Early Markers of Blood Coagulation and Fibrinolysis Activation in Argentine Hemorrhagic Fever

Summary

Junin virus, an arenaviridae, is the etiological agent of Argentine hemorrhagic fever. In addition to thrombocytopenia, patients present several alterations in both the blood coagulation and the fibrinolytic system, but diffuse intravascular coagulation could not be demonstrated. To investigate further the activation status of the two systems, levels of thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2, protein C, total and free protein S, C4bBP, antithrombin III, t-PA, PAI-1 and D-dimer were measured. Fourteen patients with a confirmed diagnosis of Argentine hemorrhagic fever were included in the study, 2 were severe, 3 moderate and 9 mild clinical cases, but hemorrhages were slight throughout. Blood samples were collected for 6 consecutive days on admission and on remission. At admission TAT and F1+2 levels were increased in 13/14 patients, reaching 0.33 nM (0.06-0.87) and 2.16 nM (0.96-6.5), respectively. PC was low in 4 cases, fPS in 6 and tPS in 2, whereas C4bBP and ATIII values were within normal range. t-PA and D-dimer levels were high in 11/14 patients, reaching 20 ng/ml (2.7-106) and 1660 ng/ml (877-3780) respectively, while PAI-1 was considerably increased in the 2 severe cases and normal in the remainder. These results suggest low level though persistent process of blood coagulation and fibrinolysis activation in this viral hemorrhagic disease. We believe these abnormalities may lead to the well described bleeding manifestations in these patients.

