Animation: "Mechanism of thrombus formation"

Section 1

Length of Video Animation (no audio): 1 minute 4 seconds

Overview

  1. Balloon insertion/inflation damages the endothelium causing plaque rupture, which results in collagen exposure and the release of platelet activators.
  2. On contact with platelet activators, platelets become activated and the GP IIb/IIIa receptors on their surfaces become exposed.
  3. Many platelet activators are able to exert their effects despite the use of anticoagulants and antiplatelet agents. Collagen is a strong platelet activator that has no inhibitor.
  4. The GP IIb/IIIa receptor is the final common pathway to thrombus formation. Blockade of the GP IIb/IIIa receptor prevents platelet aggregation, and thus prevents thrombus formation.

This sequence outlines the mechanisms by which thrombus formation occurs in damaged vessels as a result of the plaque disruption caused by coronary interventions.

At the start of the sequence, blood can be seen flowing through a plaque-filled coronary vessel. A balloon is inserted into the vessel and, as it inflates, it damages the endothelium and causes the plaque to rupture. This causes the release of platelet activators into the bloodstream, and the exposure of intravascular collagen.

The balloon is then deflated and removed from the vessel, enabling blood flow to be restored. Immediately after deflation, sections of the disrupted plaque break off and travel towards the microvasculature. An inactive (smooth) platelet can be seen traveling through the vessel and coming into contact with the exposed collagen in the damaged lesion. On contact with collagen – a platelet activator – the platelet becomes activated and adopts an irregular, uneven appearance and the GP IIb/IIIa receptor is expressed on its surface.

There are many platelet activators. For the sake of discussion, a number of well-known platelet activators and the adjunctive pharmacotherapies that inhibit them have been highlighted. This animation illustrates that, even if all of these agents are used, many platelet activators with no mitigators – such as collagen, PAF, and vasopressin – are still present and are able to exert their full effects. Collagen, which becomes exposed to blood flow after vessel injury, is quite a strong activator of platelets that is unopposed by adjunctive therapy. The GP IIb/IIIa receptor is the final common endpoint of all of these activators, and enables platelets to bind to each other. This makes the inhibition of the GP IIb/IIIa receptor such an important target for PCI.

Section 2

Length of Video Animation (no audio): 31 seconds

Overview

  1. Platelets and fibrinogen circulate freely in the blood. When platelets are not activated, these factors exist separately.
  2. Fibrinogen acts as a bridge between activated platelets – via the exposed GP IIb/IIIa receptors – enabling platelets to aggregate and thrombus formation to begin.
  3. Due to its weak affinity for the GP IIb/IIIa receptor, fibrinogen binds to and dissociates from the GP IIb/IIIa receptor and moves between platelets – a process of dynamic binding. An excess of fibrinogen maintains the binding of any given GP IIb/IIIa receptor.

Switching back to the injured vessel after the removal of a balloon, it can be seen that red blood cells, activated platelets, and fibrinogen molecules (blue) are flowing freely in the vessel. When platelets are not activated, platelets and fibrinogen exist separately. Here, the platelets are activated, and moving in closer we can see that platelet-fibrinogen aggregates are forming. Zooming in to view the aggregated platelets at the molecular level, links that have formed between the fibrinogen molecules and the exposed GP IIb/IIIa receptors can be seen. These links act as bridges to join platelets together and allow thrombus to form.

The binding of fibrinogen to the GP IIb/IIIa receptor is a dynamic process due to the relatively weak affinity of fibrinogen for the GP IIb/IIIa receptor. In the early phase of interaction, fibrinogen continually binds to and dissociates from the receptor, and often moves between receptors. An excess of fibrinogen maintains the binding of any given GP IIb/IIIa receptor.

Moving back to the vessel, large quantities of activated platelets can be seen adhering to the damaged plaque. Consequently, a thrombus is forming and blood flow through the vessel is becoming severely restricted. Simultaneously, a section of thrombus breaks away from the plaque and begins to flow along the vasculature. This is an important aspect of thrombus development – it is a very dynamic process that involves a continuous cycle of thrombosis and dethrombosis.

Centocor Logo