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Heparin modulates integrin function in human platelets
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DOI：10.1067/mva.2001.112696.png)
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Abstract
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Purpose Heparin binds to human platelets and can cause activation and aggregation, although the mechanisms are unknown. To determine how heparin alters platelet function, we identified platelet-binding sites for heparin and measured heparin's influence on the function of platelet integrin alpha (IIb)beta (3) (glycoprotein IIb/IIIa). Methods: Photoaffinity cross-linking and affinity chromatography experiments were performed to identify platelet membrane proteins that bind heparin. Heparin's effect on fibrinogen binding to platelets was measured with a radioligand-binding assay. The translocation to the cytoskeleton of Rap2, a guanosine triphosphate-binding protein, was measured from platelets aggregating in response to heparin and other agonists. Results: Cross-linking and affinity chromatographic experiments positively identified the integrin alpha (IIb)beta (3) as a heparin-binding site. Heparin aggregation was calcium dependent. Low concentrations of unfractionated porcine mucosal heparin (2-5 U/mL) significantly increased fibrinogen I 125 binding to activated platelets, whereas higher doses did not. Heparin-mediated platelet aggregation was completely blocked by GRGDS peptide (5 mmol/L), a competitive inhibitor of fibrinogen binding, and was blocked by EDTA (2 mmol/L), which dissociates the functional integrin complex. Aggregation was associated with Rap2 translocation to the cytoskeleton, a sign of outside-in signaling. Conclusions Heparin binds to the alpha (IIb)beta (3) integrin in vitro and ex vivo, and heparin increases fibrinogen binding to the integrin. Heparin-mediated aggregation requires an intact integrin and ligand and leads to Rap2 translocation to the cytoskeleton-an outside-in signal of ligand engagement. Heparin may directly modulate platelet integrin function, most likely through direct binding and modulation of integrin function.
Keywords:
VON-WILLEBRAND-FACTOR
SIGNAL-TRANSDUCTION
FIBRINOGEN BINDING
ACTIVATION
PROTEINS
CYTOSKELETON
AGGREGATION
LECTINS
CALCIUM
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