ABSTRACT
Histidine-proline-rich glycoprotein (HPRG) binds zinc, which in turn promotes HPRG binding to lymphocytes and monocytes. We examined the possibility that zinc and other transition metals also promote HPRG binding to platelets. Only non-specific, unsaturable association of HPRG with resting or activated platelets was observed in the absence of transition metals. However, nickel, cobalt, copper, cadmium, and zinc greatly increased HPRG association with the cells. In the presence of zinc, specific, saturable binding of HPRG to platelets was demonstrated. The cell binding capacity for HPRG could be increased by increasing the zinc saturation of HPRG from 10% to 30% as well as by activating the platelets with thrombin. Because platelets contain relatively high concentrations of secretable zinc, it is possible that significant amounts of HPRG bind to activated platelets at sites of blood clotting and that this has a physiologic function.
Subject(s)
Blood Platelets/metabolism , Metals, Heavy/pharmacology , Proteins/metabolism , Blood Platelets/physiology , Dose-Response Relationship, Drug , Glycoproteins/metabolism , Humans , Metals, Heavy/metabolism , Platelet Activation/drug effects , Protein Binding/drug effects , Thrombin/pharmacology , Zinc/metabolism , Zinc/pharmacologyABSTRACT
Because histidine-rich glycoprotein binds to the kringle 1-3 domain of plasminogen, it may affect fibrinolysis by reducing fibrin-dependent plasmin production, and in this way it could be mechanistically analogous to 6-aminohexanoic acid. We tested this hypothesis by comparing the effects of histidine-rich glycoprotein and 6-aminohexanoic acid in an in vitro assay of fibrin-dependent plasmin production mediated by tissue plasminogen activator. Whereas 1 mM of 6-aminohexanoic acid increased the K(m) of the reaction from approximately 0.22 microM to approximately 1.7 microM, 2 microM of histidine-rich glycoprotein had no discernible effect. Similar results were obtained in an assay based upon fibrin clot lysis. Therefore, we could not document an effect of histidine-rich glycoprotein on the rate of fibrin-dependent plasmin production.
Subject(s)
Aminocaproic Acid/pharmacology , Fibrinolysin/biosynthesis , Fibrinolysis/drug effects , Glycoproteins/pharmacology , Histidine/chemistry , Antifibrinolytic Agents/pharmacology , Fibrinolysin/drug effects , Glycoproteins/chemistry , Glycoproteins/metabolism , Humans , Kinetics , Plasminogen/metabolism , Protein Binding , Protein Structure, Tertiary , Sepharose/metabolismABSTRACT
Cancer patients with venous access devices (VADs) often receive daily flushes of heparin. Even this relatively small heparin exposure has been reported to induce immune-mediated thrombocytopenia. To estimate how frequently this occurs we tested for heparin-related antibodies in 49 patients receiving daily heparin flushes of their VADs. Although one-third of the patients showed evidence of heparin sensitization on at least one occasion during their surveillance, their antibody titers were generally low and typical of those found in other cohorts of patients who become sensitized to heparin but do not develop secondary thrombocytopenia. However, one patient developed a positive serotonin release assay indicative of a more significant sensitization, but without thrombocytopenia. Therefore, our observations suggest that heparin-induced thrombocytopenia (HIT) related to heparin flushes of VADs is uncommon but still an important diagnosis to entertain.
