Assessment of Factor V Gene G1691A Mutation (Factor V Leiden) among Chronic Hepatitis C Patients with Thrombocytopenia

Ahmed Khedr*; Ahmed B Barakat; Mohamed S Salama

**Ahmed Khedr*, Ahmed B Barakat and Mohamed S Salama**

Volume3-Issue12
Dates: Received: 2022-12-20 | Accepted: 2022-12-29 | Published: 2022-12-31
Pages: 1589-1599

Abstract

Background: Factor V plays a crucial role in the coagulation process. Factor V Leiden (FVL) is considered a mutant form of factor V, which may contribute to blood vessel thrombosis. Also, Hepatitis C Virus (HCV) infection may exert some coagulation changes leading to Portal Vein Thrombosis (PVT). Thrombocytopenia in patients with chronic HCV infection constitutes a major challenge.

Objective: This study aimed to investigate the incidence of FVL (factor V gene G1691A mutation) and its influence on coagulation among HCV chronically infected patients suffering from thrombocytopenia. Besides, it was designed to demonstrate the association of chronic HCV infection with coagulation disturbances in such patients.

Methods: This study was conducted on blood samples of a total of 54 subjects (33 HCV chronically infected patients and 21 healthy controls). HCV chronically infected patients with thrombocytopenia (Platelet Count [PLC] below 150 thousand/microliter) were selected. Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPPT) were previously determined as coagulation parameters. Protein C and protein S antigens were determined by ELISA as coagulation-regulating (anticoagulants) parameters. All samples were investigated for the presence of FVL by real-time PCR.

Results: PLC, PT, and protein C antigen showed highly significant differences (p < 0.001) between controls (group 1) and HCV chronically infected patients (group 2). Likewise, a highly significant change (p = 0.006) was achieved for the protein S antigen. A non-significant change was detected for the incidence of FVL with a heterozygous pattern between controls (group 1) and HCV chronically infected patients (group 2). Additionally, non-significant changes were detected for all of the investigated coagulation and coagulation-regulating (anticoagulants) parameters between control subjects with negative FVL (subgroup 1) and others with positive FVL (subgroup 2). Similarly, non-significant changes for such parameters were recoded for HCV chronically infected patients with negative FVL (subgroup 3) and others with positive FVL (subgroup 4).

Conclusion: Chronic HCV infection in the presence of thrombocytopenia is associated with coagulation disturbances. The incidence of FVL with its heterozygous pattern is unaffected by chronic HCV infection, and no association is shown with worsening of coagulation in chronic hepatitis C patients suffering from thrombocytopenia.

FullText HTML FullText PDF DOI: 10.37871/jbres1640

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How to cite this article

Khedr A, Barakat AB, Salama MS. Assessment of Factor V Gene G1691A Mutation (Factor V Leiden) among Chronic Hepatitis C Patients with Thrombocytopenia. 2022 Dec 31; 3(12): 1589-1599. doi: 10.37871/jbres1640, Article ID: JBRES1640, Available at: https://www.jelsciences.com/articles/jbres1640.pdf

Subject area(s)

