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Background/Objectives: Sulodexide (SDX) is a drug known for restoring the glycocalyx, thereby offering endothelial protection and regulating permeability. Additionally, it has antithrombotic and anti-inflammatory properties and has shown arterial vasodilatory effects. Endothelial cells play a crucial role in maintaining homeostasis, with their dysfunction being a key contributor to loss in vasodilatory response, especially in arterial pathologies. The aim of this study was to investigate the effects of SDX on stimulated vascular tonus in human arterial samples and to assess the function of the endothelial layer as a source of nitric oxide (NO). Methods: A total of 16 internal mammary artery remnants from coronary artery bypass graft surgeries were dissected into endothelium-intact and endothelium-denuded groups (n = 8 each). The arterial rings were equilibrated under tension, with their basal tonus recorded before and after phenylephrine stimulation. SDXs impact on arterial contraction was assessed through cumulative dose-response curves. NO synthase inhibitor (Nω-nitro-L-arginine methyl ester) was used to assess SDXs vasodilatory effect over the NO pathway. Results: SDX application resulted in concentration-dependent vasorelaxation in both endothelium-intact and endothelium-denuded groups at certain doses. However, the inhibitory effect of SDX was more pronounced in endothelium-intact rings at higher doses compared to endothelium-denuded rings (p < 0.05). Similar inhibition of contraction curves was achieved for both endothelium-intact and endothelium-denuded rings after L-NAME pre-incubation, suggesting a necessity for NO-related endothelial pathways. Conclusions: SDX exerts a concentration-dependent inhibition on arterial contraction, emphasizing the critical role of an intact endothelium and NO-mediated pathways in this process. This underscores SDXs potential in treating endothelial dysfunction-related pathologies.

Introduction. Cardiovascular diseases are still the leading cause of death worldwide. In contrast to men, in women, cardiovascular diseases, such as coronary artery disease, acute cerebrovascular accident, and thrombosis of various localization, develop later in life. A fold rise in risk begins during the menopausal transition. Given the increase in the postmenopausal period of a woman's life, it seems interesting to search for new methods of early prevention of cardiometabolic complications already in perimenopause. Aim. To optimize early non-hormonal prevention of endothelial dysfunction and perimenopausal cardiovascular complications. Materials and methods. A prospective study included 50 patients aged 45–55 years in perimenopause without obesity and other somatic or gynecological disorders with menopausal syndrome of varying severity. Patients in group 1 (n=25) received combined non-hormonal treatment of menopausal symptoms and prevention of cardiovascular complications [sulodexide 250 lipasemic units (LU) 2 times a day + phytoestrogen (cimicifuga extract) 1 capsule 2 times a day]. In group 2 (n=25), patients received only phytoestrogen according to the same regimen. Results. After 1 year of observation, the mean thickness of the intima-media complex of the common carotid artery in group 1, in which patients received complex course therapy including sulodexide (Vessel Due F), decreased by 3.7%, and in group 2 increased by 26.8%. In group 1, it was found that after 1 year of regular use, treatment contributed to a decrease in blood fibrinogen level by 11.8% and an increase in thrombin time by 24.5%, which, in combination with a decrease in prothrombin concentration and an increase in activated partial thromboplastin time by 4.7 s, indicates a pronounced therapeutic effect on the hemostasis system. Conclusion. All markers of early atherosclerosis and vascular complications progress during postmenopause and with increasing age. However, complex protective therapy, including glycosaminoglycans sulodexide), can slow down this progression while improving patients' quality of life. Non-hormonal complex therapy can not only neutralize menopausal symptoms but also prevent long-term vascular complications caused by increasing age and the lack of estrogen-protective effect.

