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Effects of Hyperglycemia and Hyperinsulinemia on Circulating Tissue Factor Procoagulant Activity and Platelet CD40 Ligand

¹ Section of Hematology, Department of Medicine and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
² Section of Endocrinology/Diabetes/Metabolism, Department of Medicine and the Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania

Address correspondence to Guenther Boden, MD, Temple University Hospital, 3401 North Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu

Abbreviations: ASVD, atherosclerotic vascular disease; CD40L, CD40 ligand; FITC, fluorescein isothiocynate; FVII, native coagulation factor VII; FVIIa, activated FVII; FVIIAg, FVII antigen; FVIIc, FVII activity; FVIII, native coagulation factor VIII; PCA, procoagulant activity; TAT, thrombin-antithrombin; TFPI, tissue factor pathway inhibitor

Individuals with chronically elevated glucose and/or insulin levels, i.e., most patients with type 2 diabetes, have accelerated atherosclerosis and are prone to acute vascular events. We have tested the hypothesis that hyperglycemia and/or hyperinsulinemia singly or combined may increase tissue factor, the primary initiator of blood coagulation. We have determined changes in circulating tissue factor procoagulant activity (PCA) and other procoagulation proteins in healthy volunteers exposed to 24 h of selective hyperinsulinemia, selective hyperglycemia, or combined hyperinsulinemia and hyperglycemia. Combined elevations of plasma insulin and glucose levels for 24 h produced a ninefold increase in tissue factor PCA, which was associated with an increase in monocyte tissue factor protein (flow cytometry) and mRNA (RT-PCR), increases in plasma thrombin-antithrombin complexes, prothrombin fragment 1.2, factor VIII coagulant activity, and platelet CD40 ligand as well as decreases in factor VIIa, factor VII coagulant activities, and factor VII antigen. Effects of selective hyperinsulinemia and selective hyperglycemia were less striking but appeared to be additive. We conclude that hyperinsulinemia and hyperglycemia but particularly the combination of both create a prothrombotic state and in addition may be proinflammatory and proatherogenic because of the proinflammatory actions of CD40 ligand and tissue factor.

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