*2.3.1 In the anticoagulant system*

*Protein C pathway:* Protein C is a vitamin K-dependent serine protease produced in the liver and metabolised to its active form, known as activated protein C (APC) by thrombin. It is a strong anticoagulant that degrades FVa and FVIIIa and limits the coagulation process. The effect of APC is hindered by protein C inhibitors, such as α2- macroglobulin and α1-antitrypsin [15].

*Thrombomodulin (TM)* is a trans-membrane receptor available on endothelial cells. TM binds to thrombin to form a TM–thrombin complex that increases the synthesis of APC through which thrombin efficiently functions as an anticoagulant, that inhibits clot generation on the undamaged endothelium area [15].

*Protein S* is a vitamin K-dependent glycoprotein produced by hepatocytes and endothelial cells. It acts as cofactor to APC in the deactivation of FVa and FVIIIa. It is available in the plasma in many forms but only the free form shows anticoagulant activity. It also has anticoagulant activities independent of APC, such as direct reversible suppression of the prothrombinase (FVa–FXa) complex [15].

*Tissue factor pathway inhibitor (TFPI)* is a polypeptide synthesised by the endothelial cells and circulates in the plasma. It is the major inhibitor of the TF pathway, named the extrinsic pathway. It inhibits the coagulation cascade through the binding of the circulating FVIIa, that has been exposed to TF. It also binds to FXa to establish a TFPI–FXa complex, which reversibly inhibited FXa. Protein S facilitates the reaction between the TFPI and FXa in the presence of calcium ions and phospholipid, the activity of which is independent of APC [15].

*Protein Z-dependent protease inhibitor (ZPI)* has been recently identified as the component of the anticoagulant system. It is a plasma enzyme synthesised by the liver. It suppresses FXa activities in an interaction that involves both PZ and calcium. The PZ is a vitamin K-dependent glycoprotein and acts as a cofactor for ZPI [15].

#### *2.3.2 In the fibrinolytic system*

*Plasmin or plasminogen* is the major enzyme of the fibrinolytic system produced in the liver, as plasminogen proenzyme is released into the circulation. Although it could not cleave fibrin but has an affinity to fibrin, which is incorporated in the clot and transformed to plasmin through the t-PA and u-PA. Plasmin acts as a serine protease that cleaves fibrin to form soluble FDP. Plasmin exhibits positive feedback on its production [15].

*Plasminogen activators:* The t-PA is a serine protease that is released into the blood through the damaged endothelial cells. It binds to fibrin and converts clot-bound plasminogen to plasmin. The t-PA significantly contribute to the dissolution of fibrin and the maintenance of vascular integrity. The u-PA is found in the blood and ECM. It binds to a specific cell surface receptor known as the u-PAR, which stimulate the cell-bound plasminogen [15].

*Fibrin as a cofactor:* t-PA and plasminogen can bind to fibrin and form a tertiary complex, which is essential for plasmin formation. Thus, fibrin serves a dual purpose as a cofactor for plasminogen activation and a final substrate for plasmin generation. The partly degraded fibrin by plasmin offers much more efficient binding sites for plasminogen, which allows for the deposition of plasminogen on the clot, resulting in facilitated plasmin formation clot lysis [16].

*Inhibitors of fibrinolysis (plasminogen activator inhibitors):* The PAIs inhibit the progress of plasminogen to plasmin. Many types of PAIs have been identified and documented, but PAI type-1 has been investigated as the major physiological inhibitor. It is a glycoprotein produced by several cell types, such as megakaryocytes, endothelial cells, hepatocytes, and adipocytes. PAI-1 suppresses fibrinolysis by irreversibly inhibiting t-PA and u-PA. PAI-1 is taken up during the process and thus described as a 'suicide inhibitor' [16].

