Thromb Haemost 2005; 93(03): 403-410
DOI: 10.1160/TH04-08-0523
Review Article
Schattauer GmbH

Effects of human cytomegalovirus infection on the coagulation system

Alessandro Squizzato
1   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Victor E. A. Gerdes
1   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Harry R. Büller
1   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 20 August 2004

Accepted after revision 20 January 2004

Publication Date:
14 December 2017 (online)

Summary

Pathophysiological mechanisms of acute vascular thrombosis are not fully understood. It has been suggested that different infectious pathogens are responsible agents of thrombotic disorders. The infection hypothesis is supported by an increasing number of reports on the interaction between acute infection and coagulation. Cytomegalovirus (CMV) is supposed to play an important role in apparently unprovoked thrombosis. We reviewed all human in vitro and in vivo studies on the influence of human CMV infection on the coagulation system, as well as all case reports of acute thrombosis during acute human CMV infection. In the published literature there is mounting evidence that human CMV may play a role in thrombotic disorders. Definitive conclusions, however, cannot be drawn, although the in vitro studies are convincing and offer insight in the pathogenesis.

 
  • References

  • 1 Weller TH, Macaulay JM, Craig JM. et al. Isolation of intranuclear inclusion producing agents from infants with illnesses resembling cytomegalic inclusion disease. Proc Soc Exp Biol Med 1957; 94: 4-12.
  • 2 Cohen I J, Corey GR. Cytomegalovirus infection in the normal host. Medicine 1985; 64: 100-14.
  • 3 Bruggeman CA. Cytomegalovirus and latency: an overview. Virchows Archiv B Cell Pathol 1993; 64: 325-33.
  • 4 Chou S. Newer methods for diagnosis of cytomegalovirus. Rev Infect Dis 1990; 12 (Suppl. 07) S727-36.
  • 5 Centers for Disease Control and Prevention (CDC), Atlanta. Cytomegalovirus (CMV) infection http://www.cdc.gov/ncidod/diseases/cmv.htm . Accessed Oct 24, 2004.
  • 6 de la Hoz RE, Stephens G, Sherlock C. Diagnosis and treatment approaches of CMV infections in adult patients. J Clin Virol 2002; 25 (Suppl. 02) S1-12.
  • 7 Landolfo S, Gariglio M, Gribaudo G. et al. The human cytomegalovirus. PharmacolTher 2003; 98: 269-97.
  • 8 Campbell PT, Li JS, Wall TC. et al. Cytomegalovirus pericarditis: a case series and review of the literature. Am J Med Sci 1995; 309: 229-34.
  • 9 McCormack JG, Bowler SD, Donnelly JE. et al. Successful treatment of severe cytomegalovirus infection with ganciclovir in an immunocompetent host. Clin Infect Dis 1998; 26: 1007-8.
  • 10 Waris E, Rasanen O, Kreus KE. et al. Fatal cytomegalovirus disease in a previously healthy adult. Scand J Infect Dis 1972; 4: 61-7.
  • 11 Tiula E, Leinikki P. Fatal cytomegalovirus infection in a previous healthy body with myocarditis and consumption coagulopathy as presenting signs. Scand J Infect Dis 1972; 4: 57-60.
  • 12 Schonian U, Crombach M, Maser S. et al. Cytomegalovirus- associated heart muscle disease. Eur Heart J 1995; 16 Suppl. O 46-9
  • 13 Golden MP, Hammer SM, Wanke CA. et al. Cytomegalovirus vasculitis. Case reports and review of the literature. Medicine 1994; 73: 246-55.
  • 14 Bamji A, Salisbury R. Cytomegalovirus and vasculitis. Br Med J 1978; 1: 623-4.
  • 15 Ho DD, Rota TR, Andrews CA. et al. Replication of human cytomegalovirus in endothelial cells. J Infect Dis 1984; 150: 956-7.
  • 16 Goodman MD, Porter DD. Cytomegalovirus vasculitis with fatal colonic hemorrhage. Arch Pathol Lab Med 1973; 96: 281-4.
  • 17 Foucar E, Mukai K, Foucar K. et al. Colon ulceration in lethal cytomegalovirus infection. Am Clin Pathol 1981; 76: 788-801.
  • 18 Koeppen AH, Lansing LS, Peng SK. et al. Central nervous system vasculitis in cytomegalovirus infection. J Neurol Sci 1981; 51: 395-410.
  • 19 Booss J, Dann PR, Winkler SR. et al. Mechanisms of injury to the central nervous system following experimental cytomegalovirus infection. Am Otolaryngol 1990; 11: 313-7.
