Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease associated with increased risk of thrombosis due to the presence of procoagulatory antibodies. APS can manifest in isolation or alongside other autoimmune diseases such as systemic lupus erythematosus (SLE). Typical clinical manifestations include recurring venous, arterial, and/or microcirculation thrombotic events (e.g., DVTs, stroke, TIAs) and obstetrical complications (e.g., recurrent miscarriages, premature births). APS should be suspected in patients with a history of thrombosis or miscarriage; diagnosis is confirmed by the detection of serum antiphospholipid antibodies (e.g., lupus anticoagulant, anticardiolipin antibodies). Management of acute thrombotic events varies widely depending on the clinical manifestation (e.g., stroke, DVT). Long-term management of APS (e.g., systemic anticoagulation with warfarin or heparin) is determined by the patient's risk of future thrombotic complications. Additional pharmacotherapy may be indicated for certain manifestations. Catastrophic antiphospholipid syndrome (CAPS) is a rare but severe form of APS that requires immediate treatment.

• Primary
  • Idiopathic
  • Associated with genetic marker HLA-DR7
• Secondary ^[1][2]
  • Systemic lupus erythematosus (most common cause of secondary APS)
  • Rheumatoid arthritis
  • Neoplasms
  • HIV, hepatitis A, hepatitis B, hepatitis C
  • Bacterial infections (e.g., syphilis, Lyme disease, tuberculosis)

• Formation of procoagulatory antiphospholipid antibodies
  • Antibodies form complexes with anticoagulant proteins, thereby inactivating them (e.g., protein C, protein S, antithrombin III).
  • Antibodies activate platelets and vascular endothelium.
• Induction of a hypercoagulable state → ↑ risk of thrombosis and embolism ^[3]

APS usually manifests with recurring thrombotic events that may affect any organ. See also “Clinical features suggestive of underlying thrombophilia”.

• Venous
  • Deep vein thrombosis
  • Pulmonary embolism
  • Livedo reticularis
  • Ulceration (see “Chronic venous insufficiency”)
• Arterial
  • Stroke, transient ischemic attacks
  • Occlusion of organ arteries (e.g., myocardial infarction)
  • Occlusion of distal extremity arteries (ischemia and gangrene)
• Capillaries: splinter hemorrhages
• Pregnancy-related: : recurrent miscarriages and premature births
• Nonthrombotic manifestations: may include valvular heart disease, neurocognitive disorders

Approach ^[2][4]

• Consider diagnostic testing based on the presence of typical symptoms, e.g.:
  • Thrombotic complications
  • Recurrent miscarriages
• Obtain antiphospholipid antibody testing to confirm diagnosis.
• Consider testing for associated autoimmune diseases (e.g., SLE), neoplasms, and infectious diseases.
• Involve rheumatology early.

Thrombosis in APS is typically unprovoked (e.g., unprovoked DVT), recurrent, and/or manifests in unusual sites (e.g., kidneys, liver, retina). It is most commonly seen in younger individuals (< 50 years of age) and in individuals with comorbid autoimmune diseases (e.g., SLE).

Routine laboratory studies ^[2][4]

Obtain for all patients; results are nonspecific but may support the diagnosis.

• CBC
  • Thrombocytopenia
  • Leukocytopenia
  • Hemolytic anemia (may be AIHA or MAHA)
• CMP: may reveal laboratory evidence of hemolysis and/or nephropathy
• Coagulation panel: prolonged aPTT (caused by lupus anticoagulant)
• Urinalysis: may show proteinuria, e.g., in patients with thrombotic microangiopathy

Antiphospholipid antibodies (aPL antibodies) ^[1][4]

Reserve testing for patients with characteristic clinical features to avoid false positives.

• Lupus anticoagulant (LA): antibodies against certain phospholipids in cellular membranes; detection involves a three-step procedure
  1. Screening for phospholipid-dependent coagulation with either:
     • Prolonged aPTT
     • Prolonged dilute Russell viper venom time (dRVVT)
  2. Mixing study: The patient's plasma is mixed with normal plasma (which contains clotting factors).
     • aPTT or dRVVT normalize: Presence of lupus anticoagulant ruled out; prolonged aPTT may be due to a lack of clotting factors.
     • aPTT or dRVVT remain prolonged: Lupus anticoagulant may be present.
  3. Confirmation of phospholipid dependence: Phospholipid is added.
     • aPTT or dRVVT normalize: Presence of lupus anticoagulants is confirmed.
     • aPTT or dRVVT remain prolonged: Consider a factor deficiency.
• Anticardiolipin antibodies (IgG and IgM): antibodies against cardiolipin, a phospholipid in cellular membranes
• Anti-β2-glycoprotein antibodies (IgG and IgM): antibodies directed against the cardiolipin ­binding factor β2­ glycoprotein I that have prothrombotic effects ^[2]

Patients with APS can test false positive for syphilis (positive VDRL or RPR) because the antigen used in syphilis tests is cardiolipin.

Interpretation ^[2][4][5]

• Symptomatic patients: The presence of ≥ 1 type of aPL antibody supports the diagnosis.
• Asymptomatic patients
  • The presence of associated antibodies is not sufficient to establish a diagnosis.
  • Persistent positivity is associated with a higher risk of thrombotic and obstetric complications.

