic data presented by Gris and colleagues are really impressive and add information on the clinical significance and the natural history of obstetric APS in terms of general thrombotic risk and type of thrombosis, as well as risk assessment by clinical and laboratory parameters. The strengths of the study are the large cohort of patients and the long and careful follow-up. The choice of the management of patients (the so-called “Nimes protocols”) may represent a limitation because it is not commonly used. However, similar approaches including the use of long-term LDA are often applied in clinical practice for women with purely obstetric APS. According to this study, LDA has no effects on the prevention of subsequent VTE whereas there may be a potential beneficial effect on the prevention of TIA or stroke. However, the risk-to-benefit ratio of LDA, if any, in the prevention of arterial thrombosis should be evaluated by randomized clinical trials. Given the higher risk for venous and arterial thrombosis observed in women with purely obstetric APS, should we use long-term anticoagulants for primary prophylaxis? At present there are no data on the risk-to-benefit ratio of this approach. As Gris et al also state in their conclusions, multicenter, randomized, prospective clinical trials are urgently needed to assess the effect of antithrombotic prophylaxis in this setting. Whether administration of continuous primary prophylaxis can be considered in the presence of high-titer LA (or triple aPLs positivity) and of additional risk factors for thrombosis including inherited thrombophilia as well as what the optimal regimen is for on-demand prophylaxis in situations at risk for women with purely obstetric APS, are still open questions. In the meantime, the decision is up to the treating physicians and the patients based on a careful evaluation and counseling on the thrombosis risk according to available data from the literature.