Platelet thrombus formation

Platelet thrombus formation . In response to vascular damage, platelets, which normally circulate as isolated cells, encounter the thrombogenic environment of the subendothelial matrix. This initiates interactions between adhesive wall proteins such as von Willebrand factor and corresponding receptors on the platelet membrane. This adhesive stage, in turn, facilitates the interaction of platelets with collagen and the start of the activation stage.

Summary

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  • 1 Generate thrombin
  • 2 Adhesion and extension of platelets
  • 3 Shear force
  • 4 Platelet aggregation
  • 5 Secretion and recruitment
  • 6 Thrombus consolidation
  • 7 Source

Generate thrombin

Thrombin is subsequently generated, which is also a strong inducer of platelet activation. Activation produces structural changes in the membrane, and shape changes with emission of pseudopods if they are circulating. A sequence of biochemical processes is also initiated, which promote the aggregation and release into the extracellular medium of granular products and releasable metabolic products such as thromboxane A2 (TXA2). Some of these substances released by platelets (ADP, serotonin, TXA2, etc.) are also platelet stimuli that enhance activation and aggregation, and promote the recruitment of new cells to the developing thrombus. Finally, activated platelets develop procoagulant activity that favors fibrin formation and thrombus consolidation.

Under normal conditions these mechanisms control bleeding. However, under pathological conditions, the control mechanisms may fail, causing thrombosis or hemorrhagic diathesis.

Platelet adhesion and extension

The adhesion process involves the transport of platelets to the reactive surface and the interaction of platelet membrane receptors with their ligands on the structures of the injured wall. Adhesive matrix proteins include: collagen, fibronectin, von Willebrand factor , laminin, vitronectin, and thrombospondin . Various platelet membrane glycoproteins and their extracellular ligands can mediate platelet adhesion to the injured endothelium.

Platelets do not adhere to normal vascular endothelial cells, but in areas of endothelial injury they do to various components of the subendothelial connective tissue. In the seconds following the injury, the platelets adhere and are activated with the collagen of the vascular subendothelium through the GPIa-IIa and GPVI. This interaction is stabilized by the adhesive interaction between the GPIb-IX-V complex and von Willebrand factor (VWF), an adhesive plasma glycoprotein that allows platelets to remain attached to the vessel wall despite high shear strength. VWF also has binding domains for subendothelial collagen. The adhesion and activation of platelets by collagen induces the activation of the GPIIb-IIIa complex that also participates in platelet adhesion, especially in high-speed local shear conditions, joining the VWF factor. Once attached to the subendothelium, the platelets spread over the surface and then additional platelets are attached (recruitment).

Shear force

The most relevant mechanical force in hemostasis is the shear force. The term “shear” has the meaning of sliding movement between two adjacent planes, while the concept “stress” denotes force per unit area. Blood is a viscous fluid with laminar flow, which is understood by the type of movement in which the fluid moves as a series of individual sheets, with each stratum moving at a different speed from its neighboring sheets. The shear force, therefore, is defined as the unit force per area between sheets, expressed in dynes / cm2. The value of this local shear force is zero in the center of the vessel and maximum at the periphery, where platelets tend to be. The shear force in veins is less than 2 dynes / cm2,

Platelet aggregation in response to high shear stress values ​​depends on the presence of plasma VWF and the GPIb-IX-V and GPIIb-IIIa receptor complexes. VWF is a multimeric plasma protein, which has binding sites for these platelet receptors and for constituents of the subendothelium (type I, III and VI collagen). The binding of the VWF with the GPIb-IX-V complex is essential for adhesion and aggregation. The binding of GPIIb-IIIa to VWF under static conditions is minimal, but in platelets under the effect of shear force the interaction has the same intensity as with GPIb-IX-V. These glycoprotein complexes have shear-force inducible VWF binding sites. Only a minority of platelets bind to VWF and the binding is reversible and not saturable. It has also been observed that the larger VWF multimers promote more effective aggregation and that the effect of shear force on platelet thrombus formation in the complex in vivo is potentiated by chemical agonists. This may be the reason why heart attacks can occur in patients with a relatively low degree of stenosis, the effect of shear force is on platelet receptors, rather than on VWF itself.

Regarding the inhibition of these platelet processes activated by shear force, cAMP or cGMP have been found to inhibit adhesion and aggregation. Aspirin has little effect in inhibiting shear force-induced aggregation. Fibrinolytic agents inhibit the platelet response to shear force, due to VWF proteolysis by plasmin and t-PA.

The exact mechanism by which shear force induces platelet aggregation is not known. An elevation of cytoplasmic Ca + 2 has been observed. VWF multimers interact with GPIb, causing increased calcium and platelet aggregation, effects that would be enhanced by the binding of VWF to the activated complex GPIIb-IIIa in the presence of ADP released by activated platelets. The involvement of a complex network of intracellular signals, involving various protein kinases and interactions between platelet membrane proteins with the cytoskeleton , is known to be discussed later.

The shear force, in addition to acting on platelets, also causes endothelial cells to secrete prostacyclin (PGI2), which has a vasodilatory action and inhibits platelet aggregation. It also secretes nitric oxide (NO), a potent vasodilator and inhibitor of platelet adhesion and aggregation.

