Antiphospholipid antibody syndrome
The antiphospholipid antibody syndrome (APS) is characterized by antibodies directed against either phospholipids or proteins bound to anionic phospholipids. The syndrome is referred to as primary APS when it occurs alone and as secondary APS when in association with SLE and other rheumatic disorders. APS can affect all organ systems and includes venous and arterial thrombosis, recurrent fetal losses, and thrombocytopenia. Four types of antiphospholipid antibodies have been characterized:
• False-positive serologic tests for syphilis
• Lupus anticoagulants
• Anticardiolipin antibodies
• Anti-b2 glycoprotein-1 antibodies
A persistently positive test (i.e. positive on at least two occasions, 6 weeks or more apart) in one or more of these assays is needed to diagnose APS. However, some people who test positive for aPL will never get APS, i.e. not all aPLs are harmful. APS can present in patients who already have another ARD, especially SLE. APS can also occur on its own (primary APS).
EPIDEMIOLOGY & DEMOGRAPHICS
• 1%-5% of healthy subjects have anticardiolipin and lupus anticoagulant antibodies.
• 12%-30% of patients with systemic lupus erythematosus have anticardiolipin antibodies and 15%-34% have lupus anticoagulant antibodies.
• Some APS-positive families exist, and HLA studies have suggested associations with HLA DR7, DR4, and Dqw7 plus Drw53.
• Other risk factors: underlying SLE and collagen-vascular diseases; other autoimmune disorders including rheumatoid arthritis, Sjogren’s syndrome, Behcet’s syndrome, and ITP; drug-induced; and AIDS.
• Most individuals are otherwise healthy and have no underlying medical condition.
• Several studies assessing presence of aPL in patients with cardiovascular and cerebrovascular disease have found a higher than expected prevalence of antibody.
PHYSICAL FINDINGS & CLINICAL PRESENTATION (BOX 1-6)
Associated conditions and effects on various systems of APS include:
• Neurology: stroke, TIA, migraine, multiinfarct dementia, epilepsy, chorea, movement disorders, transverse myelopathy, dysarthria.
• Rheumatology: SLE, DLE, sub-acute cutaneous (Ro-positive) LE, Sjogren’s syndrome; rare in RA and inflammatory vasculitides
• Cardiology: pulmonary hypertension, valvular disease (especially mitral valve involvement), intracardiac thrombosis (can mimic culture negative bacterial endocarditis), CAD, MI
• Nephrology: renal vein thrombosis, glomerulosclerosis secondary to glomerular thrombosis, ARF, hypertension (malignant and nonmalignant), intrarenal vascular lesions, thrombotic microangiopathy
• Endocrinology: Addison’s disease secondary to adrenal thrombosis, “autoimmune Addison’s” may be secondary to thrombosis
• Gastroenterology: gut ischemia, hepatic vein thrombosis, Budd-Chiari syndrome (second most common cause of BCS)
• Dermatology: livedo reticularis, recurrent skin ulcers, skin nodules
• Hematology: thrombocytopenia, autoimmune hemolytic anemia
• Obstetrics: recurrent spontaneous abortion (secondary to placental vessel thrombosis and ischemia)
• Critical care: acute multisystem organ failure: thrombocytopenia, ARDS, jaundice, death; “catastrophic antiphospholipid syndrome” with widespread multiorgan thrombosis
• Surgical: no large studies on risk of postoperative thrombosis in aPL-positive individuals; some evidence that orthopedic patients may have increased risk of avascular necrosis of femoral head
• Antibodies to phospholipids reacting with negatively charged phospholipids
• Range of possible mechanisms of thrombosis includes: effects of aPL on platelet membranes, endothelial cells, and clotting components such as prothrombin, protein C or S
• Recently shown that prephospholipids are not immunogenic and that a binding protein (b2 -glycoprotein I) may be the key immunogen in the APS
• Other hypercoagulable states (inherited or acquired)
• Inherited: ATIII/protein C, S deficiencies
• Acquired: heparin-induced thrombopathy, myeloproliferative syndromes, cancer, hyperviscosity
History: hypercoagulability patient and family
• Criteria from an international consensus conference are at least one of the following clinical criteria and at least one of the following laboratory criteria:
Clinical: Either one or more episodes of venous, arterial, or small vessel thrombosis, and/or morbidity with pregnancy.
Laboratory: The presence of IgG and/or IgM anticardiolipin antibody and/or lupus anticoagulant activity (no standardized assay; must use Russell viper venom test), found on two or more occasions, at least 6 wk apart.
Laboratory testing indicated in:
• Patient with underlying SLE or collagen-vascular disease with thrombosis
• Patient with recurrent, familial, or juvenile DVT or thrombosis in an unusual location (mesenteric or cerebral)
• Possibly in patients with lupus or lupuslike disorders in high-risk situations (e.g., surgery, prolonged immobilization, pregnancy)
Abnormal tests include:
• Positive test for syphilis (RPR/VDRL), “false-positive”
• Positive lupus anticoagulant will cause prolongation of apTT and Russell viper venom time
• IgG anticardiolipin (ELISA for anticardiolipin is most sensitive and specific test [>80%])
• Presence of anti b2 -glycoprotein I antibody
Limited data on natural history in untreated patients.
In patients with APS who have had one or more thrombosis, the recommended treatment to prevent further thrombosis is long-term anticoagulation with warfarin. Although it was previously thought that high-intensity anticoagulation (INR > 3) was essential, this is now disputed and many patients are managed with lower target INR. Pregnant patients with APS are given oral aspirin and subcutaneous heparin from early in gestation. This reduces the chance of a miscarriage but pre eclampsia and poor fetal growth remain common. There are no definite guidelines for managing patients with aPL who have never had thrombosis. Aspirin or clopidogrel are sometimes given prophylactically especially in those with high IgG aPL. Warfarin is given much more rarely in these circumstances.
ACUTE GENERAL Rx
• Anticoagulant agents: heparin, warfarin
• Positive aPL and major thrombotic events or recurrent thrombotic events: lifelong warfarin treatment, INR 3-4: Aspirin alone appears to be of no benefit for the thrombotic manifestations of APS. The addition of aspirin or dipyridamole to warfarin may help prevent recurrent arterial thrombosis.
Asymptomatic with abnormal laboratory results, no previous thrombosis:
• Questionable whether ASA (81 mg) is effective
• No routine prophylaxis
• Antithrombotic prophylaxis for major surgery, prolonged immobilization, and pregnancy
• Positive aPL antibodies, no history of nonplacental thrombotic event (e.g., DVT) or positive aPL antibodies and history of 2 spontaneous abortions: ASA, 81 mg at conception and SQ heparin, 10,000 IU q12h to mid-interval PTT.
• Positive aPLantibodies, diagnosis of APS and history of nonplacental thrombotic event (e.g., DVT): ASA, 81 mg and heparin to PTT of 1.5 to 2 x control value
• In pregnancy warfarin should not be used; low-dose subcutaneous heparin and aspirin are effective and safe; IVIG and prednisone have also been used with success if aspirin and heparin fail.
Cerebral features of lupus may be more related to thrombosis than inflammation, may respond better to anticoagulants than immunosuppression.