  • 20 Lin CS, Penha PD, Krishnan MN. et al. Cytomegalic inclusion disease of the skin. Arch Dermatol 1981; 117: 282-4.
  • 21 Zhou YF, Leon MB, Waclawiw MA. et al. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 1996; 335: 624-30.
  • 22 Blum A, Giladi M, Weineberg M. et al. High anti cytomegalovirus (CMV) IgG antibody titer is associated with coronary artery disease and may predict postcoronary ballon angioplasty restenosis. Am J Cardiol 1998; 81: 866-8.
  • 23 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: Is there a link?. Lancet 1997; 350: 430-6.
  • 24 High KP. Atherosclerosis and infection due to Chlamydia pneumoniae or Cytomegalovirus: Weighing the evidence. Clin Infect Dis 1999; 28: 746-9.
  • 25 Sorlie PD, Nieto FJ, Adam E. et al. A prospective study of cytomegalovirus, herpes simplex virus 1, and coronary heart disease: the atherosclerosis risk in communities (ARIC) study. Arch Intern Med 2000; 160: 2027-32.
  • 26 Sorlie PD, Adam E, Melnick SL. et al. Cytomegalovirus/ herpesvirus and carotid atherosclerosis: The ARIC Study. J Med Virol 1994; 42: 33-7.
  • 27 Adler SP, Hur JK, Wang JB. et al. Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis 1998; 177: 209-12.
  • 28 Carlsson J, Miketic S, Brom J. et al. Prior cytomegalovirus, Chlamydia pneumoniae or Helicobacter pylori infection and the risk of restenosis after percutaneous transluminal coronary angioplasty. Int J Cardiol 2000; 73: 165-71.
  • 29 Manegold C, Alwazzeh M, Jablonowski H. et al. Prior cytomegalovirus infection and the risk of restenosis after percutaneous transluminal coronary balloon angioplasty. Circulation 1999; 99: 1290-4.
  • 30 Neumann FJ, Kastrati A, Miethke T. et al. Previous cytomegalovirus infection and risk of coronary thrombotic events after stent placement. Circulation 2000; 101: 11-3.
  • 31 Daus H, Ozbek C, Saage D. et al. Lack of evidence for a pathogenic role of Chlamydia pneumoniae and cytomegalovirus infection in coronary atheroma formation. Cardiology 1998; 90: 83-8.
  • 32 Sambiase NV, Higuchi ML, Nuovo G. et al. CMV and transplant-related coronary atherosclerosis: an immunohistochemical, in situ hybridization, and polymerase chain reaction in situ study. Mod Pathol 2000; 13: 173-9.
  • 33 Adam E, Melnick JL, DeBakey ME. Cytomegalovirus infection and atherosclerosis. Cent Eur J Public Health 1997; 5: 99-106.
  • 34 de Boer OJ, van der Wal AC, Becker AE. Atherosclerosis, inflammation, and infection. J Pathol 2000; 190: 237-43.
  • 35 Grahame-Clarke C, Chan NN, Andrew D. et al. Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 2003; 108: 678-83.
  • 36 Rott D, Zhu J, Zhou YF. et al. IL-6 is produced by splenocytes derived from CMV-infected mice in response to CMV antigens, and induces MCP-1 production by endothelial cells: a new mechanistic paradigm for infection-induced atherogenesis. Atherosclerosis 2003; 170: 223-8.
  • 37 Levi M, Keller TT, van Gorp E. et al. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60: 26-39.
  • 38 Chanarin I, Walford DM. Thrombocytopenic purpura in cytomegalovirus mononucleosis. Lancet 1973; 2: 238-9.
  • 39 Neau D, Bonnet F, Viallard JF. et al. Thrombotic thrombocytopenic purpura and cytomegalovirus infection in an immunocompetent adult. Clin Infect Dis 1997; 25: 1495-6.
  • 40 Arav-Boger R, Reif S, Bujanover Y. Portal vein thrombosis caused by protein C an protein S deficiency associated with cytomegalovirus infection. J Pediatr 1995; 126: 586-8.
  • 41 De Celis G, Mir J, Casal J. et al. 31-year-old woman with an enlarged tender liver. Lancet 1995; 346: 1270
  • 42 Labarca JA, Rabaggliati RM, Radrigan FJ. et al. Antiphospholipid sindrome associated with cytomegalovirus infection: case report and review. Clin Infect Dis 1997; 24: 197-200.
  • 43 Inacio C, Hillaire S, Valla D. et al. Case report: cytomegalovirus infection as a cause of portal vein thrombosis. J Gastroenterol Hepatol 1997; 12: 287-8.
