Adrian R. L. Gear
Professor of Biochemistry & Molecular Genetics
D. Phil., Oxford University, England
Blood Platelet Function


Blood platelets are essential for normal blood clotting, but when overactive, can contribute to heart attacks and strokes. Understanding regulation of platelet function is therefore an important aim for developing effective ways to modulate their overactivity in cardiovascular disease. The research in our laboratory is directed toward understanding the biochemical mechanisms that link platelet activation by agents like ADP, thrombin and collagen, to the participation of these cells in clot formation and wound healing. The fundamental events in platelet function involve specific interactions of these compounds with receptors on the plasma membrane, which then trigger major responses inside the cell. Phospholipids are rapidly hydrolyzed, calcium levels increase within seconds, and many proteins become phosphorylated or even dephosphorylated. Dramatic alterations in cell morphology are associated with these biochemical changes; long pseudopodia are extended, intracellular granules are secreted and platelets stick to each other (aggegation) or to molecules such as collagen at the site of a wound (adhesion).

Specific research questions are as follows: 1) How does platelet adhesion to collagen via integrin receptors on the plasma membrane initiate changers in metabolism leading to stable adhesion? Recently-discovered roles for heat-shock proteins and phosphoprotein phosphatases appear to be directly involved. A large phosphoprotein complex exists in resting platelets, which is rapidly dissociated following adhesion. 2) How is phospholipid hydrolysis regulated following activation of platelet function? Roles of both sphingomyelin and phosphatidylinsitol are being investigated. 3) How is platelet function controlled by alterations in the synthesis and degradation of cyclic AMP and cyclic GMP, espeically the involvement of new drugs and nitric oxide? 4) The roles of chemokines produced during inflammation and activation of platelet function is being actively studied.

These research topics are being investigated with the help of a range of biochemical, biophysical and structural approaches. Some studies use very rapid mixing and quenching techniques, where reactions within second to millisecond times are studied. Such rapid rates of platelet function are required under arterial blood-flow conditions and in diseases such as atherosclerosis, where fatal clots can occur very rapidly. The study of the functional proteomics during platelet activation taking advantage of knowledge of the human genome is also possible.

Selected References

Honemann CW, Lo B, Erera JS, Polanowska-Grabowska R, Gear AR, Durieux M. (1999) "Local anesthetic effects on TXA2 receptor mediated platelet aggregation using quenched flow aggregometry." Adv Exp Med Biol. 469:269-76. [PubMed]

Polanowska-Grabowska R, Simon CG Jr, Gear AR. (1999) "Platelet adhesion to collagen type I, collagen type IV, von Willebrand factor, fibronectin, laminin and fibrinogen: rapid kinetics under shear." Thromb Haemost. 81:118-23. [PubMed]

Polanowska-Grabowska R, Gear AR. (1999) "Activation of protein kinase C is required for the stable attachment of adherent platelets to collagen but is not needed for the initial rapid adhesion under flow conditions." Arterioscler Thromb Vasc Biol. 19(12):3044-54. [PubMed]

Simon CG Jr, Holloway PW, Gear AR. (1999) "Exchange of C(16)-ceramide between phospholipid vesicles." Biochemistry. Nov 38(44):14676-82. [PubMed]

Polanowska-Grabowska R, Gear AR. (2000) "Heat-shock proteins and platelet function." Platelets. 11:6-22. [PubMed]

Simon CG Jr, Gear AR. (1999) "Sphingolipid metabolism during human platelet activation." Thromb Res. Apr 94:13-23. [PubMed]

Viisoreanu D, Polanowska-Grabowska R, Suttitanamongkol S, Obrig TG, Gear AR. (2000) "Human platelet aggregation is not altered by Shiga toxins 1 or 2." Thromb Res. Jun 98:403-10. [PubMed]

Suttitanamongkol S, Gear AR, Polanowska-Grabowska R. (2000) "Geldanamycin disrupts platelet-membrane structure, leading to membrane permeabilization and inhibition of platelet aggregation." Biochem J. Jan 345 Pt 2:307-14. [PubMed]

Suttitanamongkol S, Gear AR. (2001) "ADP receptor antagonists inhibit platelet aggregation induced by the chemokines SDF-1, MDC and TARC." FEBS Lett. Feb 490(1-2):84-7. [PubMed]

Gear AR, Suttitanamongkol S, Viisoreanu D, Polanowska-Grabowska RK, Raha S,Camerini D. (2001) "Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function." Blood. Feb 97:937-45. [PubMed]