Description

Antiphospholipid antibody syndrome (APS) is a systemic autoantibody-mediated thrombophilic disorder characterized by recurrent arterial or venous thrombosis and/or recurrent fetal loss in the presence of persistent antiphospholipid antibodies (APAs) as evidenced by lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and/or anti–β₂ glycoprotein-I (GPI) antibody. 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: no underlying condition evident
  • Secondary: most commonly associated with autoimmune diseases like systemic lupus erythematosus (SLE); transient APAs have been 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 that develops at the same time
    • High mortality if treatment is delayed

Pregnancy Considerations

• Complications include maternal venous thromboembolism, stroke, fetal demise, preeclampsia and placental insufficiency, fetal growth retardation, miscarriage, 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. With adequate treatment, >70% of patients with APS deliver viable infants.

Epidemiology

• The prevalence of APAs increases with age but is not necessarily associated with a higher risk of thrombosis.
• For APS, female > male

Incidence

• Incidence of APS is around 5 new cases per 100,000 persons per year.
• In patients with positive APAs without prior risk of thrombosis, the annual incident risk of thrombosis is 0–3.8%. This risk is increased to 5.3% in those with triple positivity. 10–15% of recurrent abortions are attributable to APS.

Prevalence
Prevalence around 40 to 50 cases per 100,000 persons per year; APAs are present in 1–5% of the general population and in ~40% of those with SLE. A higher prevalence of 10–15% is seen in those with venous thromboembolism, fetal loss, 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 is often required to manifest APS.

Genetics
Most cases of APS are acquired.

Risk Factors

• Age >55 years in males, >65 years in females
• Cardiovascular risk factors (hypertension [HTN], hyperlipidemia, diabetes, obesity, smoking, combined oral contraceptive use)
• Underlying autoimmune disease (SLE, rheumatoid arthritis, collagen vascular disease, Sjögren syndrome, idiopathic thrombocytopenic purpura, Behçet syndrome)
• Positive APAs
• Surgery, immobilization, pregnancy

General Prevention

Risk factor modification: control HTN and diabetes; smoking cessation; avoidance of oral estrogen contraceptives in high-risk patients; start thromboprophylaxis in established cases; preconception assessment

Commonly Associated Conditions

• Autoimmune diseases: SLE (most common), scleroderma, Sjögren syndrome, dermatomyositis, and rheumatoid arthritis
• SLE is the most common autoimmune disease associated with APS.
• Malignancy
• 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)