Wolfgang Miesbach: The Protein C Pathway Reaches the Clinic
Wolfgang Miesbach, Professor of Medicine at Frankfurt University Hospital, shared a post on LinkedIn:
“Exciting progress at ISTH2026: Charles Esmon’s life’s work is reaching the clinic.
Over decades, Esmon established the protein C pathway as a major endogenous anticoagulant system.
He discovered thrombomodulin and the endothelial protein C receptor (EPCR), and defined how activated protein C (APC) restrains thrombin generation by inactivating FVa and FVIIIa.
Crucially, he also showed that APC is bifunctional:
- an anticoagulant arm – FVa/FVIIIa proteolysis
- a cytoprotective, anti-inflammatory arm – EPCR-PAR1 signalling
And APC is not generated everywhere at once. It is produced locally and on demand at sites of vascular injury, giving it a spatiotemporal precision that a systemic anticoagulant simply does not have.
In haemophilia the coagulant side is already deficient, so APC’s brake tips an imbalanced system further towards bleeding.
SR604 eases that brake – but selectively.
It is designed to switch off the anticoagulant arm while preserving the cytoprotective one, restoring haemostasis without touching the missing factor and without broadly suppressing anticoagulation.
The path ran from Esmon’s pathway biology through HAPC1573 (Nat Commun 2020) to the affinity-optimised SR604 (Blood 2023).
Now the Phase IIb data in Paris that has been presented by Lijun Xia (Oklahoma Medical Research Foundation).”
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