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Recombinant human soluble thrombomodulin is active against hemophagocytic lymphohistiocytosis associated with acquired immunodeficiency syndrome

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Abstract

A 39-year-old man was admitted to our hospital to initiate highly active anti-retroviral therapy (HAART) for documented acquired immune deficiency syndrome. The HIV load was 2.5 million copies/mL and the CD4-positive lymphocyte count was only 52 cells/µL at presentation. The HAART regimen consisted of lamivudine and abacavir as the backbone, plus raltegravir and lopinavir/ritonavir as the base. The day after initiating HAART, his body temperature rose to 102.4 °F (39.1 °C), accompanied by elevated levels of liver enzymes, neutropenia, coagulopathies, and an extremely high serum ferritin level, prompting us to suspect hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC). To correct the coagulation abnormalities, recombinant thrombomodulin (rTM) was initiated at 375 U/kg. Surprisingly, fever resolved almost immediately, in parallel with dramatic decreases in serum levels of ferritin and liver enzymes and prompt normalization of coagulopathy with only two doses of rTM. The patient subsequently developed amebiasis, which was successfully treated using metronidazole. In summary, the use of rTM dramatically improved not only DIC, but also HLH, suggesting potent anti-inflammatory effects of the agent. Although further clinical reports and trials are needed, rTM appears to provide an additional therapeutic option in the management of HLH.

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References

  1. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  PubMed  Google Scholar 

  2. Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002;117:965.

    Google Scholar 

  3. Navarro WH, Kaplan LD. AIDS-related lymphoproliferative disease. Blood. 2006;107:13–20.

    Article  PubMed  CAS  Google Scholar 

  4. Baraldès MA, Domingo P, González MJ, Aventin A, Coll P. Tuberculosis-associated hemophagocytic syndrome in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1998;158:194–5.

    Article  PubMed  Google Scholar 

  5. Castilletti C, Preziosi R, Bernardini G, Caterini A, Gomes V, Calcaterra S, Carletti F, Capobianchi MR, Armignacco O. Hemophagocytic syndrome in a patient with acute human immunodeficiency virus infection. Clin Infect Dis. 2004;38:1792–3.

    Article  PubMed  Google Scholar 

  6. Gotoh M, Matsuda J, Gohchi K, Sanaka T, Kawasugi K. Successful recovery from human immunodeficiency virus (HIV)-associated haemophagocytic syndrome treated with highly active antiretroviral therapy in a patient with HIV infection. Br J Haematol. 2001;112:1090.

    Article  PubMed  CAS  Google Scholar 

  7. Lortholary A, Raffi F, Aubertin P, Barrier JH, Boibieux A, Peyramond D. HIV-associated haemophagocytic syndrome. Lancet. 1990;336:1128.

    Article  PubMed  CAS  Google Scholar 

  8. Park KH, Yu HS, Jung SI, Shin DH, Shin JH. Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis. Yonsei Med J. 2008;49:325–8.

    Article  PubMed  CAS  Google Scholar 

  9. Sasadeusz J, Buchaman M, Speed B. Reactive heamophagocytic syndrome in human immunodeficiency virus infection. J Infect. 1990;20:65–8.

    Article  PubMed  CAS  Google Scholar 

  10. Sproat LO, Pantanowitz L, Lu CM, Dezube BJ. Human immunodeficiency virus-associated hemophagocytosis with iron-deficiency anemia and massive splenomegaly. Clin Infect Dis. 2003;37:e170–3.

    Article  PubMed  Google Scholar 

  11. Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis. 2004;36:516–9.

    Article  PubMed  Google Scholar 

  12. Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367.

    Article  PubMed  CAS  Google Scholar 

  13. Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, Uchimura T, Ida N, Yamazaki Y, Yamada S, Yamamoto Y, Yamamoto H, Iino S, Taniguchi N, Maruyama I. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel anti-inflammatory mechanism. J Clin Invest. 2005;115:1267–74.

    PubMed  CAS  Google Scholar 

  14. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappa-B and mitogen-activated protein kinase pathways. J Exp Med. 2002;196:565–77.

    Article  PubMed  CAS  Google Scholar 

  15. Ikezoe T, Yang J, Nishioka C, Honda G, Furihata M, Yokoyama A. Thrombomodulin protects endothelial cells from a calcineurin inhibitor-induced cytotoxicity by upregulation of extracellular signal-regulated kinase/myeloid leukemia cell-1 signaling. Arterioscler Thromb Vasc Biol. 2012;32:2259–70.

    Article  PubMed  CAS  Google Scholar 

  16. Esmon CT, Owen WG. Identification of an endothelial cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA. 1981;78:2249–52.

    Article  PubMed  CAS  Google Scholar 

  17. Esmon CT, Esomn NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem. 1982;257:7944–7.

    PubMed  CAS  Google Scholar 

  18. Maruyama I, Salem HH, Majerus PW. Coagulation factor Va binds to human umbilical vein endothelial cells and accelerates protein C activation. J Clin Invest. 1984;74:224–30.

