CLASSIFICATION CRITERIA

The initial classification criteria for APS (Sapporo, 1998) were revised in 2006. These include clinical (vascular thrombosis and pregnancy-related morbidity) and laboratory (presence and measurement of antibody titers of lupus anticoagulant [LAC], aPL, and β₂– glycoprotein I [β2GPI]) factors.

ETIOLOGY AND PATHOGENESIS

The etiology of primary APS is unknown. The pathogenesis likely involves a primary immunologic defect leading to autoantibody production and the occurrence of clinical manifestations triggered by secondary causes such as infection, malignancy, systemic inflammation, and medications. APS is mediated by multiple components such as endothelial cells, monocytes, platelets, and complement. Organ-specific aPL may not only effect thrombosis but interact directly with the tissue itself. The major targets of these autoantibodies are now believed to be phospholipid-binding plasma proteins such as β2GPI and prothrombin. The exact physiologic function of β2GPI is unknown, but its three-dimensional structure suggests that it is perfectly adapted to interact with negatively charged phospholipids. β2GPI can also bind to other proteins related to coagulation and endothelial cells. Thrombosis results from a complex interaction between aPL, β2GPI, activated endothelium, and activated platelets. APS is also an inflammatory procoagulant process, which includes abnormalities of proteins such as protein C and annexin V. The antibodies are constantly present in circulation, but thromboses are rare and occur only in specific vascular beds.

CLINICAL PRESENTATION

Clinical presentation ranges from asymptomatic with positive aPL serology to severe multiple-organ dysfunction and failure, with resultant mortality.

Thrombotic Events. Thrombosis (arterial and venous) can occur in any vascular location. The most common site of venous thrombosis is the lower extremities and that of arterial thrombosis is the CNS, manifesting as stroke or transient ischemic attacks. Thrombosis probably contributes to manifestations such as nephropathy and obstetric complications.

Pregnancy-Related Morbidity. The most common obstetric manifestation is recurrent miscarriage, defined as three or more consecutive miscarriages before the mid-second trimester (most losses occurring before 10th week of gestation) or one or more unexplained deaths of morphologically normal fetuses of 10 or more weeks’ gestation. Other pregnancy morbidity includes fetal growth impairment, oligohydramnios, preeclampsia and eclampsia, fetal distress, premature delivery, and postpartum maternal thrombotic events.

Cutaneous Manifestations. Livedo reticularis occurs in 16% to 25% of cases and appears as a lattice (“reticulate”) pattern of blue to red subcutaneous mottling. Livedo racemosa is a more open streaklike pattern. Histopathology of livedo reticularis does not show thrombosis. The strongest association of livedo reticularis in patients with SLE is with cerebrovascular ischemia (Sneddon syndrome), but it may be associated with ocular ischemia and seizures. Other cutaneous manifestations include ulcers, skin necrosis, superficial phlebitis, splinter hemorrhages, purpura, digital gangrene, anetoderma, and pseudovasculitis.

Thrombocytopenia. Thrombocytopenia (platelet count < 100,000/mm³) occurs in 16% to 44% of primary APS. aPL are also present in about one third of patients with chronic autoimmune thrombocytopenia. Thrombocytopenia in APS is usually moderate and not associated with hemorrhage.

Cardiac Manifestations. The cardiac valves may be thickened or show noninfective, verrucous vegetations, which may embolize, causing ischemic events. Arterial thrombotic events seem to have the highest prevalence in patients with APS and valvular heart disease. The Task Force on Catastrophic Antiphospholipid Syndrome (CAPS) and Non-criteria APS Manifestations (APS Task Force) recommends a transthoracic echocardiogram in patients with APS and previous arterial thrombosis.

APS Nephropathy. This manifests as new-onset hypertension, proteinuria, hematuria, and decreased renal function. The diagnosis can be made in the right clinical setting without a renal biopsy, but this may be necessary in other situations. The histopathology shows thrombotic microangiopathy (fibrin thrombi in glomeruli and/or arterioles), intimal hyperplasia, organizing thrombi, and fibrous arterial or arteriolar occlusion. The APS Task Force recommends that “in patients with APS nephropathy lesions and persistently positive aPL, the diagnosis of APS should be considered, provided other conditions resulting in similar renal biopsy lesions are excluded.”

