8tn9

Structural highlights

Disease

FA5_HUMAN Defects in F5 are the cause of factor V deficiency (FA5D) [MIM:227400; also known as Owren parahemophilia. It is a hemorrhagic diastesis.^{[1] [2]} Defects in F5 are the cause of thrombophilia due to activated protein C resistance (THPH2) [MIM:188055. THPH2 is a hemostatic disorder due to defective degradation of factor Va by activated protein C. It is characterized by a poor anticoagulant response to activated protein C resulting in tendency to thrombosis.^{[3] [4] [5] [6] [7]} Defects in F5 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:600880. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in F5 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.^[8] Defects in F5 are associated with susceptibility to pregnancy loss, recurrent, type 1 (RPRGL1) [MIM:614389. RPRGL1 is a common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.^[9]

Function

FA5_HUMAN Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.

References

1. ↑ Castoldi E, Simioni P, Kalafatis M, Lunghi B, Tormene D, Girelli D, Girolami A, Bernardi F. Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood. 2000 Aug 15;96(4):1443-8. PMID:10942390
2. ↑ Duga S, Montefusco MC, Asselta R, Malcovati M, Peyvandi F, Santagostino E, Mannucci PM, Tenchini ML. Arg2074Cys missense mutation in the C2 domain of factor V causing moderately severe factor V deficiency: molecular characterization by expression of the recombinant protein. Blood. 2003 Jan 1;101(1):173-7. Epub 2002 Aug 15. PMID:12393490 doi:10.1182/blood-2002-06-1928
3. ↑ Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood. 1998 Feb 15;91(4):1140-4. PMID:9454742
4. ↑ van Wijk R, Nieuwenhuis K, van den Berg M, Huizinga EG, van der Meijden BB, Kraaijenhagen RJ, van Solinge WW. Five novel mutations in the gene for human blood coagulation factor V associated with type I factor V deficiency. Blood. 2001 Jul 15;98(2):358-67. PMID:11435304
5. ↑ Schrijver I, Houissa-Kastally R, Jones CD, Garcia KC, Zehnder JL. Novel factor V C2-domain mutation (R2074H) in two families with factor V deficiency and bleeding. Thromb Haemost. 2002 Feb;87(2):294-9. PMID:11858490
6. ↑ Mumford AD, McVey JH, Morse CV, Gomez K, Steen M, Norstrom EA, Tuddenham EG, Dahlback B, Bolton-Maggs PH. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol. 2003 Nov;123(3):496-501. PMID:14617013
7. ↑ Steen M, Norstrom EA, Tholander AL, Bolton-Maggs PH, Mumford A, McVey JH, Tuddenham EG, Dahlback B. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Blood. 2004 May 1;103(9):3381-7. Epub 2003 Dec 24. PMID:14695241 doi:10.1182/blood-2003-06-2092
8. ↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
9. ↑ Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2000 Oct 5;343(14):1015-8. PMID:11018168 doi:10.1056/NEJM200010053431405