Table 2 Factors affecting fibrinolysis in patients with type 2 diabetes mellitus (T2DM)
Study | No. of T2DM/controls age, BMI | Method for assessing fibrinolysis | T2DM patients | Control subjects | Relative difference and p-value* | Factors affecting fibrinolysis |
|---|---|---|---|---|---|---|
Genetic | ||||||
 Greenhalgh et al. [25] | 822/0 68 (60–75) yrs, 31.0 ± 5.4 kg/m2 | Plasma-derived clots Turbidimetric assay | 763 ± 322 s (carriers of Bβ448Lys) 719 ± 351 s (Bβ448Arg) | – | Carriers of Bβ448Lys vs. Bβ448Arg  + 6.1% p = 0.01 | Fibrinogen Bβ448Lys variant |
36/0 | Purified-fibrinogen derived clots Turbidimetric assay | 517 ± 65 s (Lys/Lys) 442 ± 87 s (Arg/Lys) 419 ± 64 s (Arg/Arg) |  | Lys/Lys vs. Arg/Arg + 23.3% p = 0.003 Lys/Lys vs. Arg/Lys + 17.0% p = 0.05 | ||
Molecular/environmental | ||||||
 Dunn et al. [21] | 25/25 61 ± 11 yrs, 29.3 ± 6.1 kg/m2 | Fibrin formed from purified fibrinogen tPA-induced lysis assessed in confocal microscope | 1.35 ± 0.37 μm/min | 2.92 ± 0.57 μm/min | − 53.8% p < 0.0001 | Decreased plasmin generation Reduced equlibrium binding between tPA and Glu-plasminogen, and fibrin Increased cross-linkage of factor XIII to fibrin HbA1c Posttranslational modifications of fibrinogen |
 Meltzer et al. [30] | 71(DM + VTE)/2389 (non-DM + VTE) 49 (19–71) yrs, n.d | Plasma-based Lisman method | 81.1 [95% CI 54.2–140.7] min | 69.3 [95% CI 49.3–102.5] min | + 17% p-value not specified | First episode of VTE |
 Meltzer et al. [139] | 22/620 57.4 yrs, n.d | Plasma-based Lisman method | 74.0 [95% CI 55.9–133.1] min | 77.7 [95% CI 57.7–108.0] min | − 4.8% not significant | First myocardial infarction |
 Alzahrani et al. [24] | 875/0 68.2 (60–75) yrs, 20.3 ± 0.3 kg/m2 | Plasma-based Turbidimetric method | 803 ± 20 (female) 665 ± 12 (male) | – | Female vs. male  + 20.8% p < 0.001 | Female sex Younger age in male Greater WCF in women HbA1c in men Lower HDL-cholesterol in women Lower eGFR Smoking in men Ischemic heart disease in men PAI-1 |
 Bochenek et al. [26] | 67(T2DM + CAD)/67 (non-T2DM + CAD) 65.6 ± 7.8 yrs, 29.6 ± 4.0 kg/m2 | Plasma-based Turbidity | 9.42 ± 1.47 min | 8.94 ± 1.23 min |  + 5.4% p = 0.04 | P-selectin vWF PAI-1 Fibrinogen |
 Neergard-Petersen et al. [96] | 148 (T2D + CAD)/433 (non-T2DM + CAD) 65 ± 8 yrs, 30 ± 5 kg/m2 | Plasma-based Turbidimetric method | 804 (618; 1002) s | 750 (624; 906) s |  + 7.2% p = 0.03 | Quantitative rather than qualitative changes in fibrinogen CRP, complement C3, interleukin-6 Female sex BMI |
Purified-fibrinogen Turbidimetric method | 605 ± 163 s | 490 ± 99 s |  + 23.5% p = 0.21 | |||
 Hess et al. [85] | 837/0 67.9 ± 4.2 yrs, 30.7 (27.3–34.4) kg/m2 | Plasma-based Turbidimetric | 618 (480–816) s | – | – | Complement C3 PAI-1 |
 Konieczynska et al. [23] | 156/0 66 (60–73) yrs, 32 ± 5.4 kg/m2 | Plasma-based William’s method | 10.2 ± 0.1 min (T2DM > 5 years) 9.3 ± 0.1 min (T2DM ≤ 5 years) | – | T2DM > 5 years vs. T2DM ≤ 5 years  + 9.7% p < 0.0001 | Time since T2DM diagnosis > 5 years HbA1c > 6.5% Fibrinogen PAI-1 antigen Peak thrombin |
