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Title: Novel factors modifying properties of fibrin and efficiency of fibrinolysis in patients with type 2 diabetes mellitus


Type 2 diabetes mellitus is associated with an unfavorable fibrin clot phenotype, characterized by a faster formation of more compact fibrin networks, which are less susceptible to lysis (hypofibrinolysis) when compared with patients without diabetes. The mechanisms involved are only partially understood. My dissertation aimed to identify novel factors modyfing properties of fibrin and efficiency of fibrinolysis in patients with type 2 diabetes mellitus. There were three cross-sectional studies, one observational study and one in vitro study. The glycated hemoglobin, hemostasis parameters, platelet activation markers, thrombin generation along with fibrin clot permeability, were investigated. Fibrinolysis efficiency was assessed using three methods, by Lisman et al. (2001), Carter et al. (2007) and Pieters et al. (2018). The first investigated factor was plasma protein oxidation. Three markers were assessed: total plasma carbonylation, concentration of thiobarbituric acid reactive substances and total antioxidant capacity. The total protein carbonylation was shown to associate with the glycated hemoglobin, time since diabetes diagnosis and concomitant cardiovascular disease. Total plasma carbonylation correlated positively with clot lysis time assessed according to Lisman et al., and negatively with clot permeability. Increased total plasma carbonylation (in top qua ; rtile) showed high discriminatory power in identifying patients with prolonged clot lysis time. The second investigated factor was NETs, i.e. neutrophil extracellular traps. Four markers of NETs were assessed: two nuclear markers, such as citrullinated histone H3 and cell-free DNA, and two cellular markers, such as myeloperoxidase and neutrophil elastase. The concentration of nuclear markers was shown to associate with glucose concentration, glycated hemoglobin and interleukin 6. The concentration of cell-free DNA was positively correlated with peak thrombin. Both citrullinated histone H3 and cell free DNA significantly contributed to the variance of clot lysis time and clot permeability. Moreover, myeloperoxidase concentration positively correlated with clot lysis time. The other predictors of clot lysis time were: plasminogen activator inhibitor 1 concentration and concomitant cardiovascular disease, as well as time since diabetes diagnosis. The third investigated factor was α2-antiplasmin incorporation into the clot. The prolonged clot lysis time in women with diabetes when compared to men with diabetes was shown to associate with enhanced α2-antiplasmin incorporation into the clot. A model was developed to describe the relationship between the clot lysis time assessed according to Carter et al. and the extent of α2-antiplasmin incorporation into the clot, plasminogen ; activator inhibitor 1 concentration, fibrinogen concentration, sex and body-mass index. Increased α2-antiplasmin incorporation into the clot (top quartile) was associated with higher peak thrombin and endogenous thrombin potential. In the next step, the post-translational modifications of fibrinogen were investigated with mass-spectrometry in plasma fibrin clots of diabetic patients before and after introducing the treatment with acetylsalicylic acid at the dose of 75 mg once daily. The administration of acetylsalicylic acid was confirmed by suppressed level of thromboxane B2. There were 10 glycation sites identified in α and β fibrinogen chains, and 6 in γ fibrinogen chain. The lysine residues found to be glycated, were previously reported to be involved in cross-linking by factor XIII (αK 208, αK-448 and αK-539) and plasmin cleavage (αK 81). There were 7 acetylation sites. Three acetylation sites were identical with FL sites (αK-195, β-247 and βK 353). Treatment with acetylsalicylic acid did not affect intensity of acetylation, as well as clot lysis time assessed according to Pieters et al. The last investigated factors were post-translational modifications of α2-antiplasmin glycated and acetylated in vitro. There were 11 glycation sites and 10 acetylation sites. Incubation of α2-antiplasmin with glucose was associated with glycation of 4 (K-418, K-427, K-434 and K-44 ; 1) out of 6 lysine residues, known to be important for mediating the interaction with plasmin. Glycation and acetylation overlapped at 9 sites. Incubation of α2-antiplasmin with glucose and acetylsalicylic acid was associated with the decreased acetylation at all these sites when compared with incubation with only acetylsalicylic acid. At lysine residues 182 and 448, decreased acetylation was associated with increased glycation intensity suggesting the possible competition between glycation and acetylation processes in relation to these two modification sites. In summary, novel identified factors that affected fibrin clot properties and lysis involved: increased protein oxidation, enhanced generation of neutrophil extracellular traps and larger incorporation of α2-antiplasmin into the clot. The post-translational modifications of fibrinogen and α2 antiplasmin were identified.

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Level of degree:

2 - studia doktoranckie

Degree discipline:

hematologia ; endokrynologia

Degree grantor:

Rada Dyscypliny Nauki medyczne


Undas, Anetta

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pol; eng

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tylko w bibliotece

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Mar 25, 2024

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May 10, 2022

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ZB-134215 Mar 25, 2024


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