This research will be done primarily in Nigeria as an extension of NIH grant #R01 HL54462. This study will examine the mechanisms involved in agonist-induced fibronectin (FN) matrix assembly by platelets adherent on various matrix proteins and the possible relevance of platelet-directed FN matrix to the pathogenesis of sickle cell disease (SCD). Activation of the coagulation system and specifically of platelets has been implicated in the vasooclusive events of SCD. We recently demonstrated that adherent platelets can be induced to assemble a matrix of FN. We will investigate the mechanisms of such assembly more completely, concentrating on the role of integrins. We then will investigate whether, as in the case with fibroblasts, thrombospondin-1 (TSP-1) deposits in the FN matrix of platelets. We will learn whether platelets of patients with SCD have the capacity to deposit a matrix of FN and TSP. Finally, we will investigate whether reticulocytes and red blood cells of patients with SCD, which have cell surface receptors for FN and TSP-1, adhere specifically to the matrix of adherent platelets. These studies may reveal an important mechanism for adherence of sickle cells that is amenable to pharmacological manipulation
