ANTIPHOSPHOLIPID SYNDROME (APS)
This is a disorder that is characterized by a propensity toward thrombus formation. Females afflicted with this disorder display an additional tendency toward spontaneous abortions. The diagnosis is established by demonstrating the presence of autoantibodies that bind phospholipid-protein complexes. There are two types of antiphospholipid antibodies, the lupus anticoagulant and anticardiolipin antibody. The precise mechanism by which these autoantibodies initiate thrombosis is unknown. Not all patients with these autoantibodies manifest an obvious thrombotic tendency, and elderly patients are more likely than younger persons to have antiphospholipid antibodies present without clinical disease. When this disorder occurs as a result of another underlying disease process, it is termed secondary antiphospholipid antibody syndrome. Primary disease occurs in the absence of any other disease known to be associated with the APS. Another distinction between primary and secondary disease is that usually patients with primary disease test positive for only one type of APS antibody whereas patients with secondary disease often test positive for both the lupus anticoagulant and anticardiolipin antibody.
Symptoms include the aforementioned thrombotic tendency, either arterial or venous (lupus anticoagulant is associated with venous thrombosis whereas anticardiolipin antibody is associated with both arterial and venous disease), cardiac emboli, verrucous endocarditis (particularly of the mitral valve), intracardiac thrombi, diffuse cardiomyopathy, livedo reticularis, cutaneous ulcerations, fetal loss (first- trimester spontaneous abortions or second-trimester fetal death), pre-eclampsia, premature delivery, and intrauterine growth retardation. Routine screening of all pregnant women is not necessary. Unless there is a high index of suspicion, screening for APS should be performed only after a female patient has suffered two consecutive spontaneous abortions.
APS should be suspected in any patient with a recurrent thrombotic tendency. The differential diagnosis in these patients should include APS, accelerated atherosclerosis, vasculitis, nephrotic syndrome, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, prothrombin G20210A, Burgers disease, polycythemia vera, occult malignancies, homocysteinemia, and hyperviscosity syndromes. When patients are receiving heparin and develop thrombocytopenia, heparin-induced thrombocytopenia is another potential etiology.
Associated lab abnormalities include transient, asymptomatic thrombocytopenia, a Coombs positive hemolytic anemia, a prolonged aPTT with a normal PT, and false-positive results on VDRL testing. The prolonged aPTT in the face of a normal PT is a good screening test although APS may exist with a normal aPTT. Not all persons with abnormal screening tests require further testing as APS may occur transiently in otherwise healthy persons; however, which patients warrant extensive diagnostic workups is controversial. The diagnosis is established by testing for lupus anticoagulant and assaying for anticardiolipin antibodies. Anticardiolipin antibodies are detected by ELISA. Tests for lupus anticoagulant include aPTT, kaolin clotting time and dilute Russells viper venom time. When using the aPTT method one must be certain that the patient has not recently received heparin. If the above screening tests for lupus anticoagulant are abnormal, the patients serum is then subjected to mixing studies (patients serum is mixed with normal serum). If the patients serum does not normalize upon mixing, an inhibitor is present and additional studies are needed. At this point it is necessary to demonstrate that the inhibitor is phospholipid dependent and can be neutralized in the presence of excess phosphate. The platelet-neutralization procedure is currently the best method available.
The best method of treatment for APS remains controversial. Asymptomatic patients do not need treatment, but all patients should be counseled to abstain from tobacco abuse and to control hypertension. Female patients should be warned not to use oral contraceptives containing estrogen. Patients who display a thrombotic tendency should be managed with intermediate to high intensity warfarin therapy (INR between 3 to 3.5). Therapy should be continued as long as patients test positive for lupus anticoagulant or anticardiolipin antibodies. Repeat testing may be done at 6-month intervals.
Female patients should be counseled regarding birth control and instructed not to get pregnant while on warfarin therapy as this medication is teratogenic. Pregnant women with this disorder who have had two previous pregnancies end in spontaneous abortion should be referred to a specialist for high-risk pregnancies. Pregnant women who cannot carry to term without treatment may be managed with combined aspirin and heparin therapy.