Abstract Number: OC 35.1
Meeting: ISTH 2021 Congress
Background: Cancer radiation therapies are complicated by coagulopathies and fibrotic syndromes. Radiological tissue insult activates platelets allowing assembly of prothrombinase (FVa/FXa) , which is inhibited by Tissue Factor Pathway Inhibitor alpha (TFPIα).
Aims: A mouse model to investigate how platelet TFPIα may modulate responses to radiation injury.
Methods: Mice lacking the first Kunitz domain (K1) of TFPI die during embryogenesis but can survive to adulthood, if they lack the platelet thrombin receptor Par4. Adult TFPI-K1 null/Par4 null mice were lethally irradiated (11Gy) and transplanted with bone marrow from Total TFPIfloxed/floxed/PF4Cre+ mice or Total TFPIflox/flox /PF4Cre- littermates. This produced TFPI-K1 null mice with platelets containing functional Par4 that differed only by having TFPIα in their platelets (6 mice) or lacking TFPIα in their platelets (11 mice).
Results: Three of 6 mice lacking platelet TFPIα died before 150 days post-transplant, while survivability increased to 100% (n=6) in mice with platelet TFPIα (p=0.055). Complete blood counts and thrombin-antithrombin levels were similar between groups indicating equivalent bone marrow engraftment and the absence of a global hypercoagulable state. Severe pathology in the heart of mice lacking platelet TFPIα, which was absent in mice with platelet TFPIα, included ventricular thrombi, clots within microvasculature, and lesions suggestive of endocardial and epicardial fibrosis. Thrombi were not observed in other tissues examined of either group. Pico red staining quantified collagen deposition and was 3-fold higher in heart of mice lacking platelet TFPIα (p<0.0001). Immunohistochemical staining for periostin identified fibroblast activation within the heart of mice lacking platelet TFPI.
Conclusions: Physiological roles for platelet anticoagulant proteins in modulating platelet procoagulant activity is an area of active investigation. The data presented here identified a role for platelet TFPIα in dampening platelet-mediated prothrombotic and fibrotic responses to radiation injury in the heart.
To cite this abstract in AMA style:Maroney S, Martinez N, Peterson J, Lincoln J, Mast A. Platelet TFPIα Dampens Prothrombotic and Fibrotic Responses to Radiation Injury in Mouse Heart [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/platelet-tfpi%ce%b1-dampens-prothrombotic-and-fibrotic-responses-to-radiation-injury-in-mouse-heart/. Accessed September 24, 2021.
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