Thrombosis In Patients With Paroxysmal Nocturnal Hemoglobinuria

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells with 2 major presentations: Classic PNH with hemolysis and aplastic anemia (AA) / PNH syndrome with marrow failure. PNH is associated with an increase incidence of thrombosis, which represent the most common cause of death. We address the thrombosis history of 460 PNH patients, diagnosed over a 55-year period (1950–2005), in France. Fifty eight hematological centers were contacted through the French Society of Hematology and/or the French Association of Young Hematologists. Patients who underwent transplantation were censored at that time. Sites and cumulative incidence of thrombotic events, as well as risk factors for thrombosis, were analyzed. The median (±SE) follow-up and survival times were 6.8 (±0.5) and 22 (±2.5) years, respectively. At time of diagnosis, 33 patients had thrombosis (7.2%) with 16 Budd Chiari (BC). During evolution, 145 episodes of deep-vein thrombosis occurred in 116 patients among the 454 assessable patients. Forty nine patients (43%) developed a BC syndrome, 35 patients (31%) presented a thrombosis of the central nervous system (CNS), 31 patients (27%) were diagnosed with limbs thrombosis and 29 patients presented thrombosis in other sites. The 10-years cumulative incidence was 31% (Interquartile range IQR: 25%–36%) in the global population, 38% in the 112 patients with Classic PNH and 28% in the 222 patients with (AA) / PNH syndrome. The median time from diagnosis to first thrombosis was 2.3 years (IQR 1.1 to 6.5). Through multivariate analysis, development of thrombosis was related to poor survival in the global population, as well as in each PNH subcategories (p<0.001). Independent factors that increased the risk of first thrombosis during the course of the disease were: age older than 55 years (hazard ratio HR: 1.8, p=0.01), thrombosis at diagnosis (HR 3.7, p<0.001), warfarin as prophylaxis (primary prophylaxis, n=18; secondary prophylaxis, n=19) (HR 5.2, p<0.001) and use of transfusions (HR 1.7, p=0.01). In addition, the use of an immunosuppressive treatment was independently associated with a decreased risk of thrombosis (HR 0.5, p=0.02). Ninety six patients died during the study. Main causes of death included 23 CNS complications (24%) with 13 thrombosis, 8 hemorrhages and 2 unknowns, 23 infectious disease (24%) and 21 BC syndrome (22%). Per patient subgroups, main causes of death included 9 BC syndrome, 6 CNS vascular complications (4 thrombosis, 1 hemorrhage and 1 unknown) and 8 infections for Classic PNH (n= 112); 5 BC syndrome, 11 CNS vascular complications (5 thrombosis and 6 hemorrhages) and 8 infections for AA-PNH syndrome (n=222). Thrombosis remains a major life-threatening PNH complication, affecting the outcome both in patients with Classic PNH but also with AA-PNH syndrome. Further improvement in prophylaxis and treatment of this particular complication is essential.