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CD248 enhances tissue factor procoagulant function, promoting arterial and venous thrombosis in mouse models
Author(s) -
Kapopara Piyushkumar R.,
Safikhan Nooshin S.,
Huang Jenny L.,
Meixner Scott C.,
Gonzalez Kevin,
Loghmani Houra,
Ruf Wolfram,
Mast Alan E.,
Lei Victor,
Pryzdial Edward L.G.,
Conway Edward M.
Publication year - 2021
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15338
Subject(s) - tissue factor , thromboplastin , coagulation , thrombus , tissue factor pathway inhibitor , chemistry , thrombosis , prothrombinase , partial thromboplastin time , microbiology and biotechnology , pathology , biology , thrombin , immunology , medicine , platelet
Abstract Background CD248 is a pro‐inflammatory, transmembrane glycoprotein expressed by vascular smooth muscle cells (VSMC), monocytes/macrophages, and other cells of mesenchymal origin. Its distribution and properties are reminiscent of those of the initiator of coagulation, tissue factor (TF). Objective We examined whether CD248 also participates in thrombosis. Methods We evaluated the role of CD248 in coagulation using mouse models of vascular injury, and by assessing its functional interaction with the TF‐factor VIIa (FVIIa)‐factor X (FX) complex. Results The time to ferric chloride‐induced occlusion of the carotid artery in CD248 knockout (KO) mice was significantly longer than in wild‐type (WT) mice. In an inferior vena cava (IVC) stenosis model of thrombosis, lack of CD248 conferred relative resistance to thrombus formation compared to WT mice. Levels of circulating cells and coagulation factors, prothrombin time, activated partial thromboplastin time, and tail bleeding times were similar in both groups. Proximity ligation assays revealed that TF and CD248 are <40 nm apart, suggesting a potential functional relationship. Expression of CD248 by murine and human VSMCs, and by a monocytic cell line, significantly augmented TF‐FVIIa‐mediated activation of FX, which was not due to differential expression or encryption of TF, altered exposure of phosphatidylserine or differences in tissue factor pathway inhibitor expression. Rather, conformation‐specific antibodies showed that CD248 induces allosteric changes in the TF‐FVIIa‐FX complex that facilitates FX activation by TF‐FVIIa. Conclusion CD248 is a newly uncovered protein partner and potential therapeutic target in the TF‐FVIIa‐FX macromolecular complex that modulates coagulation.