Elevated Thrombomodulin Plasma Levels as a Result of Endothelial Involvement in Plasmodium falciparum Malaria

Christoph J Hemmer; A Bierhaus; J v Riedesel; S Gabat; B Liliensiek; P Pitronik; J Lin; A Grauer; J Amiral; R Ziegler; S Schieffer; P Kern; R Seitz; R Egbring; M Dietrich; P P Nawroth

doi:10.1055/s-0038-1648889

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1994; 72(03): 457-464
DOI: 10.1055/s-0038-1648889

Original Article

Schattauer GmbH Stuttgart

Elevated Thrombomodulin Plasma Levels as a Result of Endothelial Involvement in Plasmodium falciparum Malaria

Christoph J Hemmer

¹The Department of Medicine, Bernhard-Nocht-lnstitute for Tropical Medicine, Hamburg, Germany

,

A Bierhaus

²Department of Medicine, University of Heidelberg, Germany

,

J v Riedesel

²Department of Medicine, University of Heidelberg, Germany

,

S Gabat

²Department of Medicine, University of Heidelberg, Germany

,

B Liliensiek

²Department of Medicine, University of Heidelberg, Germany

,

P Pitronik

²Department of Medicine, University of Heidelberg, Germany

,

J Lin

²Department of Medicine, University of Heidelberg, Germany

,

A Grauer

²Department of Medicine, University of Heidelberg, Germany

,

J Amiral

³SERBIO Research Laboratories, Gennevilliers, France

,

R Ziegler

²Department of Medicine, University of Heidelberg, Germany

,

S Schieffer

⁴Infectious Diseases and Clinical Immunology Section, University of Ulm

,

P Kern

⁴Infectious Diseases and Clinical Immunology Section, University of Ulm

,

R Seitz

⁵Department of Hematology, Hemostaseology Section, University of Marburg, Germany

,

R Egbring

⁵Department of Hematology, Hemostaseology Section, University of Marburg, Germany

,

M Dietrich

¹The Department of Medicine, Bernhard-Nocht-lnstitute for Tropical Medicine, Hamburg, Germany

,

P P Nawroth

²Department of Medicine, University of Heidelberg, Germany

› Author Affiliations

Abstract

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Summary

We used thrombomodulin (TM) to assess the participation of the vascular endothelium in human Plasmodium falciparum (P. F.) malaria. Before therapy TM plasma levels were elevated in P. F. malaria and fell to normal values during therapy. Parasitemia, TNFα, elastase and TAT levels correlated directly with TM. Elevated TM levels can not be explained by increased synthesis, since incubating HUVEC with pretherapy serum of patients with P. F. malaria, but not reconvalescence serum, suppressed TM transcription. This was partially prevented by adding a TNFα neutralizing antibody to patient serum before incubation with HUVEC. However, TNFα does not release TM from cultured HUVEC in vitro. Coincubation of HUVEC with pretherapy serum together with neutrophils resulted in endothelial cell destruction, which could be partly prevented by a TNFα neutralizing antibody. Hence the increase of TM during P. F. malaria might reflect the concerted action of cytokines and neutrophils on HUVEC.

