nach oben

Erschienen in:

01.06.2010 | Pediatric Original

Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children

verfasst von: Rachel S. Agbeko, John W. Holloway, Meredith L. Allen, Shu Ye, Katy J. Fidler, John Pappachan, Allan Goldman, David Pontefract, John Deanfield, Nigel J. Klein, Mark J. Peters

Erschienen in: Intensive Care Medicine | Ausgabe 6/2010

Einloggen, um Zugang zu erhalten

Abstract

Purpose

To determine if common polymorphisms in the endotoxin recognition complex influence the acute phase response as determined by the development of the systemic inflammatory response syndrome (SIRS) and platelet count on admission.

Methods

This was a prospective observational cohort study. Paediatric intensive care patients (n = 913) were genotyped for common functional polymorphisms in the endotoxin recognition complex, including Toll-like receptor 4 (TLR4). We also selected potentially confounding polymorphisms in other genes of the innate immune system. SIRS was defined by age-specific consensus criteria. Platelet counts were recorded on admission.

Results

The development of SIRS was primarily determined by the nature of the insult, but carriers of TLR4 variant alleles had lower platelet counts than children with wild-type genotype [mean ± standard error of the mean (SEM) 143 ± 7 vs. 175 ± 4; p = 0.0001)—independent of other innate immune system polymorphisms. These findings were validated using a patient cohort of 1,170 adults with coronary artery disease. Carriers of TLR4 polymorphisms with a history of myocardial infarction (n = 573) had lower platelet counts than those with the wild-type genotype (217 ± 7 vs. 237 ± 2.8; p = 0.021).

Conclusions

Our results show that TLR4 variant alleles are associated with lower platelet counts across a range of ages and precipitating insults but that they do not influence the incidence of SIRS. This result may reflect redundancy and ‘robustness’ in the pathways leading to SIRS or the lack of specificity of this endpoint. Platelet count may vary with TLR4 genotype because it may be sufficiently sensitive and more linearly related to inflammation than other markers or, alternatively, there may be a direct TLR4-mediated platelet effect.

Nur mit Berechtigung zugänglich

Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561PubMed

Dauphinee SM, Karsan A (2006) Lipopolysaccharide signaling in endothelial cells. Lab Invest 86:9–22CrossRefPubMed

Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P (2005) Platelets express functional Toll-like receptor-4. Blood 106:2417–2423CrossRefPubMed

Aslam R, Speck ER, Kim M, Crow AR, Bang KW, Nestel FP, Ni H, Lazarus AH, Freedman J, Semple JW (2006) Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107:637–641CrossRefPubMed

Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469CrossRefPubMed

Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376CrossRefPubMed

Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR, Abraham E (2006) Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med 173:1335–1341CrossRefPubMed

Fidler KJ, Wilson P, Davies JC, Turner MW, Peters MJ, Klein NJ (2004) Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin. Intensive Care Med 30:1438–1445CrossRefPubMed

Stephens RC, Fidler K, Wilson P, Barclay GR, Mythen MG, Dixon GL, Turner MW, Klein NJ, Peters MJ (2006) Endotoxin immunity and the development of the systemic inflammatory response syndrome in critically ill children. Intensive Care Med 32:286–294CrossRefPubMed

10.

Rallabhandi P, Bell J, Boukhvalova MS, Medvedev A, Lorenz E, Arditi M, Hemming VG, Blanco JC, Segal DM, Vogel SN (2006) Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol 177:322–332PubMed

11.

Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191CrossRefPubMed

12.

van der Graaf C, Kullberg BJ, Joosten L, Verver-Jansen T, Jacobs L, van der Meer JW, Netea MG (2005) Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. Cytokine 30:264–268CrossRefPubMed

13.

Imahara SD, O’Keefe GE (2004) Genetic determinants of the inflammatory response. Curr Opin Crit Care 10:318–324CrossRefPubMed

14.

Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, Lowry SF (2002) Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J Infect Dis 186:1522–1525CrossRefPubMed

15.

Barber RC, Aragaki CC, Rivera-Chavez FA, Purdue GF, Hunt JL, Horton JW (2004) TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet 41:808–813CrossRefPubMed

16.

Lorenz E, Mira JP, Frees KL, Schwartz DA (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162:1028–1032CrossRefPubMed

17.

Henckaerts L, Nielsen KR, Steffensen R, Van Steen K, Mathieu C, Giulietti A, Wouters PJ, Milants I, Vanhorebeek I, Langouche L, Vermeire S, Rutgeerts P, Thiel S, Wilmer A, Hansen TK, Van den Berghe G (2009) Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 37(192–201):e191–e193

18.

Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, Rodrigues SD, Li S, Hansen JA, Zhao LP, Aderem A, Boeckh M (2008) Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 359:1766–1777CrossRefPubMed

19.

Vincent JL (1997) Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med 25:372–374CrossRefPubMed

20.

Levi M, Lowenberg EC (2008) Thrombocytopenia in critically ill patients. Semin Thromb Hemost 34:417–424CrossRefPubMed

21.

Akca S, Haji-Michael P, de Mendonca A, Suter P, Levi M, Vincent JL (2002) Time course of platelet counts in critically ill patients. Crit Care Med 30:753–756CrossRefPubMed

22.

