adhesi-agregasi.doc

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Figure 1. Disruption of the endothelial lining of a blood vessel, due to injury

!, leads to exposure of subendothelial proteins !. "latelets adhereand spread over these subendothelial proteins, in an eort to seal o the site of

injury and prevent blood loss.

#ll platelet functional responses must be tightly regulated to ensure that the

formation a blood clot is of su$cient si%e to seal o the damaged area, whilstnot disrupting blood &ow to vital organs by causing vessel occlusion blockage!.'nfortunately, the conse(uences of abnormal platelet regulation are seen alltoo fre(uently in the clinical setting, with the incidence of cardiovascularrelated diseases such as heart attack and stroke, remaining some of the majorcauses of death in the western world today.

Therefore, it is important to gain acomprehensive understanding of the functionalresponses executed by platelets that participatein vessel wall maintenance, as this knowledgemay have important implications not only for ourunderstanding of existing disease states, butalso for the future development of novelantithrombotic strategies.

Figure 2. )xcessive adhesion of platelets to adiseased vessel leads to the blockage orocclusion of the vessel, preventing blood &owfrom travelling to vital organs and tissues.

Within the Platelet Signalling Unit, current research interests include:

Investigation of signalling enzymes that regulate platelet adhesivefunction

Investigation of signalling factors that regulate blood clot consolidationor "clot retraction"

Investigation of Signalling Enzymes thategulate !latelet "dhesive Function.

*any normal and pathological processes in the human body depend on theability of cells to attach +rmly to a biological surface adhesion!. # classicexample of this is the adhesion of platelets to an injured blood vessel, in orderto prevent blood loss. ur laboratory is investigating the regulation of an

important attachment protein or receptor!, called integrin -igure , ! whichis critical for platelet adhesion. This receptor is fundamental for thephysiological process of haemostasis, as evidenced by patients who suer fromsevere bleeding complications due to a lack of this receptor. Integrin aIIbb/isalso implicated in the development of pathological thrombosis, and manypharmaceutical companies have used this receptor as a candidate drug targetfor treating thrombosis.

The adhesive properties of this major platelet integrin aIIbb/must be tightlyregulated to ensure e$cient haemostasis and avoid pathological thrombosis.0ecent evidence from our laboratory and others has implicated members of the0as family of small 12proteins, 0apb and 0ho#, as critical en%ymes controlling

integrin adhesion. ur studies have demonstrated for the +rst time that theactivation of 0ho# downstream of integrin aIIbb/is responsible for maintainingstable adhesion of platelets, particularly under conditions of blood &ow. Thiseect is achieved through modulation of integrin stability itself, rather thanregulation of the platelet interaction with v3f, or initial activation of theintegrin 4choenwaelder et al, 5665!. In further studies that are ongoing, weare investigating preliminary evidence demonstrating the existence of distinctyet cooperative roles for both 0ho#, and another 0as family member, 0apb, inregulating integrin aIIbb/adhesive function 7hr%anowska23odnicka et al, 566/8manuscript submitted !

elated !ublications


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Schoen#aelder S$, 9ughan 47, :oniface ;, -ernando 4, 9oldsworth *,Thompson "), 4alem 99,


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PLATELET AGGEGAT!"#$ !#%"L%E&E#T "F T'"&B!# A#(F!B!#)"GE#*

Ton Lism+n, ees eeterin.s, +n/ Piip G /e Groot

Thrombosis and Haemostasis Laboratory, Department of Haematology, University

Medical Centre Utrecht, Utrecht, and Institute of Biomembranes, Utrecht University,Utrecht, The etherlands

F!G3ES

Fi.re 1Schematic representation of platelet adhesion and aggregation underflow conditions. A) Rolling of platelets over collagen-bound vWF mediated by G!b.") Firm attachment mediated by alpha#$)beta#%) and glycoprotein &! #G &!)binding to collagen' and by alpha#!!b)beta#() binding to collagen-bound vWF. )latelet activation' secretion' and spreading. *) Aggregate formation.
mailto:[email protected]:[email protected]


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Fi.re 2 +hrombin-mediated activation of ARs in human platelets. ,uman

platelets epress both AR-% and -. +hrombin cleaves at the /-terminaletracellular part of the receptor' thereby eposing a new /-terminus #SF00R/ andG1G2&' respectively)' which binds to the body of the receptor' leading to G-protein-coupled signal transduction.

Fi.re +hrombin-mediated activation of ARs in mouse platelets. 3ouse

platelets epress AR-( and -. AR-(' however' is not cleaved by thrombin' butrather binds thrombin with high affinity and serves as a doc4ing molecule to present


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thrombin to AR-' which is cleaved by thrombin. AR-( is necessary for AR-activation at low concentrations of thrombin. At higher thrombin levels' AR- canbe activated without the re5uirement for AR-(.

Fi.re 4Schematic representation of thrombin binding to G!b#alpha). #A)+hrombin binds to the tyrosine-sulphated region of G!b#alpha) via its eosite !!.

After binding to G!b#alpha) thrombin is able to cleave G&' resulting in the abilityto bind via eosite ! to another G!b6 molecule. +he cleavage of G& is necessaryfor this clustering as the intact G& most li4ely sterically hinders the interactionbetween the two G!b#alpha) molecules. From this point on the two crystalstructures of eli4el et al. and *umas et al. suggest opposite conse5uences. #")

eli4el et al. suggest clustering of G!b#alpha) on the same platelet via thrombin'which could subse5uently lead to intracellular signaling. #) *umas et al. suggestan adhesion mechanism' which involves the interaction of thrombin between twoG!b#alpha) molecules on two different platelets' eventually resulting in possibleplatelet aggregation.


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