Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus

Diabetologia. 2006 May;49(5):1071-80. doi: 10.1007/s00125-006-0197-4. Epub 2006 Mar 16.

Abstract

Aims/hypothesis: The aim of this study was to determine the influence of type 2 diabetes on fibrinolysis by assessing interactions between the regulatory components of fibrinolysis and the fibrin clot, using fibrinogen purified from 150 patients with type 2 diabetes and 50 matched controls.

Methods: Clot lysis rates were determined by confocal microscopy. Plasmin generation was measured using a plasmin-specific chromogenic substrate. Surface plasmon resonance was used to determine the binding interactions between fibrin, tissue-type plasminogen activator (t-PA) and Glu-plasminogen; cross-linkage of plasmin inhibitor to fibrin by factor XIII was determined using a microtitre plate assay.

Results: Lysis of diabetic clots was significantly slower than that of controls (1.35 vs 2.92 microm/min, p<0.0001) and plasmin generation was significantly reduced. The equilibrium binding affinity between both t-PA and Glu-plasminogen and fibrin was reduced in diabetic subjects: t-PA, K (D)=0.91+/-0.3 micromol/l (control subjects), 1.21+/-0.5 micromol/l (diabetic subjects), p=0.001; Glu-plasminogen, K (D)=97+/-19 nmol/l (control subjects), 156+/-66 nmol/l (diabetic subjects), p=0.001. Cross-linkage of plasmin inhibitor to fibrin by factor XIII was enhanced in diabetic subjects, with the extent of in vitro cross-linkage correlating with in vivo glycaemic control (HbA(1c)) (r=0.59, p=0.001).

Conclusions/interpretation: These results indicate that impairment of the fibrinolytic process in diabetic patients is mediated via a number of different mechanisms; these may be a consequence of post-translational modifications to fibrinogen molecules, resulting from their exposure to the abnormal metabolic milieu associated with diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / blood*
  • Drug Resistance
  • Enzyme Activation
  • Factor XIII / isolation & purification
  • Female
  • Fibrin / pharmacology*
  • Fibrinogen / chemistry
  • Fibrinogen / isolation & purification
  • Fibrinogen / metabolism
  • Fibrinolysin / pharmacology*
  • Glycated Hemoglobin A / metabolism
  • Hemolysis / drug effects*
  • Humans
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Reference Values
  • Surface Plasmon Resonance

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Fibrin
  • Fibrinogen
  • Factor XIII
  • Fibrinolysin