*6.1.1. FVIII and thrombosis*

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

138 Hematology - Latest Research and Clinical Advances

**6. Thrombosis**

**6.1. Procoagulants - thrombosis**

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].

Blood clotting occurs at the site of injury to prevent the leakage of the blood However in thrombosis, blood clots are formed in the blood vessel without any damage response and occlude the blood vessel [96]. Thrombosis is classified based on the location of the clot formation, it includes atrial thrombosis, venous thromboembolism (VTE) and pulmonary embolism (PE) [97, 98]. Thrombosis causes high mortality in United States where, annually 900,000 patients develop VTE and 300,000 people die due to PE [99–101]. Atrial emboli is found predominantly in surgical and intensive care patients due to preexisting conditions such as age, hypercoagulability, cardiac abnormalities and atherosclerosis [102]. Most often the clots are found in the veins due to low shear rates in veins (20–200/s) compared to arteries (300–800/s) [103]. Thrombosis found in veins is termed as venous thrombosis. The thrombus formation in the deep veins is termed as deep vein thrombosis. The risk factors for thrombosis are classified by Virchow and they referred as Virchow's Triad [104]. The triad includes endothelial injury, stasis or turbulence of blood flow, and blood hypercoagulability. Endothelial injuries generally happen during surgery, the turbulence of blood flow occurs due to cardiovascular disorders or hypertension [104]. Hypercoagulability is caused by the environment, unhealthy habits and age. The environmental risk factors include exposure to high altitudes and hypoxic environment [103]. The external risk factors for the thrombosis include smoking, chronic alcoholism and consumption of oral contraceptive pills [103]. Similarly, health conditions like cancer, obesity and aging promote the risk of thrombosis [103]. The molecular mechanisms under these risk factors are yet to be understood. Thrombosis is also caused by inherited factors such

as mutations in the genes that encode for coagulation factors or anticoagulants.

Serine proteases of coagulation cascade play a vital role in the progression of clot formation [3]. Mutations in the proteases convert them into hyper active forms and some of the mutations 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 event of thrombosis.
