Iranian Journal of Neurology 2017. 16(1):30-33.

Polymorphisms at activated protein C cleavage sites of factor V: Are they important in the absence of factor V Leiden?
Ehsan Kheradmand, Shaghayegh Haghjooy-Javanmard, Leila Dehghani, Mohammad Saadatnia

Abstract


Background: Activated protein C (APC) inactivates factor V (FV) by cleavage of its heavy chain at Arg306, Arg506, Arg679, and Lys994. Mutational changes, which abolish APC cleavage sites, may predispose thrombosis by altering the inactivation process of FV. FV Leiden (FVL) (Arg506Glu) has been demonstrated as a strong risk factor for thrombosis. In the current study, we have studied whether mutations in the cleavage sites of FV for APC, not due to FVL, would have a role in presenting APC resistance (APCR) and initiation of a cerebral thrombotic event.

Methods: A group of 22 patients with a history of cerebral venous thrombosis (CVT), who were not carriers of FVL enrolled in the study. The patients who had conditions associated with acquired APCR were excluded from the study. APCR test was performed on the remaining 16 patients, which showed APCR in 4 plasma samples. DNA sequencing was performed on four exons of FV of APCR patients, encoding Arg306, Arg506, Arg679, and Lys994.

Results: Mutations were not found within nucleotides encoding the cleavage sites; neither was found within their close upstream and downstream sequences.

Conclusion: Our results show that polymorphisms affecting cleavage sites of FV other than Arg506Glu it would be less likely to be the basis for APCR and its increased thrombosis susceptibility. In addition, it emphasizes on the importance of screening for APCR in the patients diagnosed with CVT.

Keywords


Cerebral Venous Thrombosis; Factor V; Activated Protein C Resistance; Cleavage Sites

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References


Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005; 352(17):1791-8.

Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol 2007; 6(2): 162-70.

Asselta R, Tenchini ML, Duga S.Inherited defects of coagulation factor V:the hemorrhagic side. J Thromb Haemost 2006; 4(1): 26-34.

Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994;269(50): 31869-80.

Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369(6475): 64-7.

Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343(8912):1536-8.

Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8(3): 445-53.

Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21(5): 731-8.

Blinkenberg EO, Kristoffersen AH, Sandberg S, Steen VM, Houge G.Usefulness of factor V Leiden mutation testing in clinical practice. Eur J Hum Genet 2010; 18(8): 862-6.

Fernandez JA, Hackeng TM, Kojima K, Griffin JH. The carbohydrate moiety of factor V modulates inactivation by activated protein C. Blood 1997; 89(12):4348-54.

Saadatnia M, Salehi M, Movahedian A, Shariat SZ, Salari M, Tajmirriahi M, et al. Factor V Leiden, factor V Cambridge, factor II GA20210, andmethylenetetrahydrofolate reductase in cerebral venous and sinus thrombosis: A case-control study. J Res Med Sci 2015;20(6): 554-62.

Labrouche S, Javorschi S, Bernard P, Freyburger G. Molecular mechanism for APC resistance in the absence of Arg 506 mutation: factor V gene sequencing strategy. Thromb Res 1997; 87(2)263-7.

Dentali F, Crowther M, Ageno W.Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis. Blood 2006;107(7): 2766-73.

Ludemann P, Nabavi DG, Junker R, Wolff E, Papke K, Buchner H, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case- control study of 55 patients. Stroke 1998;29(12): 2507-10.

Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke 1996;27(10): 1724-30.

Rahimi Z, Mozafari H, Bigvand AH, Doulabi RM, Vaisi-Raygani A, Afshari D, et al. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: association with factor V Leiden. Clin Appl Thromb Hemost 2010;16(4): 430-4.

Ashjazadeh N, Poursadeghfard M, Farjadian S. Factor V G1691A and prothrombin G20210A gene polymorphisms among Iranian patients with cerebral venous thrombosis. Neurol Asi 2012; 17(3): 199-203.

Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor VR506Q. J Biol Chem 1995; 270(8): 4053-7.

Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of ajanus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22(4): 530-8.

Federman DG, Kirsner RS. An update on hypercoagulable disorders. Arch Intern Med 2001; 161(8): 1051-6.

Norstrom E, Thorelli E, Dahlback B.Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100(2): 524-30.

Franco RF, Maffei FH, Lourenco D,Morelli V, Thomazini IA, Piccinato CE, et al. Factor V Arg306-->Thr (factor V Cambridge) and factor V Arg306-->Gly mutations in venous thrombotic disease. Br J Haematol 1998; 103(3): 888-90.

van der Neut KM, Dirven RJ, Vos HL, Tans G, Rosing J, Bertina RM. Factor Va is inactivated by activated protein C in the absence of cleavage sites at Arg-306, Arg-506, and Arg-679. J Biol Chem2004; 279(8): 6567-75.

Tran S, Dahlback B. Novel APC- cleavage sites in FVa provide insights into mechanisms of action of APC and its cofactor protein S. J Thromb Haemost2010; 8(1): 129-36.

Mumford AD, McVey JH, Morse CV, Gomez K, Steen M, Norstrom EA, et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123(3): 496-501.

Steen M, Norstrom EA, Tholander AL, Bolton-Maggs PH, Mumford A, McVey JH, et al. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Blood 2004;103(9): 3381-7.

Cramer TJ, Gale AJ. The anticoagulant function of coagulation factor V. Thromb Haemost 2012; 107(1): 15-21.

Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130(8): 643-50.


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