Neurologic Manifestations. Stroke is the major neurologic manifestation of APS. Other manifestations include multiple-infarct dementia, TIAs, myelopathy, seizures, chorea, neuro-ophthalmologic syndromes, peripheral neuropathy (including Guillain-Barré–like syndrome), migraine-like headaches, and cognitive dysfunction. The neurologic manifestations are hypothesized to result from thromboses as well as direct interaction between aPL and neurons and glial cells.

Catastrophic Antiphospholipid Syndrome (CAPS). CAPS (Asherson syndrome), a life-threatening syndrome that occurs in 1% patients with APS and associated with high mortality (44%), is characterized by multiple thromboses occurring over a short period of time (days to weeks) involving small vessels in several major organs leading to severe organ dysfunction/failure. SLE is the most common systemic autoimmune condition reported in this complication. The CAPS registry reported this complication as the presenting manifestation in young individuals in 46% of cases and that it was precipitated by infection, surgery, neoplasia, obstetric complications, medications, trauma, SLE flare, and withdrawal of anticoagulant medication. The most common initial organ involvement during CAPS was pulmonary, neurologic, and renal. Large vessel arterial or venous thromboses are less common. Mortality results from thrombotic complications such as myocardial infarction, stroke, and pulmonary embolism.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis involves other causes of thrombophilia and other diagnoses depending on clinical presentation. Recurrent pregnancy loss should be evaluated by a high-risk obstetrician and fertility expert. Inherited thrombophilic disorders may also be associated with recurrent pregnancy loss. CAPS can be mimicked by several conditions, including infective endocarditis, thrombotic thrombocytopenic purpura, and primary medium-sized or small vessel systemic vasculitides.

DIAGNOSTIC APPROACH

APS is diagnosed by clinical and laboratory criteria. The criteria require persistently (12 weeks apart) positive tests for one or more aPL in a patient with a history of arterial or venous thrombosis or recurrent pregnancy loss. International consensus criteria (2006) for classification of definite APS are used for clinical trials but may have limitations regarding diagnosis of individual patients. Identifying the triggering event and a thorough workup for underlying associated systemic disease as well as possible mimics of APS cannot be overemphasized.

Anticardiolipin Antibodies (aCL). Standard solid phase aCL antibody testing by enzyme-linked immunosorbent assay (ELISA) remains the first-line test for APS. Persistently positive medium- or high-titer (>40 U phospholipid antibody titer) tests for IgG or IgM aCL are most likely to be associated with clinical manifestations. Transiently positive and low-titer antibodies have unclear significance. Although IgA aCL have been associated with thrombocytopenia and leg ulcers, and although they may have a role in IgG and IgM aCL-negative APS, testing for IgA aCL and threshold for interpretation are not defined.

Lupus Anticoagulant (LAC). LAC antibodies are detected based on their ability to delay clotting in phospholipid-dependent coagulation reactions. They are strongly associated with thrombotic events and fetal losses. LAC testing is prone to false-positive and false-negative results from variability in laboratory techniques. The key steps in LAC testing involve prolongation of clotting in a phospholipid-dependent assay, evidence of inhibition on mixing studies, demonstration of phospholipid dependence, and, finally, exclusion of coagulation factor–specific inhibitors. It is recommended that LAC should be screened for using at least two tests; the most commonly used are activated partial thromboplastin time (aPTT) optimized for the detection of LAC (lupus aPTT) and dilute Russell viper venom (dRVVT). The mixing study helps to exclude coagulation factor deficiency. Mixing patient plasma with normal plasma will correct factor deficiency but not inhibitors such as LAC. Correction with cardiolipin suggests the presence of a β2GPI-dependent LAC. Coagulation-based assays for LAC are influenced by anticoagulant therapy, and performing thrombin time or anti–factor Xa assays may be needed.

Protein-Based Immunoassays. Most aPL are directed against β2GPI and prothrombin and not against negatively charged phospholipids. In patients with APS, most aCL antibodies detected are specific for β2GPI. An IgG and/or IgM titer greater than the 99th percentile on two or more occasions at least 12 weeks apart is part of the APS classification criteria. The current consensus statement for diagnosis of APS does not recommend testing for other aPL. Further studies are warranted to establish the significance and test characteristics of anti-prothrombin and anti-annexin A5 antibodies.

