The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease

Neergaard‐Petersen, Søs; Hvas, Anne‐Mette; Kristensen, Steen Dalby; Grove, Erik Lerkevang; Larsen, Susan Weng; Phoenix, Fladia; Kurdee, Zeyad; Grant, Peter J.; Ajjan, Ramzi

doi:10.1160/th14-05-0468

Cited by 50 publications

(44 citation statements)

References 44 publications

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“…This mechanism may not be as important among diabetic patients with AF since the primary mechanism for ischemic stroke is atrio-embolic (24). Duration of diabetes may be most important among AF populations due to enhanced thrombin generation, impaired fibrinolysis with prolonged lysis time, and unfavorably altered plasma fibrin clot structure which may increase the risk of thrombotic events (25,26). …”

Section: Discussionmentioning

confidence: 99%

Effect of Diabetes and Glycemic Control on Ischemic Stroke Risk in AF Patients

Ashburner

Chang

et al. 2016

Journal of the American College of Cardiology

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Background Diagnosed diabetes mellitus (DM) is a consistently documented risk factor for ischemic stroke in patients with atrial fibrillation (AF). Objectives To assess the association between duration of diabetes and elevated HbA1c with risk of stroke among diabetics with AF. Methods We assessed this association in the ATRIA California community-based cohort of AF patients (study years 1996-2003) where all events were clinician adjudicated. We used Cox proportional hazards regression to estimate the rate of ischemic stroke in diabetic patients according to time-varying measures of estimated duration of diabetes (≥3 years compared to <3 years) and HbA1c values (≥9.0% and 7.0-8.9% compared to <7.0%), focusing on periods where patients were not anticoagulated. Results There were 2,101 diabetic patients included in the duration analysis, 40% with duration <3 years and 60% with duration ≥3 years at baseline. Among 1933 diabetic patients included in the HbA1c analysis, 46% had HbA1c <7.0%, 36% between 7.0 and 8.9%, and 19% ≥9.0% at baseline. Duration of diabetes ≥ 3 years was associated with an increased rate of ischemic stroke compared to duration <3 years (adjusted HR: 1.74, 95% CI: 1.10-2.76). The increased stroke rate was observed in older (≥75 years) and younger (<75 years) individuals. Neither poor glycemic control (HbA1c ≥9.0%, adjusted HR: 1.04, 95% CI: 0.57-1.92) or moderately increased HbA1c (7.0-8.9%, adjusted HR: 1.21, 95% CI: 0.77-1.91) were significantly associated with an increased rate of ischemic stroke compared with patients who had HbA1c <7.0%. Conclusions Duration of diabetes is a more important predictor of ischemic stroke than glycemic control in patients who have diabetes and AF.

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Section: Discussionmentioning

confidence: 99%

Effect of Diabetes and Glycemic Control on Ischemic Stroke Risk in AF Patients

Ashburner

Chang

et al. 2016

Journal of the American College of Cardiology

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“…From the entire cohort, substudies on inflammatory biomarkers were performed comprising hs-CRP [14], IL-6 [14], calprotectin [14], fibrinogen [15,16], and C3 [15,16]. Patients included in these substudies were younger, more often had diabetes, prior MI and prior coronary revascularization, whereas renal failure and antihypertensive medication was less common, compared with patients not included.…”

Section: Methodsmentioning

confidence: 99%

Coronary artery disease-associated genetic variants and biomarkers of inflammation

et al. 2017

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IntroductionGenetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers.MethodsWe genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers.ResultsThe minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score.ConclusionsIn stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers.

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“…Further work from our laboratory has demonstrated that incorporation of C3 into the fibrin clots of T1DM subjects has a greater effect on prolongation of clot lysis compared with clots from healthy controls [107]. The association between elevated C3 plasma levels and prolonged clot lysis has also been observed in T2DM [108, 109]. In the study by Hess et al of 875 patients with T2DM, a regression analysis involving PAI-1, fibrinogen, C3 and CRP plasma levels, demonstrated that C3 was an independent predictor of fibrinolysis potential in contrast to CRP which failed to show an independent association with clot lysis.…”

Section: Mechanisms Of Hypofibrinolysismentioning

confidence: 99%

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Kearney

Tomlinson

Smith

et al. 2017

Cardiovasc Diabetol

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An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition.

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The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease

Cited by 50 publications

References 44 publications

Effect of Diabetes and Glycemic Control on Ischemic Stroke Risk in AF Patients

Effect of Diabetes and Glycemic Control on Ischemic Stroke Risk in AF Patients

Coronary artery disease-associated genetic variants and biomarkers of inflammation

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

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