In patients with paroxysmal nocturnal hemoglobinuria (PNH), thrombosis is a serious complication that affects more than one-third of individuals with the disorder, according to findings from a Greek nationwide, multicenter, retrospective, real-world study published in Frontiers in Oncology.
Thrombosis is the leading cause of death in people with PNH, a rare, acquired clonal nonneoplastic hematopoietic stem cell disorder that is potentially life-threatening and causes complement-mediated chronic hemolytic anemia, bone marrow deficiency, and acquired thrombophilia.
The current study evaluated 41 individuals who had received a PNH diagnosis at 1 of 14 national hematology centers in Greece between 2002 and 2022. Participants’ medical records were reviewed, and demographic and clinical data were obtained. Real-world data on thrombotic events (TEs) that had been reported and treated in these patients over the same time period were also collected.
Among the 41 participants, 22 were male and 19 were female. The median patient age at diagnosis was 33 years (range, 11 to 82 years). Overall, 23 patients were diagnosed with the classical form of PNH, 3 were identified as having the subclinical form of the disease, and 15 were diagnosed with PNH along with another underlying condition. Of the latter group, 7 had aplastic anemia, 4 had myelodysplastic syndrome, 2 had primary myelofibrosis, 1 had polycythemia vera, and 1 had beta-thalassemia.
Learn about experimental therapies for paroxysmal nocturnal hemoglobinuria
In all, 39.0% (16 of 41) of the patients experienced 1 or more TE, with venous thromboembolism reported in 68.8% and thus being the most common TE. Of these individuals, 43.8% (7 of 16) experienced the TE at diagnosis, 43.8% (7 of 16) of them during the disease course, and 12.5% (2 of 16) of them prior to being diagnosed with PNH; 43.8% (7 of 16) experienced multiple TEs over the course of their disease. None of the events was fatal.
The intra-abdominal veins were the most commonly reported site of TEs (29.3% [12 of 41] of patients). Among 26 patients treated with eculizumab, just 3 developed TEs.
At diagnosis of PNH, the most common signs and symptoms of the disease were: weakness in 65.9% of participants, hemoglobinuria in 39%, abdominal discomfort in 29.3%, back pain in 7.3%, headache in 4.9%, dysphagia in 4.9%, and erectile dysfunction in 4.5%. Overall, 22.0% of patients exhibited hepatic impairment, 19.5% had splenomegaly, and 9.8% exhibited renal dysfunction. Increased lactate dehydrogenase levels were observed in 78% of the participants.
In individuals with PNH, the major genetic defect involves somatic mutations in the X-linked PIGA gene. PIGA “encodes a protein that is involved in the biosynthesis of the glycosyl-phosphatidyl-inositol (GPI),” Chatzileontiadou et al explained in the study. GPI is a glycolipid that acts as an anchor to mediate the attachment of more than 150 proteins to the cell membrane. The median size of the GPI-deficient clone in the study participants was 63% for granulocytes, 73% for monocytes, and 21.9% for red blood cells.
Mechanisms of thrombosis in PNH are multifactorial, with complex interactions between the coagulation and complement cascades reported. PNH was described in a 2011 study as “the most vicious acquired thrombophilic state known in medicine,” thus highlighting the high risk for thrombosis, along with the high rates of morbidity and mortality reported among untreated patients.
The development of TEs among patients with the disease requires the use of anticoagulation therapy. With the use of anticoagulants insufficient for the prevention of new TEs, however, disease-specific treatment with complement inhibitors is thus indicated in patients with PNH. In fact, treatment with eculizumab—a first-in-class anti-C5 humanized antibody—has been shown to decrease hemolysis and the occurrence of TEs in patients with PNH.
According to the researchers, “[R]egardless of the small sample size, our study demonstrated that thrombosis is a serious consequence of PNH . . . Ongoing treatment with complement inhibitors has considerably reduced the risk of thrombosis, although it has not eliminate[d] it totally.”
Reference
Chatzileontiadou S, Hatjiharissi E, Angelopoulou M, et al. Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): real world data of a Greek nationwide multicenter retrospective study. Front Oncol. Published online March 7, 2023. doi:10.3389/fonc.2023.1128994
Luzzatto L, Gianfaldoni G, Notaro R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol. 2011;153(6):709-720. doi:10.1111/j.1365-2141.2011.08690.x
