• Arterial or venous thrombosis.
  
• Recurrent pregnancy losses.
  
• Autoantibodies to phospholipid or β2-glycoprotein I.
  
• Lupus anticoagulant activity.
  
• Can occur independently or in association with systemic lupus erythematosus (SLE).

Antiphospholipid antibody syndrome (APS) is an acquired disorder associated with circulating autoantibodies to anionic phospholipids (eg, cardiolipin) and their protein binding complexes. The primary clinical manifestations of APS are thromboses, which can affect both the arterial and venous circulations, and pregnancy loss. APS can occur independently, in which case it is called primary APS, or it can develop in the setting of another autoimmune disease, usually SLE, in which case it is called secondary APS. The diagnosis of APS relies on recognition of its clinical presentation and detection of antiphospholipid antibodies either by enzyme immunoassays or by the presence of an anticoagulant (a “lupus anticoagulant”) in a phospholipid-dependent coagulation test, such as the Russell viper venom time. Treatment usually involves anticoagulation, the level of which is still debated but depends on clinical context.

Symptoms and Signs

Deep venous thrombosis (DVT) is the most common clinical manifestation of the hypercoagulability associated with primary or secondary APS. DVTs can be single or multiple and affect either large or small veins. Most common are DVTs in the lower extremities; pulmonary embolism complicates up to one third of lower extremity DVTs associated with APS. Thromboses associated with APS can involve any component of the venous circulation; APS can cause renal vein thrombosis, retinal vein occlusion, Budd-Chiari syndrome, and adrenal hemorrhage secondary to thrombosis of the adrenal veins.

APS-associated arterial disease is common and can affect the peripheral vascular, cerebrovascular, and cardiovascular circulations. The clinical sequelae of APS- associated arterial disease depend on the size and distribution of vascular beds involved (Table 23–1).

Thromboses of medium-to-large peripheral arteries can lead to cutaneous ulceration and gangrene. Involvement of dermal capillaries can produce livedo reticularis (Plate 39), whose dusky, mottled appearance is due to a reactive hyperemia that occurs in normal skin adjacent to the regions of relative ischemia.

Cerebrovascular involvement can result in stroke, transient ischemic attack, dural sinus thrombosis, and an encephalopathy that can be difficult to distinguish from inflammatory or infectious cerebritis or cerebral vasculitis.

The cardiac manifestations of APS are protean. Thrombosis of epicardial vessels can cause myocardial infarction while subendothelial microangiopathy can lead to cardiomyopathy. APS is associated with Libman-Sacks endocarditis, which produces verrucose lesions of the endocardium and, more commonly, of the heart valves, especially the mitral valve. The histology of the valvular lesions reveals fibrin deposits accompanied by variable extents of inflammation. The severity of the valvular disease varies. Most common is thickening of the valve leaflets, which is detected by echocardiography but is not of hemodynamic significance. At the other end of the spectrum are large vegetations leading to clinically significant valvular dysfunction (regurgitation or stenosis). Embolization from Libman-Sacks vegetations is uncommon but can occur.

Renal injury in APS is most often due to thrombotic microangiopathy, an increasingly recognized complication whose histopathology is similar to that of malignant hypertension or thrombotic thrombocytopenic purpura. In cases of secondary APS associated with SLE, the distinction between lupus nephritis and thrombotic microangiopathy may require renal biopsy. Other mechanisms of kidney injury due to APS include arterial thrombi and emboli as well as renal vein thrombus. There also appears to be an association between APS and renal artery stenosis.

Acute pulmonary emboli complicating proximal DVT are the most common form of lung involvement, but APS also causes chronic pulmonary emboli as well as in situ microvascular thromboses that can progress to pulmonary capillary obliteration, pulmonary hypertension and, in rare instances, diffuse alveolar hemorrhage.

Well-recognized but nonspecific associated hematologic abnormalities include thrombocytopenia and hemolytic anemia. Thrombocytopenia associated with APS is generally mild to moderate, although patients with APS who have thrombocytopenia are reported to have a poorer prognosis when compared with patients who have APS but do not have thrombocytopenia. Hemolytic anemia can be either antibody-mediated or a consequence of microangiopathic destruction.

Pregnancy morbidity associated with APS can vary widely in its clinical presentation. Fetal demise can occur at all gestational time points, but spontaneous abortions that occur from the second trimester onward are more specific for APS than are those that occur during the first trimester. In addition to fetal loss, APS has been linked to preeclampsia, intrauterine growth retardation, and the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets).

Catastrophic antiphospholipid antibody syndrome (CAPS), which consists of an accelerated clinical course of thromboses and multiple organ failures (usually ≥3) occurring over days to weeks, develops in some patients with APS. In many instances the accelerated thrombosis occurs in the microvasculature. Specific triggers can be identified in the majority of CAPS cases, including antecedent infection, surgery, withdrawal of anticoagulation, pregnancy, and use of oral contraception; up to one third of cases, however, have no identifiable cause. CAPS can mimic other forms of systemic illness, including the systemic inflammatory response syndrome, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and HELLP. Prompt recognition of CAPS requires a high index of suspicion, and the diagnosis can be difficult to establish without adequate histopathology.

Laboratory Findings