Abstract
Genome-wide associations studies (GWAS) have linked the Tropomyosin 1 (Tpm1) gene locus to quantitative blood trait variation, but related mechanisms are unclear. Tpm1 encodes an actin-binding protein that stabilizes actin filaments and influences cell adhesion, signaling, and actomyosin contractility. Murine Tpm1 deficiency enhances embryonic hemogenic endothelial cell specification, but it was unclear if these effects extended to postnatal hematopoiesis. We used Cdh5Cre or VavCre models to conditionally ablate Tpm1 in endothelium or hematopoietic cells. Both models produced knockout mice in normal Mendelian ratios with complete Tpm1 ablation in postnatal blood. Endothelial Tpm1 deletion increased hemogenic endothelial cell specification, but did not change hematopoietic progenitor cell production nor adult blood counts. This suggested separate roles for Tpm1 in the embryonic and adult blood systems. GWAS suggested genetic architecture specifically linking decreased TPM1 expression to increased platelet count. We examined platelet lifespan and function to explain these findings. Tpm1KO increased platelet lifespan and diminished adhesion to fibronectin and fibrinogen. Decreased platelet clearance could explain increased platelet count in GWAS. Platelet fibrin binding is necessary for blood clot contraction, which reduces vascular occlusion following initial hemostasis. Tpm1KO reduced clot contraction and enhanced clot formation with worsened vascular occlusion in a ferric chloride-induced stroke model. These findings reveal a new role for Tpm1 in platelet function, offering insight into how cytoskeletal regulation impacts human platelet traits and pointing to novel targets to modify stroke risk and thrombotic disease.