INTRODUCTION

Antiphospholipid syndrome (APS) is defined by the development of thrombosis and/or adverse obstetric events in the presence of antiphospholipid antibodies (aPLs).¹ The clinical consequence of thrombosis, which is the main complication of APS, depends on the site and extent of the process. In most cases, larger vessels are involved, particularly thrombosis of the intracranial arteries (leading to cerebral ischemia) or the deep veins of the lower extremities (sometimes leading to pulmonary embolism). These events usually occur in isolation or, if recurrent, over months or years. Much less commonly, there is diffuse thrombotic occlusion of predominantly small vessels, which leads to damage and dysfunction of multiple organs concurrently or sequentially over days or weeks. The term “catastrophic” APS (CAPS) has been coined for this serious and often fatal complication.²

Data regarding management and prognosis are limited. The long-term prognosis for aPL-positive patients is most influenced by the risk of thrombosis. Thrombotic complications are unpredictable, and the mechanisms triggering these events in individual patients are ill-defined. Despite advances in studies of the mechanisms of thrombosis in APS, and the development of newer assays such as anti-β2 glycoprotein I and antiprothrombin antibodies, the serologic “fingerprint” of the patient most at risk for arterial (especially stroke) or venous thrombosis remains elusive.

PRIMARY THROMBOPROPHYLAXIS OF ANTIPHOSPHOLIPID ANTIBODY–POSITIVE SUBJECTS

The controversy concerning whether prophylactic treatment is indicated for patients with aPL who have no history of thrombosis remains unresolved. Although epidemiologic studies suggest a risk of thrombosis in subjects positive for aPL,³ some of these individuals never develop these events. It is clear that there are factors other than aPL that are necessary for the thrombosis to develop.⁴

Although low-dose aspirin (75 to 100 mg/d) has been considered a logical first option, the Physician Health Study showed that low-dose aspirin (325 mg/d) in men with aCL did not protect against deep venous thrombosis or pulmonary embolus.⁵ In contrast, hydroxychloroquine may be protective against the development of thrombosis in aPL-positive patients with SLE.^6,7

A prospective, randomized clinical trial comparing aspirin alone with aspirin plus low-intensity warfarin (international normalized ratio [INR]∼1.5) in patients with aPL who have never had thrombosis is currently underway in the United Kingdom. Until these results are available, we suggest that individuals with a persistently positive aCL (moderate to high titers) and/or unequivocally positive lupus anticoagulant tests take low-dose aspirin (75 to 100 mg/d) indefinitely. Cessation of estrogen-containing oral contraceptive use; treatment of hypertension, hyperlipidemia, or diabetes if present; and the avoidance of smoking are all additional recommended therapeutic measures. Prophylaxis with heparin administered subcutaneously should certainly be given to cover higher-risk situations, such as surgery and long-haul flights.

PREVENTION OF RECURRENT THROMBOSIS

Despite the enormous amount of work that has focused on the pathogenesis and clinical manifestations of APS, there has been surprisingly little published on the management of thrombosis associated with aPL, and there are only limited data from prospective clinical trials on which to base treatment decisions.

Acute management of venous or arterial thrombosis in patients with APS is no different from that of other patients with similar complications. Patients with venous thromboembolism are given heparin (low molecular weight in most countries) followed by warfarin. Fibrinolytic therapy has been used successfully in patients with APS.⁸

There is now good evidence from both retrospective⁹ and prospective¹⁰ studies that APS patients with thrombosis will be subject to recurrences, and that these can be prevented by long-term anticoagulation. Many patients with APS in whom anticoagulation has been stopped have had major recurrent thrombosis. It is not clear, however, whether prolonged anticoagulation is necessary in APS patients whose first thrombotic episode developed in association with surgery, oral contraceptive use, pregnancy, or other circumstantial thrombotic risk factors.

The type of thrombosis is predictive. Retrospective analysis of patients with APS and recurrent thrombosis showed that a venous thrombosis is followed by another venous thrombosis in more than 70% of cases, and an arterial thrombosis is followed by another arterial thrombosis in more than 90% of cases.^9,11

Most patients requiring long-term anticoagulant therapy respond well to warfarin targeted to an INR of 2.0 to 3.0. However, the optimal intensity of anticoagulation therapy is uncertain for patients with aPL-associated thrombosis. Retrospective studies in the 1990s suggested that thrombosis in APS patients should be managed by high-intensity (target INR 3.0 to 4.0) oral anticoagulation.^9,11 The more recent prospective studies^12,13 and a systematic review¹⁴ suggest only an INR of 2.0 to 3.0 is required. The major concern about these recent prospective and randomized studies is the fact that the majority of patients included had venous rather than arterial thrombosis. Furthermore, none of these studies achieved the expected sample size; a large number of patients were excluded because they had already had recurrent events on oral anticoagulation; and in the Crowther’s study,¹² patients with recent stroke were excluded so that in the final study 76% of the patients had previous venous thrombosis only, and review of the high-intensity arm showed that the patients were below the therapeutic range 43% of the time.

