**5.7. FXIII deficiency**

The functional FXIII consist 2 catalytic A subunits (FXIII-A) and 2 carrier subunits (FXIIIB) [85]. FXIII-B is encoded by chromosome 6 and synthesized by the cells derived from bone marrow, whereas FXIIIA is encoded by chromosome 1 and secreted from liver [85, 86]. FXIII crosslinks α and γ subunits of fibrin thereby increases the strength of fibrin clot and increases fibrinolytic resistance [86]. Prevalence of FXIII deficiency is 1 in 2 million, patients with FXIII-A have high tendency of bleeding [87]. 2–5% plasma FXIII is sufficient to prevent bleeding, FXIII concentrates are usually used to treat FXIII deficiency and frozen fresh plasma and cryoprecipitate are also recommended [87].

#### **5.8. Vitamin K dependent coagulation factors deficiency (VKCFD)**

Procoagulants such as FII, FVII, FIX and FX, as well as anticoagulants Protein C, S and Z contain a Glutamic acid rich domain [88, 89]. The Glutamate residues require γ-carboxylation to enable these proteins to bind to the phospholipid membrane in the presence of calcium and carry out their functions [90]. Hepatic γ-glutamyl carboxylase (GGCX) and its cofactor, reduced vitamin K (KH2) aids the carboxylation process and in this process vitamin K is converted into vitamin K epoxide [91, 92]. The vitamin K epoxide is recycled to reduced vitamin K by the vitamin K epoxide reductase (VKOR) enzyme complex [91, 92]. GGCX is encoded by the gene located on chromosome 2 and VKORC1 is encoded by the gene present on chromosome 16 [93, 94]. Mutations in these gene cause loss of GGCX or VKOR complex function and lead to vitamin K dependent coagulation factor deficiency [95]. The clinical manifestations of VKCFD include intracranial hemorrhage or umbilical stump bleeding [95]. Viral inactivated frozen fresh plasma is the agent of choice for VKCFD patients, who require surgical procedures or have acute bleeding [95].

prevent their degradation and enhance thrombin generation. High levels of FVIII, FIX, FVII

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

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FVIII is secreted from the hepatocytes, the mature FVIII zymogen circulates in the blood stream at a concentration of 0.1–0.2 μg/ml (<100 IU/dl) [105]. In blood FVIII is bound to vWF produced by the endothelial cells, with a dissociation constant of 0.2–0.4 nM [106]. The complex of vWF-FVIII stabilizes FVIII by preventing the cleavage of inactive FVIII by FXa and APC and it also blocks the procoagulant of FVIII by allowing the selective activation of FVIII by thrombin (**Figure 2**). vWF anchors and multimerizes at the site of tissue damage and helps in the formation of platelet plugs [106]. These vWF multimers are cleaved by ADAMTS13 (ADAMTS13 is a Disintegrin like and Metalloprotease with ThromboSpodin repeats family metalloprotease) [107]. Mutations in vWF or ADAMTS13 increases plasma FVIII levels. Increase in the plasma FVIII above 150 IU/dl increases the risk of thrombosis by 4.8 fold [105, 108]. Further each increase in FVIII level with 10 IU/dl is associated with a 10% increase in the risk of a first

FIX is a key component of intrinsic/contact pathway. Levels of FIX are important to regulate the hemostasis [3]. Lower levels of FIX antigen leads to hemophilia and recently two studies showed that higher levels of FIX lead to thrombosis [109]. Saenko et al. demonstrated that risk of thrombosis increases by 2.3–2.8 fold in the subjects with plasma FIX activity >150 IU/dl and van HylckamaVlieg et al. demonstrated that risk of thrombosis increases by 2.8 fold with plasma FIX levels >129 U/dl [110, 111]. Age, increase in blood lipids and use of oral contraceptive pills are some of the reasons for elevated plasma FIX levels [110, 111]. Some of the mutations in FIX gene lead to increase in FIX activity thereby, increase in the risk of thrombosis. FIX Padua variant is a one among the FIX mutants to show enhanced risk of thrombosis. FIX Padua is a single amino acid substitution variant where arginine 388 is mutated to leucine [112].

Tissue factor is also known as Factor III (FIII), it is a 47 kDa glycoprotein highly expressed in the pericytes and adventitial fibroblasts, low levels of TF expression are observed in CD14-positive monocytes [113]. TF is expressed in the parenchyma of highly vascularized organs such as placenta, brain, heart, kidneys, and lungs [114]. Circulatory TF is found in macrovesicles produced by apoptotic bodies, smooth muscle cells, monocytes and cancer cells. TF expression is

FXI levels more than 110 IU/dl increases the chances of thrombosis by 2 fold and inhibition of FXI in thrombosis models rescues the DVT. Prothrombin levels more than 115 IU/dl increases the risk

enhanced by pathological conditions such as bacterial infections and cancer [115, 116].

and TF are known to cause the thrombosis [105].

*6.1.1. FVIII and thrombosis*

event of thrombosis.

*6.1.2. FIX and thrombosis*

*6.1.3. Tissue factor and thrombosis*

*6.1.4. Other procoagulants and thrombosis*
