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The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model

Beeinflussung der inflammatorischen Antwort durch den FXIII VAL 34 LEU Polymorphismus in einem humanen LPS Modell

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Zusammenfassung

HINTERGRUND: Bei septischen Patienten führen die Aktivierung des Gerinnungssystems und die Blockierung der Fibrinolyse zur mikrovaskulären Thrombose. Der Val34Leu Polymorphismus beeinflusst die Funktion des Faktor XIII durch die Erhöhung des FXIII Spiegels durch die Aktivierung von Thrombin, welches zu einer erhöhten und beschleunigten Fibrinstabilisierung führt. Sepis und Multi Organ Failure (MOF) stören das fundamentale Gleichgewicht zwischen Gerinnung und Entzündung, welches einer der häufigsten Todesursachen bei Intensivpatienten darstellt. Neueste Ergebnisse von der Polymorphismen Erforschung lassen vermuten, dass es zu einer Beeinflussung des Entzündugs- und Gerinnungssystem kommt. METHODEN: In unserer Studie haben wir den Einfluss des FXIII Val34Leu Polymorphismus auf Entzündungs- und Gerinnungsparameter in einem menschlichen Sepsismodell untersucht. Gesunden Probanden wurde 2ng/kg Endotoxin (LPS, n = 62) als Bolus über 2 Minuten intravenös verabreicht. Für die Bestimmung des FXIII Promotor – Polymorphismus haben wir einen neuen PCR assay etabliert. ERGEBNISSE: FXIII Werte waren höher für homozygote Träger des Polymorphismus, im Vergleich zum wild-Type 34 Val/Val und heterozygoten Träger. Homozygote Träger hatten niedrigere Monozyten und Neutrophile Zellzahlen während des Beobachtungszeitraumes. F1+2 or D-Dimer Werte veränderten sich nicht nach LPS Gabe. KONKLUSION: Mit unseren Ergebnissen konnten wir zeigen, dass der FXIII Val34Leu Polymorphismus mit Veränderungen in bestimmten Entzündungsparametern und Veränderungen in Monozyten und Neutrophile Zellzahlen im LPS Modell in Zusammenhang steht. Dieses Ergebnis lässt den Schluss zu, dass der FXIII Val34Leu Polymorphismus bei Sepsis Patienten möglicherweise eine immunogene modulatorische Rolle spielen kann.

Summary

BACKGROUND: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. The Val34Leu polymorphism affects the function of FXIII by increasing the rate of FXIII activation by thrombin, which results in an increased and faster rate of fibrin stabilization. Sepsis and multi-organ failure cause disturbance of the normal balance of inflammation and coagulation, one of the most frequent causes of death in ICU patients. Research in polymorphism has shown the possible influence of FXIII in coagulation and inflammation. METHODS: We analyzed the influence of the common FXIII Val34Leu polymorphism on inflammatory and coagulation parameters in human experimental endotoxinemia. Healthy volunteers (n = 62) received 2 ng endotoxin (LPS) per kg body weight as a bolus infusion over 2 min. We developed a new mutagenic separated PCR assay for determination of the FXIII promoter polymorphism. RESULTS: FXIII levels were higher for homozygous carriers of the FXIII polymorphism in comparison with wild-type 34 Val/Val and heterozygous 34 Val/Leu. Interestingly, persons homozygous for the FXIII Val34Leu polymorphism had lower monocyte and neutrophil counts throughout the observation period, yet prothrombin fragment 1+2 and D-dimer levels did not differ after LPS challenge. CONCLUSION: Our findings indicate that the common FXIII Val34Leu polymorphism is associated with differences in monocyte and neutrophil cell counts in response to systemic LPS infusion in humans.

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Authors and Affiliations

  1. Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria

    Florian M. Kovar

  2. Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria

    Florian M. Kovar, Claudia L. Marsik, Christine Mannhalter, Oswald F. Wagner & Georg Endler

  3. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    Bernd Jilma

  4. Harvard Medical School, Boston, USA

    Christian Joukhadar

Authors
  1. Florian M. Kovar
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  2. Claudia L. Marsik
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  3. Bernd Jilma
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  4. Christine Mannhalter
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  5. Christian Joukhadar
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  6. Oswald F. Wagner
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  7. Georg Endler
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Correspondence to Bernd Jilma.

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Kovar, F., Marsik, C., Jilma, B. et al. The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model. Wien Klin Wochenschr 121, 515–519 (2009). https://doi.org/10.1007/s00508-009-1182-y

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  • DOI: https://doi.org/10.1007/s00508-009-1182-y

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