Anticoagulation Use and Patient Outcomes in Paroxysmal Nocturnal Hemoglobinuria: A Province-Wide Retrospective Review

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder caused by somatic mutations in hematopoietic stem cells and is characterized by hemolysis, bone marrow failure, and thrombosis. Thrombotic events are the leading cause of morbidity and mortality in PNH, but little has been published about the role of prophylactic anticoagulation to prevent thrombotic events, and the ideal anticoagulant for patients who do experience thrombosis. Additionally, to our knowledge, bleeding outcomes in patients on prophylactic and therapeutic dose anticoagulants have not been examined. Our objective was therefore to examine our practice patterns regarding the use and outcomes of anticoagulation in PNH patients in our province.

Methods: This multi-center, retrospective cohort study examined the epidemiology, management, thrombotic and bleeding complications of 31 adult patients with PNH in the province of Alberta, Canada during the period of January 1, 2000, to December 31, 2022. Patients were identified by International Classification of Diseases (ICD)-9 codes from hospital discharge summaries and ambulatory clinic records. Chart reviews were performed to collect patient demographics, clinical and laboratory characteristics, use of anticoagulation including agent and dose, and thrombotic and bleeding complications.

Results: The median age of the cohort was 50 (interquartile range, IQR 35-70) years and 10 (32%) patients were male. Concurrent aplastic anemia and myelodysplastic syndrome were present in 15 (48%) and 3 (10%) patients, respectively. Disease presentation included thrombosis in 4 (13%) patients and bleeding in 5 (16%) patients. The majority of patients (74%) were treated with a complement inhibitor, most commonly eculizumab.

Over the study period, 7 (23%) patients experienced 10 thrombotic events, including venous thromboembolism in 6 (60%) patients and arterial thromboembolism in 4 (40%) patients. The most common vascular sites of thrombosis were deep vein thrombosis of the lower extremity (3 patients) and stroke (2 patients). Of the 10 thrombotic events, 3 (30%) occurred while the patient was receiving a complement inhibitor. Thrombosis occurred at a median of 4.5 months from PNH diagnosis and the average granulocyte clone size at the time of thrombosis was 40.1% (IQR 11.3-82.9%). Of these 10 thrombotic events, 2 occurred on therapeutic-dose anticoagulation.

In total, 8 (26%) patients experienced 13 bleeding events, 4 (13%) meeting criteria for ISTH major bleeding. The average platelet count at the time of bleeding was 96 (IQR 79-139). Of the 13 bleeding events, 5 occurred on an antiplatelet, 2 occurred on prophylactic-dose anticoagulation, and 2 occurred on therapeutic-dose anticoagulation.

Thirteen (42%) patients were on anticoagulation: 7 (23%) patients on primary prophylaxis and 6 (19%) patients on secondary prophylaxis. For primary prophylaxis, 4 patients received a direct oral anticoagulant (DOAC), 3 at a prophylactic dose and 1 at a therapeutic dose, and 3 patients received warfarin at a therapeutic dose. Six (86%) patients on primary prophylaxis were also receiving a complement inhibitor. With regards to secondary prophylaxis, 2 patients received a DOAC, 3 patients received warfarin, and 1 patient received low molecular weight heparin. All secondary prophylaxis was given at a therapeutic dose. Five (83%) patients on secondary prophylaxis were also receiving a complement inhibitor. Of patients on a DOAC, 1 patient experienced a breakthrough arterial thromboembolism (stroke), and no patients experienced a breakthrough venous thromboembolism.

Conclusion: Thrombosis in PNH is common and prevention is key to prevent long-term morbidity and mortality. Our practice patterns indicate that DOACs are being used in our province as primary prophylaxis, even in patients who are concurrently being treated with a complement inhibitor. DOACs are also being used more frequently than other anticoagulants as secondary prophylaxis, despite there not being robust data for DOAC use in this patient population. DOACs appear to be effective against VTE with no occurrence of breakthrough venous thrombosis. Major bleeding complications were observed at a higher rate than has been described in the literature and therefore the use of anticoagulants in this patient population must be weighed against the bleeding risk.