    Article  PubMed  CAS  Google Scholar 

  19. McClain K, Gehrz R, Grierson H, et al. Virus-associated histiocytic proliferations in children. Frequent association with Epstein–Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hematol Oncol. 1988;10:196.

    Article  PubMed  CAS  Google Scholar 

  20. Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of acute human immunodeficiency virus infection. Int J Hematol. 2003;78:450.

    Article  PubMed  Google Scholar 

  21. Chuang HC, Lay JD, Hsieh WC, et al. Epstein–Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood. 2005;106:3090.

    Article  PubMed  CAS  Google Scholar 

  22. Aricò M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. 2001;114:761.

    Article  PubMed  Google Scholar 

  23. Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005;105(4):1648–51 Epub 2004 Oct 5.

    Article  PubMed  CAS  Google Scholar 

  24. van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76(12):2520–6.

    PubMed  Google Scholar 

  25. Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg. 1995;130(7):739–48.

    Article  PubMed  CAS  Google Scholar 

  26. Osterud B, Rao LV, Oslon JO. Induction of tissue factor expression in whole blood-lack of evidence for the presence of tissue factor expression on granulocytes. Thromb Haemost. 2000;83:861.

    PubMed  CAS  Google Scholar 

  27. Cuccuini W, Poitevin S, Poitevin G, Dignat-George F, Cornillet-Lefebvre P, Sabatier F, Nguyen P. Tissue factor up-regulation in proinflammatory conditions confers thrombin generation capacity to endothelial colony-forming cells without influencing non-coagulant properties in vitro. J Thromb Haemost. 2010;8(9):2042–52.

    Article  PubMed  CAS  Google Scholar 

  28. Sato K, Misawa N, Nie C, Satou Y, Iwakiri D, Matsuoka M, Takahashi R, Kuzushima K, Ito M, Takada K, Koyanagi Y. A novel animal model of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in humanized mice. Blood. 2011;117(21):5663–73.

    Article  PubMed  CAS  Google Scholar 

  29. Ikezoe T, Ikenoue N, Uchikawa N, Kojima S, Fukaya T, Yokoyama A. Use of recombinant human soluble thrombomodulin in the management of HELLP syndrome complicated by DIC. Thromb Res. 2010;126:e238–40.

    Article  PubMed  CAS  Google Scholar 

  30. Yamakawa K, Ogura H, Fujimi S, Morikawa M, Ogawa Y, Mohri T, Nakamori Y, Inoue Y, Kuwagata Y, Tanaka H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med. 2013.

  31. Ogawa Y, Yamakawa K, Ogura H, Kiguchi T, Mohri T, Nakamori Y, Kuwagata Y, Shimazu T, Hamasaki T, Fujimi S. Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis. J Trauma Acute Care Surg. 2012;72:1150–7.

    PubMed  CAS  Google Scholar 

  32. Okamoto T, Tanigami H, Suzuki K, Shimaoka M. Thrombomodulin: a bifunctional modulator of inflammation and coagulation in sepsis. Crit Care Res Pract. 2012;2012:614545.

    PubMed  Google Scholar 

  33. Carnemolla R, Patel KR, Zaitsev S, Cines DB, Esmon CT, Muzykantov VR. Quantitative analysis of thrombomodulin-mediated conversion of protein C to APC: translation from in vitro to in vivo. J Immunol Methods. 2012;384(1–2):21–4. doi:10.1016/j.jim.2012.06.012 Epub 2012 Jun 27.

    Article  PubMed  CAS  Google Scholar 

  34. Bouwens EA, Stavenuiter F, Mosnier LO. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost. 2013;11(Suppl 1):242–53. doi:10.1111/jth.12247.

    Article  PubMed  Google Scholar 

  35. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109:3161–72.

    Article  PubMed  CAS  Google Scholar 

  36. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD, PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64.

    Article  PubMed  CAS  Google Scholar 

  37. Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27:3.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by JSPS KAKENHI Grant Number 23591421 and Uehara Memorial Foundation.

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Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, 783-8505, Japan

    SungGi Chi, Takayuki Ikezoe, Asako Takeuchi, Masato Takaoka & Akihito Yokoyama

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  1. SungGi Chi
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  2. Takayuki Ikezoe
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Correspondence to Takayuki Ikezoe.

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Chi, S., Ikezoe, T., Takeuchi, A. et al. Recombinant human soluble thrombomodulin is active against hemophagocytic lymphohistiocytosis associated with acquired immunodeficiency syndrome. Int J Hematol 98, 615–619 (2013). https://doi.org/10.1007/s12185-013-1450-5

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  • DOI: https://doi.org/10.1007/s12185-013-1450-5

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