Coagulation Primer

Coagulation & Thrombosis

Pharmacologic treatment of thrombotic and coagulopathic disorders requires an understanding of the steps in platelet adhesion, platelet activation, platelet aggregation, and thrombus formation.   Clots, which are clumps of coagulated blood, form both within the venous and arterial system.  Clots are referred to as a thrombus when adhered to the wall of a blood vessel and become and emboli when detached from the wall of the blood vessel and floats freely within the vasculature.  

Most drugs available are used in the treatment or prevention of thrombosis. Conditions such as deep vein thrombosis (DVT) and pulmonary embolism (PE), which are venous thrombotic conditions, are treated differently than conditions such as myocardial infarction and stroke, which are the result of arterial thrombosis.  Prevention of thrombotic complications in stroke, myocardial infarction, and in the post-operative state also require unique treatment.  

Arterial clots tend to be triggered by atherosclerotic disease and result in clots that are rich in platelets. Venous clots tend to be rich in fibrin with fewer platelets and result from blood stasis, for example, long distance flights without regular ambulation.

Formation of a Blood Clot

Platelet activation and activity is central to the formation of clots. Platelets constantly circulate through the vascular system ready to respond to activating signals.  Endothelial cells are primarily responsible for promoting activation of platelets.

In the healthy state, endothelial cells release prostacyclin, which inhibits platelet activation. Prostacyclin binds to receptors on the platelet membrane that promote intracellular production of cAMP, which decreases intracellular calcium and platelet activation.  

Effects of prostacyclin on platelets in the healthy, normal state

Platelet Activation

When endothelial cells are injured, prostacyclin is no longer released at the same levels, which decreases production of intracellular cAMP in platelets, and thus, increases intracellular calcium levels. Rising intracellular calcium levels trigger the association of GP IIb and GP IIIa to form an activated receptor complex known as GP IIb/IIIa.

Platelet activation in the setting of a vascular injury

Platelet Aggregation

Platelets also have receptors that bind to thromboxanes, collagen, and thrombin. When platelets bind to any of these via receptors, granules of chemical mediators are released. The chemical mediators include thromboxane A2, ADP, serotonin, thrombin, and platelet activating factor (PAF). The chemical mediators activate receptors on other platelets, which results in intracellular release of calcium, and ultimately, expression of activated GP IIb/IIIa receptors on the platelet surface.  GP IIb/IIIa receptors allow platelets to bind to other platelets via linkages to fibrinogen.  

Aggregation of activated platelets

Hemostatic Plug Formation

Local tissue factors and mediators on the surface of platelets also trigger activation of the coagulation cascade.  Thrombin is formed by this process. Thrombin is an enzyme that catalyzes the conversion of fibrinogen to fibrin.  Fibrin incorporates into the forming clot and creates a mesh by cross-linking with other fibrin strands.  This complex of platelets and fibrin is the framework for the hemostatic plug.  

As you may expect, if this process were to continue unabated, the clot would form larger and larger until all of the platelets, mediators, and fibrin were consumed, which would result in tissue ischemia due to the formation of unhealthy levels of clot. Fibrinolysis is the process that is in place to counteract the platelet-activating cascade.  Fibrinolysis occurs when plasminogen is activated to plasmin by enzymes.  Plasmin acts to degrade fibrin, and thus, dissolves formed clots.  

Coagulation

Thrombin production is a result of the intrinsic and extrinsic coagulation pathway. Thrombin catalyzes the conversion of fibrinogen to fibrin, which forms a fibrin clot and assists with hemostasis.  There are two pathways that can result in the production of factor Xa, which catalyzes the conversion of prothrombin (factor III) to thrombin (factor IIa).  

The extrinsic pathway results in the formation of factor Xa after blood is exposed to tissue factor underneath a damaged endothelial layer of a blood vessel.  When blood contacts tissue factor (thromboplastin), factor VII is converted to factor VIIa, which catalyzes the conversion of factor X to factor Xa.  

The intrinsic pathway is activated when factor XII contacts collagen present in damaged blood vessel walls. Factor XII is converted to factor XIIa, which continues through a cascade of factor activations including factor XI, Factor IX, and culminates with factor X conversion to factor Xa, which converts prothrombin to thrombin.

Coagulation cascade