Management Strategies in Persons with Inherited Hemophilia Requiring Antithrombotic Therapy: A Scoping Review

Background: Cardiovascular disorders (CVD) and venous thromboembolism (VTE) are increasingly reported in people with hemophilia (PWH) whose life expectancy has improved dramatically over the past decades. While management of thrombotic events among PWH requires navigating the delicate balance between recurrent ischemic events and hemorrhage, current practices are highly variable and largely informed by expert opinion.

Objective: We sought to examine and summarize what is known about the management, practice variation and outcomes of PWH requiring antithrombotic therapy (ATT) for cardiovascular disorders (CVD) or venous thromboembolism (VTE). We also aimed to identify current knowledge and practice gaps in the management of CVD and VTE in PWH.

Methods: We conducted a scoping review guided by Arksey and O'Malley (2002), and Levac et al.'s (2010) methodological frameworks. We also adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A search strategy, developed iteratively in collaboration with a medical librarian, was performed on MEDLINE, EMBASE, and Scopus from inception to May 3, 2021. Studies of any design, published in English or French, in full-text or abstract, were included if they reported on more than two patients with inherited hemophilia A or B requiring ATT for CVD or VTE. Following eligibility assessment in duplicate, data from each study was charted by two independent reviewers to report the type of research designs, population, geographical location, interventions, and outcomes. Conflicts were resolved by consensus. We conducted a descriptive analysis and narrative synthesis to identify common themes and knowledge gaps.

Results: We screened 3929 articles and selected 38 studies for inclusion (23 full-text and 15 abstracts). Published studies were largely retrospective (28/38, 73.7%), single center (25/38, 65.8%), and from Europe (25/38, 65.8%). A total of 567 patients with hemophilia A or B were reported. Common indications for ATT use included: coronary artery disease (26/38, 68.4%), including a history of percutaneous coronary intervention or coronary artery bypass procedures (14/38, 36.8%), atrial fibrillation (13/38, 34.2%), VTE treatment or prevention (10/38, 26.3%), cerebrovascular disease (9/38, 23.7%) and valvular heart disease (7/38, 18.4%). ATT included single antiplatelet therapy (28/38, 73.7%), heparins (21/38, 55.3%), dual antiplatelet therapy (19/38, 50%), vitamin K antagonists (10/38, 26.3%), and direct oral anticoagulants (5/38, 13.2%). The use of hemostatic therapies, either on-demand or prophylactically, was reported in 36 studies (94.7%). Clotting factors concentrates were used in 35 studies (92.1%). Other agents included desmopressin (2/38, 5.2%) and emicizumab (1/38, 2.6%). Only 19 studies (50%) reported target factor levels (peak and/or trough) while on ATT. Outcomes related to bleeding while on ATT were described in 36 studies (94.7%). Bleeding events resulting in a change in hemostatic regimen occurred in 9 studies (25%), while bleeding resulting in a change or discontinuation of ATT occurred in 10 studies (27.8%). In 10 studies (26.3%), no pathologic bleeding was observed in PWH on ATT. Four key themes were generated iteratively to describe the observed wide practice variation in the management of PWH requiring ATT: (1) Deviation from established and evolving CVD/VTE-related standards of care; (2) Difficulty weighing competing bleeding and thrombotic risks; (3) Advocacy for individualized strategies and multidisciplinary care; and (4) Absence of high-quality and long-term data for PWH.

Discussion and Conclusion: Our scoping review highlights unmet needs in the management of an aging population of PWH with increasing prevalence of CVD and VTE. Management patterns are inconsistent and diverge from those of non-hemophilic patients. Current literature provides limited information on key issues such as hemostatic regimen, target factor levels, bleeding events and long-term outcomes. Prospective, clinically actionable data are needed to inform optimal and evidence-based management strategies of CVD and VTE in PWH. Higher quality data should culminate in much needed guidelines co-produced with patient partners and medical experts in hemophilia, CVD, and VTE.