#### *Anticoagulants and Hypercoagulability DOI: http://dx.doi.org/10.5772/intechopen.103774*

*The a*2*-Antiplasmin (a*2*-AP)* is the main inhibitor of plasmin. It is a circulating glycoprotein synthesis by the liver, which suppresses plasmin activity in one of the fastest proteins–protein interactions. The α2-Macroglobulin is also produced by the liver and has been recognised as the secondary inhibitor of plasmin in plasma. It functions to deactivate plasminogen activators, APC, and thrombin [16].

*Thrombin activatable fibrinolysis inhibitor (TAFI)* is a plasma proenzyme that is produced by the liver and described as procarboxypeptidase U (unstable procarboxypeptidase), plasma procarboxypeptidase B, or procarboxypeptidase R. It is stimulated to carboxypeptidase by thrombin. TAFIa creates a useful link between coagulation and fibrinolytic systems. It removes lysine (and arginine) residues from the C-terminal of fibrin, which is essentially required for the binding of plasminogen to t-PA. This makes fibrin an ineffective co-factor, which lead to a decreased t-PA-mediated plasminogen activation. It also enhances the inhibition of plasmin by a2-antiplasmin [15].

#### **2.4 Diseases of the anticoagulant system (hypercoagulable states)**

#### *2.4.1 Virchow's triad*

In 1845, the German physician, anthropologist, pathologist, prehistorian, and biologist, Rudolf Ludwig Carl Virchow hypothesised that three factors are important to the development of thrombosis; vascular endothelial injury, haemodynamic alterations and hypercoagulability, which interact with each other (**Figure 3**) [17]. The vascular endothelial injury was identified first as the main initiator of arterial thrombosis alongside traumatic or endocardial damaged. Moreover, the dysfunctional endothelial cells can secrete a significant concentration of procoagulant agents, including platelet adhesion molecules, TF, and PAI-1 while generating little anticoagulant effectors, such as TM and PCL [18]. The haemodynamic changes may promote procoagulant activities and leucocytic adhesions by modifying the gene expression of the endothelial cells. Although blood stasis is the main trigger for venous thrombosis, turbulent blood flow could also facilitate cardiac and arterial thrombosis. In hypercoagulability, blood clotting factors themselves facilitate thrombogenesis through heritable hypercoagulable states, such as mutations in Factor V Leiden (FVL) and prothrombin. Additionally, disseminated intravascular coagulopathy (DIC), heparin-mediated thrombocytopenia, and Trousseau's syndrome have been linked with hypercoagulability [18].

Hypercoagulability or thrombophilia defines a pathologic condition of exaggerated coagulation or coagulation without bleeding episode. It represents the increased risk for thrombose [19]. Hypercoagulability states are either acquired or inherited but real thrombosis originates as a result of interactions of both genetic and environmental agents. It encompasses a wide range of coagulation abnormalities characterised by a thrombotic event, such as deep vein thrombosis (DVT) and pulmonary embolism (PE). Congenital hypercoagulability included prothrombin G20210A gene mutation, deficiencies in protein C and protein S, AT deficiency and a single-point mutation on the FVL. Acquired conditions usually result from trauma or surgery, certain medications while the APS has been identified as the most common acquired thrombophilia in the general population [20]. The genetic abnormalities of the fibrinolytic system are not common, however, the acquired hyperfibrinolysis has been identified as the major cause of severe haemorrhage [15].

#### **Figure 3.**

*Mechanisms of Virchow Triad in the Pathophysiology of Thrombus Formation: Rudolf Virchow proposed a triad of conditions that predisposes to thrombotic formation. They include abnormalities in the blood vessel wall, blood stasis and hypercoagulability. Inflammation, endothelial dysfunction, and atherosclerosis constituted abnormalities in the blood vessel wall. Abnormal blood flow arises from haemorheology and turbulence at bifurcations and stenotic sites. The hypercoagulability encompasses the abnormal blood constituents, including dysfunctional platelet, coagulation and endogenous fibrinolytic abnormalities, and metabolic factors.*
