Abstract 132: VLX-1005 Effectively Treats Heparin-induced Thrombocytopenia (HIT) Without Increasing The Risk For Bleeding
| Autor: | Victoria Putzbach, Reheman Adili, James Michael, David J Maloney, Steven E McKenzie, Michael A Holinstat |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 42 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Heparin-induced thrombocytopenia (HIT) is a rare, but deadly disease that occurs in a small percentage of patients following administration of heparin. In these patients, heparin interacts with platelet factor 4 (PF4) resulting in an immune response to the heparin/PF4 complex. This immune complex can then bind to the immune receptor on the platelet, FcγRIIa, to induce platelet activation, clot formation, thrombosis, consumption, and bleeding. This potentially deadly disease results in both a thrombotic event as well as bleeding. Currently, there is only one FDA-approved intervention for HIT, the direct thrombin inhibitor argatroban. However, many patients on argatroban remain at risk for thrombosis, bleeding, and in some cases death. Therefore, we sought to develop a new drug to intervene in patients with HIT by targeting the 12-lipoxygenase enzyme in the platelet which regulates FcγRIIa activity in the platelet. Using mouse models of HIT as well as ex vivo administration of the 12-lipoxygenase inhibitor VLX-1005 (previously known as ML355). In mice expressing the human immune receptor on their platelets, we were able to show that administration of VLX-1005 following induction of HIT in these mice resulted in a blunted thrombocytopenia as well as reduced platelet activation and thrombus formation in the blood. We further demonstrated that coagulation was not impacted by VLX-1005 using thromboelestography while argatroban significantly delayed onset of coagulation and clot formation. Furthermore, bleeding time in these mice was not altered with VLX-1005, while mice on argatroban required cauterization of their tails to stop the bleeding. Finally, Human whole blood was shown in whole blood aggregometry as well as high shear arterial flow chamber experiments to be protected from platelet activation and clot formation in the presence of VLX-1005. The studies presented here demonstrate the potential effectiveness of VLX-1005 in intervention of platelet activation, clot formation, and thrombosis in both mouse models and human blood and support VLX-1005 as a new class of drug for the treatment of HIT in patients without the risk of bleeding. |
| Databáze: | OpenAIRE |
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