Platelet count and shear force are directly related to collision frequency (number of platelet-platelet contacts per unit time) and collision efficiency (platelet collisions resulting in adhesion or aggregation), thereby promoting aggregation platelet.

In the bloodstream, high shear force (due to rapid blood flow) tends in part to dilute procoagulant molecules and prevent the formation of insoluble fibrin. The thrombogenic phenomenon is multifactorial and there is a greater propensity for it to occur when blood flow is slow. As noted, platelets do not adhere to an intact layer of endothelial cells, although they are subject to high shear force, but they do so strongly to an exposed subendothelium. Various molecules of the subendothelium have been studied to try to define which molecule is the most important in mediating adhesion under the effect of shear force: Fibrillar collagen type I and III is present in high concentrations in arteries and both bind VWF. VWF monomers show two binding sites for these types of collagen, of which only one is relevant. Type VI also joins this factor, but it is less in the arterial sector.

This type of collagen does not respond to high shear force, but it responds to low shear force, thus binding to platelets; this fact suggests that type VI collagen mediates platelet adhesion in venules and capillaries, where shear strength is less. Subendothelial VWF, derived from endothelial cells , may be more active than plasma VWF in initiating slow flow adhesion, but by itself does not promote platelet adhesion in the absence of shear stress; however, in the company of other components, lower the threshold level of this force for adhesion to occur. Fibrinogen is also found on the surface of the vascular endothelium and next to fibrin in atherosclerotic plaques.

Fibrin also binds to platelets and platelet thrombus formation on fibrin has been found to be relatively more dependent on VWF and GPIbα at high shear forces, while at lower levels it is relatively more dependent on GPIIb-IIIa. Other molecules involved in adhesion and that would interact with platelet glycoproteins are laminin, thrombospondin, fibulin-1, and fibronectin. The fibulin-1, recently described, is a protein that can be associated with other constituents of the matrix such as laminin and fibronectin and also with fibrinogen; promotes adhesion by forming fibrinogen bridges with platelets. Fibronectin mediates platelet adhesion through its binding to GPIc-IIa and GPIIb-IIIa on platelets. Thrombospondin is thought to bind to CD36.

Platelet aggregation

Platelet aggregation is the process of joining platelets together to form the thrombus. Among the platelet agonists that have been studied in vitro, those with the greatest physiological relevance appear to be thrombin, ADP, adrenaline, collagen, and arachidonic acid. Table 19-4 shows the agonists, classified according to their platelet activation capacity. Strong agonists include those that can induce secretion independently of aggregation, and at high concentrations, independently of thromboxane synthesis. In contrast, weak agonists require thromboxane aggregation and synthesis for a complete response.

If the activation is carried out in suspended platelets, the first morphological response to the inductor is its change in shape, from disk to sphere with emission of pseudopods. From a biochemical point of view, the conformational change of the GPIIb-IIIa receptor to the adhesive form is necessary, capable of binding fibrinogen and forming bridges between physically close platelets to produce platelet aggregation with any inducer. The binding of fibrinogen, in turn, reinforces platelet activation, and favors the biochemical sequence that leads to the secretion and synthesis of TXA2.

The use of aggregometric techniques has allowed the biochemical and pathophysiological study of this process. Optical aggregometry is the most widely used method and has provided the most information on platelet pathophysiology and the effect of antithrombotic drugs.

Secretion and recruitment

The release reaction consists of the extrusion of the cytoplasmic granules and their contents into the extracellular medium. The secretion of the α granules requires less stimulation than that of dense granules or lysosomes. This process is dependent on cytosolic calcium. Morphologically, in a first stage, the centralization of the granules takes place and later a fusion of the same with the membrane of the open canalicular system and the subsequent exit through the pores that communicate this system with the exterior.

The secretion is of great functional importance since it amplifies the activating response of the initial stimulus in the secretory platelets. Additionally, the released from activated platelets is a complex physiological agonist that promotes the activation of other platelets by inducing recruitment, an essential stage in thrombus growth. Recent studies indicate that both platelet secretion and the recruiting activity of those released from activated platelets are modulated by their interaction with other blood cells. The leukocyte-platelet interaction inhibits, while the erythrocyte-platelet interaction increases platelet reactivity. These are biochemically regulated processes and modify the effect of some antithrombotic drugs, especially aspirin. On the other hand,

Thrombus consolidation

Platelet activation releases coagulation factors contained in its granules and turns the platelet surface into a procoagulant surface that contributes to the generation of thrombin. Damage to the endothelium also initiates the coagulation cascade that culminates in the generation of thrombin and in the transformation of fibrinogen into fibrin. Thrombin formation is the final stage of primary hemostasis. The fibrin formed is sandwiched between the cells of the platelet thrombus and on its external surface. The thrombus is consolidated by retracting the clot, a process mediated by GPIIb-IIIa, which strongly associates cells with fibrin, making the hemostatic plug practically impermeable and able to resist the pressure of blood flow.

Activation of platelets with collagen or thrombin produces the emission of microvesicles, with a diameter of 200-800 nm. In general, they expose procoagulant phospholipids and can bind some coagulation factors such as Xa, Va, protein S and fibrin, which is why they are believed to contribute to procoagulant activity and thrombus formation. It has also been found that they can expose P-selectin , and therefore interact with other cells that bind the ligand, such as leukocytes or other platelets.

 

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