Annals of RSCB Vol. XVII, Issue 1/2012

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1 CORRELATIONS BETWEEN ENDOTHELIAL DYSFUNCTION AND GLYCEMIA IN VENOUS THROMBOSIS PATHOGENESIS Codruţa Bădescu 1, Oana Bădulescu 2, Manuela Ciocoiu 2, Magda Bădescu 2, M. Costuleanu 2 1 DEPARTMENT OF INTERNAL MEDICINE, 2 DEPARTMENT OF PATHOPHYSIOLOGY, UNIVERSITY OF MEDICINE AND PHARMACY "GRIGORE T. POPA" IASI Summary Venous thromboembolism (VTE), including deep venous thrombosis (DVT) is a major cause of morbidity and death. Thrombus formation and propagation depend on the presence of abnormalities of blood flow, blood vessel wall, and blood inflamatory components, known collectively as Virchow's triad. Epidemiologic studies consider vascular complications as the first cause of death in diabetic patients. The objective of this study was to determine the thrombotic risk in patients with type 2 diabetes mellitus (DM) with or without VTE compared with non-diabetic patients with VTE disease. The study comprises patients hospitalized in the Second Medical Clinic of the Sf. Spiridon Hospital between January 1, 5 and January 1, 211. The patients were investigated by determining two factors of coagulation profile: von Willebrand Factor (vwf) and DD-imers. The highest levels of the two studied parameters were found in the diabetic groups (DM+VTE) (p<,1) and (DM-VTE) (p<,5). The elevated levels of vwf and DD-imers in diabetic patients, reflect the effects of hyperglycemia on endothelium and the existence of platelet-vwf interaction, which would explain the accelerated venous thromboembolism in this patients. But diabetics vascular pathology it is also based on a lack of balance between the thrombosis-thrombolysis processes, to the benefit of thrombosis, followed by the occurrence of ischemic events Key words. thrombosis, von Willebrand Factor, DD-imers, hyperglycaemia. Introduction Venous thromboembolism is a frequent disease with an age-adjusted incidence of 1 to 2 events per of the general population and constitutes a major health care problem because of its high morbidity and mortality (Heit, 8). About one-third of patients suffering from a first episode of deep venous thrombosis (DVT) or pulmonary embolism (PE) develops a recurrence of VTE within 1 years (Heit et al., 2). From a clinical perspective, it would be extremely helpful to have biomarkers that enable early identification of patients at high or low risk of primary and recurrent VTE and allow prompt diagnosis and therapy assessment. Venous thromboembolism results from a combination of hereditary and acquired risk 143 magda.badescu@gmail.com factors, also known as thrombophilia or hypercoagulable states. In addition, vessel wall damage, venous stasis, and increased activation of clotting factors first described by Rudolf Virchow more than a century ago still remain the fundamental basis for our understanding of thrombosis. Virchow proposed that 3 elements venous stasis, endothelial injury, and hypercoagulability were the major factors responsible for the development of VTE (Snow et al., 7). Since that time, the role of each of these elements of the triad have been extensively evaluated, venous thromboembolism is associated with nearly a doubling in the risk for death among diabetic patients. The venous endothelium is thrombogenically inactive, yet its injury

2 exposes the subendothelial layers, which come into contact with the blood. The thrombus occurs further to coagulation cascade activation (Ageno et al., 8). Altered blood composition (hyperlipoproteinemia, polycythemia, inflammation) is associated with a high risk of thrombosis. In order to fulfill its function, the endothelium produces a variety of mediators-regulators including the von Willebrand factor (VWF), adhesion molecules and DD-imers (Wells et al., 3). Material and methods The study comprises patients (Women 135, Men 115) hospitalized in the Second Medical Clinic of the Sf. Spiridon Hospital between January 1, 5 and January 1, 211. The patients were distributed in the following groups: - group 1 Diabetic women with venous thromboembolism (DM+VTE), - group 2 Diabetic women without venous thromboembolism (DM-VTE), - group 3 Diabetic men with clinical venous thromboembolism (DM+VTE), - group 4 Diabetic men without venous thromboembolism (DM-VTE), - group 5 Non-diabetic women with venous thromboembolism (VTE), - group 6 Non-diabetic men with venous thromboembolism (VTE), The major objective of our study was: the determination of the thrombotic risk in patients with type 2 diabetes mellitus with or without venous thromboembolism compared with non-diabetic patients with venous thromboembolism. In the studied group, we followed the values of two parameters (von Willebrand factor and DDimers), in correlation with the duration of the diabetes mellitus. Results and disscussions The women had had diabetes for 2 to 1 years, exhibiting high value dispersion (32.8 vs CV%), whereas the men had had it for 2 to 9 years, also exhibiting 144 high value series dispersion (31.42 vs CV%). Comparisons between the Von Willebrand factor (vwf) values in women revealed the most homogeneous individual values in DVT diabetic women (13.3 CV%). In the women s groups, all the 1 cases exhibited vwf values higher than normal (16%), and no significance tests could be performed. r= Duration of the disease - Age Diabetic women with VTE r= Duration of the disease - Age Diabetic women without VTE r= Non-diabetic women with VTE Fig.1: Correlation between the Von Willebrand factor (%) and patients age