  • 44 Ailani RK, Simms R, Caracioni AA. et al. Extensive mesenteric inflammatory veno-occlusive disease of unknown aetiology after primary cytomegalovirus infection: first case. Am J Gastroenterol 1997; 92: 1216-8.
  • 45 Kinsara AJ, Khazindar A, Abdelaal MA. Cytomegalovirus- associated haemophagocytic syndrome and acute myocardial infarction in a young patient: possible association. J Intern Med 1998; 244: 91-2.
  • 46 Uthman I, Tabbarah Z, Gharavy AE. Hughes syndrome associated with cytomegalovirus infection. Lupus 1999; 8: 775-7.
  • 47 Ofotokun I, Carlson C, Gitlin SD. et al. Acute cytomegalovirus infection complicated by vascular thrombosis: a case report. Clin Infect Dis 2001; 32: 983-6.
  • 48 Lanari M, Lazzarotto T, Papa I. et al. Neonatal aortic arch thrombosis as a result of congenital cytomegalovirus infection. Pediatrics 2001; 108: E114
  • 49 Estival JL, Debourdeau P, Zammit C. et al. Thrombose porte spontanèe associèe à une infection aigue à cytomegalovirus chez une patiente immunocompètente. Press Med 2001; 30: 1876-8.
  • 50 Dueñas C, Grande C, Martín A. et al. Mesenteric thrombosis associated with cytomegalovirus infection in an immunocompetent patient. Enferm Infec Microbiol Clín 2002; 20: 96-7.
  • 51 Abgueguen P, Delbos V, Chennebault JM. et al. Vascular thrombosis and acute cytomegalovirus infection in immunocompetent patients: report of 2 cases and literature review. Clin Infect Dis 2003; 36: e134-9.
  • 52 Benoist S, Laisne M, Joly F. et al. Cytomegalovirus infection as a cause of acute superior mesenteric vein thrombosis with jejunal infarction. Surgery 2003; 133: 222-3.
  • 53 Youd P, Main J, Jackson E. Cytomegalovirus infection and thrombosis: a causative association?. J Infect 2003; 46: 141-3.
  • 54 Garcia I, Fainstein V, Rios A. et al. Non bacterial thrombotic endocarditis in a male homosexual with Kaposi’s sarcoma. Arch Intern Med 1983; 143: 1243-4.
  • 55 Bagley PH, Scott DA, Smith LS. et al. Cytomegalovirus infection, ascending myelitis, and pulmonary embolism. Ann Intern Med 1986; 104: 587
  • 56 Powers P, Stahl-Bayliss CM. Cytomegalovirus thrombophlebitis after successful DPHG therapy. Ann Int Med 1987; 106: 632-3.
  • 57 Min KW, Wickemeyer WJ, Chandran P. et al. Fatal cytomegalovirus infection and coronary arterial thombosis after heart transplantation: a case report. J Heart Tranplant 1987; 5: 100-5.
  • 58 Meyohas MC, Roullet E, Rouzioux C. et al. Cerebral venous thrombosis and dual primary infection with human immunodeficiency virus and cytomegalovirus. J Neurol Neurosurg Psychiatry 1989; 52: 1010-1.
  • 59 Aguado S, Gorostidi M, Gomez E. et al. Cytomegalovirus (CMV) infection complicated with renal arterial thrombosis. Rapid diagnosis of CMV infection. Clin Transpl 1989; 300-1.
  • 60 Jenkins RE, Peters BS, Pinching AJ. Thromboembolic disease in AIDS is associated with cytomegalovirus disease. AIDS 1991; 5: 1540-2.
  • 61 Smith KJ, Skelton HG, Yeager J. et al. Cutaneous thrombosis in human immunodeficiency virus type 1-positive patients and cytomegalovirus viremia. Arch Dermatol 1995; 131: 357-8.
  • 62 Mansour AM, Li H, Segal I E. Picture resembling hemicentral retinal vein occlusion in the acquired immunodeficiency syndrome : is it related to cytomegalovirus?. Ophthalmologica 1996; 210: 108-11.
  • 63 Conway MD, Tong P, Olk RJ. Branch retinal artery occlusion (BRAO) combined with branch retinal vein occlusion (BRVO) and optic disc neovascularization associated with HIV and CMV retinitis. Int Ophthalmol 1995–96 19: 249-52.
  • 64 Muldoon J, O’Riordan K, Rao S. et al. Ischemic colitis secondary to venous thrombosis: a rare presentation of cytomegalovirus vasculitis following renal transplantation. Transplantation 1996; 61: 1651-3.
