**5.4. FVII deficiency**

**5. Rare bleeding disorders**

136 Hematology - Latest Research and Clinical Advances

molecular diagnosis [56].

**5.1. Fibrinogen deficiency**

therapy by cryoprecipitate [63].

bin complex concentrate and fresh frozen plasma [67].

**5.2. Prothrombin deficiency**

**5.3. Factor V deficiency**

Rare inherited bleeding disorders (RBDs) include deficiencies of coagulation factors such as fibrinogen, factor II (FII), FV, combined deficiency of FV and FVII, FVIII, FX, FXI, FXIII and vitamin K dependent factors. RBDs are mostly autosomal recessive disorders varying from 1 in 500,000 to 1 in 2–3 million [56]. These disorders are diagnosed by clotting assays such as thrombin time, prothrombin time and activated partial thromboplastin time followed by

Fibrinogen is a 340 kDa hexamer assembled by the combination of 3 homologous polypeptide chains (Aα, Bβ and γ) [57]. Fibrinogen plays an important role in clot formation where thrombin converts fibrinogen into soluble fibrin which further forms an insoluble polymer mesh, fibrin also plays an active role in platelet aggregation by binding to glycoprotein IIb/ IIIa on the activated platelets [57]. The genes encoding for Bβ (FGB), Aα (FGA) and γ (FGG) are located on chromosome 4 from centromere to telomere [58]. Fibrinogen is primarily synthesized in liver [59]. Fibrin deficiency is identified as two phenotypes termed as afibrinogenemia/hypofibrinogenemia and it is characterized by low plasma and platelet fibrinogen antigens whereas, dys/hypodysfibrinogenemia is characterized by the deficiency of functional fibrinogen levels [60, 61]. Afibrinogenemia is detected by prolonged prothrombin time, thrombin time, activated partial thromboplastin time, impaired platelet adhesion and impaired platelet aggregation induced by ADP [60, 62]. Clinical manifestations of fibrinogen include umbilical stump bleeding, possible gastrointestinal bleeding, recurrent episodes of intracranial hemorrhage [60, 63]. Treatment for fibrinogen deficiency include replacement

Prothrombin is a vitamin K dependent glycoprotein synthesized in the liver [64]. Prothrombin is encoded by 21 kb gene present on chromosome 11 [65, 66]. Prothrombin deficiency is observed in 1 in 2 million [65]. Prothrombin deficiency is classified into two types, hypoprothrombinemia caused by low prothrombin production and dysprothrombinemia is caused by deficiency of functional prothrombin [65]. Hypoprothrombinemia with less than 5% prothrombin antigen is characterized by severe bleeding whereas dysprothrombinemia causes variable bleeding tendencies [65]. Treatments for prothrombin deficiency include prothrom-

FV is a single polypeptide encoded by chromosome 1 and primarily synthesized in the liver and some evidences show that FV is also produced by megakaryocytes [68–70]. The activated FV acts as a cofactor for FXa, to form a prothrombinase complex and it also serves as a target for APC-PS complex in inhibiting the coagulation cascade [71]. Patients with FV deficiency FVII is a 50 Kda single chain polypeptide encoded by F7 gene located on chromosome 13 and FVII levels are influenced by age, sex and health condition such as blood cholesterol and triglyceride levels [73, 74]. FVII deficiency is observed in 1 in 500,000, with variable phenotypes [74]. Some patients do not show bleeding phenotype despite very low FVII levels, whereas others with similar FVII antigen levels show severe bleeding phenotype [74]. The bleeding phenotypes of FVII deficiency include central nervous system hemorrhage, epistatic and menorrhagia [74]. Frozen fresh plasma, prothrombin complex concentrates, plasma derived FVII concentrate, recombinant FVIIa are typically used to treat FVII deficiency [75, 76].