Genomics

References

WHO Global Hepatitis Report. 2017.
Roudot-Thoraval F. Epidemiology of hepatitis C virus infection. Clin Res Hepatol Gastroenterol. 2021 May;45(3):101596. doi: 10.1016/j.clinre.2020.101596. Epub 2021 Feb 17. PMID: 33610022.
Sy T, Jamal MM. Epidemiology of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3(2):41-6. doi: 10.7150/ijms.3.41. Epub 2006 Apr 1. PMID: 16614741; PMCID: PMC1415844.
Leticia OI, Andrew A, Ifeanyi OE, Ifeoma UE, Ugochukwu A . The effect of viral hepatitis on APTT, PT, TT, fibrinogen and platelet among blood donors at FMC, Umuahia. IOSR Journal of Dental and Medical Sciences. 2014;13:57-63.
Dahal S, Upadhyay S, Banjade R, Dhakal P, Khanal N, Bhatt VR. Thrombocytopenia in Patients with Chronic Hepatitis C Virus Infection. Mediterr J Hematol Infect Dis. 2017 Mar 1;9(1):e2017019. doi: 10.4084/MJHID.2017.019. PMID: 28293407; PMCID: PMC5333732.
Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG, Shiffman ML, Fontana RJ, Di Bisceglie AM, Bonkovsky HL, Dienstag JL; HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010 Oct;8(10):877-83. doi: 10.1016/j.cgh.2010.03.025. Epub 2010 Apr 1. PMID: 20362695; PMCID: PMC3771318.
Karasu Z, Tekin F, Ersoz G, Gunsar F, Batur Y, Ilter T, Akarca US. Liver fibrosis is associated with decreased peripheral platelet count in patients with chronic hepatitis B and C. Dig Dis Sci. 2007 Jun;52(6):1535-9. doi: 10.1007/s10620-006-9144-y. Epub 2007 Apr 27. PMID: 17464564.
Samant H, Asafo-Agyei KO, Garfield K. Portal Vein Thrombosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
Costache RS, Dragomirică AS, Dumitraș EA, Mariana J, Căruntu A, Popescu A, Costache DO. Portal vein thrombosis: A concise review (Review). Exp Ther Med. 2021 Jul;22(1):759. doi: 10.3892/etm.2021.10191. Epub 2021 May 13. PMID: 34035856; PMCID: PMC8135136.
González-Reimers E, Quintero-Platt G, Martín-González C, Pérez-Hernández O, Romero-Acevedo L, Santolaria-Fernández F. Thrombin activation and liver inflammation in advanced hepatitis C virus infection. World J Gastroenterol. 2016 May 14;22(18):4427-37. doi: 10.3748/wjg.v22.i18.4427. PMID: 27182154; PMCID: PMC4858626.
Thompson A, Patel K, Tillman H, McHutchison JG. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges. J Hepatol. 2009 Jan;50(1):184-94. doi: 10.1016/j.jhep.2008.10.011. Epub 2008 Nov 4. PMID: 19022518.
Ibrahim MK, Khedr A, Bader El Din NG, Khairy A, El Awady MK. Increased incidence of cytomegalovirus coinfection in HCV-infected patients with late liver fibrosis is associated with dysregulation of JAK-STAT pathway. Sci Rep. 2017 Sep 4;7(1):10364. doi: 10.1038/s41598-017-10604-7. PMID: 28871140; PMCID: PMC5583286.
Selim FO, Abdalla TM, Hosny TAM. Thrombophilia in hepatocellular carcinoma. Egypt Liver Journal. 2019. doi: 10.1186/s43066-019-0003-x.
Galli L, Gerdes VE, Guasti L, Squizzato A. Thrombosis Associated with Viral Hepatitis. J Clin Transl Hepatol. 2014 Dec;2(4):234-9. doi: 10.14218/JCTH.2014.00031. Epub 2014 Dec 15. PMID: 26357629; PMCID: PMC4521234.
Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326-36. doi: 10.3109/10409238.2015.1050550. Epub 2015 May 28. PMID: 26018600; PMCID: PMC4826570.
Lam W, Moosavi L. Physiology, Factor V. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
Ornstein DL, Cushman M. Cardiology patient page. Factor V Leiden. Circulation. 2003 Apr 22;107(15):e94-7. doi: 10.1161/01.CIR.0000068167.08920.F1. PMID: 12707252.
Huang JN, Koerper MA. Factor V deficiency: a concise review. Haemophilia. 2008 Nov;14(6):1164-9. doi: 10.1111/j.1365-2516.2008.01785.x. PMID: 19141156.
Lippi G, Favaloro EJ, Montagnana M, Manzato F, Guidi GC, Franchini M. Inherited and acquired factor V deficiency. Blood Coagul Fibrinolysis. 2011 Apr;22(3):160-6. doi: 10.1097/MBC.0b013e3283424883. PMID: 21245750.
Kraus M, Zander N, Fickenscher K. Coagulation assay with improved specificity to factor V mutants insensitive to activated protein C. Thromb Res. 1995 Nov 1;80(3):255-64. doi: 10.1016/0049-3848(95)00174-p. PMID: 8578552.
