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Circulating Tissue Factor Procoagulant Activity and Thrombin Generation in Patients with Type 2 Diabetes: Effects of Insulin and Glucose

Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center (G.B., C.H., P.C.), Division of Hematology and the Sol Sherry Thrombosis Research Center (V.R.V., A.K.R.), Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Address all correspondence and requests for reprints to: Guenther Boden, M.D., Temple University Hospital, 3401 North Broad Street, Philadelphia, Pennsylvania 19140. E-mail: bodengh{at}tuhs.temple.edu; or A. Koneti Rao, M.D., Temple University School of Medicine, Sol Sherry Thrombosis Research Center, 3400 North Broad Street, Philadelphia, Pennsylvania 19140. E-mail: koneti{at}temple.edu.

Context: Type 2 diabetes mellitus (T2DM) is a hypercoagulable state. Tissue factor (TF) is the principal initiator of blood coagulation.

Objective: Our objective was to examine the effects of hyperglycemia and hyperinsulinemia on the TF pathway of blood coagulation in T2DM.

Design: Three study protocols were used: 1) acute correction of hyperglycemia (with iv insulin) followed by 24 h of euglycemia, 2) 24 h of selective hyperinsulinemia, and 3) 24 h of combined hyperinsulinemia and hyperglycemia.

Setting: The study took place at a clinical research center.

Study Participants: Participants included 18 T2DM patients and 22 nondiabetic controls.

Results: Basal TF-procoagulant activity (TF-PCA), monocyte TF mRNA, plasma coagulation factor VII (FVIIc), and thrombin-anti-thrombin complexes were higher in T2DM than in nondiabetic controls, indicating a chronic procoagulant state. Acutely normalizing hyperglycemia over 2–4 h resulted in a small (7%) but significant decline in TF-PCA with no further decline over 24 h. Raising insulin levels alone raised TF-PCA by 30%, whereas raising insulin and glucose levels together increased TF-PCA (by 80%), thrombin-anti-thrombin complexes, and prothrombin fragment 1.2. Plasma FVIIa and FVIIc declined with increases in TF-PCA.

Conclusion: We conclude that the combination of hyperglycemia and hyperinsulinemia, common in poorly controlled patients with T2DM, contributes to a procoagulant state that may predispose these patients to acute cardiovascular events.