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Title: Fibrin clot propertiesin patients with retinal vein occlusion


The thrombin – mediated conversion of plasma fibrinogeninto fibrin and the formation of clots relatively resistant to fibrinolysis are the final steps in the blood coagulation. Abalance between clot formation and fibrinolysis largely determines clot stability. A fibrin clot composed of compact fibrin fiber networks, resistant to fibrinolysis, predisposes to arterial and venous thrombotic events. Reduced fibrin clot permeability and impaired fibrinolysis have been reported in patients with myocardial infarction, ischemic stroke, but also in patients with venous thromboembolism. Retinal vein occlusion (RVO) is the most common primary retinal vascular disease. Its pathogenesis is not fully understood. Depending on thrombus location, there are two main types of RVO: branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). The data on the association between known thrombophilic factors and RVO are inconsistent. The aim of this study was to evaluate ex vivo structure and properties of plasma fibrin clots in patients who experienced RVO. We enrolled 59 consecutive patients with diagnosed RVO (26 females, 33 males, aged 54.95 ± 11.04 years) and 59 control subjects matched forage, sex, body mass index (BMI), medications, and cardiovascular risk factors. A mean time from the diagnosis to enrolment was 14.4 ± 9.9 months (range, 5–36 months).The diagnosis of RVO was ; based on the presence of typical findings in the fundus of the eye documented in digital photography, fluorescein angiography, and opticalcoherence tomography.The University Bioethical Committee approved the study (KBET/114/B/2008). In all patients complete ophthalmology examination was performed and we measured lipid profile, glucose, alanine aminotransferase (AlAT), creatinine, total homocysteine, Creactive protein (CRP), fibrinogen, tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor-1antigen (PAI-1), activated partial thromboplastin time (APTT), and prothrombin time (PT). In RVO patients thrombophilia screening was done. Moreover, ex vivo fibrin clots obtained from citrate plasma samples were used for the measurement of clot permeation, expressed as the permeability coefficient, Ks (Darcy constant). Turbidity offibrin clot formation, reflected by the lag phase of theturbidity curve and maximum absorbency at plateau(ΔAbmax), tPA – induced fibrinolysis characterized bymaximum rates of increase in D-dimer levels (D-Drate) andmaximum D-dimer concentrations (D-Dmax) wereevaluated. The time required for 50% decrease in maximumclot absorbency (t50%) was chosen as an additional markerof the clot susceptibility to fibrinolysis after simultaneous addition of thrombin and recombinant tPA to plasma. ; Both RVO and control groups did not differ with regard toage, ; gender, BMI, smoking status, medications, a previous myocardial infarction/ stroke, lipid profile, creatinine,AlAT, PAI-1, and a percentage of patients with CRP level≥3.36 mg/l. RVO patients had higher percentage of arterial hypertension (by 58%, p = 0.01) and higher glucose (by 4%,p = 0.01), fibrinogen (by 17%, p = 0.03) and tPA (by 59%, p= 0.001) compared with controls. Platelet count (by 10%, p= 0.001) and total homocysteine (by 14.5%, p = 0.001) were lower in RVO group compared with controls. RVO patients were characterized by unfavorably altered plasma fibrin clot properties. Thirty per cent lower clot permeability was found in RVO patients compared with the control group (6.9[5.9–8.0] vs 9.8 [8.5–10.5] 10-9 cm2, p <0.0001). Compared with controls, RVO patients had 11% shorter lag phase(41.42 ± 4.59 vs 46.42 ± 4.12 s, p <0.0001) indicating faster fibrin formation, and 19% greater ΔAbmax (0.86 [0.80–0.94] vs 0.72 [0.66–0.77], p <0.0001), indicating thicker fibrin fibers. D-Dmax indicating thrombotic mass available for fibrinolytic agents was 22% higher in the RVO group (4.04 [3.48–4.55] vs 3.32 [3.26–3.43] mg/l, p <0.0001) and29% longer t50% (9.3 [8.5–10.2] vs 7.2 [6.8–7.7] min, p<0.0001) compared with controls. Only D-Drate was similarin both groups (0.071 [0.063–0.074] vs 0.069 [0.063–0.073]mg/l/min, p = 0.223). The differences remained statistically significant after ad ; justment for fibrinogen, glucose and platelet count. In the RVO group fibrinogen inversely correlated with Ks (tau-b = –0.414, p <0.0001), lag phase(tau-b = –0.383, p <0.0001), D-Drate (tau-b = –0.490, p<0.0001) and positively correlated with ΔAbmax (tau-b =0.276, p = 0.002), t50% (tau-b = 0.350, p <0.0001) and DDmax (tau-b = 0.324, p <0.0001). RVO patients with CRP≥3.36 mg/l had higher ΔAbmax (0,95 [0.87–1.01] vs 0,85[0.79–0.91], p = 0.024), longer t50% (10.0 [9.8–11.9] vs 9.1[8.5–10.1] min, p = 0.007), higher D-Dmax (4.75 [4.04–5.45] vs 3.95 [3.44–4.42] mg/l, p = 0.004) and lower D-Drate (0.063 [0.059–0.79] vs 0.071 [0.065–0.079]mg/l/min, p = 0.035) compared with the RVO patients with CRP <3.36 mg/l. In RVO patients age correlated positively with t50% (tau-b = 0.182, p = 0.047). None of the parameters of fibrin clot showed associations with sex, smoking status, previous stroke or myocardial infarction,time from the RVO occurrence, PAI-1, tPA, lipid variables, and glucose in RVO patients. Fibrin clot properties did not differ between patients with diagnosed BRVO or CRVO, with or without neovascurarization and macular edema,visual acuity <0.1 or ≥0.1, indicating the lack of correlation between severity of RVO and plasma fibrin clot properties.Two times higher prevalence of factor V Leiden was observed in RVO patients (10.2%) than in Polish general population (approximately 5%), ; but it was not associated with unfavorably altered plasma fibrin clot properties. In conclusion, the current results show that less porousplasma fibrin clots composed of thicker fibrils, displaying reduced susceptibility to lysis, are formed in RVO patients, like in those with coronary artery disease and deep vein thrombosis. Plasma fibrinogen and CRP levels have been recognized as the most important modulators of fibrin function in RVO. This original observation highlights a role of blood coagulation, particularly alterations in fibrin formation and degradation, in the pathogenesis of RVO.

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2 - studia doktoranckie

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Wydział Lekarski


Undas, Anetta

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Mar 17, 2023

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ZB-115817 Mar 17, 2023


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