Potze W, Arshad F, Adelmeijer J, Blokzijl H, van den Berg AP, Meijers JC, Porte RJ, Lisman T. Decreased tissue factor pathway inhibitor (TFPI)-dependent anticoagulant capacity in patients with cirrhosis who have decreased protein S but normal TFPI plasma levels. Br J Haematol. 2013 Sep;162(6):819-26. doi: 10.1111/bjh.12462. Epub 2013 Jul 11. PMID: 23841464.
Duga S, Asselta R, Tenchini ML. Coagulation factor V. Int J Biochem Cell Biol. 2004 Aug;36(8):1393-9. doi: 10.1016/j.biocel.2003.08.002. PMID: 15147718.
Dahlbäck B. Pro- and anticoagulant properties of factor V in pathogenesis of thrombosis and bleeding disorders. Int J Lab Hematol. 2016 May;38 Suppl 1:4-11. doi: 10.1111/ijlh.12508. Epub 2016 May 9. PMID: 27161771.
Gottlieb JL, Blice JP, Mestichelli B, Konkle BA, Benson WE. Activated protein C resistance, factor V Leiden, and central retinal vein occlusion in young adults. Arch Ophthalmol. 1998 May;116(5):577-9. doi: 10.1001/archopht.116.5.577. PMID: 9596492.
Van Cott EM, Khor B, Zehnder JL. Factor V Leiden. Am J Hematol. 2016 Jan;91(1):46-9. doi: 10.1002/ajh.24222. Epub 2015 Nov 17. PMID: 26492443.
Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011 Jan;13(1):1-16. doi: 10.1097/GIM.0b013e3181faa0f2. PMID: 21116184.
Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res. 2014 Jun;49(2):85-94. doi: 10.5045/br.2014.49.2.85. Epub 2014 Jun 25. PMID: 25025009; PMCID: PMC4090343.
Wright M, Goldin R, Hellier S, Knapp S, Frodsham A, Hennig B, Hill A, Apple R, Cheng S, Thomas H, Thursz M. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut. 2003 Aug;52(8):1206-10. doi: 10.1136/gut.52.8.1206. PMID: 12865283; PMCID: PMC1773738.
Higuchi R, Dollinger G, Walsh PS, Griffith R. Simultaneous amplification and detection of specific DNA sequences. Biotechnology (N Y). 1992 Apr;10(4):413-7. doi: 10.1038/nbt0492-413. PMID: 1368485.
Dashti AA, Jadaon MM, Lewis HL. Factor V Leiden mutation in Arabs in Kuwait by real-time PCR: different values for different Arabs. J Hum Genet. 2010 Apr;55(4):232-5. doi: 10.1038/jhg.2010.11. Epub 2010 Mar 12. PMID: 20224595.
Abdel Hameed MR, Elbeih EAS, Abd El-Aziz HM, Afifi OA, Khalaf LMR, Ali Abu Rahma MZ, Sabry A. Epidemiological Characteristics and Etiology of Budd-Chiari Syndrome in Upper Egypt. J Blood Med. 2020 Dec 30;11:515-524. doi: 10.2147/JBM.S278678. PMID: 33408545; PMCID: PMC7779296.
Pircher J, Czermak T, Merkle M, Mannell H, Krötz F, Ribeiro A, Vielhauer V, Nadjiri J, Gaitzsch E, Niemeyer M, Porubsky S, Gröne HJ, Wörnle M. Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2. PLoS One. 2014 Nov 24;9(11):e113351. doi: 10.1371/journal.pone.0113351. PMID: 25419735; PMCID: PMC4242623.
Falasca K, Mancino P, Ucciferri C, Dalessandro M, Zingariello P, Lattanzio FM, Petrarca C, Martinotti S, Pizzigallo E, Conti P, Vecchiet J. Inflammatory cytokines and S-100b protein in patients with hepatitis C infection and cryoglobulinemias. Clin Invest Med. 2007;30(5):E167-76. doi: 10.25011/cim.v30i5.2892. PMID: 17892758.
Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica. 2000 Sep;85(9):967-72. PMID: 10980636.
Ishii H, Horie S, Kizaki K, Kazama M. Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor. Blood. 1992 Nov 15;80(10):2556-62. PMID: 1330076.
Hodowanec AC, Lee RD, Brady KE, Gao W, Kincaid S, Plants J, Bahk M, Mackman N, Landay AL, Huhn GD. A matched cross-sectional study of the association between circulating tissue factor activity, immune activation and advanced liver fibrosis in hepatitis C infection. BMC Infect Dis. 2015 Apr 17;15:190. doi: 10.1186/s12879-015-0920-1. PMID: 25884329; PMCID: PMC4411753.
Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001 Jan;119(1 Suppl):176S-193S. doi: 10.1378/chest.119.1_suppl.176s. PMID: 11157648.
Dieterich DT, Spivak JL. Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis. 2003 Aug 15;37(4):533-41. doi: 10.1086/376971. Epub 2003 Aug 1. PMID: 12905138.
Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002 Nov 15;100(10):3457-69. doi: 10.1182/blood.V100.10.3457. PMID: 12411315.
Adinolfi LE, Giordano MG, Andreana A, Tripodi MF, Utili R, Cesaro G, Ragone E, Durante Mangoni E, Ruggiero G. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. Br J Haematol. 2001 Jun;113(3):590-5. doi: 10.1046/j.1365-2141.2001.02824.x. PMID: 11380442.
Giannini E, Borro P, Botta F, Fumagalli A, Malfatti F, Podestà E, Romagnoli P, Testa E, Chiarbonello B, Polegato S, Mamone M, Testa R. Serum thrombopoietin levels are linked to liver function in untreated patients with hepatitis C virus-related chronic hepatitis. J Hepatol. 2002 Nov;37(5):572-7. doi: 10.1016/s0168-8278(02)00274-x. PMID: 12399221.
Wald O, Pappo O, Safadi R, Dagan-Berger M, Beider K, Wald H, Franitza S, Weiss I, Avniel S, Boaz P, Hanna J, Zamir G, Eid A, Mandelboim O, Spengler U, Galun E, Peled A. Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus. Eur J Immunol. 2004 Apr;34(4):1164-74. doi: 10.1002/eji.200324441. PMID: 15048728.
Gear AR, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation. 2003 Jun;10(3-4):335-50. doi: 10.1038/sj.mn.7800198. PMID: 12851650.
Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, Van Geet C, Cassiman D. Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008 Jun 1;27(11):1017-29. doi: 10.1111/j.1365-2036.2008.03674.x. Epub 2008 Mar 5. PMID: 18331464.
Panasiuk A, Prokopowicz D, Zak J, Matowicka-Karna J, Osada J, Wysocka J. Activation of blood platelets in chronic hepatitis and liver cirrhosis P-selectin expression on blood platelets and secretory activity of beta-thromboglobulin and platelet factor-4. Hepatogastroenterology. 2001 May-Jun;48(39):818-22. PMID: 11462931.
Gürsoy S, Başkol M, Torun E, Yurci A, Soyuer I, Eser B, Güven K, Ozbakir O, Yücesoy M. Importance of anticoagulant proteins in chronic liver diseases. Turk J Gastroenterol. 2005 Sep;16(3):129-33. PMID: 16245221.
Saray A, Mesihovic R, Vanis N, Amila M. Protein C Deficiency in Chronic Hepatitis C: Correlation With Histological Extent of Liver Fibrosis. Clin Appl Thromb Hemost. 2017 Jan;23(1):72-77. doi: 10.1177/1076029615587356. Epub 2015 May 24. PMID: 26008227.
Dahlbäck B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol. 2004 Feb;79(2):109-16. doi: 10.1532/ijh97.03149. PMID: 15005336.
Castelino DJ, Salem HH. Natural anticoagulants and the liver. J Gastroenterol Hepatol. 1997 Jan;12(1):77-83. doi: 10.1111/j.1440-1746.1997.tb00351.x. PMID: 9076629.
Turco L, de Raucourt E, Valla DC, Villa E. Anticoagulation in the cirrhotic patient. JHEP Rep. 2019 Jul 16;1(3):227-239. doi: 10.1016/j.jhepr.2019.02.006. PMID: 32039373; PMCID: PMC7001584.
Singhal A, Karachristos A, Bromberg M, Daly E, Maloo M, Jain AK. Hypercoagulability in end-stage liver disease: prevalence and its correlation with severity of liver disease and portal vein thrombosis. Clin Appl Thromb Hemost. 2012 Nov;18(6):594-8. doi: 10.1177/1076029612440034. Epub 2012 Apr 11. PMID: 22496089.
Hung HC, Lee JC, Cheng CH, Wang YC, Wu TH, Lee CF, Wu TJ, Chou HS, Chan KM, Lee WC. Protein S for Portal Vein Thrombosis in Cirrhotic Patients Waiting for Liver Transplantation. J Clin Med. 2020 Apr 20;9(4):1181. doi: 10.3390/jcm9041181. PMID: 32326024; PMCID: PMC7230503.
El-Ghonemy MS, El Sharawy S, Fahmi MW, El-Ashwah S, Denewer M, El-Baiomy MA. Thrombophilic Risk of Factor V Leiden, Prothrombin G20210A, MTHFR, and Calreticulin Mutations in Essential Thrombocythemia Egyptian Patients. Adv Hematol. 2020 Mar 30;2020:7695129. doi: 10.1155/2020/7695129. PMID: 32292481; PMCID: PMC7149341.
Arsov T, Miladinova D, Spiroski M. Factor V Leiden is associated with higher risk of deep venous thrombosis of large blood vessels. Croat Med J. 2006 Jun;47(3):433-9. PMID: 16758522; PMCID: PMC2080416.
Jadaon MM. Epidemiology of activated protein C resistance and factor v leiden mutation in the mediterranean region. Mediterr J Hematol Infect Dis. 2011;3(1):e2011037. doi: 10.4084/MJHID.2011.037. Epub 2011 Sep 8. PMID: 22224194; PMCID: PMC3251907.