Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043 patient/years analysis

• Thrombosis in atypical sites is often the first sign of PNH and anti-coagulation/anti-complement combination is the mainstay of treatment

• DOACs are potential options for PNH-related thrombosis and discontinuation is safe in cases with complete control of intravascular hemolysis

Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anti-complement treatment has revolutionized the natural history of PNH with control of the hemolytic process and abolition of thrombotic events (TE). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anti-coagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anti-coagulants (DOACs). Herein, we accrued a large real-world cohort of PNH patients from four US centers to explore features, predictors of TE and anti-coagulation strategies. Among 267 patients followed-up for a total of 2043 patient/years, 56 (21%) developed TE. This occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TE was halved in patients receiving complement inhibitors (21 vs 40 TE per 1000 patient/years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3% respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (>2 mutations or less) and variant allelic frequency of PIGA mutations. Anti-coagulation with warfarin (39%), DOACs (37%), and low-molecular-weight heparin (16%) was administered for a median of 29 months (9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (8.9-45) while 14 cases discontinued anti-coagulation without TE recurrence at a median time of 51.4 months (29.9-86.8).