The antiphospholipid syndrome (APS) is the association of thrombosis, pregnancy loss, and morbidity, and certain other clinical manifestations with antiphospholipid antibodies (aPLs) (lupus anticoagulant [LA], anticardiolipin antibodies [aCL], and/or anti–β 2 -glycoprotein I antibodies [aβ 2 GPI]). International consensus classification criteria for definite APS ( Table 11-1 ) have been developed to facilitate research in the field. Although they were not designed for clinical use, these criteria highlight the need for appropriate documentation of clinical events and the importance of antibody titer and persistence. It should be kept in mind that certain clinical manifestations associated with aPL, for example, valvular heart disease (Libman-Sacks endocarditis), livedo reticularis, and thrombocytopenia, were not included in the classification criteria ( Table 11-2 ). These manifestations can occur in patients with or without a history of thrombosis or pregnancy loss.
Using a case-based approach, this chapter reviews current recommendations for the treatment of APS. Management of APS is often challenging. Although there is general consensus on approaches to treatment, the application of these principles in clinical practice is often difficult. In other words, “the devil is in the details.” In the initial evaluation of patients, the relative contribution of aPL to clinical events may not be clear. Positivity of aPL tests and antibody titers may vary over time. Also, patients with aPL may have other inherited and acquired risk factors for thrombosis and/or pregnancy loss. For patients in whom aPLs are clinically relevant, there are relatively few prospective clinical trials to provide therapeutic guidance and a number of important variables have not been studied.
A 25-year-old white woman presents with a 2-day history of a blue, painful right index finger. Her past medical history is notable for two pregnancies, both of which were fetal deaths (at 15 and 17 weeks’ gestation, 2 years and 6 months prior, respectively) and frequent headaches. She does not smoke cigarettes, has no prior history of blood clots, and is taking no medications. Physical examination is normal except for diffuse livedo reticularis ( Fig. 11-1 ) of the upper and lower extremities, a decreased right radial artery pulse, and cyanosis of the right index finger distal to the distal interphalangeal joint. An arteriogram shows complete occlusion of the right radial artery at the navicular level. Significant laboratory tests include a positive antinuclear antibody (ANA), 1:160 in a nucleolar pattern, immunoglobulin G (IgG) aCL and aβ 2 GPI greater than 80 units (high positive), negative immunoglobulin M (IgM) and immunoglobulin A (IgA) aCL and aβ 2 GPI, negative LA test, normal complement levels, and a normal platelet count. A thorough evaluation for other hypercoagulable conditions is negative. Echocardiography is normal. Treatment with intravenous heparin followed by warfarin at a target international normalized ratio (INR) of 3.0 results in gradual improvement of her finger.
MANAGEMENT OF ACUTE THROMBOSIS AND SECONDARY THROMBOSIS PREVENTION
The differential diagnosis of acute peripheral arterial thrombosis in a young woman includes trauma, an embolic event, and a hypercoagulable state. A list of thrombophilic conditions is shown in Table 11-3 . This patient’s history of pregnancy losses and the physical finding of livedo reticularis suggest the possibility of APS. It should be noted that other thrombophilic conditions, for example, factor V Leiden and inherited deficiencies of protein C and protein S, may also be associated with pregnancy loss. In the past, the association of livedo reticularis with arterial thrombosis (typically stroke) in young women has been termed Sneddon’s syndrome. Studies indicate that many patients with Sneddon’s syndrome have aPLs.
The location of this patient’s thrombosis, a small peripheral artery, is somewhat uncommon in APS. Although thrombosis in almost every location in the vasculature has been reported in association with aPL, stroke and transient ischemic attack (TIA) are the most common types of arterial thrombosis. Lower extremity deep vein thrombosis (DVT), with or without associated pulmonary embolism, is the most common type of venous events. In patients with APS, recurrent thrombotic events tend to be of the same type, that is, patients with an initial arterial event tend to have subsequent arterial events and patients with venous events tend to have subsequent venous events. That said, some patients with APS have both arterial and venous thromboses.
The characterization of this patient as having APS should be considered tentative at this stage in the clinical evaluation. The strongest association of aPLs with thrombosis is for a persistently positive LA or persistently positive IgG or IgM aCL/aβ 2 PI at medium to high titer. Transient or low-titer aPLs may occur in apparently healthy individuals and in association with certain infections. In this patient, aPL positivity has been documented on only one occasion. The high titer and isotype of the antibody (in this case, IgG aCL and aβ 2 GPI), suggests that this is a clinically significant finding; however, aPL testing should be repeated. The optimal time interval for repeat testing is not known. Current classification criteria require that positive tests be demonstrated at least 12 weeks apart, whereas the original iteration of these criteria required a minimum interval of only 6 weeks. Twelve weeks is reasonable due, in large part, to the fact that critical treatment decisions affected by repeat testing (e.g., how long to continue full anticoagulation after the acute thrombotic event) do not usually need to be made before 12 weeks.
Identification of persistent moderate- to high-titer aPLs in a patient with thrombosis does not obviate the need to evaluate the patient for additional causes of thrombophilia (inherited and acquired) and, importantly, to identify any reversible thrombotic risk factors (see Table 11-3 ). Approximately 50% of patients with APS with thrombotic events have one or more reversible or modifiable risk factors for thrombosis at the time of their acute events.
