Adp

Pyrophosphate Serotonin Calcium Magnesium

3. Lysozomes Lysozyme

4. Peroxisomes Catalase layer to which other platelets or leukocytes can adhere. Additionally, and as part of the link between platelet-dependent hemostasis and strict coagulation, activated platelets undergo the so-called "flip-flop" reaction and provide an anionic phosphatidylserine-rich surface for the efficient assembly of a prothrombinase complex with consequent thrombin formation. Therefore, strategies aimed at interrupting platelet activation and aggregation may also result in decreased thrombin generation, both in vitro (21) and in vivo (22).

Platelet Secretion

Because platelets are anucleate cells, it was long thought that they were incapable of any protein synthesis. However, it has recently been discovered that platelets, especially after thrombin stimulation, are indeed capable of translating constitutive mRNAs in their cytoplasm and of rapidly synthesizing interleukin (IL)-ip (23), which may actively participate in thrombotic and inflammatory phenomena for extended periods of time. In addition, platelets contain potent pro-aggregatory mediators prepackaged in various granules (Table 1). a-Granules release a vast array of proteins, while dense granules contain several mediators that greatly amplify the activation and aggregation processes.

Some of the proteins contained within the a-granules are synthesized by the megakaryocyte and are subsequently passed on to platelets during their production in the bone marrow, while other proteins may simply enter the platelet by receptor-mediated endo-cytosis or fluid-phase pinocytosis (20).

Platelet Aggregation

Unlike the many receptors that intervene in platelet adhesion, GP Ilb/IIIa seems to be the main receptor responsible for the final phases of platelet aggregation. The GP IIb/IIIa receptor (also denominated aIIbb3 in the integrin nomenclature) is the most abundant receptor expressed on the platelet surface, with a density of about 70,000-90,000 receptors on the surface of a quiescent platelet, but which can be increased to more than 100,000 receptors per cell after platelet activation and translocation of an internal pool of GP IIb/IIIa located in a-granules (24). Like other members of the integrin superfamily, GP IIb/IIIa is a heterodimeric molecule with a large extracellular domain for cation ion-facilitated ligand binding, and short intracytoplasmic tails involved in "outside-in" signaling after its ligation (25) (Fig. 2). Several different molecules, such as vWf, fibrinogen, fibronectin, and vitronectin, serve as ligands to this receptor, nevertheless, fibrinogen appears to play the main role in the aggregation process (26). On the other hand, vWf is believed to be the principal ligand mediating shear-induced platelet aggregation (17,27). Two sequences are recognized by GP IIb/IIIa: (i) the RGD (Arg-Gly-Asp) sequence (28), which is present on several ligands including vWf, fibrinogen, and fibronectin; and (ii) the KQAGDV (Lys-Gln-Ala-Gly-Asp-Val) sequence, which is only present in fibrinogen (29). In the resting state, GP IIb/IIIa has a low affinity for fibrinogen binding, however, platelet agonists functionally up-regulate this integrin via "inside-out" signaling, inducing conformational changes that lead to a binding-competent status (30) (Fig. 3). Therefore, during platelet activation, GP IIb/IIIa becomes receptive to ligand binding with the consequent formation of fibrinogen bridges between other GP IIb/IIIa receptors on platelets, thus forming platelet-rich thrombi (Fig. 4). In addition, fibrinogen may also form a bridge between activated GP IIb/IIIa on platelets and MAC-1 (aMb2 or CD11b/CD18) integrins expressed on leukocytes, thus forming platelet-leukocyte aggregates (31), which are likely to have an important role on inflammation linked to thrombosis.

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