• References

• 1 Schwarz ER, Mando OG, Maiztegui JI, Vilches AM. Síntomas y signos iniciales de mayor valor diagnóstico en la Fiebre hemorrágica argentina. Medicina (Bs As) 1970; 30 Suppl (Suppl. 01) 8-14
• 2 Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine hemorhagic fever and association between treatment and a late neurological syndrome. Lancet 1979; 2: 1216-1219
• 3 Enria D, Garcia FrancoS, Ambrosio A, Vallejos D, Levis S, Maiztegui J. Current status of the treatment of Argentine hemorrhagic fever. Med Microbiol Immunol 1986; 175: 173-176
• 4 Schwarz ER, Mando OG, Maiztegui JI, Vilches A, Otero ER, Berrutti ZC. Alteraciones de la coagulación en la Fiebre hemorrágica argentina. Medicina (Bs As) 1972; 32: 247-259
• 5 Molinas FC, de Bracco MM E, Maiztegui JI. Coagulation studies in Argentine hemorrhagic fever. J Infect Dis 1981; 143: 1-6
• 6 de Bracco MM E, Rimoldi MT, Cossio P, Rabinovich A, Maiztegui JI, Carballal G, Arana R. Argentine hemorrhagic fever. Alterations of the complement system and anti-Junin virus response N Engl J Med 1978; 299: 216-221
• 7 Molinas FC, de Bracco MM E, Maiztegui JI. Hemostasis and the complement system in Argentine hemorrhagic fever. Rev Infect Dis 1989; 11 Suppl (Suppl. 04) 762-767
• 8 Levis S, Saavedra MC, Ceccoli C, Falcoff E, Feuillade M, Enria D, Maiztegui JI, Falcoff R. Endogenous interferon in Argentine hemorrhagic fever. J Infect Dis 1984; 149: 428-433
• 9 Levis S, Saavedra MC, Ceccoli C, Feuillade MR, Enria DA, Maiztegui JI, Falcoff R. Correlation between endogenous interferon and the clinical evolution of patients with Argentine hemorrhagic fever. J Interf Res 1985; 5: 383-389
• 10 Heller MV, Saavedra MC, Falcoff R, Maiztegui JI, Molinas FC. Increased tumor necrosis factor-alpha levels in Argentine hemorrhagic fever. J Infect Dis 1992; 166: 1203-1204
• 11 Molinas FC, Maiztegui JI. Factor VIIIC and factor VIIIR:Ag in Argentine hemorrhagic fever. Thromb Haemost 1981; 46: 525-527
• 12 Molinas FC, Kordich L, Porterie P, Lerer G, Maiztegui JI. Plasminogen abnormalities in patients with Argentine hemorrhagic fever. Thromb Res 1987; 48: 713-720
• 13 Ponzinibbio C, Gonzalez PH, Maiztegui JI, Laguens RP. Estudio morfológico de la médula ósea humana en la Fiebre hemorrágica argentina. Medicina (Bs As) 1979; 34: 441-446
• 14 Cummins D, Molinas FC, Lerer G, Maiztegui JI, Faint R, Machin SJ. A plasma inhibitor of platelet aggregation in patients with Argentine hemorrhagic fever. Am J Trop Med Hyg 1990; 42: 470-475
• 15 Marta RF, Heller MV, Maiztegui JI, Molinas FC. Further studies on the plasma inhibitor of platelet activation in Argentine hemorrhagic fever. Thromb Haemost 1993; 69: 526-527
• 16 MacKay DG, Margaretten W. Disseminated intravascular coagulation in virus diseases. Arch Intern Med 1967; 120: 129-152
• 17 Johnson KM. Fiebres hemorrágicas de América del Sur. Medicina (BsAs) 1070 30 Suppl (Suppl. 01) 99-110
• 18 Gallardo F. Fiebre hemorrágica argentina. Hallazgos histopatológicos en diez necropsias Medicina (Bs As) 1970; 30 Suppl (Suppl. 01) 77-84
• 19 Elsner B, Schwarz E, Mando OG, Maiztegui JI, Vilches A. Pathology of 12 fatal cases of Argentine hemorrhagic fever. Am J Trop Med Hyg 1973; 22: 229-236
• 20 Molinas FC, Paz RA, Rimoldi MT, de Bracco MM E. Studies of blood coagulation and pathology in experimental infection of guinea pigs with Junin virus. J Infect Dis 1978; 137: 740-746
• 21 Molinas FC, Giavedoni E, Frigerio MJ, Calello MA, Barcat JA, Weissenbacher MC. Alteration of blood coagulation and complement system in Neotropical primates infected with Junin virus. J Med Virol 1983; 12: 281-292
• 22 Agrest A, Sanchez-Avalos JC, Arce M, Slepoy A. Fiebre hemorrágica argentina y coagulopatía por consumo. Medicina (Bs As) 1969; 29: 194-201
• 23 Waage A, Halstensen A, Espevik T. Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987; 1: 355-357
• 24 Girardin E, Grau GE, Dayer J-M, Roux-Lombard P. The J5 study group, Lambert P-J: Tumor necrosis factor and interleukin 1 in the serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397-400
• 25 Hemmer CJ, Kern P, Hoslt FG, Radtke KP, Egbring R, Bierhaus A, Nawroth PP, Dietrich M. Activation of the host responses in human plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels. Am J Med 1991; 91: 37-44
• 26 Bauer K, ten Cate H, Barzegar S, Spriggs D, Sherman M, Rosenberg R. Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanisms of humans. Blood 1989; 74: 165-172
• 27 van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJ H, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622-1627
• 28 Pelzer H, Schawarz A, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-159
• 29 Pelzer H, Schawarz A, Heimburger N. Determination of thrombin-antithrombin complex in plasma with an enzyme-linked immunoabsorvent assay. Thromb Haemost 1988; 59: 101-106
• 30 Dawson EK, Trapp R. In Bioestadistica Médica. Ed. Manual Modemo EL. Buenos Aires: 1993. Original English language edition published by Appleton & Lange, 1990;
• 31 Levi M, de Boer JP, Roem D, ten Cate W, Hack CE. Plasminogen activation in vivo upon intravenous infusion of DDAVP. Thromb Haemost 1992; 67: 111-116
• 32 Shifman MA, Pizzo SV. The in vivo metabolism of antithrombin III and antithrombin III complex. J Biol Chem 1983; 257: 3243-3248
• 33 Bauer KA, Goodman TL, Kass BL, Rosenberg RD. Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. J Clin Invest 1985; 76: 826-836
• 34 Monteagudo J, Pereira A, Reveter JC, Pijoan J, Tusell J, Puig L, Ordinas A, Castillo R. Thrombin generation and fibrinolysis in the thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Thromb Haemost 1991; 66: 515-519
• 35 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot bound thrombin is protected from inhibition by heparin-intithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-391
• 36 Griffin JH, Gruber A, Fernandez JA. Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin. Blood 1993; 79: 3203-3211
• 37 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-745
• 38 Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Csi USA 1986; 83: 4533-4537
• 39 van Hinsberg V, Kooistra T, van den Berg E, Princen H, Friers W, Emies J. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1988; 72: 1467-1473
• 40 van Hinsberg VW M, Bauer KA, Kooistra T, Kluft C, Dooijewaard G, Sherman ML, Nieuwenhuizen W. Progress of fibrinolysis during tumor necrosis factor infusions in humans Concomitant increase of tissue type plasminogen activator, plasminogen activator inhibitor type 1, and fibrin(ogen) degradation products. Blood 1990; 76: 2284-2289
• 41 van der Poll T, Levi M, Buller HR, van Deventer S, de Boer J, Hack CE, ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-732
• 42 Juhan-Vague I, Alessi MC, Raccah D, Aillaud MF, Billerey M, Ansaldi J, Phillip-Joet C, Vague P. Daytime fluctuations of plasminogen activator inhibitor 1 (PAI-1) in populations with high PAI-1 levels. Thromb Haemost 1992; 67: 76-82
• 43 Andrews BS, Theofilopoulos AN, Peters CJ, Loakotoff DJ, Brandt W, Dixon FJ. Replication of dengue and Junin viruses in cultured rabbit and human endothelial cells. Infect Immunol 1978; 20: 776-781
• 44 van der Poll T, van Deventer S, Pasterkamp G, van Mourik J, Buller H, ten Cate JW. Tumor necrosis factor induces von Willebrand factor release in healthy humans. Thromb Haemost 1992; 67: 623-626
• 45 Heller MV, Sassetti B, Maiztegui JI, Molinas FC. Ausencia de actividad de elastasa leucocitaria en el plasma de pacientes con Fiebre hemorrágica argentina. Medicina 1991; 50: 99 (abstr)
• 46 Heller MV. Estudio de citoquinas, reactantes de fase aguda y su relación con las alteraciones de la hemostasia en pacientes con Fiebre hemorrágica argentina. Tesis de Doctorado, Facultad de Farmacia y Bioquímica Universidad de Buenos Aires, Argentina: 1993
• 47 Ponzinibbio C, Gonzalez P, Chambo J, Laguens RP. Efecto del virus Junin sobre leukocitos polimorfonucleares humanos cultivados in vitro. Medicina (Bs As) 1981; 41: 683 (abstr)