Abstract Number: PB0719
Meeting: ISTH 2022 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Rare Bleeding Disorders
Background: Glanzmann Thrombasthenia (GT) is a severe platelet disorder caused by lack of functional integrin αIIbβ3. Acute bleeds in GT can be managed with recombinant FVIIa (rFVIIa), which enhances thrombin generation in a platelet-dependent manner. HMB-001 is a bispecific antibody that accumulates endogenous FVIIa and recruits it to the surface of activated platelets by binding FVIIa with one arm and the platelet TREM-like transcript 1 (TLT-1) receptor with the other. It thereby aims to restore clot formation in GT and enable long-term bleed prevention.
Aims: To evaluate the potentiation of FVIIa activity by HMB-001 on platelets in GT.
Methods: Platelet TLT-1 expression and plasma FVIIa levels were evaluated in GT patients and healthy controls. Effects of HMB-001 were evaluated with light transmission aggregometry in αIIbβ3-inhibited (GT-like) washed platelets with purified coagulation factors and in GT-like whole blood in a microfluidic flow chamber. Results were confirmed in blood of GT patients. Ethical committee approval was obtained.
Results: TLT-1 expression on activated GT platelets was normal and plasma FVIIa levels in GT patients and healthy controls were similar. Aggregation of activated GT-like platelets was absent, but aggregation occurred when fibrin formation was initiated with rFVIIa. Aggregation onset shortened with increasing FVIIa concentrations. HMB-001 lowered FVIIa requirements for aggregation 10-fold but had no effect in absence of FVIIa. Similar results were obtained with GT platelets. Addition of excess soluble TLT-1 attenuated the effects of HMB-001, confirming that HMB-001 is TLT-1-dependent. Perfusion of recalcified GT-like whole blood over a collagen surface at a shear rate of 300 s-1 resulted in platelet adhesion, but not in fibrin formation. Addition of rFVIIa caused a dose-dependent increase in fibrin formation on adhered GT-like platelets. HMB-001 strongly potentiated FVIIa-dependent fibrin formation on adhered platelets in flowing blood.
Conclusion(s): HMB-001 potentiates FVIIa-dependent fibrin formation on platelets in GT.
To cite this abstract in AMA style:
Zivkovic M, Gandhi P, Ostergaard H, Olsen E, Rea C, Sorensen B, Faber J, Schutgens R, Bjorn S, Urbanus R. The novel bispecific antibody HMB-001 enhances the haemostatic response in models of Glanzmann Thrombasthenia by targeting FVIIa to activated platelets [abstract]. https://abstracts.isth.org/abstract/the-novel-bispecific-antibody-hmb-001-enhances-the-haemostatic-response-in-models-of-glanzmann-thrombasthenia-by-targeting-fviia-to-activated-platelets/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-novel-bispecific-antibody-hmb-001-enhances-the-haemostatic-response-in-models-of-glanzmann-thrombasthenia-by-targeting-fviia-to-activated-platelets/