Description

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) (1). The APAs enhance clot formation by interacting with phospholipid-binding plasma proteins. The resulting APS can cause significant morbidity and mortality in both pregnant and nonpregnant individuals:

• Types of APS (based on clinical presentation):
  • Primary: Occurs without an associated underlying disease
  • Secondary: Associated with autoimmune diseases (systemic lupus erythematosus [SLE] is most common). Transient APAs may be associated with certain infections, drugs, and malignancy.
  • Catastrophic APS (CAPS) a.k.a Asherson syndrome (<1%):
    • Most severe form of disease characterized by thrombotic microangiopathy. It is associated with multiorgan involvement and a high mortality rate if treatment is delayed.
    • Severe thrombocytopenia, hemolytic anemia, and DIC may be additional features.
  • Associated clinical features: Livedo reticularis, cardiac valve disease, thrombocytopenia, nephropathy
  • Of note, the 2006 updated criteria recommend that additional risk factors such as age, atherosclerosis, and inherited thrombophilia should be used to risk-stratify patients for APS.

• Complications include maternal thrombosis (stroke, VTE) fetal death, pre-eclampsia and placental insufficiency, fetal growth retardation and preterm birth.
• Low-dose aspirin and low-molecular-weight (LMWH) or unfractionated heparin are the drugs of choice in pregnancy. (See “Treatment” section below.)
• Prophylactic-dose heparin is recommended in the postpartum period (unless patient is on therapeutic anticoagulation) given high risk of thrombosis during this time.

Epidemiology

• 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, and anti-β2-glycoprotein I antibodies positive).
• 10–15% of recurrent abortions are attributable to APS.

Prevalence
APAs are present in 1–5% of the general population and in ~40% of those with SLE. A higher prevalence is also seen in those with venous thromboembolism and those with stroke.

Risk Factors

• Age >55 in males, >65 in females
• Cardiovascular risk factors (hypertension, diabetes, obesity; smoking, combined oral contraceptive use)
• Inherited thrombophilia
• Surgery, immobilization, pregnancy.

Genetics
Most cases of APS are acquired. There are a few studies of familial occurrence of anticardiolipin (aCL) antibodies and lupus anticoagulant (LAC). A valine 247/leucine polymorphism in β2-glycoprotein I could be a genetic risk for the presence of anti-β2GPI antibodies and APS.

General Prevention

Risk factor modification: Control HTN and diabetes; smoking cessation; avoidance of oral contraceptives. Thromboprophylaxis in established cases.

Pathophysiology

• It is now known that the anti-β2-glycoprotein-1 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 the annexin V cellular shield.
  • Platelet activation resulting in adhesion and aggregation
  • Interference of innate anticoagulant pathways, like 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
  • Placental thrombosis

Etiology

• Proposed mechanisms: Excess production of natural antibodies, molecular mimicry due to infections, exposure of phospholipid antigens during platelet activation, cardiolipin peroxidation, and genetic predisposition (2)
• A “second hit” by environmental factors may be required to produce thrombosis.

Commonly Associated Conditions

• Autoimmune diseases: SLE (most common), scleroderma, Sjögren syndrome, dermatomyositis, and rheumatoid arthritis
• Malignancy
• Various infections including viral, bacterial, parasitic, and rickettsial
• Certain drugs may be associated with APA production without increased risk of thrombosis; these include phenothiazines, hydralazine, procainamide, and phenytoin
• HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy)
• Sneddon syndrome (APS variant syndrome with livedo reticularis, HTN, and stroke)