Plasma prothrombin antigenic levels across thrombotic and hemorrhagic phenotypes in triple-positive antiphospholipid patients with antiprothrombin antibodies

Background The concomitant presence of 4 antiphospholipid antibody types, namely lupus anticoagulant (LA), anticardiolipin antibodies, anti–β2-glycoprotein I, and antiprothrombin antibodies (tetra-positive), constitutes a high-risk antiphospholipid antibody profile and predisposes to thrombosis and catastrophic antiphospholipid syndrome (CAPS). However, tetra-positivity is also seen in asymptomatic carriers with LA-hypoprothrombinemia syndrome (LAHS). Objectives Given the central role of (pro)thrombin in hemostasis, we investigated the relationship between plasma prothrombin antigenic levels and autoantibodies across these different clinical scenarios. Methods We studied 30 healthy controls and 92 tetra-positive samples. Of those, 23 carriers without thrombosis, 30 patients with thrombotic antiphospholipid syndrome (APS) off warfarin, 30 with thrombotic APS receiving warfarin, 6 with CAPS, and 3 with LAHS. Immunoglobulin G/M anticardiolipin antibodies, anti–β2-glycoprotein I, and antiphosphatidylserine/prothrombin antibodies were measured by ELISA, whereas LA was assessed by dilute Russell viper venom time and silica clotting time. Plasma prothrombin antigenic levels and immunocomplexes were measured by ELISA. Results Median plasma prothrombin antigenic levels were 90% (IQR, 77%-99%) in controls, 55% (IQR, 45%-77%) in carriers, 59% (IQR, 44%-78%) in patients with APS off warfarin, 40% (IQR, 30%-58%) in patients with APS on warfarin, 28% (IQR, 25%-39%) in patients with CAPS, and 12% (IQR, 8%-28%) in patients with LAHS. Plasma prothrombin antigenic levels were lower in all patient groups and inversely correlated with antiphosphatidylserine/prothrombin antibody titers. Circulating immunoglobulin G/prothrombin immune complexes progressively increased across the clinical spectrum, from carriers to patients with CAPS and LAHS. Conclusion A biological continuum exists in which decreasing plasma prothrombin antigenic levels gradually influence the shift between thrombotic and hemorrhagic phenotypes in tetra-positive patients. Assessing prothrombin antigen levels in these patients could aid in risk stratification and guide therapy decisions.