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Essential Thrombocythaemia

clot contraction involving contraction of the cytoskeletal actin filaments in platelets.

• The progression and development, or embolisation, of a developing thrombus could be controlled in part by negative regulation by metalloproteinase-mediated ectodomain shedding of platelet receptors, such as GPIbα (ligand-binding subunit) of GPIb- IX-V or GPVI, or by the switching on of inhibitory signalling pathways downstream of receptors such as leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR-1) or platelet endothelial cell adhesion molecule 1 (PECAM-1).

This sequence of events could be envisaged where there is damage of the blood vessel wall leading to exposure of collagen/vWF in the subendothelial matrix; however, other physiological or pathological circumstances are also capable of initiating thrombus formation. An important example is found in some forms of autoimmune disease, where antibodies activating platelets via the Fc receptor, FcγRIIa, can trigger thrombosis. Another example is coagulopathy caused by aberrant generation of thrombin, a potent platelet agonist, acting at PAR-1 and PAR-4.

Platelet Interaction with Leukocytes and the Endothelium

The interaction between platelets, leukocytes and the endothelium can occur in different ways. Platelets can first form conjugates with leukocytes and support leukocyte recruitment to the endothelium via activation of leukocyte adhesion receptors. Alternatively, platelets adherent on the endothelium can chemoattract leukocytes and provide a sticky surface for neutrophil–endothelium interaction. The net result of these events is the infiltration of inflammatory cells into the vessel wall.28,29

procoagulant molecule, is a highly negatively charged multimer that appears to play a key role in activation of the intrinsic coagulation pathway by activation of FXII.30

In experimental models, FXII/FXI-

initiated coagulation is important in formation of a stable occlusive thrombus, although the intrinsic pathway seems dispensable for normal haemostasis.31 activated platelets,32

The receptor GC1qR/p33 is also expressed on and can assemble a procoagulant complex

involving FXII, high-molecular-weight kininogen and pre-kallikrein that is involved in the initiation of the intrinsic coagulation pathway.

Together, the capacity of circulating platelets to transport diverse prothrombotic and procoagulant substances throughout the bloodstream, and to rapidly release them into the local environment when triggered, has significant consequences in health and disease.

Cross-talk Between Platelets and the Coagulation Cascade

Platelet activation and activation of the coagulation cascade are complementary processes. Coagulation factors bind to platelets through either glycoprotein receptors or through anionic phospholipids exposed on the outer surface of the plasma membrane after platelet activation (see Figure 1D). For example, binding of collagen to GPVI activates platelets, exposes phosphatidylserine and supports thrombin formation and clot stabilisation.33


Platelets therefore play additional roles beyond haemostasis and thrombosis. Platelet-mediated inflammation provides the basis for plaque formation before actual vessel occlusion; platelets thus link the diverse processes that culminate in atherogenesis.

Secretion of Growth Factors from Platelets Activated platelets rapidly release a multitude of growth factors from intracellular storage granules. These growth factors include platelet- derived growth factor (PDGF), a potent chemotactic agent, and transforming growth factor-β (TGF-β), which stimulates the deposition of extracellular matrix (ECM) as well as performing other functions. Both of these growth factors have been shown to play a significant role in the repair and regeneration of connective tissues. Other growth factors produced by platelets include basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), platelet-derived epidermal growth factor (PDEGF) and vascular endothelial growth factor (VEGF). These factors promote inflammation by stimulation of leukocytes as part of the normal defence against infection, as well as pathologically in inflammatory disease.

The intracellular granule-expressed protein P-selectin mediates adhesion between activated platelets and neutrophils via the counter- receptor, P-selectin glycoprotein ligand-1 (PSGL-1). Platelets also secrete platelet agonists, such as ADP or TXA2, that act in an autocrine or paracrine fashion as prothrombotic factors, and adhesive proteins such as vWF or thrombospondin, which promote platelet adhesion under shear stress by binding to GPIbα or other receptors.21

Other important secreted factors, including coagulation factors and fibrinolytic proteins, regulate coagulation. Polyphosphate, a secreted


interaction is also responsible for the shedding of membrane blebs into the circulation, which provides procoagulant microvesicles. Bleb formation and phosphatidylserine exposure rely on the induction of prolonged increases in intracellular calcium resulting from platelet activation by ADP, TXA2, thrombin and collagen. ADP is also responsible for the induction of platelet procoagulant activity through interaction with P2Y1 and P2Y12.34

Platelet secretion products

contribute to the procoagulant activity of activated platelets by providing factor V, factor VIII and fibrinogen. Activated platelets support the initiation phase of coagulation by providing binding sites for FXI and prothrombin. These functions reveal the dual role of platelets in thrombus formation and coagulation (see Figure 1D). Thus, sP-selectin might be involved in phosphatidylserine exposure in monocytes and in the genesis of leukocyte-derived microparticles containing active TF, which enhance thrombin generation and fibrin deposition through a PSGL-1-dependent mechanism.35

In addition, sCD40L induces platelet P-selectin expression, aggregation, leukocyte activation, platelet–leukocyte conjugation and platelet release of reactive oxygen intermediates.36

Role of Platelets in Immunity

Platelets also appear to play an active role in both innate and adaptive immunity.37,38

GPIbα with endothelial cells (P-selectin) or leukocytes (αMβ2), or activated platelet P-selectin with leukocytes (PSGL-1), can support

leukocyte rolling and activation on a mural thrombus. In addition, the secretion of cytokines can recruit leukocytes to sites of tissue damage. Platelets also express immune receptors such as FcγRIIa,39


immunologically relevant molecules such as CD40L and toll-like receptors, which functionally modulate innate immunity. Platelets also interact with Gram-positive or -negative bacteria and spirochetes, which can activate platelets and promote an inflammatory or immune response through secreted proinflammatory factors. Bacteria are also a potentially important risk factor for cardiovascular thrombotic disease.39–41

EUROPEAN ONCOLOGY & HAEMATOLOGY For example, platelet adhesive interactions, such as

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