Antiphospholipid Antibody Syndrome
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Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated thrombophilic disorder characterized by recurrent arterial or venous thrombosis and/or recurrent fetal loss in the presence of antiphospholipid antibodies (APAs). The APAs enhance clot formation by interacting with phospholipid-binding plasma proteins. The resulting APS can cause morbidity and mortality in both pregnant and nonpregnant individuals:
- Types of APS (based on clinical presentation)
- Primary: occurs without associated underlying disease
- Secondary: associated with autoimmune diseases (systemic lupus erythematosus [SLE] is most common); transient APAs linked to certain infections, drugs, and malignancies.
- Catastrophic APS (CAPS) a.k.a. Asherson syndrome (<1%)
- Most severe form of disease; characterized by thrombotic microangiopathy and associated with multiorgan failure
- High mortality if treatment is delayed
- Severe thrombocytopenia, hemolytic anemia, and DIC are additional features.
- Associated clinical manifestations: livedo reticularis, cardiac valvular disease, thrombocytopenia, nephropathy, hemolytic anemia, coronary artery disease, and cognitive impairment
- Complications include maternal thrombosis (stroke, venous thromboembolism [VTE]), fetal death, preeclampsia and placental insufficiency, fetal growth retardation, and preterm birth.
- Low-dose aspirin and low-molecular-weight heparin (LMWH) or unfractionated heparin are the drugs of choice in pregnancy.
- Prophylactic-dose heparin is recommended in the postpartum period (unless patient is on therapeutic anticoagulation) given high risk of thrombosis during this time. With adequate treatment, >70% of patients with APS deliver viable infants.
- The prevalence of APAs increases with age but is not necessarily associated with a higher risk of thrombosis.
- For APS, female > male
- In patients with positive APAs without prior risk of thrombosis, the annual incident risk of thrombosis is 0–3.8%. This risk is up to 5.3% in those with triple positivity (anticardiolipin antibodies, lupus anticoagulant [LAC], and anti–β2-glycoprotein-1 (GP1) antibodies positive).
- 10–15% of recurrent abortions are attributable to APS.
APAs are present in 1–5% of the general population and in ~40% of those with SLE. A higher prevalence is seen in those with VTE and stroke.
Etiology and Pathophysiology
- Anti–β2-GP1 antibodies play a central role in the pathogenesis of APS. The procoagulant effect is mediated by various possible mechanisms:
- Endothelial effects: inhibition of prostacyclin production and loss of annexin V cellular shield
- Platelet activation resulting in adhesion and aggregation
- Interference of innate anticoagulant pathways (such as inhibition of protein C)
- Complement activation
- Pregnancy-related complications are also a result of autoantibody-mediated effects:
- Interference with expression of trophoblastic adhesion molecules resulting in abnormal placentation and placental thrombosis
- Proposed mechanisms: excess production of natural antibodies, molecular mimicry due to infections, exposure of phospholipid antigens during platelet activation, cardiolipin peroxidation, and genetic predisposition
- A “second hit” by environmental factors may be required to produce thrombosis.
Most cases of APS are acquired. There are a few studies of familial occurrence of anticardiolipin antibodies and LAC. A valine 247/leucine polymorphism in β2-GP1 could be a genetic risk for the presence of anti–β2-GP1 antibodies and APS.
- Age >55 years in males, >65 years in females
- Cardiovascular risk factors (hypertension, diabetes, obesity, smoking, combined oral contraceptive use)
- Underlying autoimmune disease (SLE, rheumatoid arthritis, collagen vascular disease, Sjögren syndrome, idiopathic thrombocytopenic purpura, Behçet syndrome)
- Surgery, immobilization, pregnancy
Risk factor modification: Control HTN and diabetes; smoking cessation; avoidance of oral contraceptives in high-risk patients; start thromboprophylaxis in established cases.
Commonly Associated Conditions
- Autoimmune diseases: SLE (most common), scleroderma, Sjögren syndrome, dermatomyositis, and rheumatoid arthritis
- Infections: viral, bacterial, parasitic, and rickettsial
- Certain drugs associated with APA production without increased risk of thrombosis: phenothiazines, hydralazine, procainamide, and phenytoin
- Hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy (HELLP) syndrome
- Sneddon syndrome (APS variant syndrome with livedo reticularis, HTN, and stroke)