CC BY-NC-ND 4.0 · Thromb Haemost 2023; 123(09): 867-879
DOI: 10.1055/a-2071-0477
Coagulation and Fibrinolysis

Activation of the Acute-Phase Response in Hemophilia

Lynn M. Knowles
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Medical Center, Homburg, Germany
Carolin Wolter
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Medical Center, Homburg, Germany
Michael D. Menger
2   Institute for Clinical and Experimental Surgery, Saarland University and University Medical Center, Homburg, Germany
Matthias W. Laschke
2   Institute for Clinical and Experimental Surgery, Saarland University and University Medical Center, Homburg, Germany
Lars Beyer
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Medical Center, Homburg, Germany
Ulrich Grün
3   Department of Orthopedic Surgery, Saarland University and University Medical Center, Homburg, Germany
Hermann Eichler
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Medical Center, Homburg, Germany
Jan Pilch
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Medical Center, Homburg, Germany
› Author Affiliations
Funding This work was supported by the Bayer Joint Health Award (J. P.), CSL Behring GmbH (J. P. and H. E.), the Pfizer ASPIRE Award (J. P.), and the Hans Egli Stipend of the Gesellschaft für Thrombose-und Hämostaseforschung e.V. (L. M. K.).


To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) ≥30. Subgroup analysis of the remaining nonobese hemophilia patients (BMI: 18–29.9) revealed a significant spike of IL-6, CRP, and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients who did not experience recent bleeding had IL-6, CRP, and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a fourfold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia.

Authors' Contribution

L. M. K. and J. P. designed the research; J. P., H. E., and U. G. evaluated patients and blood donors; L. M. K., C. W., L. B., and J. P. performed the experiments and analyzed the data; M. D. M. and M. W. L. provided expertise and reagents for the histological analysis and critically reviewed the data; L. M. K. and J. P. wrote the manuscript. All authors approved the final manuscript prior to submission.

Supplementary Material

Publication History

Received: 13 September 2022

Accepted: 22 March 2023

Accepted Manuscript online:
10 April 2023

Article published online:
23 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

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