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Tissue factor initiation of disseminated intravascular coagulation in filovirus infection
Medical Hypotheses Medical Hypotheses(1995) 45, 380-382 © PearsonProfessionalLtd 1995
tissue Factor Initiation of Disseminated Intravascular Coagulation in Filovirus Infection C. GROB 206A Dewey Building, State University At Stony Brook, Stony Brook, NY 11794, USA
Abstract - - Filovirus infections in humans and primates cause intrinsic activation of the clotting cascade. Tissue factor, the normal activator of the clotting cascade, is released into the bloodstream from activated leukocytes and viral budding from infected cells. This release of tissue factor, a trans-membrane protein found in large amounts in cells preferred by filoviruses for replication, initiates the hemorrhagic complications characteristic of filovirus infection. These complications contribute to the high mortality rates of filovirus infections. Directing chemotheraputic measures at the release of tissue factor, which causes the hemorrhagic complications, will result in significant reductions of mortality rates in man and primates.
Introduction Formation of clots in the human body is dependent on several proteins interacting with one another in a cascade, the end result of which is polymerization of fibrin as a clot (1). This cascade is normally triggered by injury to blood vessels exposing tissue factor (TF), a membrane-bound protein found in high concentration in tissues immediately behind endothelial cells lining blood vessels such as smooth muscle and fibroblasts (2). Leukocytes have been found to release TF protein in response to bacterial infections (3). This release of soluble TF causes widespread clot formation in the blood (4). Termed disseminated intravascular coagulation or DIC, this condition often results in hemorrhagic complications as minute clots lodge in capillaries (5,6). Filoviruses cause severe hemorrhagic fevers in humans and primates: currently there is little understanding of these infections, no treatment and no
vaccine (7-9). The virus family Filovirius has three subtypes: Marburg, Ebola and Reston (10). DIC is a prominent manifestation of filovirus infection, which in the Ebola (7,13) and Marburg (8) subtypes contributes to very high mortality rates in humans. The Reston subtype appears to cause severe symptoms only in primates and has served as the experimental model for filovirus infection (9). Anticoagulant therapy to control the DIC associated with infection has been limited for the most part to heparin infusion (11), its success being controversial (7). This communication focuses on tissue factor (TF) release from viral budding of infected cells, and TF release from activated leukocytes as initiators of DIC in filovirus infections.
Hypothesis It is believed that, as monocytes exposed to bacterial
Date received 5 April 1995 Date accepted 12 M a y 1995
380
TISSUE FACTOR INITIATIONOF DISSEMINATEDINTRAVASCULARCOAGULATIONIN FILOVIRUSINFECTION
endotoxin generate TF, exposure to viral envelope glycoproteins causes similar production of monocyte TF (Fig.). Enhancement of this TF production with interleukin stimulation, is considered to be an upregulatory mechanism for production of monocyte TF. Since the primary antibody associated with infection is directed at viral envelope glycoprotein (7,8), it is tempting to speculate that the antibody reduces expression of this protein and thus invalidates this hypothesis. However, decreased B-cell antibody production due to immunosuppressive proteins (18) and interaction with other viral structural proteins are events that could enable viral monoctye activation to occur.
The viral budding mechanism is the second mechanism for TF activation of the clotting cascade considered in this paper. As mature virions lyse infected cells, large amounts of fragmented TF-rich cell membrane are released into the blood stream (Fig.). These minute membrane fragments are thought to cause intrinsic activation of the clotting cascade. Tissues that filoviruses prefer for replication, such as interstitial fibroblasts and tissue-bound leukocytes, are rich in TF protein (9). This mechanism can occur in conjunction with the vh'al glycoprotein mechanism described earlier. Infected monocytes that have been stimulated by viral glycoprotein into producing TF will exacerbate the hemorrhagic complications 10fold if they themselves are infected and budding occurs. In addition, significant variation in the morphology of mature virions exists between the subtypes (12).
Virus particles of the Reston subtype display the most variation in shape, the effect these misshapen virions have on the activation of the clotting cascade may be significant. Budding of the oddly shaped virions could rupture host cell membrane differently, some shapes releasing more TF than others in the budding process. Host cell membrane architecture is different in humans and primates, viral activation of the clotting cascade in the two species might reflect these subtle differences. This may be one of the reasons why the Reston strain is lethal for primates and not for humans (9). Each mechanism described in this communication occurring in conjunction with the other compounds the amount of soluble TF in circulation (Fig.). Presumably, viral ability to exponentially increase the amount of soluble TF in circulation mediates the hemorrhagic complications of infection. In this respect, consumption of clotting proteins as a result of viral budding and activated monocytes promotes the thrombocytopenia described by investigators in many of the severe cases (7,8).
