Regulation of venous thrombosis by platelet protein S

In this issue of Blood, Calzavarini et al solve the long-standing puzzle of the function of protein S (PS) that has been derived from platelets (PS_plt) by showing that PS_plt limits thrombin formation in large veins.¹ 

You discover a leaky pipe and apply putty, hoping that the putty will remain at the leak site and will not swell or drip onto the floor. Our circulatory system faces similar challenges in response to blood vessel injury. Platelets (the putty) rush to the scene and help block the leak. What ensures that platelets remain at the injury site? What controls the size of the surrounding thrombus? Calzavarini and colleagues report that, in large veins, PS_plt restrains thrombin generation and promotes confinement of activated platelets and fibrin to the injury site. The authors also show that these PS_plt functions are quiescent in large arteries. These findings are critical for our understanding of the activity of PS_plt, and they have implications for therapeutic intervention in patients with bleeding disorders.

PS is an essential vitamin K–dependent plasma anticoagulant. Homozygous deficiency of PS usually causes life-threatening purpura fulminans at birth,²  and heterozygous PS deficiency elevates the risk of venous thrombosis.³  Plasma PS acts primarily as an anticoagulant by enhancing the function of activated protein C (APC),⁴  by serving as a cofactor to tissue factor pathway inhibitor α (TFPIα) in inhibition of free factor Xa (FXa) in the initial phase of coagulation,⁵  and by inhibiting FIXa to block FX activation.⁶ 

PS_plt, which is about 2.5% of total PS, is stored in platelet α granules and released by platelet stimulation.⁷  Unlike its well-defined plasma counterpart, the function of PS_plt in thrombosis and hemostasis has been largely unknown. Calzavarini et al closed this knowledge gap with an elegant mouse model in which they ablated PS_plt expression specifically in the megakaryocyte precursors of platelets. The investigators found that PS_plt was essential for regulating thrombosis in veins, at last giving much-needed clarity to an unchartered area.

One of the most exciting findings by Calzavarini et al is that PS_plt regulates venous thrombosis but not arterial thrombosis. The difference seems to be based on shear rate. Earlier, Begent and Born⁸  assessed the effect of venous shear rate on thrombus formation. They discovered that thrombus growth in a large vein (diameter of 40-60 μm) reached a maximum at a low blood flow of about 400 μm/s, a point at which the number of platelets transported to an injured site remained in balance with the number that adhered to the vessel wall. At a low shear rate, activated platelets secrete PS_plt, which then acts as a cofactor for APC and TFPI, thereby controlling FXa and thrombin generation within the thrombus. Conversely, arterial thrombosis occurs at a high shear rate when platelet rich thrombi are formed around ruptured atherosclerotic plaques and damaged endothelium; platelets are crucial in the development of arterial thrombosis at these sites.⁹  The reason that PS_plt does not contribute to control of arterial thrombosis is because at a high shear rate, the platelets accumulate quickly at the injury site; thus, most of the platelets are not activated to release PS_plt.

Another remarkable finding from Calzavarini et al is that mice lacking PS_plt had significant reductions in bleeding time and blood loss, presumably because of unrestrained thrombus growth. This observation raises the intriguing possibility, suggested by Calzavarini et al, that targeting PS_plt for inactivation might constitute a valuable therapeutic avenue for patients with bleeding disorders.

In summary, by selectively inhibiting the expression of PS_plt in a transgenic mouse model, Calzavarini et al explained, for the first time, the function of PS_plt in blood coagulation and thrombosis. Unraveling the importance of platelet PS in vivo is breakthrough work in the fields of thrombosis and hemostasis.