**2. Pathophysiology**

#### **2.1 Factor V Leiden**

Factor V Leiden is an autosomal dominant transmissible gene abnormality that shows incomplete penetrance; therefore, the disease will not be developed by all carriers of the mutation. In terms of pathophysiological mechanism, factor V Leiden is also known as factor V Arg506Gln and as factor V R506Q, due to a single mutation of the factor V gene in which guanine replaces arginine at nucleotide 1691. Consequently, just one amino acid change, replacing arginine with glutamine, suppresses the binding site to the activated proteolytic protein C of factors V and Va [7, 8]. With the malformed binding site, the natural anticoagulant protein C can no longer bind and cleave factor V and Va to inactivate it, therefore factor V concentration increases and disrupts the pro−/anticoagulant balance, leading to an increased risk of thrombosis [7]. The result of the so-called activated protein C resistance phenotype is blamed in up to 95% of cases as a consequence of a factor V mutation, which has resulted in a 7-fold increase in the relative risk of developing deep vein thrombosis in patients [8].

#### **2.2 Prothrombin G20210A**

Prothrombin G20210A is a specific genetic mutation of nucleotide 20210A of the second factor of the coagulation cascade (factor II—prothrombin) and consists of a change of guanine to adenine, with a higher concentration of prothrombin found in mutation carriers [9]. Although several attempts have been made to explain why this happens, the exact mechanism of how the mutation leads to increased protein production, thereby increasing the overall risk of thrombosis, is not yet fully understood [10]. Caucasians have a higher risk of developing this condition, but the risk of thrombosis is minimal for heterozygotes in whom no other risk factors are identified. However, in the presence of other secondary risk factors, such as prolonged bed rest or pregnancy, the risk is greatly increased. Homozygous carriers face an increased risk of thrombosis by 2 to 3 folds [11].

### **2.3 Protein C**

Protein C and its activated form are vitamin K-dependent zymogens with an important role in the regulation of anticoagulation by inactivating coagulation factors Va and VIIIa [12].

Protein C deficiency is a rare abnormality that alters the activity of protein C, a consequence of which is the loss of activated protein C function and, consequently, its inability to control coagulation [13].

Mutations in the PROC gene are responsible for the development of congenital protein C deficiency and are transmitted in an autosomal dominant manner, affecting heterozygous carriers much less than homozygous carriers. To date, more than 160 PROC mutations have been identified, which can affect protein C concentration (type I) or result in the production of an altered protein with reduced activity and ineffective anticoagulant function (type II) [13].

Protein C is activated by interactions with thrombin after the latter has attached to thrombomodulin expressed on the endothelial cell surface. Activated protein C then proceeds to reduce clotting by cleaving and inactivating clotting factors Va and VIIIa. Low concentrations or structural alterations of protein C disturb the coagulation balance, favoring the development of a hypercoagulable state [13].
