What is the role of Protein C (Protein C) in the management of antiphospholipid syndrome (APS)?

Role of Protein C in Antiphospholipid Syndrome

Direct Answer

Protein C plays a critical pathophysiological role in APS as a target of antiphospholipid antibodies, but it has no direct therapeutic role in management—warfarin remains the cornerstone of treatment regardless of protein C levels. 1, 2, 3

Pathophysiological Mechanism

Antiphospholipid antibodies interfere with the protein C anticoagulant pathway, creating a prothrombotic state through multiple mechanisms:

• Antiphospholipid antibodies directly inhibit activated protein C (APC) activity, leading to acquired APC resistance that contributes to thrombosis risk 4, 5
• High-avidity anti-protein C antibodies are present in 60% of APS patients and correlate with greater APC resistance and more severe thrombotic phenotypes 5
• Patients with high-avidity anti-protein C antibodies have an 80% rate of category I APS (the highest risk classification with arterial thrombosis, recurrent venous thrombosis, or small vessel thrombosis) 5
• Decreased protein C activity occurs in 31.6% of APS patients compared to 8.3% of controls, with the strongest association in patients with high-titer anticardiolipin and anti-β2-glycoprotein I antibodies 4
• Neutrophil extracellular traps (NETs) further amplify APC resistance in APS patients, particularly in triple-positive and lupus anticoagulant-positive patients, creating an additional prothrombotic mechanism 6

Clinical Implications for Risk Stratification

While protein C abnormalities help explain APS pathophysiology, they do not change management:

• Testing for protein C deficiency should be deferred or repeated at least 4-6 weeks after acute thrombosis as protein levels may be altered during the acute phase 2
• The presence of anti-protein C antibodies may serve as a marker for severe thrombotic phenotype, defined as recurrent VTE on therapeutic anticoagulation or both venous and arterial thrombosis 5
• Patients with inherited protein C deficiency who develop thrombosis require the same anticoagulation approach as other thrombophilic conditions—warfarin with target INR 2.0-3.0 for 6-12 months, with indefinite therapy suggested for idiopathic thrombosis 7

Standard Treatment Approach (Unaffected by Protein C Status)

Warfarin with target INR 2.5 (range 2.0-3.0) is the gold standard for thrombotic APS, regardless of protein C levels or anti-protein C antibody status 1, 2, 3, 7:

• For venous thrombosis in APS: Long-term (often indefinite) warfarin with target INR 2.0-3.0 1, 2, 3
• For arterial thrombosis in APS: Warfarin with target INR 2.0-3.0 plus low-dose aspirin (75-100 mg daily) 2, 3
• For triple-positive APS: Warfarin is mandatory; rivaroxaban is explicitly contraindicated due to excess thrombotic events 1, 2, 3

Critical Pitfalls Regarding Protein C

Do not attempt to treat low protein C activity with protein C concentrate in APS patients—the issue is antibody-mediated interference with the protein C pathway, not true deficiency 4, 5:

• Warfarin itself can transiently decrease protein C levels during initiation, creating a theoretical hypercoagulable state, which is why heparin bridging for 5-7 days is recommended when starting warfarin in APS 1, 7
• Lupus anticoagulant can affect phospholipid-dependent coagulation monitoring tests, including protein C assays, so results may not reflect true protein C activity 8
• Do not withhold or reduce anticoagulation based on protein C levels—the thrombotic risk in APS is driven by multiple mechanisms beyond protein C dysfunction 4, 5, 6

Special Monitoring Considerations

When monitoring anticoagulation in APS patients with protein C abnormalities:

• INR monitoring remains the standard for warfarin therapy despite lupus anticoagulant interference with some coagulation tests 8
• Chromogenic factor X assays may be more reliable than PT/INR in patients with strong lupus anticoagulant when INR results are discordant with clinical status 8
• Thrombin generation assays can assess APC resistance but are research tools, not routine clinical tests for guiding therapy 5, 6

Pregnancy Considerations

Protein C status does not alter pregnancy management in APS, which requires:

• Therapeutic-dose low molecular weight heparin plus low-dose aspirin throughout pregnancy and postpartum for thrombotic APS 2, 3
• Prophylactic-dose heparin plus aspirin for obstetric APS 2, 3
• Warfarin is contraindicated during pregnancy regardless of protein C levels due to teratogenicity 3, 7