Peters MJ, Ross-Russell RI, White D, Kerr SJ, Eaton FE, Keengwe IN, Tasker RC, Wade AM, Klein NJ (2001) Early severe neutropenia and thrombocytopenia identifies the highest risk cases of severe meningococcal disease. Pediatr Crit Care Med 2:225–231CrossRefPubMed

23.

Nguyen TC, Carcillo JA (2006) Bench-to-bedside review: thrombocytopenia-associated multiple organ failure—a newly appreciated syndrome in the critically ill. Crit Care 10:235CrossRefPubMed

24.

Ohtaki Y, Shimauchi H, Yokochi T, Takada H, Endo Y (2002) In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs. Thromb Res 108:303–309CrossRefPubMed

25.

Yang IA, Holloway JW, Ye S (2003) TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis 170:187–190CrossRefPubMed

26.

American College of Chest Physicians/Society of Critical Care Medicine (1992) American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874

27.

Smirnova I, Hamblin MT, McBride C, Beutler B, Di RA (2001) Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics 158:1657–1664PubMed

28.

Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW, Netea MG (2008) Functional consequences of Toll-like receptor 4 polymorphisms. Mol Med 14:346–352CrossRefPubMed

29.

Klinger MH, Jelkmann W (2002) Role of blood platelets in infection and inflammation. J Interferon Cytokine Res 22:913–922CrossRefPubMed

30.

Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, Wilmer A, Bobbaers H (2000) Thrombocytopenia and prognosis in intensive care. Crit Care Med 28:1871–1876CrossRefPubMed

31.

Ragazzi S, Pierro A, Peters M, Fasoli L, Eaton S (2003) Early full blood count and severity of disease in neonates with necrotizing enterocolitis. Pediatr Surg Int 19:376–379CrossRefPubMed

32.

Zarbock A, Polanowska-Grabowska RK, Ley K (2007) Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 21:99–111CrossRefPubMed

33.

Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494CrossRefPubMed

34.

Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384CrossRefPubMed

35.

Zeni F, Freeman B, Natanson C (1997) Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 25:1095–1100CrossRefPubMed

36.

Bone RC (1996) Why sepsis trials fail. JAMA 276:565–566CrossRefPubMed

37.

Oda K, Kitano H (2006) A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2:2006.0015

38.

Shashkin PN, Brown GT, Ghosh A, Marathe GK, McIntyre TM (2008) Lipopolysaccharide is a direct agonist for platelet RNA splicing. J Immunol 181:3495–3502PubMed

39.

Patrignani P, Di Febbo C, Tacconelli S, Moretta V, Baccante G, Sciulli MG, Ricciotti E, Capone ML, Antonucci I, Guglielmi MD, Stuppia L, Porreca E (2006) Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo. Blood 107:3572–3574CrossRefPubMed

40.

Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:185–192CrossRefPubMed

41.

Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, Yeh T, Kim SS, Cafaro DP, Scannon PJ, Giroir BP (2000) Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 356:961–967CrossRefPubMed

42.

Michalek J, Svetlikova P, Fedora M, Klimovic M, Klapacova L, Bartosova D, Elbl L, Hrstkova H, Hubacek JA (2007) Bactericidal permeability increasing protein gene variants in children with sepsis. Intensive Care Med 33:2158–2164CrossRefPubMed

43.

Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A, Aucan C, Segal S, Moore CE, Knox K, Campbell SJ, Lienhardt C, Scott A, Aaby P, Sow OY, Grignani RT, Sillah J, Sirugo G, Peshu N, Williams TN, Maitland K, Davies RJ, Kwiatkowski DP, Day NP, Yala D, Crook DW, Marsh K, Berkley JA, O’Neill LA, Hill AV (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39:523–528CrossRefPubMed

44.

Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Marodi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL (2007) Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 204:2407–2422CrossRefPubMed

45.

Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD (1999) A Polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20:976–983PubMed

46.

Hubacek JA, Skodova Z, Adamkova V, Lanska V, Vlasakova Z, Poledne R (2004) Association of the −159C –> T polymorphism in the CD14 promoter with variations in serum lipoproteins in healthy subjects. Blood Coagul Fibrinolysis 15:365–366CrossRefPubMed

47.

Hubacek JA, Stuber F, Frohlich D, Book M, Wetegrove S, Ritter M, Rothe G, Schmitz G (2001) Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med 29:557–561CrossRefPubMed

48.

Barber RC, O’Keefe GE (2003) Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis. Am J Respir Crit Care Med 167:1316–1320CrossRefPubMed

49.

Shann F, Pearson G, Slater A, Wilkinson K (1997) Paediatric index of mortality (PIM): a mortality prediction model for children in intensive care. Intensive Care Med 23:201–207CrossRefPubMed

Titel: Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children
verfasst von: Rachel S. Agbeko
John W. Holloway
Meredith L. Allen
Shu Ye
Katy J. Fidler
John Pappachan
Allan Goldman
David Pontefract
John Deanfield
Nigel J. Klein
Mark J. Peters
Publikationsdatum: 01.06.2010
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 6/2010
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-010-1857-x

Update AINS

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

hier abonnieren

Springer Medizin

Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children