Blocking Coagulation Factor XIIIa (FXIIIa) in risk patients

The physiological functions of coagulation factor XIIIa - also called plasma transglutaminase - are well known. Factor XIII is activated by thrombin to factor XIIIa and subsequently cross-links fibrin fibers. This covalent cross-linking reaction augments blood clot strength several fold and influences the visco-elastic properties. Further, the clot is covalently decorated by a2-antiplasmin increasing clot stability against fibrinolysis by plasmin. In summary, factor XIII is the major factor influencing clot stability, clot maturation and clot lysis.

Currently vitamin K antagonists and heparins, both used for decades in anticoagulation, face the appearance of novel direct acting oral drugs blocking either factor Xa or thrombin. Independently of the mode of action, all these drugs have one feature in common: a dramatically reduced thrombin activity. This leads to good anticoagulation efficiency but unfortunately increases the risk for severe bleeding events.

Safer medication is therefore still needed. Addressing factor XIIIa may open the gate to a “high efficiency - low bleeding” anticoagulation drug.

Factor XIIIa inhibition does not affect thrombin generation and therefore does not impair primary clot formation. This is the central difference compared to current anticoagulants, which affect both platelet aggregation and fibrin clot formation. By inhibiting factor XIIIa, the clot may form but be neither cross-linked nor decorated with antifibrinolytics like α2-antiplasmin. The resulting “soft” clot may rapidly be hydrolysed by plasmin, the major fibrinolytic protease. Thrombotic events will thus be drastically reduced, providing a reduced bleeding probability compared to current anticoagulation drugs.

Zedira’s factor XIIIa blockers have the highest efficacy demonstrated to date. We are currently on the way to developing a drug candidate for pre(clinical) development. Our compounds have the potential to provide a novel therapeutic option with a superior risk/benefit ratio.

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