  • 65 Vielhauer V, Schewe CK, Schlondorff D. Bilateral thrombosis of the internal jugular veins with spasmodic torcicol patient with acquired immunodeficiency syndrome and disseminated cytomegalovirus infection. J Infect 1998; 37: 90-1.
  • 66 Schiemann U, Steins M, Knospe V. et al. Coincidence of cytomegalovirus retinitis and central vein occlusion in a patients with hemophilia B and AIDS. AIDS Patient Care STDs 1999; 13: 7-9.
  • 67 Wolf G, Porth J, Stahl RA. Thrombosis associated with cytomegalovirus infection in patients with ANCA-positive vasculitis. Am J Kidney Dis 2001; 38: e27
  • 68 Kazory A, Ducloux D, Coaquette A. et al. Cytomegalovirus- associated venous thromboembolism in renal transplant recipients: a report of 7 cases. Transplantation 2004; 7: 597-9.
  • 69 Sullivan PS, Dworkin MS, Jones JJ. et al. Epidemiology of thrombosis in HIV-infected individuals. AIDS 2000; 14: 321-4.
  • 70 Saif MW, Greenberg B. HIV and Thrombosis: a review. AIDS Patient Care STDs 2001; 15: 15-24.
  • 71 Stange BJ, Glanemann M, Nuessler NC. et al. Hepatic artery thrombosis after adult liver transplantation. Liver Transpl 2003; 9: 612-20.
  • 72 Heffron TG, Pillen T, Welch D. et al. Hepatic artery thrombosis in pediatric liver transplantation. Transplantation Proc 2003; 35: 1447-8.
  • 73 Pastacaldi S, Teixeira R, Montalto P. et al. Hepatic artery thrombosis after orthotopic liver transplanation : a review of nonsurgical causes. Liver Transpl 2001; 7: 75-81.
  • 74 Madalosso C, de Souza NF, Ilstrup DM. et al. Cytomegalovirus and its association with hepatic artery thrombosis after liver transplantation. Transplantation 1998; 66: 294-7.
  • 75 Gunsar F, Rolando N, Pastacaldi S. et al. Late hepatic artery thrombosis after orthotopic liver transplantation. Liver Transpl 2003; 9: 605-11.
  • 76 Oh CK, Pelletier SJ, Sawyer RG. et al. Uni- and multi-variate analysis of risk factors for early and late hepatic thrombosis after liver transplantation. Transplantation 2001; 71: 767-72.
  • 77 Grandaliano G, Teutonico A, Allegretti A. et al. The role of hyperparathyroidism, erythropoietin therapy, and CMV infection in the failure of arteriovenous fistula in hemodialysis. Kidney Int 2003; 64: 715-9.
  • 78 van Dam-Mieras MCE, Muller AD, van Hinsbergh VWM. et al. The procoagulant response of Cytomegalovirus infected endothelial cells. Thromb Haemost 1992; 68: 364-70.
  • 79 Bouwmann JJM, Visseren FLJ, Bosch MC. et al. Procoagulant and inflammatory response of virus-infected monocytes. Eur J Clin Invest 2002; 32: 759-66.
  • 80 Visseren FLJ, Bouwman JJM, Bouter KP. et al. Procoagulant activity of endothelial cells after infection with respiratory viruses. Thromb Haemost 2000; 84: 319-24.
  • 81 Van Geelen AG, Slobbe-van Drunen ME, Muller AD. et al. Membrane related effects in endothelial cells induced by human cytomegalovirus. Arch Virol 1995; 140: 1601-12.
  • 82 Visseren FL, Verkerk MS, Bouter KP. et al. Interleukin- 6 production by endothelial cells after infection with influenza virus and cytomegalovirus. J Lab Clin Med 1999; 134: 623-30.
  • 83 Bruggeman CA, Debie WH, Muller AD. et al. Cytomegalovirus alters the von Willebrand factor content in human endothelial cells. Thromb Haemost 1988; 59: 264-8.
  • 84 van Dam-Mieras MCE, Bruggeman CA, Muller AD. et al. Induction of endothelial cell procoagulant activity by cytomegalovirus infection. Thromb Res 1987; 47: 69-75.
  • 85 Maisch T, Kropff B, Sinzger C. et al. Upregulation of CD40 expression on endothelial cells infected with human cytomegalovirus. J Virol 2002; 76: 12803-12.
  • 86 Mach F, Schonbeck U, Sukhova GK. et al. CD40 signaling in vascular cells: a key role in atherosclerosis?. Atherosclerosis 1998; 137 (Suppl) S89-S95.
