Fibronectin modulates formation of PF4/heparin complexes and is a potential factor for reducing risk of developing HIT

Author:

Krauel Krystin12,Preuße Patricia1,Warkentin Theodore E.34,Trabhardt Catja1,Brandt Sven2,Jensch Inga2,Mandelkow Martin2,Hammer Elke5,Hammerschmidt Sven6,Greinacher Andreas1

Affiliation:

1. Institut für Immunologie und Transfusionsmedizin and

2. Zentrum für Innovationskompetenz–Humorale Immunreaktionen bei kardiovaskulären Erkrankungen, Universität Greifswald, Greifswald, Germany;

3. Department of Pathology and Molecular Medicine and

4. Department of Medicine, McMaster University, Hamilton, ON, Canada; and

5. Abteilung Funktionelle Genomforschung, Interfakultäres Institut für Genetik und Funktionelle Genomforschung, and

6. Abteilung Molekulare Genetik und Infektionsbiologie, Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Universität Greifswald, Greifswald, Germany

Abstract

Abstract Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating anti–platelet factor 4 (PF4)/heparin antibodies. Platelet activation assays that use “washed” platelets are more sensitive for detecting HIT antibodies than platelet-rich plasma (PRP)–based assays. Moreover, heparin-exposed patients vary considerably with respect to the risk of PF4/heparin immunization and, among antibody-positive patients, the risk of subsequent “breakthrough” of clinical HIT with manifestation of thrombocytopenia. We used washed platelets and PRP, standard laboratory HIT tests, and physicochemical methods to identify a plasma factor interfering with PF4/heparin complexes and anti-PF4/heparin antibody–platelet interaction, thus explaining differences in functional assays. To investigate a modulating risk for PF4/heparin immunization and breakthrough of HIT, we also tested 89 plasmas from 2 serosurveillance trials. Fibronectin levels were measured in 4 patient groups exhibiting different degrees of heparin-dependent immunization and expression of HIT. The heat-labile plasma protein, fibronectin, inhibited PF4 binding to platelets in a dose-dependent fashion, particularly in washed (vs PRP) systems. Fibronectin also inhibited PF4/heparin binding to platelets, anti-PF4/heparin antibody binding to PF4/heparin complexes, and anti-PF4/heparin antibody–induced platelet activation as a result of PF4/heparin complex disruption. In addition, plasma fibronectin levels increased progressively among the following 4 patient groups: enzyme-linked immunosorbent assay (ELISA)+/serotonin-release assay (SRA)+/HIT+ < ELISA+/SRA+/HIT− ∼ ELISA+/SRA−/HIT− < ELISA−/SRA−/HIT−. Altogether, these findings suggest that fibronectin interferes with PF4/heparin complex formation and anti-PF4/heparin antibody–induced platelet activation. Reduced fibronectin levels in washed platelet assays help to explain the greater sensitivity of washed platelet (vs PRP) assays for HIT. More importantly, lower plasma fibronectin levels could represent a risk factor for PF4/heparin immunization and clinical breakthrough of HIT.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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