Increased prothrombin fragment 1+2 and D-dimer in first-degree relatives of type 2 diabetic patients

Abstract

To evaluate whether or not activated coagulation is present in the preclinical phases of type 2 diabetes mellitus, we studied 46 non-diabetic first-degree relatives of type 2 diabetic patients and 21 matched controls with no family history of diabetes. We determined the plasma levels of prothrombin fragment 1 + 2, D-dimer, fibrinogen, plasminogen activator inhibitor type 1, tissue plasminogen activator, von Willebrand factor and coagulation factors VII and VIII. Glucose tolerance, beta-cell function and insulin sensitivity were assessed in all subjects by a continuous glucose infusion of 5 mg.kg ideal body weight-1.min-1 for 60 min with model assessment of glucose, insulin and C-peptide values. Plasma levels of prothrombin fragment 1 + 2 (median 1.24 vs 0.68 nmol.l-1; P = 0.0001) and D-dimer (331 vs 254 micrograms.l-1 UEF; P = 0.018) were higher in relatives, without significant differences in the other haemostatic variables. Relatives showed higher fasting (5.5 vs 4.9 mmol.l-1, P = 0.004) and post-infusion (9.3 vs 8.3 mmol.l-1, P = 0.02) serum glucose, no differences in insulin or C-peptide levels, lower beta-cell function (122% vs 147%; P = 0.02) and no significant differences in insulin sensitivity. Fifteen relatives were glucose-intolerant and had lower beta-cell function and insulin sensitivity than glucose-tolerant relatives. Both subsets of relatives exhibited higher levels of prothrombin fragment 1 + 2 and D-dimer than control subjects. Thus, first-degree relatives of type 2 diabetic patients present an activated coagulation, even in the absence of minor degrees of glucose intolerance. These abnormalities can play a role in the pathogenesis of cardiovascular diseases frequently seen at diagnosis of type 2 diabetes.

Hemostasis and Fibrinolysis Factors in First-Degree Relatives of Patients with Type 2 Diabetes without Hypertension

“…These data confirm the results of other clinical observations that showed activated coagulation even in the presence of a lesser degree of glucose intolerance [14] and increased insulin resistance in first-degree relatives of type 2 diabetic patients [22,23]. The fact that DD and F1+2 levels in subjects with a family history of type 2 diabetes mellitus associated with hypertension are higher than in relatives of diabetics without a family history of hypertension seems to suggest that blood coagulation in these subjects is genetically influenced.…”

“…The offspring of patients with diabetes have an increased risk of developing the same disease [13] and others [14][15][16][17][18][19]. The aim of this study was to determine whether there is a possible hemostatic impairment in first-degree relatives of type 2 diabetic patients regarding D-dimer (DD), tissue-type plasminogen activator (t-PA), plasminogen activator-inhibitor (PAI-1) and prothrombin fragment 1 + 2 (F1+2) levels and to analyze the influence of the presence/absence of a family history of hypertension on the hemostatic system.…”

Impaired vascular reactivity is present despite normal levels of von Willebrand factor in patients with uncomplicated Type 2 diabetes

“…We did not find any correlation between levels of von Willebrand factor and FMD or NTG-induced vasodilatation, and speculate that impaired vascular reactivity is a more sensitive marker of vascular dysfunction than levels of von Willebrand factor. This is supported by studies of healthy first-degree relatives of patients with Type 2 diabetes where differences in endothelial function can be found using FMD [48], but not levels of von Willebrand factor [49], as well as a recent study of healthy subjects with UAE in the upper normal range [50].…”

Insulin sensitivity and haemostatic factors in men at high and low cardiovascular risk

“…There are data suggesting that subjects with type 2 diabetes mellitus and their relatives have elevated levels of prothombin fragment 1 + 2 and thrombin/antithrombin complex [34, 35]. In these groups of non‐diabetic men, no association between these haemostatic variables and insulin sensitivity was observed.…”