Oral anticoagulation therapy carries an inevitable risk of serious hemorrhage. In APS, serious bleeding complications may occur, but their risk is not higher than that observed in other thrombotic conditions warranting oral anticoagulation.¹⁵ In APS patients with previous arterial events, the dangers of thrombosis and stroke far outweigh the risk of anticoagulant-induced bleeding. The traditional fear of cerebral hemorrhage has almost certainly resulted in the undertreatment of many patients with cerebral APS.¹⁶ We recommend that APS patients with previous venous thrombotic events should have moderate-intensity (INR 2.0 to 3.0) anticoagulation. However, those with previous arterial events merit high-intensity (INR 3.0 to 4.0) anticoagulation until there is evidence to the contrary.^16,17

Concerns exist over the validity of the INR in the control of oral anticoagulant dosing if lupus anticoagulant is present. The inhibitor occasionally increases the prothrombin time, and the INR may not reflect the true degree of anticoagulation.¹⁸ This phenomenon seems to be more likely when certain recombinant thromboplastin reagents are used, and can usually be circumvented by careful selection of the thromboplastin to be used for the prothrombin time test.¹⁹

The increasing use of oral anticoagulation therapy has increased the need for anticoagulant monitoring and encouraged a move towards “point of care” or “near-patient” testing and self-monitoring. Several trials have suggested that such monitoring might be equal to or even better than standard monitoring. A recent systematic review and meta-analysis of all randomized controlled trials showed that self-management improves the quality of oral anticoagulation. Patients capable of monitoring and self-adjusting therapy have fewer thromboembolic events and lower mortality.²⁰ However, self-monitoring is not feasible for all patients, and requires identification and education of suitable candidates. Patients’ self-monitoring of oral anticoagulation have a greater degree of autonomy and particularly suits young patients with busy lifestyles who find attending the anticoagulation clinics irksome. Certainly, patient self-monitoring is associated with a higher level of patient satisfaction and quality of life than supervised management when assessed by questionnaires.²¹ We have used self-monitoring in motivated APS patients with success. However, all the data on self-monitoring relate to running an INR of 2.0 to 3.0, not 3.0 to 4.0. We propose to formally study this group to ensure that they are attaining satisfactory anticoagulation.

Some patients with APS continue to have recurrent thrombotic events despite an INR of 3.0 to 4.0. Whether additional therapy with low-dose aspirin is efficacious in this situation is not known, but the risk of hemorrhage is increased when aspirin is used alongside oral anticoagulant therapy.²² Hydroxychloroquine use may aid preventing thrombosis in lupus patients. Due to its excellent safety profile, this drug might empirically be given to APS patients with insufficient control despite optimal oral anticoagulation.

One of the features of APS is that some patients appear relatively resistant to warfarin, with some requiring up to 25 mg/d to maintain adequate anticoagulation. In our experience, most of these patients were receiving other drugs and, notably, azathioprine, at the same time as warfarin therapy. Azathioprine interacts with warfarin, reducing its efficacy by possible hepatic enzyme induction.²³ Conversely, patients on warfarin who stop azathioprine may be at risk of bleeding and should be monitored carefully.

Autoimmune thrombocytopenia is an accompanying problem in 25% of individuals with APS.²⁴ Generally, it is mild (platelet counts of 50,000 to 150,000/mm³), but occasionally severe thrombocytopenia occurs. The treatment of thrombosis and thrombocytopenia in the same patient is a difficult clinical problem, and requires careful management. It is worth noting that thrombocytopenia does not necessarily protect patients against thrombosis,²⁵ and platelet counts of 50,000 to 100,000/mm³ in APS should not modify the treatment policy of thrombosis with warfarin.

The role of steroids and immunosuppressive drugs in the treatment of patients with aPL and thrombosis is uncertain. Such drugs do not always suppress aPL, and they have severe side effects when given for prolonged periods. Furthermore, in a large series of patients with APS, corticosteroids and immunosuppressive therapy, prescribed for some patients to control lupus activity, did not prevent further thrombotic events.⁹ The use of these drugs is probably justified only in patients with life-threatening conditions with repeated episodes of thrombosis despite adequate anticoagulation therapy, namely CAPS.²

Patients with CAPS frequently present to the intensive care unit with the challenging differential diagnosis of multisystem failure. The diagnosis requires a high degree of clinical awareness but, once the condition is suspected clinically, the diagnosis is generally confirmed by the demonstration of aPL (anticardiolipin antibody and/or lupus anticoagulant).

CAPS is a serious complication with mortality in reported cases of approximately 50%.^2,26 The optimal management of CAPS is not known. Most cases have been treated by corticosteroids, anticoagulation, plasmapheresis, high-dose intravenous immunoglobulin (IVIG), and cyclophosphamide, usually in some form of combination of these. The best outcome (70% survival) was seen in patients treated with a combination of corticosteroids, anticoagulation, plasmapheresis, and/or IVIG. The addition of cyclophosphamide was associated with a lower rate of survival, although these patients may have had more severe disease.²

Appropriate management plans when aPLs are found in association with various clinical features and in asymptomatic individuals are outlined in Tables 47.1 and 47.2.

TABLE 47.1 PRIMARY THROMBOPROPHYLAXIS AND PREVENTION OF RECURRENT THROMBOSIS IN ANTIPHOSPHOLIPID SYNDROME

TABLE 47.2 MANAGEMENT OF PREGNANT WOMEN WITH ANTIPHOSPHOLIPID SYNDROME