Real-World Use of Therapeutic Anticoagulation in Patients with Paroxysmal Nocturnal Hemoglobinuria. Results of a Survey of Physicians in Australia
Authors: Szer Jeffrey , Forsyth Cecily J , Giese Anja 
Published: October 2019

Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. Patients with PNH are at increased risk of thromboembolism and premature death. This risk is predominantly due to the effects of chronic hemolysis and platelet activation. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis and dramatically reduce the rate of thromboembolism. A previous publication (Kelly et al, 2011) suggested that cessation of therapeutic anticoagulation (TAC) in PNH patients on eculizumab with no prior history of thrombosis is safe. There are very few reports on the outcomes of cessation of TAC in PNH patients on eculizumab who have a prior history of thrombosis or on the use of non-vitamin K antagonist oral anticoagulant (NOAC) agents in PNH patients with a history of thrombosis.
In Australia, patients with PNH are predominantly managed by individual hematologists rather than at a single centre and hence anticoagulation practices following the introduction of eculizumab therapy are variable. We surveyed Australian hematologists managing eculizumab-treated patients with PNH to obtain the details of anticoagulation management and incidence of thrombotic events in their patients.
We received responses from 30 hematologists caring for a total of 58 patients with PNH on eculizumab (1-17 patients per hematologist) and the table summarises the results. TAC as primary prophylaxis had been ceased in 10 patients with no recurrent thrombotic events. One (1) patient remains on primary prophylaxis due to persistently high D-dimer and factor VIII levels. TAC for secondary prophylaxis had been ceased in 2 patients due to bleeding (1 patient with subdural hematoma, 1 patient with gastrointestinal bleeding) and neither of these patients had a further thrombotic event. One patient, with a prior history of thrombosis, requested cessation of TAC and subsequently developed a provoked thrombosis.
Three patients not receiving TAC when eculizumab was commenced developed thrombosis; two (2) patients had provoked deep venous thromboses and one patient developed a splanchnic vein thrombosis following a cholecystectomy in association with severe sepsis.
One patient had a portal vein thrombosis immediately prior to commencing eculizumab therapy but has never received TAC due to severe coexistent thrombocytopenia from myelodysplasia. This patient has not had a recurrent thrombosis.
Three (3) patients with thrombotic events prior to eculizumab therapy (1 patient with pulmonary emboli, 1 patient with cerebral venous sinus thrombosis and 1 patient with inferior vena cava thrombosis) had anticoagulant therapy changed from warfarin to rivaroxaban. At a follow-up of at least twelve months for all 3 patients there have been no recurrent thrombotic events and no bleeding complications.
In conclusion, these Australian data are consistent with those reported by Kelly suggesting that cessation of primary prophylaxis in PNH patients on eculizumab is safe. Cessation of TAC in PNH patients on eculizumab with a prior thrombosis can be considered if there are clear contraindications to anticoagulation. Thromboprophylaxis in situations of increased risk of venous thromboembolism remains essential for all PNH patients not on TAC, even when they are on eculizumab therapy. The three patients on rivaroxaban as secondary prophylaxis are, to our knowledge, the first reported patients with PNH treated on a NOAC.
Table. Number of patients New thrombotic events Eculizumab treated 58 Ceased TAC: Total1. As 1o prophylaxis2. As 2o prophylaxis(i) Due to bleeding(ii) At patient request 1410431 -None-None1 (provoked) TE in patients not on TAC at commencement of eculizumab 3 3 (provoked) NOAC as 2o prophylaxis 3 None

Disclosures
Szer: Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Forsyth:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giese:Alexion: Employment.