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Table 2 Factors affecting fibrinolysis in patients with type 2 diabetes mellitus (T2DM)

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

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
  1. Numerical data were presented as mean ± standard deviation, or median (interquartile range) or median [95% confidence interval, CI]. Relative difference and p-value have been plotted between T2DM patients and control groups, unless stated otherwise
  2. BMI body-mass-index, CAD coronary artery disease, cfDNA cell-free DNA, CRP C-reactive protein, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, HbA1c glycated hemoglobin, H3Cit citrullinated histone H3, HDL high-density lipoprotein, LDL low-density lipoprotein, n.d. no data, PAI-1 plasminogen-activator inhibitor, tPA tissue plasminogen activator, VTE venous thrombomebolism, vWF von Willebrand factor, WCF waist circumference