Protein C activation in NIDDM patients

Abstract

Alteration of the clotting system in diabetic patients is presently the focus of increasing interest due to its potential role in the pathogenesis of large and smallvessel disease in diabetes mellitus. It is believed that enhanced pro-coagulant activity is linked to the excessive cardiovascular morbidity and mortality among diabetic patients which have not been fully explained by major risk factors such as arterial hypertension, cigarette smoking and hypercholesterolaemia. Perturbance of haemostasis has also been implicated in the development of complications such as nephropathy and retinopathy and in the acceleration of atherogenesis observed in diabetic patients [1,2]. Diabetologia (1996Diabetologia ( ) 39: 1455Diabetologia ( -1461 Protein C activation in NIDDM patients Summary Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble Eselectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein C inhibitor complex (7.4 ± 3.8 vs 3.0 ± 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 ± 2.6 vs 35.3 ± 3.0 ng/ml) was markedly lower (p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated protein C-protein C inhibitor complex (5.5 ± 0.6 vs 8.6 ± 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 ± 2.9 vs 23.4 ± 2.6 %, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin.

Coagulation and Fibrinolysis Parameters in Type 2 Diabetic Patients with and without Diabetic Vascular Complications

“…Equally, Asakawa et al [29] had shown that fibrinogen level was significantly higher in diabetic patients with retinopathy or nephropathy than in patients without these complications. The detection of microalbuminuria, another well-known independent indicator of much greater risk of premature death from cardiovascular complications, has been demonstrated to correlate significantly with various hemostatic variables [3,26,27,30,31]. Accordingly, some coagulation factors did not differ between the diabetic patients and control subjects.…”

“…This activation of blood coagulation has recently been implicated as an important contributing factor for the occurrence of vascular complications in dia- betes [27,28]. In large epidemiological studies, the procoagulant factors (fibrinogen and factor VII) have been described as independent predictors of cardiovascular events in diabetic and nondiabetic subjects.…”

Visceral Obesity and Hemostatic Profile in Patients with Type 2 Diabetes: the Effect of Gender and Metabolic Compensation

“…Data on the relationship between C protein and obesity and diabetes is scarce and controversial [30,31]. The study by Vegilo did not show the relationship between BMI and the activity of C protein, nor did diabetes treatment affect its activity [31].…”

Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice

“…5 However, in pathologic conditions associated with increased consumption of protein C or deficient activation of protein C disruption of the balance between thrombin and APC occurs in favor of thrombin, resulting in excessive coagulation and inflammatory responses. 7,29 Insufficient generation of APC also occurs in the airways of patients with chronic asthma. 9 In agreement with this, in our present BA model, the concentration of APC remained unchanged, and the APC/thrombin ratio was significantly decreased in mice of the OVA group compared with the nonsensitized SAL group.…”