Conclusion
While this paper intimates that the majority of tissue factor initiating DIC in filovirus infection results from viral budding, monocytes may have an active role as initiators or contributors in DIC. Treatment of both these mechanisms is possible with antibodies directed at TF (14). This method has proven to be effective in E. coli bacterial infections by reducing septic shock
Thrombocytopenia Viral infection ~-and lysis of 4 ~ other cells i
Monocyte TF ,
activates clotting cascad~
~
Infected c~ ~ A Fig.
Consumption of Clotting,pProteins
Capillaries and rupture endothelia
Serum IF
3 81
/
° "~-~ ~
Cascade
Diagram to explain production of monocyte TF as a result of exposure to viral envelope glycoproteins.
382 (15) and acting as a potent anticoagulant (16,17). Additional viral mechanisms have been found that demonstrate the complexity of these viruses and their lethal nature (18). As we gain a clearer understanding of these viral mechanisms, more strategies for treating these viral infections will emerge. Using monoclonal antibodies or perhaps pentoxyfilline (14) to control TF activation of the clotting cascade should reduce mortality rates associated with these virulent pathogens in man and primate. Modern air transportation places every city on earth within a day's travel of an outbreak. For this reason alone, development of antiviral compounds to combat these exotic viruses is of paramount importance.
References 1. Coleman R W, Marder V J, Salzman E W, Hirsch J. Overview of hemostasis. In: Coleman R W, Hirsch J, Marder V J, Salzman E W. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: JB Lippincott, 1987. 2. Nemerson Y. Tissue factor and hemostasis. Blood 1988; 7l: 1-8. 3. Edwards R L, Ricktes F R, Bobrove A M. Mononuclear cell tissue factor: cell of origin and requirements for activation. Blood 1979; 54: 359-370. 4. Rivers R P A, Hathaway W E, Weston W L, The endotoxininduced coagulant activity of human monocytes. Br J Haematol 1975; 30: 311-316. 5. Preston F E, Malia R G, Sworn M J, Blackburn E K. Intravascular coagulation and E. coli septicaemia. J Clin Pathol 1973; 26: 120-125.
MEDICALHYPOTHESES 6. Neimetz J. Coagulant activity of leukocytes: tissue factor activity. J Clin Invest 1972; 51: 307-313. 7. Pattyn S R. Ebola Virus Haemorrhagic Fever. Amsterdam: Elsevier/North-Holland, 1978. 8. Martini G A, Siegert R. Marburg Virus Disease. BerlinHeidelburg: Springer-Verlag, 1971. 9. Jahrling P B. Filoviruses and arenavimses. In: Balows A, ed. Manual of Clinical Microbiology. Washington DC: American Society for Microbiology, 1991. 10. Kiley M P, Bowen E T W, Eddy G A et al. Filoviridae: a taxonomic home for Marburg and Ebola viruses? Intervirology 1982; 18: 24-32. 11. Corrigan J J, Jordan C M. Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970; 283: 778. 12. Buchmeier M J, DeFries R U, McCormick J B e t al. Comparative analysis of the structural polypeptides of Ebola viruses from Sudan and Zaire. J Infect Dis 1983; 147: 276-281. 13. McCormick J B, Bauer S P, Elliot L H et al. Biologic differences between strains of Ebola virus from Zaire and Sudan. J Infect Dis 1983; 147: 264-267. 14. Levi M, ten Cate H, Bauer K A et al. Inhibition of endotoxininduced activation of coagulation and fibrinolysis by pentoxyfylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93:114-120. 15. Taylor F B, Chang A, Ruf W e t al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-134. 16. Cate T C, Bauer K A, Levi M et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest 1993; 92: 1207-1212. 17. RufW, Edgington T S. An anti-tissue factor monoclonal antibody which inhibits TF-VIIa complex is a potent anticoagulant in plasma. Thromb Haemost 1991; 66: 529-533. 18. Volchkov V E, Bilnov V M, Netesov S V. The envelope glycoprotein of Ebola virus contains an immunosuppressive domain similar to oncogenic retroviruses. FEBS Lett 1992; 305: 181-184.
