The role and function of protein S (PS) in coagulation has been studied and documented extensively. PS serves as a cofactor for activated protein C (APC) and tissue factor pathway inhibitor (TFPI). Dr. Sara Calzavarini from Switzerland et al. assessed the in vivo role of PS located in platelets. Although platelet PS is comparable to plasmatic PS, its role in thrombosis has not yet been elucidated. Why the interest? While the majority of PS circulates in plasma, 2.5% is produced by megakaryocytes, stored in platelets and released upon activation.

Dr. Calzavarini et al. observed that inactivation of platelet PS expression in mice using the Pf4-Cre transgene (Pros1lox/loxPf4-Cre+) resulted in complete PS deficiency in platelets, whereas PS level was comparable in plasma of Pros1lox/loxPf4-Cre+ and Pros1lox/loxPf4-Cre mice. As expected, ex vivo TF-initiated thrombin generation demonstrated an increased thrombin potential in platelet-rich plasma in line with the loss of APC- and TFPI-dependent activities in Pros1lox/loxPf4-Cre+ mice. In the TF-induced venous thromboembolism model, their survival rate was reduced by 50%. They developed occlusive thrombosis in mesenteric arterioles (FeCl3-injury model) twice as fast, and their thrombi were more extended than in Pros1lox/loxPf4-Cre mice. Factor Xa and thrombin formation, fibrin staining and P-selectin+ platelets were distributed homogeneously in the thrombus of Pros1lox/loxPf4-Cre+ mice, but remained located at the injury boundary site in Pros1lox/loxPf4-Cre mice. In the vena cava FeCl3-injury model, thrombus volume was more than 3 times larger in Pros1lox/loxPf4-Cre+ than in Pros1lox/loxPf4-Cre mice. Fibrin and PS colocalized in both genotypes. However, PS staining was intense in Pros1lox/loxPf4-Cre thrombi and faint in Pros1lox/loxPf4-Cre+ thrombi. In contrast, there was no difference between the 2 genotypes in the carotid artery FeCl3-injury model.

As evidenced by this work, Dr. Calzavarini et al. stated that “platelet PS released by activated platelets limits thrombin generation, further platelet activation and excessive fibrin formation in the growing thrombus. In a large artery, where the kinetics of platelet activation is slow, the impact of platelet PS on thrombus growth is not significant.”

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