High-Risk aPL Profile. The APS Clinical Research Task Force report (2011) concluded that (1) a positive LAC test is a better predictor of clinical events compared with other aPL tests, (2) higher titers of IgG aCL and anti-β2GPI have higher specificity for clinical events, (3) triple aPL positivity (LAC, aCL, anti-β2GPI) is more commonly associated with clinical events compared with double or single aPL positivity, (4) documentation of persistent (≥12 weeks apart) aPL is crucial for diagnostic purposes and to exclude other causes of transient aPL, and (5) thrombotic risk in aPL-positive patients rises with increasing risk factors.

MANAGEMENT AND THERAPY

The management of patients with APS can be thought of as primary prevention (before the clinical event) and secondary prevention (prevention of recurrent clinical events).

Primary Prevention—Asymptomatic aPL. This remains controversial, but risk stratification of patients based on their other risk factors and aPL profile may be useful. Unless contraindicated, low-dose aspirin is commonly recommended for asymptomatic individuals with aPL, including women with a history of obstetric APS who are not pregnant. Low-dose aspirin may lower the thrombotic risk, has a low incidence of adverse side effects, and is inexpensive. Hydroxychloroquine in patients with SLE has been associated with decreased thrombotic events but has not yet become the standard of care for primary prevention of thrombosis in SLE.

Secondary Prevention (for Recurrent Thrombosis). The risk of recurrence for patients with a thrombotic event ranges from 3% to 24%. Long-term anticoagulation is the mainstay of therapy. Warfarin is recommended (after bridging with heparin) and is effective in prevention of arterial and venous thromboses. High-intensity anticoagulation (goal INR 3.0 to 4.0) has not been found to be more effective than moderate intensity (goal INR 2.0 to 3.0) in the prevention of thrombosis. Unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) may also be used. In general, anticoagulation is indefinite. Because this is associated with significant bleeding risk, the decision to institute such therapy must be individualized based on the patient’s age, compliance, current medications, and comorbidities. The decision to discontinue anticoagulation, and if so, the timing for this, in patients with APS and previous clinical thrombotic events is controversial.

Prevention of Thromboses During Pregnancy. The American College of Chest Physicians (ACCP) guidelines for management of APS in pregnancy recommend antepartum prophylactic UFH or intermediate-dose UFH or prophylactic LMWH combined with aspirin for women with previous pregnancy-related complications, a positive aPL, and no history of venous or arterial thrombosis. Two other indications for aspirin throughout pregnancy are women considered at high risk for preeclampsia and women with prosthetic valves at high risk of thromboembolism. The safety of aspirin during the first trimester remains uncertain, and use should be individualized. The ACCP recommends that, during pregnancy, UFH or LMWH should replace vitamin K antagonists (grade 1A). LMWH is also recommended for prevention and treatment of venous thromboembolism (VTE) (grade 2C). For acute VTE during pregnancy, after using LMWH or UFH (grade 1B), the ACCP guidelines recommend anticoagulation for at least 6 weeks post partum (total minimum duration of therapy = 6 months). For pregnant women with prior VTE on long-term anticoagulation, the ACCP guidelines recommend LMWH or UFH throughout pregnancy followed by resumption of long-term anticoagulation post partum (grade 1C).

Other Therapeutic Approaches. In patients with SLE and aPL, hydroxychloroquine has been reported to lower thrombosis risk. The role of agents such as clopidogrel in APS is unknown. Rituximab may be effective in APS, especially in patients with refractory CAPS. Intravenous immunoglobulin has been used in CAPS in addition to anticoagulation and high-dose glucocorticoids. Statins may have a role, but this has not been formally tested in clinical trials. Cyclophosphamide and plasma exchange have also been used in patients with severe refractory CAPS in addition to anticoagulation and high-dose glucocorticoids, with limited success.

Avoiding Errors. Given the risks of long-term anticoagulation, it is important to determine which patients clearly have APS and require treatment. Ideally, the presence of aPL (LAC, medium- to high-titer aCL or anti-β2GPI antibodies) should be confirmed on two or more occasions at 12 or more weeks apart. A prolonged routine aPTT alone is not sufficient to establish the presence of LAC. Once treatment is initiated, close monitoring is warranted to mitigate toxicity.

In the future, standardized tests for antibodies to other phospholipid proteins may become available, facilitating early recognition and likely timely intervention. A better understanding of APS pathogenesis could grow our therapeutic armamentarium to include therapies targeted against the offending antibodies or downstream pathways such as intracellular protein kinases and complement.