  • 87 Span AHM, van Dam-Mieras MCE, Mullers W. et al. The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells. Eur J Clin Invest 1991; 21: 331-8.
  • 88 Span AH, Mullers W, Miltenburg AM. et al. Cytomegalovirus induced PMN adherence in relation to an ELAM-1 antigen present on infected endothelial cell monolayers. Immunology 1991; 72: 355-60.
  • 89 Bolovan-Fritts CA, Wiedeman JA. Mapping the viral genetic determinants of endothelial cell tropism in human cytomegalovirus. J Clin Virol 2002; 25 (Suppl. 02) S97-109.
  • 90 Gerna G, Percivalle E, Sarasini A. et al. Rescue of human cytomegalovirus strain AD169 tropism for both leukocytes and human endothelial cells. J Gen Virol 2003; 84: 1431-6.
  • 91 Gerna G, Percivalle E, Sarasini A. et al. The attenuated Towne strain of human cytomegalovirus may revrt to both endothelial cell tropism and leuko-(neutrophiland monocyte-) tropism in vitro. J Gen Virol 2002; 83: 1993-2000.
  • 92 Gerna C, Percivalle E, Baldanti F. et al. Lack of transmission to polymorphonuclear leucokytes and human umbilical vein endothelial cells as marker of attenuation of human cytomegalovirus. J Med Virol 2002; 66: 335-9.
  • 93 Pryzdial ELG, Wright FJ. Prothrombinase assembly on an enveloped virus: evidence that the cytomegalovirus surface contains procoagulant phospholipids. Blood 1994; 84: 3749-57.
  • 94 Sutherland MR, Raynor CM, Leenknegt H. et al. Coagulation initiated on herpesviruses. Proc Natl Acad Sci USA 1997; 94: 13510-14.
  • 95 Schambeck CM, Hinney K, Gleixner J. et al. Venous thromboembolism and associated high plasma factor VIII levels: linked to cytomegalovirus infection?. Thromb Haemost 2000; 83: 510-1.
  • 96 The TH, Kas-Deelen AM, de Maar EF. et al. Cellular and humoral parameters for vascular damage in blood during cytomegalovirus infections. Transplant Proc 2001; 33: 1813
  • 97 Nieto JF, Sorlie P, Comstock GW. et al. Cytomegalovirus infection, lipoprotein(a) and hypercoagulability: an atherogenic link?. Arterioscler Thromb Vasc Biol 1997; 17: 1780-5.
  • 98 Friedman HM. Infection of endothelial cells by common human viruses. Rev Infect Dis 1989; 11 (Suppl. 04) S700-S704.
  • 99 Friedman HM, Wolfe J, Kefalides NA. et al. Susceptibility of endothelial cells derived from different blood vessels to common viruses. In Vitro Cell Dev Biol 1986; 22: 397-401.
  • 100 Hoxie JA, Matthews DM, Cines DB. Infection of human endothelial cells by human T-cell leukaemia virus type I. Proc Natl Acad Sci USA 1984; 81: 7591-5.
  • 101 Wiley CA Schrier RD, Nelson JA. et al. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 1986; 83: 7089-93.
  • 102 Friedman HM, Macarak EJ, MacGregor RR. et al. Virus infection of endothelial cells. J Infect Dis 1981; 143: 266-73.
  • 103 Levi M. CMV endothelitis as a factor in the pathogenesis of atherosclerosis. Cardiovasc Res 2001; 50: 432-3.
  • 104 Tarnacka B, Gromadzka G, Czlonkowska A. Increased circulating immune complexes in acute stroke: the triggering role of Chlamydia pneumoniae and cytomegalovirus. Stroke 2002; 33: 936-40.
  • 105 Gabrylewicz B, Mazurek U, Ochala A. et al. Cytomegalovirus infection in acute myocardial infarction. Is there a causative relationship?. Kardiol Pol 2003; 59: 283-92.
  • 106 Nieto FJ. Viruses and atherosclerosis: a critical review of the epidemiologic evidence. Am Heart J 1999; 138: S453-60.
  • 107 O'Connor S, Taylor C, Campbell LA. et al. Potential infectious etiologies of atherosclerosis: a multifactorial perspective. Emerg Infect Dis 2001; 7: 780-8.
  • 108 Potena L, Frascaroli G, Grigioni F. et al. Hydroxymethyl- Glutaryl Coenzyme A Reductase inhibition limits cytomegalovirus infection in human endothelial cells. Circulation 2004; 109: 532-6.