Hypofibrinolysis in type 2 diabetes and its clinical implications: from mechanisms to pharmacological modulation

Cardiovasc Diabetol. 2021 Sep 22;20(1):191. doi: 10.1186/s12933-021-01372-w.

Abstract

A prothrombotic state is a typical feature of type 2 diabetes mellitus (T2DM). Apart from increased platelet reactivity, endothelial dysfunction, hyperfibrinogenemia, and hypofibrinolysis are observed in T2DM. A variety of poorly elucidated mechanisms behind impaired fibrinolysis in this disease have been reported, indicating complex associations between platelet activation, fibrin formation and clot structure, and fibrinolysis inhibitors, in particular, elevated plasminogen antigen inhibitor-1 levels which are closely associated with obesity. Abnormal fibrin clot structure is of paramount importance for relative resistance to plasmin-mediated lysis in T2DM. Enhanced thrombin generation, a proinflammatory state, increased release of neutrophil extracellular traps, elevated complement C3, along with posttranslational modifications of fibrinogen and plasminogen have been regarded to contribute to altered clot structure and impaired fibrinolysis in T2DM. Antidiabetic agents such as metformin and insulin, as well as antithrombotic agents, including anticoagulants, have been reported to improve fibrin properties and accelerate fibrinolysis in T2DM. Notably, recent evidence shows that hypofibrinolysis, assessed in plasma-based assays, has a predictive value in terms of cardiovascular events and cardiovascular mortality in T2DM patients. This review presents the current data on the mechanisms underlying arterial and venous thrombotic complications in T2DM patients, with an emphasis on hypofibrinolysis and its impact on clinical outcomes. We also discuss potential modulators of fibrinolysis in the search for optimal therapy in diabetic patients.

Keywords: Cardiovascular mortality; Fibrinolysis; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • Complement C3 / metabolism
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / mortality
  • Extracellular Traps / metabolism
  • Fibrinolysis* / drug effects
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Inflammation Mediators / blood
  • Prognosis
  • Thrombosis / blood*
  • Thrombosis / drug therapy
  • Thrombosis / etiology
  • Thrombosis / mortality

Substances

  • Complement C3
  • Fibrinolytic Agents
  • Hypoglycemic Agents
  • Inflammation Mediators