3 There is no significant correlation between the vwf factor and the age of the women patients in the three study groups, as they are independent variables in the deep vein thrombosis groups and they establish a poor direct correlation in the group of diabetic women without VTE. In the VTE diabetic women group, the vwf factor is directly correlated with the history of diabetes (r=.86), which points out that high vwf values are significantly associated with a long history of diabetes, whereas in women without VTE, high vwf values are detected in patients with a short history of diabetes, and the correlation is indirect (r = -.22). r= diabetic men with VTE The comparisons between the Von Willebrand factor (vwf) values conducted in men have the same outcome as the same comparisons carried out in women: the most homogeneous individual Von Willebrand factor values are reported in the VTE diabetic men group (28.47 CV%). r= diabetic men without VTE 145 r= nondiabetic m en w ith VTE Fig.2: Correlation between the Von Willebrand factor (%) and patients age The values of this parameter are above normal (16%) in diabetic men, i.e. in 9 and 8 cases, respectively, yet when compared with the group of non-diabetic men (5 cases above normal) the difference is not statistically significant (χ 2 =4.43; GL=2; p=.19). The vwf factor exhibits no significant correlation with the age of the patients in the three study groups; it establishes a poor direct correlation with age in the VTE diabetic patient group and indirect correlations in the other groups (Stegenga et al., 6). In the VTE diabetic men group, the vwf factor establishes a poor direct correlation with the history of diabetes (r=.21), whereas in diabetic patients without CI, the high vwf values are moderately associated with a longer history of diabetes (r =.59). The average vwf values reveal no significant differences either between the two sexes, or between the study groups. As concerns the von Willebrand factor, there is currently no data supporting the assumption according to which a high von Willebrand factor level in the plasma is

4 a risk factor for deep venous thrombosis. When considered from the viewpoint of this assumption related to VWF significance, the values we recorded are not surprising. The higher plasma levels are probably the expression of the endotheliopathy characterizing the prothrombotic status (Geerts et al., 8). The highest values were reported in the group of diabetic patients who also suffered from deep venous thrombosis. As far as the group of diabetic patients without venous complications is concerned, one may assume the existence of vascular involvement manifested subclinically, especially since it has been proven that endotheliopathy precedes not only the onset of cardiovascular diseases, but also the onset of diabetes mellitus (the synthesis and release of glycoproteins of endothelial origin are stimulated by metabolic disorders (Tamariz et al., 4). DD-imers In men, it was observed that DDimers had the most homogeneous individual values in group of diabetic men with venous thromboembolism (DM+VTE)(6,88CV%). a direct correlation with the duration of the disease (r=,23) it was observed in group of diabetic men with venous thromboembolism (DM+VTE); an indirect correlation (r = -,42) it was observed in diabetic men without venous thromboembolism (DM -VTE); The mechanisms linking the elevated levels of DD-imers to insulin resistance and type 2 diabetes may be related to the presence of underlying endothelial dysfunction and or inflammation, both of which are involved in the development of insulin resistance (Eichinger et al., 8) r= duration of the disease (years) diabetic men with VTE r= duration of the disease (years) diabetic men without VTE Fig.3: Correlations between DD-imers values () and the duration of the DM, in men In women, DD-imers had the most homogeneous individual values in the group of diabetic women without venous thromboembolism(dm- VTE)(16,22CV%). it was observed an direct correlation (r=,58) with the duration of the disease in diabetic women with venous thromboembolism (DM+VTE); the DDimers' values increase with the history of DM. in the group of diabetic women without venous thromboembolism (DM- VTE) it was observed a indirect correlation (r = -,24) with the duration of the disease; In vitro, glycated albumin has been reported to increase tissue factor expression in umbilical vein endothelial cells to indicate a mechanism by which glycation might initiate coagulation processes (Righini et al., 8). 146