tissue Factor Initiation of Disseminated Intravascular Coagulation in Filovirus Infection C. GROB 206A Dewey Building, State University At Stony Brook, Stony Brook, NY 11794, USA
Abstract - - Filovirus infections in humans and primates cause intrinsic activation of the clotting cascade. Tissue factor, the normal activator of the clotting cascade, is released into the bloodstream from activated leukocytes and viral budding from infected cells. This release of tissue factor, a trans-membrane protein found in large amounts in cells preferred by filoviruses for replication, initiates the hemorrhagic complications characteristic of filovirus infection. These complications contribute to the high mortality rates of filovirus infections. Directing chemotheraputic measures at the release of tissue factor, which causes the hemorrhagic complications, will result in significant reductions of mortality rates in man and primates.
Introduction Formation of clots in the human body is dependent on several proteins interacting with one another in a cascade, the end result of which is polymerization of fibrin as a clot (1). This cascade is normally triggered by injury to blood vessels exposing tissue factor (TF), a membrane-bound protein found in high concentration in tissues immediately behind endothelial cells lining blood vessels such as smooth muscle and fibroblasts (2). Leukocytes have been found to release TF protein in response to bacterial infections (3). This release of soluble TF causes widespread clot formation in the blood (4). Termed disseminated intravascular coagulation or DIC, this condition often results in hemorrhagic complications as minute clots lodge in capillaries (5,6). Filoviruses cause severe hemorrhagic fevers in humans and primates: currently there is little understanding of these infections, no treatment and no
vaccine (7-9). The virus family Filovirius has three subtypes: Marburg, Ebola and Reston (10). DIC is a prominent manifestation of filovirus infection, which in the Ebola (7,13) and Marburg (8) subtypes contributes to very high mortality rates in humans. The Reston subtype appears to cause severe symptoms only in primates and has served as the experimental model for filovirus infection (9). Anticoagulant therapy to control the DIC associated with infection has been limited for the most part to heparin infusion (11), its success being controversial (7). This communication focuses on tissue factor (TF) release from viral budding of infected cells, and TF release from activated leukocytes as initiators of DIC in filovirus infections.
Hypothesis It is believed that, as monocytes exposed to bacterial
Date received 5 April 1995 Date accepted 12 M a y 1995
380
TISSUE FACTOR INITIATIONOF DISSEMINATEDINTRAVASCULARCOAGULATIONIN FILOVIRUSINFECTION
endotoxin generate TF, exposure to viral envelope glycoproteins causes similar production of monocyte TF (Fig.). Enhancement of this TF production with interleukin stimulation, is considered to be an upregulatory mechanism for production of monocyte TF. Since the primary antibody associated with infection is directed at viral envelope glycoprotein (7,8), it is tempting to speculate that the antibody reduces expression of this protein and thus invalidates this hypothesis. However, decreased B-cell antibody production due to immunosuppressive proteins (18) and interaction with other viral structural proteins are events that could enable viral monoctye activation to occur.
The viral budding mechanism is the second mechanism for TF activation of the clotting cascade considered in this paper. As mature virions lyse infected cells, large amounts of fragmented TF-rich cell membrane are released into the blood stream (Fig.). These minute membrane fragments are thought to cause intrinsic activation of the clotting cascade. Tissues that filoviruses prefer for replication, such as interstitial fibroblasts and tissue-bound leukocytes, are rich in TF protein (9). This mechanism can occur in conjunction with the vh'al glycoprotein mechanism described earlier. Infected monocytes that have been stimulated by viral glycoprotein into producing TF will exacerbate the hemorrhagic complications 10fold if they themselves are infected and budding occurs. In addition, significant variation in the morphology of mature virions exists between the subtypes (12).
Virus particles of the Reston subtype display the most variation in shape, the effect these misshapen virions have on the activation of the clotting cascade may be significant. Budding of the oddly shaped virions could rupture host cell membrane differently, some shapes releasing more TF than others in the budding process. Host cell membrane architecture is different in humans and primates, viral activation of the clotting cascade in the two species might reflect these subtle differences. This may be one of the reasons why the Reston strain is lethal for primates and not for humans (9). Each mechanism described in this communication occurring in conjunction with the other compounds the amount of soluble TF in circulation (Fig.). Presumably, viral ability to exponentially increase the amount of soluble TF in circulation mediates the hemorrhagic complications of infection. In this respect, consumption of clotting proteins as a result of viral budding and activated monocytes promotes the thrombocytopenia described by investigators in many of the severe cases (7,8).
