Abstract
BackgroundPatients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear. Prothrombotic fibrin clot properties have been shown in T2DM and cardiovascular disease. We hypothesized that formation of denser clots, which are resistant to fibrinolysis, has a negative impact on cardiovascular mortality in T2DM.MethodsWe studied 133 T2DM patients aged 43–83 years. Plasma fibrin clot turbidity, permeation, compaction, and efficiency of clot lysis using 3 assays including the determination of maximum concentration (D-Dmax) and rate of increase in D-dimer concentration (D-Drate) released during tissue plasminogen activator-induced degradation, were evaluated at the time of enrollment, along with thrombin generation and fibrinolytic proteins. During a median follow-up period of 72 months, cardiovascular mortality was recorded.ResultsCardiovascular deaths (n = 16, 12%) occurred more frequently in patients with increased D-Dmax (> 4.26 mg/l, hazard ratio [HR] 5.43, 95% confidence interval [CI] 1.99–14.79), or decreased D-Drate (< 0.07 mg/l/min, HR 2.97, 95% CI 1.07–8.23), or increased peak thrombin (> 283.5 nM, HR 5.65, 95% CI 2.07–15.51). These predictors had an even more potent impact on cardiovascular mortality in patients with prior cardiovascular disease (64.7%) and with corresponding risks as follows: HR 6.18, 95% CI 2.02–18.96; HR 8.98, 95% CI 2.99–26.96; and HR 5.35, 95% CI 1.62–17.72, respectively. Other investigated fibrin variables and fibrinolytic proteins did not associate with cardiovascular mortality. In multivariable analysis, cardiovascular mortality was predicted by D-Dmax > 4.26 mg/l, age > 65 years, prior cardiovascular disease, and C-reactive protein > 3 mg/l.ConclusionsThis study is the first to show that formation of denser fibrin clots resistant to fibrinolysis could be a risk factor for long-term cardiovascular mortality in T2DM.
Highlights
Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear
It has been suggested that hypofibrinolysis in T2DM is associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1) [15] and thrombin-activatable fibrinolysis inhibitor (TAFI) [16], along with increased cross-linking of α2-antiplasmin into fibrin networks [8, 17], and glycation of fibrinogen [18] and plasminogen [19], while the mechanical properties of fibrin are independent from fibrinogen glycation [20]
Patients who died from cardiovascular causes did not differ from the survivors in terms of demographic data and time since T2DM diagnosis, but they more commonly had nephropathy at baseline and less commonly were treated with metformin when compared to the survivors (Table 1)
Summary
Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear. Prothrombotic fibrin clot properties have been shown in T2DM and cardiovascular disease. Over the last 15 years, the mortality and incidence of cardiovascular events has declined both in patients with and without T2DM, though at a slower rate among diabetic patients [2]. Cardiovascular disease affects 32.2% of T2DM patients and leads to mortality in 9.9% of patients having T2DM of more than 10 years duration [3]. Prolonged T2DM duration might contribute to prothrombotic fibrin clot alterations including impaired fibrinolysis [12], with enhanced oxidative stress playing a substantial role [21]. Asymptomatic women with coronary plaques, as visualized by coronary computed tomography angiography, have reduced fibrin clot lysability compared to men with and without coronary plaques, and women without coronary plaques, suggesting a sex-dependent link between coronary atherosclerosis and fibrin clot lysability [22]
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