# Challenges in Balancing Hemostasis and Thrombosis in Therapy Tailoring for Hemophilia: A Narrative Review

## TL;DR

This review discusses the challenges of balancing bleeding and clotting risks in hemophilia therapy, especially with aging and new treatments.

## Contribution

The paper highlights novel rebalancing agents and FXI inhibitors as potential solutions for managing both hemostasis and thrombosis in hemophilia.

## Key findings

- Emerging therapies like emicizumab and FXI inhibitors may reduce bleeding risks while managing thrombosis.
- Aging-related comorbidities increase thrombotic risks in hemophilia patients.
- Global laboratory assays are needed to personalize hemophilia treatments.

## Abstract

Hemostasis and thrombosis reflect a delicate balance, regulated by the interplay between procoagulant and anticoagulant mechanisms. Hemophilia is traditionally viewed as a bleeding disorder, but emerging evidence highlights the paradoxical risks of thrombosis in hemophilia patients. We explore the landscape of hemophilia management, emphasizing challenges of balancing hemostasis in the context of aging, novel non-factor replacement therapies (NRTs), and comorbidity-driven thrombotic complications. Therapeutic approaches, including innovative NRTs, such as emicizumab, or rebalancing agents (e.g., concizumab, marstacimab, fitusiran), offer promising advancements in bleeding prophylaxis but may increase thrombotic risks. Conversely, novel anticoagulants, such as FXI inhibitors, offer potential thrombosis protection with minimal bleeding risk. Our review examines the impact of aging-related comorbidities, including cardiovascular disease, atrial fibrillation, HIV-associated complications, and acute coronary syndromes, on thrombotic risk in hemophilia patients. Evidence-based strategies for balancing hemostasis and thrombosis are outlined alongside experimental models, thrombin generation assays, and advancements in rebalancing coagulation through natural anticoagulant modulation. FXI inhibition emerges as a paradigm shift in thrombosis management, offering reduced bleeding risks while preserving vascular health. Finally, this review highlights the need for global laboratory assays to personalize treatments, emphasizing strategies to optimize safety and efficacy, particularly as hemophilia patients live longer with complex comorbidity profiles.