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

Abstract

Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs 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. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).

Graphical abstract

Figure 1.

Features of Budd-Chiari syndrome in PNH. (A) A pie chart illustrates the type of TEs. (B) A cartoon showcases the anatomic site of origin of thromboses. (C) Left panel shows magnetic resonance imaging (MRI) of a 59-year-old man, whereby on the axial postcontrast VIBE (volumetric interpolated breath-hold examination), the hepatic veins are decreased in caliber (thin arrows) and demonstrate peripheral pruning, however there is no residual hepatic venous filling defect to suggest thrombus. The intrahepatic inferior vena cava (IVC; thick arrow) is significantly narrowed without IVC thrombosis. On the right, a Doppler ultrasound image of the IVC of an 89-year-old male shows the hypoechoic and nonocclusive thrombus in the lumen (arrow). (D) A swimmer plot illustrates the longitudinal follow-up, and anticomplement and anticoagulation strategies in patients experiencing TEs in our cohort. ∗Patients for whom precise dates on subsequent thrombotic events (5 episodes for UPN 9 and 3 episodes for UPN 13) are lacking.

Figure 2.

Rate of TEs in our PNH cohort. (A-B) Bar charts show thrombosis rates per 1000 patient-years in our cohort according to PNH granulocytes and RBC clone sizes. (C) Bar chart on the left indicates rate of thrombosis based on receiving or not receiving anticomplement treatment, and on the right a subanalysis on treated cases according to the type of complement inhibitors received is shown. (D) Cumulative incidence of thrombosis in hemolytic disease is shown. At 2 years, the incidence of thrombosis was 18.3% (12.8%-24.7%) in untreated (death and anticomplement treatment initiation as competing events) vs 3.9% (1.3%-9.1%) upon therapy commencement (landmark time = treatment start, death as competing event). Numbers at risk are indicated below the curve.

Figure 3.

Radiologic features of thrombosis at diagnosis and follow-up of a 45-year-old woman with PNH. (A) Axial postcontrast VIBE MRI of a 45-year-old woman demonstrates heterogeneous enhancement of the liver. There is bland thrombus in 3 hepatic veins (thin arrows) and decreased IVC caliber without discrete thrombus (thick arrow). (B) After treatment, axial postcontrast VIBE image demonstrates significantly decreased thrombus burden from the prior (thin arrows) with persistent thrombus within middle hepatic vein (dashed arrow). The star indicates an incidental cyst in the liver periphery.