Is ferritin elevated in catastrophic antiphospholipid syndrome?

Is Ferritin Elevated in Catastrophic Antiphospholipid Syndrome (CAPS)?

Yes, ferritin is markedly elevated in catastrophic antiphospholipid syndrome (CAPS), with 71% of CAPS patients demonstrating hyperferritinemia and mean ferritin levels reaching 816 ± 847 ng/mL—significantly higher than non-catastrophic APS patients (120 ± 230 ng/mL, p < 0.001). 1

Understanding the Hyperferritinemic Syndrome

CAPS belongs to a distinct group of life-threatening conditions characterized by extreme hyperferritinemia, collectively termed the "hyperferritinemic syndrome." 2, 3 This syndrome includes:

• Catastrophic antiphospholipid syndrome (CAPS)
• Adult-onset Still's disease (AOSD)
• Macrophage activation syndrome (MAS)
• Septic shock

These conditions share remarkably similar clinical presentations, laboratory abnormalities, and treatment responses, suggesting a common pathogenic mechanism involving ferritin as both a biomarker and active mediator of cytokine storm. 2, 3

Ferritin Levels in CAPS: The Evidence

Prevalence and Magnitude

• 71% of CAPS patients exhibit hyperferritinemia (defined as ferritin >300 ng/mL in most studies), compared to only 9% of non-catastrophic APS patients 1
• Mean ferritin levels in CAPS are approximately 7-fold higher than in regular APS (816 ng/mL vs. 120 ng/mL) 1
• Ferritin elevation in CAPS typically ranges from several hundred to several thousand ng/mL, though levels rarely reach the extreme elevations (>10,000 ng/mL) seen in hemophagocytic lymphohistiocytosis 4, 2

Clinical Correlations

Among APS patients, elevated ferritin correlates with:

• Venous thrombosis 1
• Cardiac manifestations 1
• Neurological involvement 1
• Hematological abnormalities 1
• Presence of anti-CMV-IgM antibodies 1

Pathophysiologic Significance

Ferritin in CAPS is not merely a passive acute-phase reactant but likely functions as an active immunomodulator contributing to the cytokine storm. 2, 3 The exceptionally high ferritin levels observed in CAPS may:

• Directly induce pro-inflammatory cytokine expression (TNF-α, IL-6, IL-1β) 2, 3
• Amplify the inflammatory cascade leading to multi-organ thrombosis 2
• Serve as both a biomarker and pathogenic mediator of the catastrophic event 1, 2

This dual role distinguishes CAPS-associated hyperferritinemia from the modest ferritin elevations seen in common inflammatory conditions. 2, 3

Diagnostic Implications

When to Suspect CAPS

Consider CAPS when you encounter:

• Known APS patient with acute multi-organ involvement (≥3 organs affected over days to weeks) 1, 2
• Ferritin >500-1000 ng/mL in the setting of new thrombotic events 1, 2
• Systemic inflammatory response with fever, elevated inflammatory markers, and cytopenias 2, 3

Distinguishing CAPS from Other Hyperferritinemic Conditions

While ferritin elevation is common to the hyperferritinemic syndrome, certain features help differentiate CAPS:

• CAPS: Multi-organ thrombosis predominates, with ferritin typically 500-2000 ng/mL 1, 2
• MAS/HLH: Highest ferritin levels (often >5,000-10,000 ng/mL), with prominent cytopenias and hepatosplenomegaly 4, 2
• AOSD: Glycosylated ferritin fraction <20% (93% specific), with quotidian fevers and salmon-pink rash 5, 2
• Septic shock: Positive cultures, with ferritin elevation proportional to severity 2, 3

Critical Pitfall to Avoid

Do not dismiss moderately elevated ferritin (300-1000 ng/mL) in an APS patient with acute clinical deterioration. 1 While this level is below the extreme hyperferritinemia of MAS/HLH (>5,000 ng/mL), it represents a 7-fold elevation above baseline APS and strongly suggests evolution to CAPS. 1, 2

Clinical Context

Hyperferritinemia in CAPS may serve as an early warning sign of impending catastrophic events, potentially allowing earlier aggressive immunosuppression. 1, 2 The association between ferritin elevation and specific organ involvement (cardiac, neurological, hematological) suggests that serial ferritin monitoring in high-risk APS patients could identify those requiring intensified anticoagulation and immunomodulatory therapy. 1

Infections, particularly viral infections like Chikungunya, can trigger the hyperferritinemic syndrome in susceptible individuals, precipitating CAPS in patients with underlying APS. 6 The correlation between elevated ferritin and anti-CMV antibodies in APS patients supports this infection-triggered mechanism. 1