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Essential Thrombocythaemia

Figure 1: Platelet Production and Function A

Platelets Activaton/secretion Aggregation vWF C Adhesion

Megakaryocyte B GPIb-IX-V S GPIbβ GPIX GPIbβ N S S P166 609 S P166 P P P 590 587 Platelet

Activated platelet phospholipids

Secreted polyphosphates

Anucleate platelets are released preformed into the bloodstream from tubular structures on megakaryocytes (A). Platelets express unique adhesion receptors such as the glycoprotein (GP) Ib-IX-V complex, which binds von Willebrand factor (vWF), and the collagen receptor, GPVI (B). These receptors support initial platelet adhesion to the injured or diseased vessel wall under shear-flow conditions, leading to rapid platelet activation and secretion, and activation of the integrin αIIbβ3, which binds vWF or fibrinogen and mediates platelet aggregation (C). Concomitant with thrombus formation, platelets play an important role in coagulation through receptors such as GPIbα (the ligand-binding subunit of GPIb-IX-V), which binds adhesive ligands, and coagulation factors and thrombin by expression of phospholipids on activated platelets involved in assembly of procoagulant complexes, and/or by secretion of procoagulant factors such as polyphosphates from dense granules that potentially activate coagulation factors of the intrinsic pathway (convert factor XII [FXII] to FXIIa).

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Refrigeration of platelets used for transfusion (<15ºC, one hour) results in accelerated clearance upon reperfusion, with an apparent role for platelet glycoprotein (GP) Ibα and αMβ2 on Kupffer cells.4

Platelet ‘apoptosis’ induced by drugs or chemicals, for example chemotherapeutics (either in vivo or in vitro treatment prior to reperfusion), can result in increased apoptotic markers and rapid clearance of systemic platelets, as well as potential effects on megakaryocytes and platelet production, resulting in thrombocytopaenia.

In the case of cold-related platelet lesions, alterations of platelet receptor glycosylation and clustering of receptors on the surface may trigger clearance. It is also generally recognised that platelet receptor surface expression levels decrease with age, and metalloproteinase- mediated ectodomain shedding potentially plays some part in regulating platelet clearance. In this regard, there is experimental evidence that sequestering of 14-3-3ζ or other proteins by the cytoplasmic domain of GPIb-IX-V, a platelet adhesion receptor, could control 14-3-3ζ-dependent regulation of interactions between cellular death/survival factors.

Platelet Adhesion Receptors

Platelets express unique receptors adapted to fulfil their role and enable rapid transition from a resting circulating state to an adherent activated state under high shear rates (see Figure 1B and 1C). GPIb-IX- V is constitutively expressed on the surface of resting platelets, but the


binding site for its major adhesive ligand, von Willebrand factor (vWF), is non-functional, preventing interaction with plasma vWF. It is only when the vWF-binding domain of GPIbα (N-terminal 282 residues) or the GPIbα-binding domain of vWF (A1 domain) is activated that the adhesive interaction occurs.5


Adhesive ligands


vWF-A1 αmβ2

P-selectin Thrombospondin S E282


THrombin FVIIa

Coagulation factors


Matrix of collagen/vWF

The GPIbα–vWF-A1 interaction is induced

in vivo by high shear stress resulting in an active conformation of GPIbα, vWF or both, or by immobilisation of vWF in the subendothelial matrix. This allows GPIb-dependent platelet adhesion and activation at sites of vascular injury (haemostasis) or disease (atherothrombosis or vascular stenosis generating pathological shear stress). Functional studies, molecular evidence and in silico modelling reveal how shear- induced conformational changes enhance the bond strength for the interaction through ‘catch–slip’ bonds as the shear rate increases. This molecular adaptation enables GPIb/vWF-dependent platelet adhesion under pathological shear conditions.6–9

GPIb-IX-V comprises multiple subunits, all of which are members of the leucine-rich repeat family of proteins (see Figure 1B). GPIbα (~135kDa) is disulphide-linked to two GPIbβ subunits (~25kDa), and non-covalently associated with GPIX (~20kDa) and GPV (~82kDa). The ligand-binding domain of GPIbα is elevated from the membrane by a sialomucin core, and interacts with multiple adhesive ligands such as vWF and thrombospondin, receptors such as P-selectin (activated

platelets or endothelial cells) or αMβ2 (activated leukocytes) and coagulation factors such as factor XII (FXII), FXI, thrombin and high- molecular-weight kininogen; this receptor clearly plays a central role in


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