Antiphospholipid syndrome (APS)
Antiphospholipid syndrome (APS), sometimes known as Hughes syndrome, is a disorder of the immune system that causes an increased risk of blood clots. Primary antiphospholipid syndrome (APS) is diagnosed in patients who have venous or arterial occlusions or pregnancy complications (ie, three or more first-trimester miscarriages, unexplained fetal death and premature birth before 34 weeks of gestation attributable to severe preeclampsia, eclampsia or placental insufficiency) in the presence of persistent (12 weeks or longer), high-titer, diagnostic antiphospholipid antibodies but no other features of SLE.
Diagnostic antiphospholipid antibodies are IgG or IgM anticardiolipin, or 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.
Signs and symptoms
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 among patients with the APS.
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 younger than 50 years in whom stroke developed, the odds ratio for having the lupus anticoagulant is 43.1.
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.
A variety of other symptoms and signs are often attributed to the APS, including thrombocytopenia, mental status changes, livedo reticularis, skin ulcers, microangiopathic nephropathy, and cardiac valvular dysfunction—typically mitral regurgitation due to Libman-Sacks endocarditis.
Livedo reticularis is strongly associated with the subset of patients with APS in whom arterial ischemic events develop.
Pregnancy losses that are associated with APS include unexplained fetal death after the first trimester, one or more premature births before 34 weeks because of eclampsia or preeclampsia, or three or more unexplained miscarriages during the first trimester.
As noted in the discussion of SLE, three types of antiphospholipid antibody 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). Antibodies to cardiolipin and to beta-2 glycoprotein are typically measured with enzyme immunoassays.
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. 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 I or anticardiolipin.
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). In the presence of a lupus anticoagulant, the RVVT is prolonged and does not correct with mixing studies but does with the addition of excess phospholipid.
The exclusion of other autoimmune disorders, particularly those in the SLE spectrum, is essential because such disorders may be associated with additional complications 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.
Patients should be given warfarin to maintain an INR of 2.0–3.0. The efficacy and safety of direct-acting oral anticoagulants for the antiphospholipid syndrome have not been established. Patients who have recurrent thrombotic events on this level of anticoagulation may require higher INRs (greater than 3.0), but the bleeding risk increases substantially with this degree of anticoagulation.
Guidelines indicate that patients with APS should be treated with anticoagulation for life. Because of the teratogenic effects of warfarin, subcutaneous heparin and low-dose aspirin (81 mg) is the usual approach to prevent pregnancy complications in women with APS. In patients with catastrophic APS, a three-pronged approach is taken in the acute setting: intravenous heparin, high doses of corticosteroids, and either intravenous immune globulin or plasmapheresis.