5 r= duration of the disease 15 diabetic women with VTE r= duration of the disease (years) diabetic women without VTE Fig.4: Correlations between DD-imers values () and the duration of the DM, in women Regarding the values of DD-imers', these presented the following differences: there were not significant differences between genders; in women, diabetic patients with venous thromboembolism (DM+VTE) have significantly higher mean values than diabetic patients without venous thromboembolism (DM-VTE) (p<,5) ; in men, no significant differences were recorded in mean values of DD-imers, in the studied groups. The elevated levels of vwf and DD-imers are an indication of endothelial cell damage and are correlated with other cardiovascular risk factors (Wakefield et al., 8). Many studies have reported an association between elevated FVIII and/or vwf levels, the presence of VTE disease (Cosmi et al., 8) and the risk of future cardiovascular events in patients with VTE (Eichinger et al., 3). The mechanisms linking the elevated levels of vwf DDimers to insulin resistance and type 2 diabetes may be related to the presence of underlying endothelial dysfunction and or inflammation, both of which are involved in the development of insulin resistance. Hyperglycemia per se has been implicated in the development of prothrombotic changes in clamp studies (Stegenga et al., 6) where under conditions of euinsulinaemic hyperglycemia, twofold increases in thrombin antithrombin complexes and circulating soluble tissue factor were documented. Hyperinsulinemia in the presence of euglycaemia led to increases in vwf, and the authors made the observation that glucose modulated thrombotic processes whilst insulin regulated fibrinolysis. In vitro, glycated albumin has been reported to increase tissue factor expression in both monocytes and umbilical vein endothelial cells to indicate a mechanism by which glycation might initiate coagulation processes. Association studies in nondiabetic subjects have indicated correlations between serum advanced glycation end products (AGE) and both vwf and DD-imers levels to support the concept that AGE accumulation may stimulate prothrombotic changes in man. In addition, higher levels of glycation were associated with endothelial cell apoptosis which might contribute to vascular damage (Verhovsek et al., 8. Visceral fat produces proinflammatory cytokines such as interleukin-6 and TNF-α, which in turn elevate fibrinogen levels. These cytokines are responsible for some of the endothelial dysfunction that causes an increase in vwf. There is also some experimental evidence to support the notion that the coagulopathy is driven by hyperglycemia rather than hyperinsulinemia (Stegenga et al., 6). Conclusions The assessment of the blood flow, vascular reactivity and certain endothelial dysfunction markers has been shown to be associated with an unfavorable cardiovascular prognosis. In DM, 147

6 hyperglycemia and the metabolic syndrome components directly or indirectly cause endothelial dysfunction. The development of endothelial dysfunction, in pacients with type 2 diabetes mellitus, promotes vasospasm, thrombosis and inflammation, processes that may all be involved in the early stages of VTE disease, a view supported by clinical studies. DM is by itself a major thrombosis risk factor. The risk of developing cardiovascular events is higher in DM patients, because hyperglycemia determines subsequent metabolic disorders, by forming AGE and then by triggering quantitative and qualitative changes in serum lipoproteins, mechanisms which would explain the atherosclerosis acceleration in these patients. References Ageno W., Becattini C., Brighton.T,: Cardiovascular risk factors and venous thromboembolism: A meta-analysis. Circulation., 117: (1): 93-12, 8. Cosmi B., Legnani C., Cini M. D-dimer and factor VIII are independent risk factors for recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thromb. Res.; 122: , 8. Eichinger S., Hron G., Kollars M.: Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer. Clin. Chem.; 54: , 8. Eichinger S., Minar E., Bialonczyk C.: D-dimer levels and risk of recurrent venous thromboembolism. JAMA.; 29: , 3. Geerts W.H., Berqqvist D., Pineo G.F.,: Prevention of venous thromboembolism: American College of Chest. Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest., 133: (6 Suppl): 381S- 453S, 8. Heit J.A., O Fallon W.M., Petterson T.M.: Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: A population-based study. Arch. Intern. Med., 162: (11): , 2. Heit J.A., The epidemiology of venous thromboembolism in the community. Arterioscler Thromb. Vasc. Biol.; 28: , Righini M., Perrier A., De Moerloose P. et al.: D-Dimer for venous thromboembolism diagnosis: 2 years later. J. Thromb. Haemost.; 6: , 8. Snow V., Qaseem A., Barry P.: Management of venous thromboembolism: A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann. Intern. Med., 146:(3): 24-21, 7. Stegenga M.E., van der Crabben S.N., Levi M.. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes; 55: , 6. Tamariz L.J., Eng J., Segal J.B.: Usefulness of clinical prediction rules for the diagnosis of venous thromboembolism: A systematic review. Am. J. Med.;117: (9): , 4. Verhovsek M., Douketis J.D., Yi Q., Shrivastava S., Tait R.C., Baglin T., Poli D., Lim W.: Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann. Intern. Med.; 149: , W494; 8. Wakefield T.W., Myers D.D., Henke P.K.: Mechanisms of venous thrombosis and resolution. Arterioscler. Thromb.Vasc. Biol.; 28: ; 8. Wells P.S., Anderson D.R., Rodger M., Forgie M., Kearon C., Dreyer J., Kovacs G., Mitchell M., Lewandowski B., Kovacs M.J.; Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N. Engl. J. Med.; 349: ; 3.