Our August 2026 QQ asked: “Which is NOT an endogenous coag control protein?” Our 29 participants answered…
1. Antithrombin: 1 (3%)
2. APC: 2 (7%)
3. TFPI: 4 (14%)
4. VKA: 22 (76%)
VKA is the correct answer. VKA is the general term for the therapeutic anticoagulant warfarin (once called Coumadin®), which suppresses vitamin K activity. Vitamin K catalyzes the γ-carboxylation of FII (prothrombin), FVII, FIX, and FX, enabling these factors to bind phosphatidylserine and become active in the coagulation cascade.
Antithrombin (AT), previously named antithrombin III (ATIII), is a serine protease inhibitor that, when activated by heparin or endogenous heparan sulfate, suppresses the activity of FIIa (thrombin) and FXa. AT deficiency may be acquired or congenital. The prevalence of hereditary AT deficiency is ~1 in 5000 and is associated with VTE. Fitusiran (Qfitlia®, approved in 2025) is a small interfering RNA (siRNA) that reduces AT to ~30% to manage hemophilia bleed rates.
TFPI is a serine protease inhibitor that controls coagulation by binding and reducing the activity of FX and the TF:FVII complex. The anti-TFPI monoclonal antibodies concizumab (Alhemo®, 2024) and marstacimab (Hympavzi®, 2024) reduce TFPI activity, a second means for rebalancing therapy employed in hemophilia.
PC forms a complex with PS, forming APC, which controls coagulation as it binds and inactivates FV and FVIII. Protein C and protein S deficiencies are associated with VTE. Efforts are underway to manage hemophilia bleeds through suppressing APC activity.
Consult your local medical library for this review of current and developing hemophilia therapeutics. Giuffrida AC, Focosi D, Bodini M, Zani M, Franchini M. New and novel pharmacotherapies for hemophilia A: an update. Expert Opin Pharmacother. 2026 Aug 20. doi: 10.1080/14656566.2026.2722319. Epub ahead of print. PMID: 42619563.
ABSTRACT
Introduction
Hemophilia A (HA) management has progressed significantly, yet standard and extended half-life (EHL) clotting factors present persistent limitations, including intravenous burden and suboptimal trough levels.
Areas covered
This narrative review highlights recently approved agents and phase III candidates for HA. In replacement therapy, efanesoctocog alfa maintains normal-to-near-normal factor VIII (FVIII) levels weekly by bypassing endogenous von Willebrand factor dependence. In non-replacement therapies, the focus centers on rebalancing agents—the anti-tissue factor pathway inhibitor (TFPI) monoclonal antibodies concizumab and marstacimab, and the antithrombin-targeting small interfering RNA (siRNA) fitusiran—as well as next-generation FVIII-mimetics like denecimig. With this objective, a structured literature search of the main original manuscripts and reviews published in English in major medical databases, including PubMed, EMBASE, and Cochrane Library from 2016 to now was conducted.
Expert opinion
While these innovators promise near-zero bleeding rates and subcutaneous convenience, they introduce unique challenges. Rebalancing therapies present potential thromboembolic risks, complex breakthrough bleed protocols, and standard laboratory assay interference (requiring antithrombin monitoring or specialized assays). Critical goals for contemporary hemophilia management include tailoring therapies through multidisciplinary collaboration, monitoring subclinical joint disease via point-of-care ultrasound, and implementing standardized, real-world protocols for emergency hemostasis.
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