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References

References
1 Hemmer ChJ, Kern P, Holst FGE, Radtke KP, Egbring R, Bierhaus A, Nawroth PP, Dietrich M. Activation of the host response 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
2 Horstmann RD, Dietrich M. Hemostatic alterations in malaria correlate to parasitemia. Blut 1985; 51: 329-335
3 Pukrittayakamee S, White NJ, Clemens R. Activation of the coagulation cascade in falciparum malaria. Trans R Soc Trop Med Hyg 1989; 83: 762-766
4 Mac Pherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria. Am J Pathol 1985; 119: 385-401
5 Udeinya IJ, Miller LH. Plasmodium falcipamm: Effect of infected erythrocytes on clotting time of plasma. Am J Trop Med 1987; 372: 246-249
6 Ockenhouse ChF, Tandon N, Magowan C, Jamieson GA, Chulay JD. Identification of a platelet membrane glycoprotein as a falciparum malaria sequestration receptor. Science 1989; 243: 1469-1471
7 Ockenhouse ChF, Magowan C, Chulay J. Activation of monocytes and platelets by monoclonal antibodies or malaria-infected erythrocytes binding to the CD36 surface receptor in vitr. J Clin Invest 1989; 84: 468--75
8 Fajardo LF. Malarial parasites in mammalian platelets. Nature 1973; 243: 298-289
9 Kelton JG, Keystone J, Moore J, Denomme G, Tozman E, Glynn M, Neame PB, Gauldie J, Jensen J. Immune mediated thrombocytopenia of malaria. J Clin Invest 1983; 17: 832-836
10 Sucharit P, Chongsuphajaisiddhi T, Harinsuta T, Tongprasroeth N, Kasem-suth R. Studies on coagulation and fibrinolysis in cases of falciparum malaria. Southeast Asian J Trop Med Public Health 1975; 6: 33-39
11 Oo MM, Aikawa M, Thn T. Human cerebral malaria - a pathological study. J Neuropathol Exp Neurol 1987; 46: 223-31
12 Kaul DK, Roth EF, Nagel Jr RL, Howard RJ, Handunnetti SM. Rosetting of plasmodium falciparum infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions. Blood 1991; 78: 812-819
13 Grau G, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 1987; 237: 1210-1212
14 Clark IA, MacMicking JD, Gray KM, Rockett KA, Cowden WB. Malaria mimicry with tumor necrosis factor. Am J Pathol 1992; 140: 325-336
15 Clark IA, Cowden WB, Butcher GA, Hunt NH. Possible roles of tumor necrosis factor in the pathology of malaria. Am J Pathol 1987; 129: 192-199
16 Kern P, Hemmer ChJ, van Damme J, Gruss HJ, Dietrich M. Elevated tumor necrosis factor a and interleukin-6 serum levels as markers for complicated plasmodium falciparum malaria. Am J Med 1989; 87: 139-143
17 Nawroth PP, Handley D, Esmon CT, Stern D. Interleukin-1 induces endothelial procoagulant while suppressing cell surface anticoagulant activity. Proc Natl Acad Sci USA 1986; 83: 3460-3464
18 Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stem DM. Tumor necrosis factor/cachectin interacts with endothelial cells to induce release of interleukin-1. J Exp Med 1986; 163: 1363-1375
19 Nawroth PP, Stern DMe. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-755
20 Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterisation and comparison with the actions of interleukin-1. Proc Natl Acad Sci USA 1986; 83: 4533-4537
21 Nawroth PP, Handley DA, Matsueda G, deWaal R, Gerlach H, Blohm D, Stern DM. Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth-A fibrosarcomas. J Exp Med 1988; 68: 637-647
22 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235: 1348--52
23 Dittmann WA, Majerus PW. Structure and function of thrombomodulin: A natural anticoagulant. Blood 1990; 75: 329-36
24 Taylor FB, Chang A, Esmon CT, D’Angelo A, Vigano D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of escherichia coli infusion into the baboon. J Clin Invest 1987; 79: 918-925
25 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemostas 1991; 65: 618-623
26 Kurosawa S, Galvin JB, Esmon N, Esmon CT. Proteolytic formation and properties of functional domains of thrombomodulin. J Biol Chem 1987; 262: 2206-2212
27 Ishii H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76: 2178-2181
28 Westlin FW, Gimbrone Jr MA. Neutrophil-mediated damage to human vascular endothelium: Role of cytokine activation. Am J Pathol 1993; 142: 117-128
29 Bevilacqua M, Pober JS, Wheeler ME, Cotran RS, Gimbrone Jr MA. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 1985; 76: 2003-2011
30 Wen D, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE. Human thrombomodulin: Complete cDNA sequence and chromosome localisation of the gene. Biochemistry 1987; 26: 4350-4362
31 Feinberg AP, Vogelstein B. A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983; 1132: 6-13
32 Chirgwin JM, Przbyla AE, Macdonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 1979; 18: 5294-5299
33 Thomas PS. Hybridisation of denatured RNA and small fractions of DNA transferred to nitrocellulose. Proc Natl Acad Sci USA 1980; 77: 5201-5
34 Ye RD, Wun TC, Sadler JE. cDNA-cloning and expression of a plasminogen activator inhibitor from human placenta. J Biol Chem 1987; 262: 3718-3725
35 Almendral JM, Sommer D, MacDonald Bravo H, Burckhardt J, Perera J, Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol 1988; 8: 2140-8
36 Greenberg ME, Ziff EB. Stimulation of 3T3 cells induces transcription of the c-fos protoonpogene. Nature 1984; 311: 433-438
37 Lentz SR, Tsiang M, Sadler JE. Regulation of thrombomodulin by tumor necrosis factor a; Comparison of transcriptional and posttranscriptional mechanisms. Blood 1991; 77: 542-550
38 Soff GA, Jackman RW, Rosenberg RD. Expression of thrombomodulin by smooth muscle cells in culture: Different effects of tumor necrosis factor and cyclic adenosine monophosphate on thrombomodulin expression by endothelial cells and smooth muscle cells in culture. Blood 1991; 77: 515-518
39 McCachreen SS, Diggs J, Weinberg JB, Dittman WA. Thrpmbomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood 1991; 78: 3128-3132
40 Maruyama I, Bell EC, Majerus PW. Thrombomodulin is found on endothelium of arteries, veins, capillaries and lymphatics and on syncytiotroph-oblast of human placenta. J Cell Biol 1985; 101: 363-71
41 DeBault L, Esmon N, Olson JR, Esmon CT. Distribution of thrombomodulin antigen in the rabbit vasculature. Lab Invest 1986; 54: 172-178
42 Maruyama I, Yonezawa S, Sato E, Igata A. Endothelium and thrombomodulin: Expression and distribution of thrombomodulin on altered endothelium and neoplastic syncytiotrophoblast. Acta Haematol JPN 1989; 51: 150-155
43 Yonezawa S, Maruyama I, Sakae K, Iagata E, Majerus PW, Sato A. Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin. Am J Clin Pathol 1987; 88: 405-11
44 Ito T, Ogura M, Morishita Y, Takamatsu J, Maruyama I, Yamamoto S, Ogawa K, Saito H. Enhanced expression of thrombomodulin by intracellular cyclic AMP-increasing agents in two human megakaryoblastic leukemia cell lines. Thromb Res 1990; 58: 615-624