Effect of poor glycaemic control on plasma levels and activity of protein C, protein S, and antithrombin III in type 2 diabetes mellitus

Abstract

Background Type 2 diabetes mellitus (T2DM) patients are predisposed to several diabetes-related complications. Dysregulation of the haemostatic mechanisms have been implicated. There are however no current studies assessing the levels and activity of protein C (PC), protein S (PS), and antithrombin III (AT III), which are essential in haemostatic regulation, in a single cohort of T2DM patients. This study evaluated the effect of poorly-managed T2DM on the levels and activity of PC, PS, and AT III. Methods This cross-sectional study was conducted at the Diabetes Clinic, Cocoa Clinic in Kumasi, Ghana. A total of 242 T2DM patients, comprising 152 patients with poorly-managed diabetes and 90 well-managed diabetes patients, were recruited for the study. Fasting blood glucose, liver function tests and lipid profile were performed for each respondent. Glycated haemoglobin (HbA1c) was estimated by turbidimetric inhibition immunoassay. The levels and activity of PC, PS and AT III were measured by solid phase sandwich ELISA method. Results There was a negative correlation between HbA1c and the levels and activity of PC, PS and AT III. The levels and activity of PC [(5.78 vs 4.64 μg/ml, p<0.0001) and (42.22 vs 36.21 U/ml, p = 0.01) respectively], PS [(22.55 vs 20.29 μg/ml, p = 0.010) and (235.94 vs 211.67 U/ml, p<0.0001) respectively] and AT III [(16.28 vs 14.41μg/ml, p<0.0001) and (176.01 vs 160.09 U/ml, p = 0.03) respectively] were significantly increased in patients with well-managed T2DM compared to the poorly-managed diabetes patients. Likewise, the levels and activity of PC, PS, and AT III was higher among T2DM patients using statins than patients

Coagulatory Defects in Type-1 and Type-2 Diabetes

“…Changes in plasma protein concentrations as well as plasma glucose levels lead to an increase in plasma viscosity in T2DM [44] and an increasing trend has been measured in T1DM, especially in individuals with bad glycaemic control [45,46]. Most but not all changes in the protein concentration of coagulatory proteins in plasma are due to uncontrolled glycaemia and so can often be reversed through control of blood glucose levels: for example, protein C, protein S and antithrombin concentrations have been demonstrated to increase in T2DM subjects following improvement in glycaemic control [47]. Some proteomic alterations are influenced by genetic factors.…”

“…Pro-coagulant proteins ↑ vWF [12] ↑ vWF [10][11][12] ↑ prekallikrein [13] ↑ kininogen [23] ↑ tissue factor procoagulant activity [17] ↑ kallikrein [14] ↑ factor V [15] ↑ soluble tissue factor [16,24] ↑ (activated) factor VII [15,17] ↑ factor V [15] ↑ factor VIII [15] ↑ (activated) factor VII [15,16] ↑ factor X [15] ↑ factor VIII [15,18] ↑ factor XI [14] ↑ factor IX [18] ↓ activated factor XII [27] ↑ factor X [15] ↑ prothrombin [15] ↑ factor XI [14] ↓ fibrinogen [22], ↑ fibrinogen in diabetic complications [21] ↑ (activated) factor XII [18,25] ↑ factor XIII [26] ↑ prothrombin [15] ↑ fibrinogen [19,20] Anticoagulant proteins ↓ antithrombin activity [49,50] ↑ antithrombin [18,33], ↓ antithrombin [32], ↓ antithrombin activity with bad glycaemic control [47] ↓ protein C [15,19,28] ↓ protein C [15,19,29], ↓ protein C activity with bad glycaemic control [47] ↓ protein S [30] ↓ protein S [30]…”

“…Thus, thrombin generation (followed by measuring levels of the thrombin-antithrombin complex) is increased in individuals with T2DM or T1DM [28,58]. Good glycaemic control is also important for anticoagulant activity, with better glycaemic control in T2DM leading to a reduction of thrombin generation [59] and an increase of the anticoagulant activity of antithrombin, protein C and protein S [47].…”

“…Furthermore, lipid lowering treatment with statins can limit the level of circulating microparticles by reducing thrombin generation and the expression of tissue factor, GPIIIa and P-selectin on platelet-derived microparticles in patients with peripheral vascular diseases [170,210]. They also increase the levels and anticoagulant activity of protein C, protein S and antithrombin, reduce the levels of pro-coagulatory proteins prothrombin, factor V, factor VII, factor VIII, factor IX and factor X, reduce the levels of anti-fibrinolytic PAI-1 and reduce the expression of tissue factor by endothelial cells [4,47,211]. However, statins have been reported to both increase [47] and decrease [211] the levels of antithrombin.…”

“…They also increase the levels and anticoagulant activity of protein C, protein S and antithrombin, reduce the levels of pro-coagulatory proteins prothrombin, factor V, factor VII, factor VIII, factor IX and factor X, reduce the levels of anti-fibrinolytic PAI-1 and reduce the expression of tissue factor by endothelial cells [4,47,211]. However, statins have been reported to both increase [47] and decrease [211] the levels of antithrombin. Statins have been shown to reduce endogenous thrombin potential and thrombosis risk in T2DM and they reduce atherosclerotic risk through a reduction in inflammation and endothelial dysfunction [4].…”