Thrombospondin‐1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor

Abstract

Acute thrombotic arterial occlusion is the leading cause of morbidity and mortality in the Western world. Von Willebrand factor is thought to be the only indispensable adhesive substrate to promote thrombus formation in high shear environments. We found that thrombospondin-1, a glycoprotein enriched in arteriosclerotic plaques, might function as an alternative substrate for thrombus formation. Platelets adhered to thrombospondin-1 in a shear dependent manner with an optimum shear as found in stenosed arteries. Adhesion is extremely firm, with no detachment of platelets up to a shear rate of 4000 s(-1). Experiments using platelets from a patient completely lacking von Willebrand factor showed that von Willebrand factor is not involved in platelet binding to thrombospondin-1. Platelet adhesion to thrombospondin-1 is not mediated via beta3-integrins or GPIa. CD36 partially mediates the adhesion of pre-activated platelets. We identified GPIb as high shear adhesion-receptor for thrombospondin-1. Soluble GPIb, as well as antibodies against the GPIb, blocked platelet adhesion almost completely. The new discovered thrombospondin-1-GPIb adhesion axis under arterial shear conditions might be important, not only during thrombus formation but also for pathological processes where other cells bind to the endothelium or subendothelium, including arteriosclerosis, inflammation and tumor metastasis, and a promising therapeutic target.

Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage

“…Our study showed the critical role for the platelet GPIb␣, because the replacement of its extracellular domain resulted in abnormal angiogenesis. Beside VWF and P-selectin, GPIb has other ligands such as the leukocyte integrin Mac-1 (54) and thrombospondin I (55). In addition, GPIb is a thrombin receptor and binds other coagulation factors (56).…”

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

“…First discovered in platelets as a thrombin-sensitive protein (1), THBS1 was later shown to be a major component of platelet ␣-granules, comprising some 25% of the total protein (2). Once released, THBS1 exerts various functions on the vascular system under physiological and pathophysiological conditions causing platelet activation (3,4) and adhesion (5) in addition to endothelial cell adhesion (6), promotion of angiogenesis (7), and inhibition of angiogenesis (8), wound healing (9) as well as pathological states such as tumor progression and metastasis (10,11). THBS1 is important not only in cancer progression but also in inflammatory autoimmune diseases such as rheumatoid arthritis (12).…”

Molecular analysis of early host cell infection by Trypanosoma cruzi

“…cruzi must navigate the ECM in order to infect mammalian cells. Amongst the glycoproteins of the ECM, thrombospondins constitute a set of unique multidomain proteins that are synthesized, secreted and incorporated into the ECM by many cell types (115)(116). Thrombospondins are unique members of the ECM in that they have been described as 'matricellular' proteins because they modulate cell function but they do not play a direct role in the structure of the ECM.…”