Conclusion
While this paper intimates that the majority of tissue factor initiating DIC in filovirus infection results from viral budding, monocytes may have an active role as initiators or contributors in DIC. Treatment of both these mechanisms is possible with antibodies directed at TF (14). This method has proven to be effective in E. coli bacterial infections by reducing septic shock
Thrombocytopenia Viral infection ~-and lysis of 4 ~ other cells i
Monocyte TF ,
activates clotting cascad~
~
Infected c~ ~ A Fig.
Consumption of Clotting,pProteins
Capillaries and rupture endothelia
Serum IF
3 81
/
° "~-~ ~
Cascade
Diagram to explain production of monocyte TF as a result of exposure to viral envelope glycoproteins.
382 (15) and acting as a potent anticoagulant (16,17). Additional viral mechanisms have been found that demonstrate the complexity of these viruses and their lethal nature (18). As we gain a clearer understanding of these viral mechanisms, more strategies for treating these viral infections will emerge. Using monoclonal antibodies or perhaps pentoxyfilline (14) to control TF activation of the clotting cascade should reduce mortality rates associated with these virulent pathogens in man and primate. Modern air transportation places every city on earth within a day's travel of an outbreak. For this reason alone, development of antiviral compounds to combat these exotic viruses is of paramount importance.
References 1. Coleman R W, Marder V J, Salzman E W, Hirsch J. Overview of hemostasis. In: Coleman R W, Hirsch J, Marder V J, Salzman E W. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: JB Lippincott, 1987. 2. Nemerson Y. Tissue factor and hemostasis. Blood 1988; 7l: 1-8. 3. Edwards R L, Ricktes F R, Bobrove A M. Mononuclear cell tissue factor: cell of origin and requirements for activation. Blood 1979; 54: 359-370. 4. Rivers R P A, Hathaway W E, Weston W L, The endotoxininduced coagulant activity of human monocytes. Br J Haematol 1975; 30: 311-316. 5. Preston F E, Malia R G, Sworn M J, Blackburn E K. Intravascular coagulation and E. coli septicaemia. J Clin Pathol 1973; 26: 120-125.
MEDICALHYPOTHESES 6. Neimetz J. Coagulant activity of leukocytes: tissue factor activity. J Clin Invest 1972; 51: 307-313. 7. Pattyn S R. Ebola Virus Haemorrhagic Fever. Amsterdam: Elsevier/North-Holland, 1978. 8. Martini G A, Siegert R. Marburg Virus Disease. BerlinHeidelburg: Springer-Verlag, 1971. 9. Jahrling P B. Filoviruses and arenavimses. In: Balows A, ed. Manual of Clinical Microbiology. Washington DC: American Society for Microbiology, 1991. 10. Kiley M P, Bowen E T W, Eddy G A et al. Filoviridae: a taxonomic home for Marburg and Ebola viruses? Intervirology 1982; 18: 24-32. 11. Corrigan J J, Jordan C M. Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970; 283: 778. 12. Buchmeier M J, DeFries R U, McCormick J B e t al. Comparative analysis of the structural polypeptides of Ebola viruses from Sudan and Zaire. J Infect Dis 1983; 147: 276-281. 13. McCormick J B, Bauer S P, Elliot L H et al. Biologic differences between strains of Ebola virus from Zaire and Sudan. J Infect Dis 1983; 147: 264-267. 14. Levi M, ten Cate H, Bauer K A et al. Inhibition of endotoxininduced activation of coagulation and fibrinolysis by pentoxyfylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93:114-120. 15. Taylor F B, Chang A, Ruf W e t al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-134. 16. Cate T C, Bauer K A, Levi M et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest 1993; 92: 1207-1212. 17. RufW, Edgington T S. An anti-tissue factor monoclonal antibody which inhibits TF-VIIa complex is a potent anticoagulant in plasma. Thromb Haemost 1991; 66: 529-533. 18. Volchkov V E, Bilnov V M, Netesov S V. The envelope glycoprotein of Ebola virus contains an immunosuppressive domain similar to oncogenic retroviruses. FEBS Lett 1992; 305: 181-184.