Antiphospholipid Syndrome

The clinical features of primary antiphospholipid syndrome (APS) are venous or arterial occlusions or certain pregnancy complications.

Laboratory criteria include the identification of at least one of the following three antiphospholipid antibodies: IgG or IgM anti-cardiolipin, IgG or IgM antibodies to beta-2-glycoprotein 1, and lupus anticoagulant.

In less than 1% of patients with antiphospholipid antibodies, a potentially devastating syndrome known as the “catastrophic antiphospholipid syndrome” occurs, leading to diffuse thromboses, thrombotic microangiopathy, and multiorgan system failure. Catastrophic APS has a mortality rate approaching 50%.

Diagnostic Essentials

• Hypercoagulability; recurrent arterial or venous thromboses.
• Thrombocytopenia is common.
• Recurrent fetal loss.
• Recurrent events are frequent; lifetime anticoagulation with warfarin is recommended.

Clinical Findings

Symptoms and Signs

Patients are often asymptomatic until suffering a thrombotic complication of this syndrome or a pregnancy loss.

Thrombotic events may occur in either the arterial or venous circulations. Thus, deep venous thromboses, pulmonary emboli, and cerebrovascular accidents are typical clinical events.

Budd-Chiari syndrome, cerebral sinus vein thrombosis, myocardial or digital infarctions, hemorrhagic infarction of the adrenal glands (due to adrenal vein thrombosis), and other thrombotic events also occur.

Other symptoms and signs of APS include thrombocytopenia, mental status changes, livedo reticularis, skin ulcers, microangiopathic nephropathy, and cardiac valvular thickening or vegetations.

Pregnancy losses include unexplained fetal death after 10 weeks’ gestation; one or more premature births before 34 weeks because of eclampsia, preeclampsia, or placental insufficiency; or three or more unexplained miscarriages before 10 weeks’ gestation.

Laboratory Findings

Thrombocytopenia occurs in 22–42% of patients and is usually moderate (platelet counts above 50,000/mcL [50 × 10⁹/L]). The presence of thrombocytopenia does not reduce the risk of thrombosis.

Three types of antiphospholipid antibodies are associated with this syndrome: (1) anti-cardiolipin antibodies, (2) antibodies to beta-2-glycoprotein, and (3) a “lupus anticoagulant” that prolongs certain phospholipid-dependent coagulation tests (see below).

Anti-cardiolipin antibodies can produce a biologic false-positive test for syphilis (ie, a positive rapid plasma reagin but negative specific anti-treponemal assay). In general, IgG anti-cardiolipin antibodies are believed to be more pathologic than IgM.

In case-control studies, 3.1% of patients in the general population who experienced a venous thrombotic event (in the absence of cancer) tested positive for the lupus anticoagulant (versus 0.9% of controls, yielding an odds ratio of 3.6). For women < 50 years in whom a thrombotic stroke developed, the odds ratio for having the lupus anticoagulant is 43.1. Presence of the lupus anticoagulant is a stronger risk factor for thrombosis or pregnancy loss than is the presence of antibodies to either beta-2-glycoprotein 1 or anti-cardiolipin. A clue to the presence of a lupus anticoagulant, which may occur in individuals who do not have SLE, may be detected by a prolongation of the partial thromboplastin time (which, paradoxically, is associated with a thrombotic tendency rather than a bleeding risk). Testing for the lupus anticoagulant involves phospholipid-dependent functional assays of coagulation, such as the Russell viper venom time (RVVT).

Differential Diagnosis

The exclusion of other autoimmune disorders, particularly those in the SLE spectrum, is essential because such disorders may be associated with manifestations requiring alternative treatments. Other genetic or acquired conditions associated with hypercoagulability such as protein C, protein S, or antithrombin deficiency and factor V Leiden should be excluded.

Catastrophic APS has a broad differential, including sepsis, pulmonary-renal syndromes, systemic vasculitis, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.

Treatment

Patients should be given warfarin to maintain an INR of 2.0–3.0; DOACs are less effective than warfarin. Patients who have recurrent thrombotic events while taking warfarin may require higher INRs (> 3.0), but the bleeding risk increases substantially with this degree of anticoagulation.

For pregnancy-associated APS, the combination of prophylactic doses of low-molecular-weight heparin (Table 14–14) and low-dose aspirin (81 mg) is the usual approach to prevent pregnancy complications.

In pregnant women with a history of thrombotic events outside of pregnancy, full-dose low-molecular-weight heparin is administered (Table 14–16). Anticoagulation is typically continued through pregnancy and the early postpartum period for thromboprophylaxis. The benefit of using corticosteroids and intravenous immunoglobulin in these patients is unclear; neither treatment is recommended.

However, in patients with catastrophic APS, either intravenous immunoglobulin or plasmapheresis plus intravenous heparin and high doses of corticosteroids are administered. Resistant disease may require biologic therapy with monoclonal antibodies against CD20 on B cells (rituximab) or against complement component C5 (eculizimab), although data to support these therapies are limited to case series.