Chapter 15 Treatment of Thrombosis in the Antiphospholipid Syndrome

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Abstract

Thromboses are among the most severe manifestations of the antiphospholipid syndrome (APS), particularly those affecting cerebral arteries. Thus, correct management of thrombotic complications is paramount to improving the prognosis of patients with antiphospholipid antibodies (aPL). However, the optimal therapeutic approach is a matter of debate. Currently available evidence on this issue is weak, due to the lack of well-designed clinical trials including patients fully representative of the clinical spectrum of APS. Taking into account these limitations, we recommend indefinite anticoagulation to a target international normalized ratio (INR) of 2.0–3.0 for patients with definite APS and first venous thrombosis, and indefinite anticoagulation to a target INR of 3.0–4.0 for those with recurrent and/or and arterial events. On the other hand, patients with thrombosis who do not fulfill classification criteria for APS should receive the same treatment as the general population. As primary thromboprophylaxis, we recommend that patients with systemic lupus erythematosus (SLE) and lupus anticoagulant, and/or persistently positive anticardiolipin antibodies take hydroxychloroquine and low-dose aspirin. For patients with purely obstetric APS, we recommend low-dose aspirin. Asymptomatic carriers of aPL are part of the no therapy or low-dose aspirin group. Strict control of vascular risk factors and adequate thromboprophylaxis in high-risk situations (surgery, post-partum, prolonged immobilization) should be warranted in all patients with aPL.

Introduction

Thromboses are among the most severe manifestations of the antiphospholipid syndrome (APS), particularly those affecting cerebral arteries (Cervera et al., 2002). Thus, correct management of thrombotic complications is paramount to improving the prognosis of patients with antiphospholipid antibodies (aPL). In fact, the ideal approach would be to prevent patients with aPL from developing full APS, that is, to keep them asymptomatic. Unfortunately, on many occasions the clinical event comes first, and it is at that time when we notice the presence of aPL. We all agree that whatever the clinical scenario—patients with thrombosis or asymptomatic aPL carriers—every effort must be made to prevent clotting events. However, the optimal treatment regimes are sometimes a matter of intense debate.

Mirroring what usually occurs in the field of systemic autoimmune diseases, the initial studies in APS consisted of observational cohorts (Rosove and Brewer, 1992; Khamashta et al., 1995). It was after the publication of these series that the recommendation of prolonged (indefinite) anticoagulant treatment for patients with APS and thrombosis ensued. Over the following years, studies with higher quality have been published, including two randomized controlled trials (RCTs) (Crowther et al., 2003; Finazzi et al., 2005), a subgroup analysis of a RCT (Levine et al., 2004), and two systematic reviews (Lim et al., 2006; Ruiz-Irastorza et al., 2007).

Unfortunately, observational and experimental studies have often reached different conclusions. While RCTs are studies of higher quality, in this specific field they are often limited by difficulty recruiting large enough groups of patients to represent the whole spectrum of the syndrome. On the other hand, observational series, although methodologically weaker, have the potential advantage of the larger size and the inclusion of non-selected, “real world” patients. Indeed, important management issues involving patients with systemic lupus erythematosus (SLE) and other autoimmune diseases are based on observational studies (Urowitz and Gladman, 2005). Thus, any available information is potentially useful and the final conclusions must take into account both methodological and population-based limitations.

An important issue to take into account when making therapeutic decisions is the immunological profile of patients with aPL. Those with lupus anticoagulant (LAC) should be considered to be at the highest risk of thrombosis (Galli et al., 2003), particularly if concomitant high levels of anticardiolipin (aCL) or anti-β2 glycoprotein I (anti-β2GPI) are demonstrated (Forastiero et al., 2005). In patients with SLE, LAC and persistently positive aCL seem to be predictive of thrombosis, while occasional aCL, even if repeatedly positive, do not increase the thrombotic risk (Martinez-Berriotxoa et al., 2007).

Section snippets

Prevention of recurrent thrombosis

In 2006, Lim and colleagues published a systematic review in JAMA that focused on the therapeutic aspects of APS (Lim et al., 2006). For patients with thrombosis, the authors recommended that patients with aPL experiencing a venous or non-cerebral arterial thromboembolism should be treated with oral anticoagulation at a target international normalized ratio (INR) of 2.0–3.0. However, those patients having a stroke should receive either low-dose aspirin or warfarin at a lower aimed INR

Primary thromboprophylaxis

Given the severity of APS, the ideal approach would be to avoid the progression from asymptomatic aPL carriers to patients with the syndrome. Retrospective studies suggest that patients with SLE and aPL have a 50% chance of suffering APS manifestations within 10 years (Shah et al., 1998). A Spanish series has recently quantified the risk of thrombosis in this group of patients: 3.93 events per 100 patient-years (Martinez et al., 2006). Women with obstetric APS also seem to be at a high risk of

Other therapies

Animal and in vitro models show an antithrombotic effect of hydroxychloroquine, reducing the size and the time of persistence of aCL-induced clots in a mouse model (Edwards et al., 1997) and in aPL-induced human platelet activation (Espinola et al., 2002), with both effects taking place in a dose-dependent fashion.

Earlier, Wallace (1987) published the observation that lupus patients taking antimalarials were less likely to develop thrombosis (45.5% of patients with thrombosis took

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