Wolfgang Miesbach: The Benefit with Hemophilia Rebalancing Agents Is Real, But So Are The Open Questions
Wolfgang Miesbach, Professor of Medicine at Frankfurt University Hospital, shared on LinkedIn about a recent article by Michael Makris, published in JTH:
”The benefit is real. But so are the open questions
Great comment by Michael Makris: Rebalancing agents are a genuine paradigm shift – inhibiting antithrombin (fitusiran) or TFPI (concizumab, marstacimab) to restore thrombin generation without replacing the missing factor.
But as Makris notes, the term ‘rebalancing’ gives a false sense of security.
Antithrombin has a normal range of 85–115% – far narrower than any other coagulation factor – and heterozygous deficiency alone carries a 17-fold elevated thrombotic risk.
What the studies show:
- Fitusiran (initial fixed-dose regimen): 23 events/1,000 pt-years – trial paused; the approved AT-based regimen (targeting antithrombin levels of 15–35%) still yields 8/1,000 pt-years
- Befovacimab: development terminated after 3 events – ischaemic stroke, retinal artery occlusion, cerebral venous sinus thrombosis
- Concizumab: 1.9% of trial patients affected – full person-year data still unpublished
- Marstacimab: clean phase 3 BASIS data – but events in phase 1, OLE, and a fatal thrombotic stroke reported at EAHAD 2026
Makris demands: full transparency on thrombotic rates per 1,000 person-years with 95% CIs.
The EUHASS registry, with rates of 0.93/1,000 pt-years for emicizumab and ~2.5 for bypassing agents, sets the reference point.
His pragmatic advice: avoid these agents for now in high-risk patients – elderly, CVD, thrombophilia, obesity, poorly mobile, cancer, uncontrolled hypertension, or family history of thrombosis — until EUHASS and other registries provide robust real-world evidence.
The benefit is real. But so are the open questions.”
Title: How real is the thrombotic risk with the rebalancing agents used to treat hemophilia?
Author: Michael Makris
Read the Full Article on JTH
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