20.1 Introduction to Clotting and Coagulation

Blood Coagulation

Human blood moves as a fluid; however, when injury occurs, hemostasis is accomplished in two major ways: primary hemostasis and secondary hemostasis. Primary hemostasis is the process of platelet adhesion to form a platelet plug, or platelets that are aggregated on the injured vessel wall or tissues. Platelets can be activated in response to collagen released during tissue damage or by a number of other substances. A few of the substances most important for pharmacology are highlighted below and are shown in Figure 20.2:

• Thromboxane A2, synthesized by the cyclooxygenase pathway
• Adenosine diphosphate, which interacts with P2Y12 receptors on the platelet surface
• Thrombin, produced in the coagulation cascade described below
• Von Willebrand factor and fibrinogen, which bind to the glycoprotein IIb/IIIa (GPIIbIIIa) receptor to facilitate platelet adhesion to other platelets and to the blood vessel wall

Each of these activation steps represents a potential drug target in treatment of pathologic thromboses; they will be expanded upon within the text for the relevant drugs.

Figure 20.2 Platelet activation occurs through thromboxane A2, adenosine diphosphate, thrombin, von Willebrand’s factor, and fibrinogen, among other substances. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Upon tissue injury, secondary hemostasis can be activated via the coagulation cascade. The coagulation cascade can be thought of as a chain reaction. The coagulation cascade is made up of clotting factors, which are proteins that work to activate different parts of the coagulation cascade. The factors are named numerically with Roman numerals (e.g., factor X, factor VII). An activated form of a factor is denoted by “a” suffix (e.g., factor Xa, factor VIIa). Figure 20.3 depicts the clotting cascade; it may be helpful to follow the figure simultaneously while reading through the text.

Figure 20.3 The coagulation cascade can be activated by either the intrinsic or extrinsic pathways. Clotting factors form a chain reaction and converge on a common pathway that ends in formation of a stable fibrin clot. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

The coagulation cascade can be activated by either the intrinsic pathway or extrinsic pathway, which converge on a common final pathway. Although they are discussed as separate pathways, the physiology is less linear and more complex, with significant crossover and both pathways being activated in response to tissue damage.

• The extrinsic pathway is activated by injury to blood vessels, which release tissue factor when damaged. Tissue factor works with factor VIIa to activate factor X to factor Xa, which is part of the common pathway.
• The intrinsic pathway is activated by collagen that is exposed when there is endothelial damage. Collagen facilitates the activation of factor XII. Factor XIIa then facilitates the activation of factor XI, which in its activated form facilitates the activation of factor IX. Factor IXa and factor VIIIa work together to facilitate activation of factor X.
• The common pathway begins with factor X. Recall from above that factor X is activated by both the intrinsic and extrinsic pathways. Factor Xa facilitates the activation of factor II, which is also known as thrombin. Thrombin facilitates the activation of fibrinogen to fibrin. Thrombin also has other roles within the clotting cascade; it activates factor VIII in the intrinsic pathway and factor V in the common pathway. Thus, activation of thrombin contributes to increased upstream activation as well, which continues down the cascade and activates more thrombin. Fibrin monomers link together to form fibers and branches that make up a solid fibrin clot.

It is noteworthy that many other substances are involved in synthesis and regulation of the clotting cascade. Vitamin K, a vitamin present in foods such as green, leafy vegetables, is a cofactor needed for synthesis of clotting factors II, VII, IX, and X. Calcium is also necessary for activation of several clotting factors.

Coagulation is in homeostatic balance with fibrinolysis, or breakdown of fibrin, as shown in Figure 20.4. This is accomplished when the enzyme tissue plasminogen activator (tPA) facilitates conversion of plasminogen to plasmin, which degrades fibrin. Other natural anticoagulants include proteins C and S, which work together to inhibit the activation of many clotting factors including factors VIIIa, Va, X, and prothrombin; antithrombin, which inhibits the action of many clotting factors including factor Xa and thrombin; and tissue factor pathway inhibitor (TFPI), which inhibits the action of factor Xa.

Figure 20.4 Clotting and fibrinolysis are in constant balance. Excessive activation of the coagulation cascade can lead to thrombosis, the formation of a clot inside a blood vessel that can block blood flow. Excessive fibrinolysis, mediated by plasmin, can lead to bleeding. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Thrombus Formation

The pathologic formation of thrombi (plural of thrombus) occurs as the result of endothelial injury, hypercoagulability, and stasis of blood flow; this is known as Virchow’s Triad and is depicted in Figure 20.5. Endothelial injury activates clotting as described above and occurs due to events such as catheter placement, surgery, or trauma (Ashorobi, 2022). Hypercoagulability refers to a prothrombotic state due to circumstances such as an excess of clotting factors or relative insufficiency of natural anticoagulants. Abnormal blood flow can occur due to prolonged immobility (such as during travel, surgeries, or hospitalization), atherosclerosis within a blood vessel, or an abnormal heart rhythm called atrial fibrillation, where blood pools in the atria because there is no organized contraction of the chambers.

Figure 20.5 Virchow’s Triad describes the causes of clot formation. (See Kushner, et al., 2022, and McLendon, et al., 2023; attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

While formation of a clot can be lifesaving during bleeding events, formation of a thrombus can occlude a blood vessel, prohibiting the delivery of blood to downstream tissues. The most common types of thrombi are described below, although this list is not all-inclusive.