Plasma-based Lisman method | 101.5 ± 1.8 min (T2DM > 5 years) 89.7 ± 1.6 min (T2DM ≤ 5 years) |  | T2DM > 5 years vs. T2DM ≤ 5 years  + 13.2% p < 0.0001 | |||
 Lados-Krupa et al. [100] | 163/0 65 ± 8.8 yrs, 31.9 ± 5.2 kg/m2 | Plasma-based Tissue factor and tPA | 95.9 [95% CI: 91.0–100] min (Hba1c > 7%) 94.7 [95% CI: 91.5–97.9] min (Hba1c ≤ 7%) | – | Hba1c > 7% vs. Hba1c ≤ 7%  + 1.3% p = 0.069 | Oxidized LDL-cholesterol |
 Gajos et al. [75] | 165/0 Data available for subgroups | Plasma-based Thrombin and tPA | 10.49 ± 0.97 min (low glucose, < 4.5 mmol/l) 9.55 ± 0.91 min (medium glucose, 4.5–6.0 mmol/l) 9.79 ± 1.11 min (high glucose, > 6.0 mmol/l) | – | Medium glucose vs. low  − 9.0% p < 0.05 | Glucose < 4.5 mmol/l |
High glucose vs. low  − 6.7% p < 0.05 | ||||||
 Bryk et al. [58] | 113/0 63.8 ± 8.2 yrs, 32 (29.4–37.2) kg/m2 | Plasma-based Lisman method | 114.0 (99.3–126.8) min (H3Cit ≥ 7.36 ng/ml) 87.0 (78.3–100.0) min (H3Cit < 7.36 ng/ml) | – | H3Cit ≥ 7.36 ng/ml vs. H3Cit < 7.36 ng/ml  + 31.0% p < 0.001 | H3Cit cfDNA PAI-1 CVD |
 Bryk et al. [89] | 113/0 63.8 ± 8.2 years, 32 (29.4–37.2) kg/m2 | Plasma-based Turbidity | 471 (401–555) s (α2-antiplasmin incorporation ≥ 29.79 mg/dl) vs. 383 (345–435) s (α2-antiplasmin incorporation < 29.79 mg/dl) | – | α2-antiplasmin incorporation ≥ 29.79 mg/dl vs. α2-antiplasmin incorporation < 29.79 mg/dl  + 23.0% p < 0.001 | α2-antiplasmin incorporation Fibrinogen Female gender PAI-1 BMI |
Pharmacological | ||||||
 Grant [140] | 25/23 n.d., > 25 kg/m2 | Euglobulin clot lysis time | 50.9 ± 98.9 min (mean change from baseline after 12 wks of treatment with 3 g metformin) | n.d | Change from baseline after 12 wks of treatment with 3 g metformin no baseline data p = 0.026 | HbA1c, insulin, glucose, triglycerides, cholesterol PAI-1, tPA |
60.6 ± 84.7 min (mean change from baseline after 6 months of treatment with 1.5 g metformin) | Change from baseline after 6 months of treatment with 1.5 g metformin no baseline data p = 0.012 | |||||
 Pieters et al. [97] | 7/5 53 (49.1–56.9) yrs, n.d | Fibrin formed from purified fibrinogen tPA-induced lysis assessed in confocal microscope | 3.08 [2.48;3.25] μm/min (at baseline) | 8.52 [6.18; 8.59] μm/min | T2DM at baseline vs. control at baseline − 63.8% p = 0.06 | Glycemic control Fibrinogen glycation |
3.27 [2.92;3.72] μm/min (after treatment with insulin) | 8.21 [6.50; 8.64] μm/min | Baseline T2DM vs. T2DM after treatment with insulin -5.8% p = 0.02 | ||||
 Bryk et al. [99] | 7/0 62 (60–63) yrs, n.d | Plasma-based Pieters method | 130.0 (117.8–233.5) min (at baseline) 127.5 (125.0–262.0) min (after 1-month treatment with 75 mg aspirin once daily) | – | Baseline vs. after treatment with aspirin  + 2.0% p = 1.0 | Fibrinogen glycation and acetylation sites |