INTRODUCTION
This chapter provides information on the coagulation cascade, and intrinsic and extrinsic coagulation pathways. The chapter also highlights the three phases of coagulation as well as regulatory mechanisms involved in the coagulatory process.
OVERVIEW OF HEMOSTASIS
Hemostasis is a highly conserved mechanism that allows the human body to repair damaged blood vessels, maintain the fluid state of blood, and remove blood clots after the restoration of vascular integrity (Fig. 1). Coagulation, commonly known as blood clotting, plays an essential role in hemostasis.1
Fig. 1: The process of hemostasis.1
Coagulation Cascade
The coagulation cascade was proposed in 1964 as a series of coordinated enzymatic conversions. The coagulation cascade was explained as a stepwise interaction of clotting factors with one another, resulting in activation of these factors and consequently, the formation of fibrin.2 The important coagulation proteins are listed in table 1.3
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The coagulation cascade has been described under two pathways, viz., the (i) intrinsic and (ii) extrinsic pathways.2
Intrinsic Pathway
This pathway is so called, as all the components involved in this pathway are present in the blood.1 It is dependent on contact activation by a negatively charged surface. It involves coagulation factors XII, XI, IX, VIII, and V.2
Extrinsic Pathway
This pathway is so called, as it requires an external factor for initiation of coagulation (tissue factor from the extravascular tissue).1 Thus, this pathway is triggered by the exposure of tissue factor to the circulation; along with the tissue factor, this pathway involves factor VII.2
Both these individual pathways then converge to activate factor X, ultimately causing the conversion of prothrombin (factor II) to thrombin (factor IIa). This results in the conversion of fibrinogen to fibrin (Fig. 2).2
In this cascade model, the initial recruitment of platelets was considered to be an independent mechanism.2
With the latest research and advances in the understanding of coagulation process, there has been a shift in the understanding of the coagulation process from stepwise intrinsic and extrinsic pathways to a more all-encompassing model. According to the latest understanding, there is an intricate interlinking of the stepwise patterns explained in the classical coagulation cascade. Now there is also a better understanding of regulatory mechanisms. Furthermore, the potency of several key factors within the pathway, to achieve appropriate and regulated hemostasis, is also better understood.23
Fig. 2: Classic coagulation cascade2Source: Adams RL, Bird RJ. Review article: Coagulation cascade and therapeutics update: relevance to nephrology. Part 1: Overview of coagulation, thrombophilias and history of anticoagulants. Nephrology (Carlton). 2009; 14(5):462-70.
Three Phases of Coagulation
While the coagulation cascade has been commonly used to understand the process of coagulation, a cell biological model of coagulation is also gaining attention. According to this current model of coagulation, the process can be divided into three separate phases (Fig. 3).1
Initiation Phase
Classically known as the extrinsic phase, the initiation phase begins with the exposure of subendothelial cells and fibroblasts to the blood stream due to the damage to the vasculature. With this, a key initiator of the coagulation cascade, tissue factor, is exposed.4
Fig. 3: Phases of coagulation1
Tissue factor acts as a cofactor for factor VII and activates it to VIIa. The tissue factor/VIIa complex also produces traces of factors IXa and Xa. Factor Xa then associates with the cofactor, factor Va, to form a prothrombinase complex on tissue factor—expressing cells; this ultimately leads to the conversion of prothrombin (factor II) to thrombin (Fig. 4).1
Amplification Phase
The thrombin produced in the initiation phase, though low in quantity, keeps activating the platelets that have gathered in the region of injury. Parallelly, thrombin activates the platelet-derived factor V to Va. This further amplifies prothrombinase activity, and also activates factor VIII to VIIIa. Activated factor VIIIa acts as a cofactor to factor IXa on the surface of activated platelets and supports the activation of factor X. Furthermore, thrombin also activates factor XI to XIa.1
Fig. 4: Mechanisms involved in different phases of coagulation2
Propagation Phase
The propagation phase takes place on surfaces of activated platelets, which contain procoagulant phospholipids. Activated factor XIa further activates factor IX to IXa, which then associates with thrombin-cleaved factor VIII. On phosphatidylserine-exposing cell membranes, the tenase complex of activated factors IXa/VIIIa helps in the activation of factor X to Xa. The factor Xa/Va complex then produces adequate quantities of thrombin to form fibrin fibers. Finally, the thrombin-activated factor XIIIa helps in the formation of covalent crosslinks between fibrin chains to form an elastic, polymerized fibrin clot.1
Fibrinolysis
The removal of the clot by fibrinolysis is essential, both following the formation of a clot in response to vascular damage or due to pathological thrombosis (arterial or venous), and atherosclerosis. Fibrinolysis is primarily mediated by plasmin, which is produced by the proteolytic cleavage of circulating plasminogen by two main effectors:2
- Tissue-type plasminogen activator (released from endothelial cells in response to thrombin and venous occlusion)
- Urokinase-type plasminogen activator [secreted as prourokinase, and activated by plasmin and contact factors (kininogen, prekallikrein, and factor XII)]
Inappropriate plasmin generation is prevented by the abundance of plasminogen activator inhibitors in the flowing blood. These plasminogen activator inhibitors form inactivating complexes with the tissue-type and urokinase-type plasminogen activators explained above.2
Plasmin cleaves fibrin at specific lysine and arginine residues, resulting in the production of fibrin degradation products.2
REGULATION OF COAGULATION
Each level and phase of the coagulation process is regulated by inhibitory factors, either by enzymatic inhibition or by modulation of cofactor activity. Various regulatory proteins of the coagulation cascade and their point of action are summarized in table 2.2
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REFERENCES
- Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev. 2013;93(1):327–58.
- Adams RL, Bird RJ. Review article: Coagulation cascade and therapeutics update: relevance to nephrology. Part 1: Overview of coagulation, thrombophilias and history of anticoagulants. Nephrology (Carlton). 2009;14(5):462–70.
- Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem. 2000;46(8 Pt 2):1260–9.