Fig. 1
Mechanisms involved in hypofibrinolysis in type 2 diabetes mellitus (T2DM) patients. The main contributors to hypofibrinolysis in T2DM are platelet activation, endothelial cells (ECs) dysfunction, enhanced thrombin generation, proinflammatory state, increased fibrinogen level along with its modifications, and altered fibrin structure. Obesity represented by high body mass index (BMI), hyperinsulinemia, and hyperglycemia (high glucose, Glc) all lead to platelet activation reflected by increased release of thromboxane A2 (TXA2), P-selectin, plasminogen activator inhibitor 1 (PAI-1), and platelet microparticles (PMPs). Another contributor to platelet activation is oxidative stress, which is reflected by increased synthesis of F2-isoprostane 8-iso-prostaglandin F2α (8-iso-PGF2α), a product of low-density-lipoprotein (LDL) cholesterol peroxidation, represented by oxidized LDL (oxLDL). Down-regulation of the insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3-kinase (PI3K) pathways with enhancement of mitogen-activated protein kinase (MAPK) result in decreased nitric oxide (NO) synthesis and increased PAI-1 release, leading to endothelial dysfunction. Advanced glycation end-products (AGE) stimulate overactive NADPH oxidases (NOX), reactive oxygen species (ROS)-producing enzyme complexes, which in turn generates tissue factor (TF) in ECs. AGE stimulate monocytes (Mo)/macrophages (Ma) to produce increased amounts of TF. Another source of TF are the vascular smooth muscle cells (VSMCs). Increased TF initiates the extrinsic pathway of coagulation and together with factor VII (VIIa, activated factor VII) lead to enhanced thrombin generation. Weibel-Palade bodies release increased amounts of von Willebrand factor (vWF), which along with increased factor VIII (VIIIa, activated factor VIII) and factor IX (IXa, activated factor IX), form the intrinsic pathway of thrombin generation. Increase in both components of the prothrombinase complex, activated factor X (Xa) and V (Va). Other factors underlying enhanced thrombin generation are central obesity represented by increased waist-hip circumference (WHC) ratio, elevated C-reactive protein (CRP), low glycemia, and time since T2DM diagnosis exceeding 5 years. Hyperglycemia, increased interleukins 6 and 8 (IL-6 and IL-8), along with ROS stimulate neutrophils to form the neutrophil extracellular traps (NETs), with an important stage of chromatin decondensation mediated by peptidylarginine deiminase 4 (PAD4), followed by a release of nuclear components depicted in light blue, i.e., cell-free DNA (cfDNA), citrullinated histone H3 (H3Cit), and granular components depicted in dark blue, i.e., myeloperoxidase (MPO) and neutrophil elastase (NE). Obesity represented by increased BMI elevates both CRP and complement C3 (C3) levels. IL-6 and insulin resistance contribute to elevated fibrinogen concentration, while hyperglycemia and ROS result in posttranslational modifications, such as fibrinogen glycation (–Glc) and oxidation (–ROS). The fibrin network formed from modified fibrinogen, with increased amounts of incorporated α2-antiplasmin (a2AP), NETs, and complement C3, characterized by enhanced crosslinking by factor XIII (FXIII), dense and less permeable, being composed of thinner and highly branched fibrin fibers. Additionally, increased amount of polyhedrocytes are found in the contracted thrombi of diabetic patients. Decreased plasmin generation, diminished binding of plasminogen and tissue plasminogen activator (tPA) to fibrin, along with increased PAI-1, originating from adipocytes and hepatocytes, are also involved in hypofibrinolysis observed in T2DM. Glycation of plasminogen was reported in type 1 diabetes mellitus patients and therefore is marked with asterisks. α2-antiplasmin is another protein implicated in fibrinolysis and found to be glycated in T2DM. FDP, fibrin degradation products