Fibronectin modulates formation of PF4/heparin complexes and is a potential factor for reducing risk of developing HIT
| Autor: | Sven Brandt, Patricia Preuße, Elke Hammer, Krystin Krauel, Inga Jensch, Catja Trabhardt, Theodore E. Warkentin, Martin Mandelkow, Andreas Greinacher, Sven Hammerschmidt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Blood Platelets Immunology 030204 cardiovascular system & hematology Pharmacology Platelet Factor 4 Biochemistry 03 medical and health sciences 0302 clinical medicine medicine Humans Platelet Platelet activation biology Chemistry Heparin Antibodies Monoclonal Anticoagulants Cell Biology Hematology Platelet Activation Prognosis Blood proteins Fibronectins Thrombocytopenia Fibronectin 030104 developmental biology Case-Control Studies biology.protein Antibody Platelet factor 4 medicine.drug |
| Zdroj: | Blood. 133(9) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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