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Research Article Free access | 10.1172/JCI116382

Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease.

A Slungaard, G M Vercellotti, T Tran, G J Gleich, and N S Key

Department of Medicine, University of Minnesota Medical School Minneapolis 55455.

Find articles by Slungaard, A. in: PubMed | Google Scholar

Department of Medicine, University of Minnesota Medical School Minneapolis 55455.

Find articles by Vercellotti, G. in: PubMed | Google Scholar

Department of Medicine, University of Minnesota Medical School Minneapolis 55455.

Find articles by Tran, T. in: PubMed | Google Scholar

Department of Medicine, University of Minnesota Medical School Minneapolis 55455.

Find articles by Gleich, G. in: PubMed | Google Scholar

Department of Medicine, University of Minnesota Medical School Minneapolis 55455.

Find articles by Key, N. in: PubMed | Google Scholar

Published April 1, 1993 - More info

Published in Volume 91, Issue 4 on April 1, 1993
J Clin Invest. 1993;91(4):1721–1730. https://doi.org/10.1172/JCI116382.
© 1993 The American Society for Clinical Investigation
Published April 1, 1993 - Version history
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Abstract

Thromboembolism is a prominent but poorly understood feature of eosinophilic, or Loeffler's endocarditis. Eosinophil (EO) specific granule proteins, in particular major basic protein (MBP), accumulate on endocardial surfaces in the course of this disease. We hypothesized that these unusually cationic proteins promote thrombosis by binding to the anionic endothelial protein thrombomodulin (TM) and impairing its anticoagulant activities. We find that MBP potently (IC50 of 1-2 microM) inhibits the capacity of endothelial cell surface TM to generate the natural anticoagulant activated protein C (APC). MBP also inhibits APC generation by purified soluble rabbit TM with an IC50 of 100 nM without altering its apparent Kd for thrombin or Km for protein C. This inhibition is reversed by polyanions such as chondroitin sulfate E and heparin. A TM polypeptide fragment comprising the extracellular domain that includes its naturally occurring anionic glycosaminoglycan (GAG) moiety (TMD-105) is strongly inhibited by MBP, whereas its counterpart lacking the GAG moiety (TMD-75) is not. MBP also curtails the capacity of TMD-105 but not TMD-75 to prolong the thrombin clotting time. Thus, EO cationic proteins potently inhibit anticoagulant activities of the glycosylated form of TM, thereby suggesting a potential mechanism for thromboembolism in hypereosinophilic heart disease.

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