VII.10.B. Platelet (thrombocyte) activation

The vascular damage induces vasoconstriction and the release of vasoactive molecules. Two parallel processes therefore start: coagulation and thrombocyte activation.

The thrombocytes bind through their cell surface glycoproteins (GP) to the collagens of the damaged vessel wall. Certain coagulant factors have roles in the process (Ib-IX-V and the von Willebrand factor, vWF).

During the process, various mediator molecules are released from the bound platelets.

Thrombin effects

The platelet conformation changes, and

their Ca²⁺ level increases.

The shape of the platelets changes, while

the GP IIb and IIIa in the surface of the platelets promote further aggregation of the thrombocytes. 

PLA₂ activation

PLA₂ produces arachidonic acid from the membrane lipids,  

and then PGH and TXA2 from arachidonic acid by COX.

Its increased activity is a cardiovascular risk factor.

TXA₂

increases the platelet Ca²⁺ level and activates the thrombocytes, thereby enhancing aggregation.

It has a vasoconstrictor effect.

COX-1 is inhibited by aspirin treatment, and the TXA₂ level therefore decreases. Unfortunately, this effect is inhibited by hyperglycemia (and/or DM).   

Adenosine diphosphate (ADP):

It increases the platelet Ca²⁺ level and activates thrombocytes, enhancing aggregation.

It exerts its influence through the P2Y₁ and P2Y₁₂ receptors.

The P2Y₁ antagonist clopidogrel and P2Y₁₂ prasugrel treatment decrease the cardiovascular risk factors more effectively than aspirin in DM patients.

The 5-HT effect:

It increases the platelet Ca²⁺ level, activates thrombocytes, and hence enhances aggregation.

The effects of Epinephrine:

It decreases the platelet cAMP level via the alpha2 receptors, and

activates the surrounded thrombocytes.

Platelet-activating factor (PAF):

This stimulates aggregation in inflammation.

P-selectin

            stimulates aggregation

PAI-1, also known as protease inhibitor (serin)

It binds to plasminogen activator (PA) molecules (tissue or urokinase types), and therefore inhibits plasmin production, and it accelerates and preserves coagulation processes.  

It stimulates the adipose tissue volume.

The PAI-1 concentration is 6-80 ng/ml. Its increased level correlates well with atherothrombosis and myocardial infarction.

It is synthetized in the liver, adipose tissue, platelets, macrophages and vascular walls.

After aggregation, the shape of the thrombocytes undergoes special changes. 

            An ameboid shape is formed from a coin shape by actin filaments. The process is stimulated by PKC.

The myosin filaments are then activated, which induces a contraction (retraction).

In the last step of coagulation, a fibrin polymer is formed from fibrin monomer molecules. The process is catalyzed by thrombin. A cross-linked fibrin polymer is produced from fibrin polymers by factor XIIIa.

Finally, an interwoven thrombus is produced by fibrin filaments (fibrinogen-vWF-GPIIb-IIa-activated thrombocytes-endothelium).

The above process is stimulated by CD40L protein released from the platelets. This protein has a structure similar to that of TNF-α. The protein binds to the GPIIb/IIa complex, and hence promotes the formation of stable bonds, and it increases the inflammatory and proliferation process in the endothelium.  

A physiological protective process occurs to avoid total obstruction of the vascular lumen by precipitated platelets, through a decrease of the aggregation.  

The anti-aggregation factors:

Prostacyclin (PGI₂)

It is released from intact endothelial cells into the blood, and increases the cAMP level of the platelets, which decreases their Ca²⁺ level and their predisposition to aggregation. 

It exerts a strong vasodilator effect.

Nitric oxide (NO)

By increasing the cGMP level, its effect is similar to that of prostacyclin.  

Adenosine

It decreases aggregation by causing adenine breakdown.

The coagulation process can be slowed down by various factors:

activated protein C;

thrombin and thrombomodulin are formed from protein C;

it inhibits coagulation factors (Va and VIIIa);

its amount is decreased by inflammatory pathways and cytokines.

Plasmin

It is formed from plasminogen.

It cuts fibrin polymer filaments (fibrinolysis).

Its effect is inhibited by plasmin inhibitor enzyme (PI), PAI (serpin) and fibrinolysis inhibitor (thrombin-activatable fibrinolysis inhibitor, TAFI).

Antithrombin

It binds thrombin.

The continuously fat-containing adipocytes synthesize proinflammatory factors in obesity (TNF-α, IL-6, complement C3, PAI-1 and some elements of the RAS). The level of adiponectin (an insulin sensitizer) falls and the level of leptin produced by the adipocytes increases. The increased production of macrophages and proinflammatory factors stimulates thrombin and fibrinogen synthesis; thrombin and fibrinogen play key roles in the inflammatory process. The glycosylation (lysine) or nitralization (tyrosine) of fibrinogen change the coagulation and the fibrinolysis process.

Insulin resistance and hyperglycemia decrease endothelial NO production, which causes vasoconstriction. 

Obesity enhances the TXA₂, CD40L and P-selectin levels. A 10% decrease in body weight significantly increases the NO and prostacyclin levels, and decreases the CD40L and P-selectin levels, and the ADP sensitivity of the platelets. These data correlate well with the HOMA index. 

It is suggested that insulin decreases the Ca²⁺ level of the platelets and inhibits P2Y₁₂ receptor-mediated signal transduction. The platelets have IGF-1 receptors, but their role is not known. 

Insulin resistance and obesity increase the PAI-1 level. This level is probably influenced by the abdominal and liver fat. The levels of inflammatory cytokines are also increased by IL-6. The concentration of PAI-1 is decreased by metformin drugs produced for the treatment of T2DM:

The levels of the matrix-breaking matrix metalloproteinases (MMP-1 and MMP-9) increase in a hyperglycemic condition, which induces the development of acute coronary syndrome (ACS).

It has recently been reported that thrombin has various pleiotropic effects. It increases the growth, adhesion, inflammatory processes and infiltration of cells. Its effects are mediated by the PARs (protease-activated receptors). Adipocytes synthesize IL-1, IL-6 and MCP-1 through the action of thrombin (PAR4 receptor). Treatment with the anti-thrombin agrotroban decreases macrophage infiltration and the level of MCP-1. The inhibition of MCP-1 abolishes insulin resistance. Accordingly, an increased thrombin level may be a connecting link between obesity and insulin resistance.