Positive lupus anticoagulant is associated with the highest risk of thrombosis.

A finding of positive aPL antibodies without clinical features is not sufficient to confirm a diagnosis of APS.

Additional studies ^[4]

• Nonclassic aPL antibodies: may further support the diagnosis
  • Positive antibodies against annexin, protein C, and/or protein S
  • Positive ANAs and/or anti-Ds-DNA antibodies
• Imaging studies
  • May be indicated to evaluate for associated conditions and thrombotic events
  • Examples:
    • Stroke imaging
    • Lower extremity venous ultrasound for DVT
    • TTE to evaluate for valvular heart disease
• Histopathology: may be needed to confirm thrombosis ^[1]

Management should be specialist-guided.

Approach ^[4][5]

• Treat acute thrombotic events (e.g., DVT, MI). ^[5]
• Provide urgent management for CAPS in acutely ill patients with multiorgan failure due to thrombosis.
• Initiate long-term thromboprophylaxis.
  • Primary thromboprophylaxis: low-dose aspirin therapy
  • Secondary thromboprophylaxis
    • First-line: warfarin
    • Second-line: LMWH or UFH
  • Thromboprophylaxis in pregnant individuals: low-dose aspirin therapy PLUS heparin (LMWH or UFH)
• Provide supportive care.

Systemic anticoagulation is the cornerstone of treatment for thrombotic APS.

Thromboprophylaxis ^[4][5]

Primary thromboprophylaxis

• Consider for patients with no history of thrombosis who have:
  • A history of obstetric APS
  • Positive aPL antibodies without an APS diagnosis, especially those with:
    • High-risk aPL antibody profile
    • ASCVD risk factors
    • Comorbid autoimmune diseases (e.g., SLE)
• Recommended regimen: low-dose aspirin therapy

Decisions on primary thromboprophylaxis should be made by a specialist based on individual thrombosis risk and bleeding risk.

Secondary thromboprophylaxis

• Indication: APS with a history of thrombosis
• Recommended regimens
  • First-line: warfarin
    • Target INR: usually 2–3
    • Provide bridging anticoagulation (e.g., enoxaparin ) until target INR is reached.
    • For patients with recurrent thrombosis despite target INR: Adjust therapy under specialist guidance.
  • Second-line
    • Heparins: including LMWH (e.g., enoxaparin ) and UFH ^[4]
    • DOACs (not recommended for arterial thrombosis): e.g., dabigatran ^[5]
• Treatment duration
  • Unprovoked thrombosis: Continue long-term.
  • Provoked thrombosis (e.g., after surgery):
    • Stop according to general population guidelines.
    • See also “Anticoagulation for PE” and “Therapeutic approach to DVT.”

Antiphospholipid antibodies can prolong the aPTT and consequently provide falsely elevated INR results, which may lead to inadequate anticoagulation. Consider measurement of factor X activity to confirm adequate anticoagulation. ^[4]

Thromboprophylaxis for APS during pregnancy ^[2][5]

• Patients without an APS diagnosis with positive aPL antibodies (with or without SLE): Consider low-dose aspirin therapy.
• Patients with an APS diagnosis
  • Low-dose aspirin therapy PLUS heparin (LMWH or UFH)
    • History of thrombotic APS: Use therapeutic heparin dosages.
    • History of obstetric APS (without thrombosis): Use prophylactic heparin dosages.
  • Patients require close monitoring and management by a team of specialists to reduce the risk of miscarriage and thrombosis.

Warfarin is teratogenic and therefore contraindicated during pregnancy.

Supportive care ^[5]

• Management of additional risk factors for thrombosis
  • Atherosclerotic risk factors: ASCVD risk assessment and management
  • Risk factors for VTE
    • Avoidance of medications that contain estrogen
    • Pharmacological thromboprophylaxis during the perioperative period
• Patient counseling (e.g., about VKA treatment, contraceptives, hormone therapy)
• Counseling on lifestyle modifications (e.g., healthy diet, physical activity)
• Management of complications (e.g., thrombocytopenia, nephropathy)

Management of catastrophic antiphospholipid syndrome ^[6][7]

CAPS is a rare but severe form of APS caused by acute and systemic small vessel thrombosis.

• Suspect in acutely ill patients with multiorgan failure due to thrombosis.
• Consider other differential diagnoses of platelet disorders.
• Diagnosis of CAPS is based on:
  • Simultaneous involvement of ≥ 3 organs, systems, or tissues
  • Confirmation of positive aPL antibodies
• Start treatment as soon as CAPS is suspected; do not wait for laboratory confirmation.
• Treatment is not standardized but may include the following: ^[4][5]
  • Combination of high-dose glucocorticoids, heparin, plasma exchange, and IV immunoglobulin
  • Management of triggers: e.g., infections (most common), surgical interventions, neoplasms

Diagnosis of CAPS is difficult because clinical presentation varies widely and approximately 50% of affected individuals have no history of aPL antibody positivity. ^[6]

The mortality rate of CAPS is approximately 50%, even with treatment. ^[6]