Two other aspects of this patient’s case are worth mentioning, that is, the positive ANA and the history of severe headache. A positive ANA, and occasionally more specific autoantibodies associated with systemic lupus erythematosus (SLE), may be present in patients with APS. APS may occur in association with SLE or other autoimmune diseases, or in the absence of these conditions (primary APS). Approximately a third of SLE patients have aPLs, and about a third of these (approximately 10%–15% of SLE patients) have clinical manifestations of APS. Primary APS and APS associated with SLE probably represent two extremes of a spectrum. It is not unusual for patients with primary APS to have some serologic features of SLE. Because of the association of APS with SLE, patients with APS should have a thorough history and physical examination to evaluate for SLE and other systemic autoimmune diseases. Secondly, an association between migraine headache and aPL has been reported but is controversial owing to the relatively high prevalence of headaches in the general population.
There are no APS-specific recommendations for the management of acute thrombosis. Anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin, followed by warfarin, is the initial treatment strategy for both aPL-positive and aPL-negative patients with acute thrombosis.
An important issue in the long-term management of APS (prevention of recurrent thrombosis, that is, secondary thrombosis prevention), is the optimal intensity of anticoagulation with warfarin. Previous retrospective studies indicated that high-intensity treatment (INR = 3.0) warfarin was more effective than moderate-intensity warfarin or low-dose aspirin for the prevention of recurrent thrombosis in aPL-positive patients. More recently, two randomized controlled trials demonstrated that high-intensity anticoagulation (INR 3.1–4.0) was no better that moderate intensity (INR 2.0–3.0). Based on these studies, moderate-intensity anticoagulation is the current standard of care. Several caveats to this recommendation should be considered. These studies did not separate patients with arterial and venous thrombosis. It is possible that larger studies of these patient subsets would yield different recommendations. Some clinicians assume that prevention of arterial thrombosis requires more intensive therapy, perhaps due to the clinical impact of arterial thrombi, for example, stroke or loss of a limb. This may or may not be the case, however. The Antiphospholipid Antibodies and Stroke Study found no difference between warfarin (INR 1.4–2.8) and aspirin (325 mg/day) for prevention of recurrent stroke or death in patients following an initial stroke. Drawbacks to this study are that patients were tested only once for aPL and that most aPL were low-titer aCL. The use of newer antiplatelet agents, such as clopidogrel, to prevent recurrent arterial thrombosis associated with aPL is potentially interesting but has not been studied.
Duration of anticoagulation is another difficult issue. Although the optimal duration of therapy is not known, it is recommended that warfarin be continued indefinitely. Schulman and colleagues found an increased incidence of recurrent venous thrombosis following a 6-month course of anticoagulation in patients with aCL as compared with those without aCL (29% versus 14%, risk ratio 2.1, 95% confidence interval [CI] 1.3–3.3, P < 0.01). It is not known whether it might be safe to discontinue or reduce the intensity of anticoagulation for patients whose aPL tests become persistently negative months or years after their last thrombotic event. In evaluating such a patient, it is important to consider whether there were reversible non-aPL thrombosis risk factors, for example, an estrogen oral contraceptive, at the time of the thrombotic event.
There may be difficulties in monitoring warfarin therapy in patients with aPLs. Antiphospholipid antibodies may interfere with the prothrombin time assay, causing an unreliable INR. This occurs in 6.5% to 10% of patients with positive LA tests. Another, more general concern with using the INR to guide warfarin therapy is that not all vitamin K proteins affect the INR equally. The INR is affected by levels of factor II (prothrombin), factor VII, and factor X, with factor VII having the greatest impact. In contrast, the prothrombin level is thought to be the most important determinant of the therapeutic effect of warfarin. For these reasons, Kasthuri and Roubey have suggested the following approach. Once a patient with APS has been started on warfarin and the INR is in the 2.0 to 3.0 range, a factor II activity assay should be checked simultaneously with an INR. If the INR is in the target range and the factor II level is therapeutic (15%–25%), the patient is adequately anticoagulated and the INR is a reliable indicator. In contrast, if the INR is in range but the factor II level is greater than 30%, the patient is not adequately anticoagulated. For subsequent monitoring, an INR range corresponding to a therapeutic factor II level should be established, or the factor II level could be followed in lieu of the INR. A chromogenic factor X level can also be used in a similar fashion. It should be noted that this approach, although rational, has not been studied in clinical trials.
Corticosteroids and other immunosuppressive agents are not effective and not recommended for prevention of recurrent thrombosis in APS.
MANAGEMENT OF PREGNANCY MORBIDITIES
In general, pregnancy losses are classified into four main groups: preembryonic loss (conception through the 4th week of gestation); embryonic loss (5th through 9th weeks of gestation); fetal loss (10th week of gestation until delivery); and neonatal loss . Early pregnancy losses (less than 10 weeks) are common in the general population, and aPL testing should be interpreted cautiously in women with early losses. In the current classification criteria, embryonic deaths are considered as clinical evidence for definite APS only if there are three or more consecutive unexplained early losses.
A 27-year-old white woman with past medical history of single fetal loss (28 weeks’ gestation) 6 months prior (gravida: 1, para: 0) seeks advice regarding her future pregnancy options. She was asymptomatic during the pregnancy, and fetal death was detected on a routine sonogram. She is currently asymptomatic and denies any history of thrombosis. The workup within the last 6 months showed a positive LA (tested twice 3 months apart), negative aCL (IgG, IgM, and IgA), negative aβ 2 GPI (IgG and IgM), normal uterine, karyotypic, and hormonal assessments, and no genetic hypercoagulable conditions (see Table 11-3 ). Histologic evaluation of the placenta demonstrated ischemic-hypoxic changes, extensive maternal floor infarction due to uteroplacental/spiral artery thrombosis, and decidual vasculopathy ( Fig. 11-2B ).