**1. Introduction**

Blood carries a set of zymogen serine proteases called procoagulants these serine proteases are activated upon injury and promote the formation of a clot [1]. The clot formation initiates by two mechanisms [1–4]. One of the mechanisms is termed as tissue factor pathway or extrinsic pathway, and the other pathway is called as contact pathway or intrinsic pathway [2]. Extrinsic pathway or tissue factor pathway is initiated by the tissue factor (TF) released form the damaged cell [1–4]. TF proteolytically cleaves a zymogen factor VII (FVII) and activates it [1–4]. Activated factor VII (FVIIa) forms a complex with TF, forming a potent protease complex which activates the downstream cascade by limited proteolysis. TF-FVIIa complex converts the inactive factor IX (FIX) and factor X to activated factor IX (FIXa) and activated factor X (FXa). The activated FIXa binds to activated Factor VIIIa(FVIIIa) to form X-ase complex on the

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

phosphatidylserine-rich membrane surface, this complex converts FX to FXa. Intrinsic/ contact pathway is initiated by artificial surfaces in the plasma. Artificial surfaces induce conformational change in factor XII (FXII) and results in activation of small amount of FXII. Activated factor XII (FXIIa) activates high molecular weight kininogen (HK) and plasma prekallikrein (PK) and this acts as a positive feedback loop for FXII activation [1–4]. Further, FXIIa activates Factor XI (FXI) to FXIa, which intern activates FIX. Both extrinsic and intrinsic pathways collaborate with a common pathway that involves activated FXa. FXa binds to activated factor V (FVa), forming prothrombinase complex and Prothrombinase complex cleaves prothrombin to generate activated thrombin. Thrombin cleaves fibrinogen to fibrin, these fibrin monomers polymerizes to form insoluble fibrin polymer (**Figure 1A**).

formation [5–7]. TFPI directly binds to FVIIa and Xa complex and inhibits their function and the TFPI function is accelerated in presence of PS. APC proteolytically cleaves FVIIIa and FVa [7]. PS was discovered as a cofactor for TFPI, APC and recent reports demonstrated that PS can directly bind and inhibit the functions of FVa, FIXa and FXa [5–7]. Protein Z-dependent protease inhibitor inhibits FXa and FXIa, in the presence of PZ and calcium [8] (**Figure 1C**-**E**). Blood clots from the healthy system are removed by fibrinolytic system [9]. In the fibrinolysis process tissue specific plasminogen activators (tPA) or urokinase plasminogen activator activates plasminogen by proteolytically cleaving it into activated plasmin. Plasmin cleaves the

Understanding the Clotting Cascade, Regulators, and Clinical Modulators of Coagulation

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Quantitative or qualitative defects in the coagulation factors lead to hemostatic defects such as hemophilia or thrombosis [10, 11]. Hemophilia is characterized by defects in clotting factors and it is characterized by spontaneous or periodic bleedings [11]. Whereas, thrombosis is caused by the high amount of procoagulants in the plasma, hyper activation of procoagulants or defects in anticoagulants [10]. Thrombosis is characterized by systemic clots which impair the normal hemostasis. Bleeding disorders are also classified hereditary and acquired disorders. Hereditary disorders are associated with gene mutations and inherited to the offspring [11]. The major hereditary disorders are hemophilia, rare bleeding disorders and thrombosis. Acquired disorders are caused by several factors such as infections, habits and environmental effects [12].

Hemophilia is an inherited bleeding disorder, caused by the deficiency of procoagulants. Deficiency of FVIII is known as hemophilia A, deficiency of FIX is known as hemophilia B and deficiency of FXI is known as hemophilia C [13–17]. The hemophilia A and B are X chromosome linked disorders and they are mainly observed in the male population [14, 15, 17]. Hemophilia A cases are observed in 1 in 5000 males whereas, hemophilia B cases are observed in 1 in 20,000 males (https://www.hemophilia.org/About-Us/Fast-Facts). Hemophilia is classified based on the functional antigen levels. Patients with <1% activity with spontaneous bleeding are termed as severe hemophilia, patients with 1–5% activity are called moderate

Hemophilia A is majorly caused by deficiency in FVIII antigen levels or mutations in FVIII gene that effect FVIII functions [18, 19]. FVIII is encoded by the gene that localized on the long arm of X chromosome and the gene consists of 26 exons [18, 19]. A total of 2537 mutations are identified on FVIII gene [20]. FVIII is highly expressed in the liver [21, 22]. The mature FVIII protein consists of 2332 amino acids with 6 domains. These domains include A1, A2, B, A3, C1 and C2 [23, 24]. In the blood FVIII is activated by thrombin or FXa [25, 26]. Thrombin cleaves FVIII at R372, R740 and R1689 and removes B domain [26]. Similarly, FXa cleaves FVIII at

hemophilia and individuals with >5%, <40% are termed as mild hemophilia [17].

insoluble fibrin polymers into soluble peptides [9] (**Figure 1F**).

**2. Defects in hemostasis**

**3. Hemophilia**

**3.1. Hemophilia a and factor VIII**

Along with the clotting factors, platelets play a vital role in regulating the hemostasis by forming a cellular plug at the site of injury. The circulating platelets get immobilized at the sub endothelial surface of the site of injury by binding to the von Willebrand factor (VWF) [3]. Platelet receptor GPIb-IXV is essential for this process. Similarly, receptor GPVI helps to anchor the platelets at the site of injury with the help of collagen. Further these platelets get activated and expose phosphatidylserine, which provides a lipid surface for the clotting factors [3]. Among the clotting factors, fibrin helps in activating the platelets by cleaving the protease activated receptors (PARs) that include PAR1 and PAR4 (**Figure 1B**).

Hemostasis is tightly monitored by feedback mechanisms, where anticoagulants inhibit the protease function of coagulation favors by directly inhibiting them or their cofactors [1–4]. The natural anticoagulants include tissue factor pathway inhibitor (TFPI), Activated protein C (APC), Protein S (PS) and Protein Z (PZ). These anticoagulants help in regulating blood clot

**Figure 1.** (A) Schematic representation of coagulation cascade. (B) Schematic representation of platelet plug formation. (C) TFPI pathway. (D) APC function. (E) PZI pathway. (F) Clot lysis.

formation [5–7]. TFPI directly binds to FVIIa and Xa complex and inhibits their function and the TFPI function is accelerated in presence of PS. APC proteolytically cleaves FVIIIa and FVa [7]. PS was discovered as a cofactor for TFPI, APC and recent reports demonstrated that PS can directly bind and inhibit the functions of FVa, FIXa and FXa [5–7]. Protein Z-dependent protease inhibitor inhibits FXa and FXIa, in the presence of PZ and calcium [8] (**Figure 1C**-**E**).

Blood clots from the healthy system are removed by fibrinolytic system [9]. In the fibrinolysis process tissue specific plasminogen activators (tPA) or urokinase plasminogen activator activates plasminogen by proteolytically cleaving it into activated plasmin. Plasmin cleaves the insoluble fibrin polymers into soluble peptides [9] (**Figure 1F**).
