Abstract Number: PB1425
Meeting: ISTH 2020 Congress
Background: Heparin is widely used clinically. Some patients treated with heparin will form an immune complex resulting in activation of the platelet immune receptor FcγRIIa. FcγRIIa engagement results in platelet activation, thrombus formation, and platelet clearance resulting in an increase in thrombosis as well as bleeding due to thrombocytopenia. Traditional antiplatelet drugs have failed to prevent platelet activation due to immune-receptor activation and the only FDA-approved intervention for HIT is the factor IIa inhibitor, argatroban, which carries with it a significant risk for bleeding. Hence, a new target for prevention of HIT is needed for adequate treatment of this rare disease.
Aims: To identify the utility of inhibiting platelet 12-lipoxygenase (12-LOX) as a viable target for prevention and intervention in HIT. Previous work by our lab and others have shown that inhibition of 12-LOX may be a new approach that both prevents thrombosis without increased risk in bleeding.
Methods: The 12-LOX inhibitor, VLX-1005 (previously denoted as ML355), was used to assess bleeding as well as prevention and intervention of platelet activation during HIT in the mouse model.
Results: Mice were treated with or without VLX-1005 followed by induction of HIT. VLX-1005 prevented platelet loss and thrombus formation for all times assessed compared to control animals. Further, to assess the utility of VLX-1005 in patients already diagnosed with potential HIT, mice were treated with anti-CD9 to induce HIT followed after a specified time with or without VLX-1005. VLX-1005-treated mice showed no significant platelets loss and only minimal platelet accumulation in the vascular lung space. Finally, using the mouse tail-bleeding assay, argatroban administration resulted in increased bleeding in the mouse, while VLX-1005 showed no increase in bleeding compared to control.
Conclusions: Targeting 12-LOX with VLX-1005 is a new therapeutic approach for prevention and intervention of HIT with no increased risk in bleeding.
To cite this abstract in AMA style:Adili R, Putzbach V, Holinstat M. Inhibition of 12-LOX with VLX-1005 Has Clinical Utility for Prevention and Intervention of HIT [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/inhibition-of-12-lox-with-vlx-1005-has-clinical-utility-for-prevention-and-intervention-of-hit/. Accessed February 20, 2024.
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