Objective To explore the role of sulodexide (SDX) in neointimal hyperplasia of arteriovenous fistulas (AVFs) in chronic kidney disease (CKD) rats and its possible mechanism. Methods A total of 18 male rats (weighing 300±50 g) were randomly and equally divided into AVF group, CKD+AVF group (CKD induction followed by AVF surgery and then gavaged with normal saline for 2 months), and CKD+AVF+SDX group[treated as in the CKD+AVF group but with 8 mg/(kg·d) SDX gavage].HE staining was used to observe the degree of neointimal hyperplasia.The expression of Hippo pathway related molecules, Yes-associated protein (YAP), pYAP and connective tissue growth factor (CTGF, YAP downstream target protein, one of mesenchymal marker) was detected by immunofluorescence assay.After human umbilical vein cell fusion EAHy926 cells were treated with 0, 2.5, 5, 10, 20 or 40 μg/mL SDX for 24 h, and with 2.5 μg/mL SDX for 24, 48 or 72 h, respectively, CCK-8 assay was used to measure cell survival rate.Moreover, the serum sample from CKD rat was used to treat EAHy926 cells, and then the cells were treated with SDX or YAP inhibitor verteporfin.The expression levels of YAP, pYAP, CTGF and endothelial cell marker CD31 were detected by Western blotting. Results HE staining and immunofluorescence assay showed that CKD rats had serious neointimal hyperplasia in AVFs (P < 0.05), and slightly lower expression of pYAP and enhanced expression of CTGF (P < 0.05) when compared with the rats of the AVF group.While, SDX treatment alleviated the neointimal hyperplasia of AVFs, enhanced the expression of pYAP and reduced the expression of CTGF (P < 0.05).CCK-8 assay showed that cell survival rate was decreased significantly in a dose-and time-dependent manner after SDX treatment (P < 0.05).Western blotting revealed that SDX increased the expression of pYAP and CD31 while inhibited the expression of CTGF in EAHy926 cells (P < 0.05), which was consistent with the effect of verteporfin treatment. Conclusion SDX can block YAP activation caused by CKD and attenuate neointimal hyperplasia in AVFs.

The lipid peroxidation product 4-hydroxynonenal (HNE) may be involved in vascular endothelial cell damage by induction of oxidative stress, apoptosis, and loss of redox homeostasis. There is evidence that stimulation of endothelial cells with 4-HNE induces the activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap-1) pathway. Sestrin2 protein (SESN2) is one of the key regulators of Nrf2 and is involved in the cellular response to oxidative stress. However, the function of SESN2 in HNE-induced endothelial injury is not yet understood. Sulodexide (SDX) is a mixture of glycosaminoglycans used in clinical practice in the treatment of chronic venous and arterial diseases. While SDX has well-documented endothelial protective properties, little is known about its antioxidant effects. The aim of this study was to elucidate the molecular mechanisms activated by SDX in human umbilical endothelial cells (HUVECs) under HNE-induced oxidative stress. In this experimental model, we decided to evaluate the anti-apoptotic and antioxidant potential of SDX and its effect on the SESN2/Nrf2/GSH pathway. HUVECs were treated with 25 µM HNE or HNE combined with 0.5 LRU/mL SDX for 4 hours. Cell viability, apoptosis and intracellular reactive oxygen species (ROS) production were assessed by MTT assay and fluorescence microscopy. The expressions of Bax, cleaved caspase-3, Keap-1 and Nrf2 were determined by Western blot analysis. The intracellular concentrations of reduced glutathione (GSH) and oxidized glutathione (GSSG) were measured by colorimetric assay. SESN2, glutamate-cysteine ligase catalytic subunit (GCLc) and glutathione synthase (GSS) were assessed using ELISA. RT-qPCR was performed to detect Nrf2, GCLc and GSS mRNA levels. Transient Nrf2 silencing was obtained by short interfering RNA (siRNA). We have demonstrated that SDX can reduce the negative impact of HNE on HUVECs. SDX significantly protected HNE-treated HUVECs from apoptosis (p<0.001) and oxidative stress (p<0.001). SDX treatment significantly reduced Bax (p<0.05) and cleaved caspase-3 (p<0.01) expression. Co-administration of HNE and SDX increased GSH content (p<0.001) and GSH:GSSG ratio (p<0.001) as well as decreased SESN2 concentration (p<0.001) and Nrf2 (p<0.01), GCLc (p<0.05) and GSS (p<0.01) gene expression compared with the HNE group. Moreover, we revealed a negative correlation between SESN2 levels and GSH concentrations (p<0.001). Nrf2 silencing significantly decreased the effect of HNE and SDX on the induction of GCLc and GSS genes. SDX also significantly ameliorated the increase of nuclear Nrf2 in response to HNE (p<0.05). The results confirmed that SDX may protect against HNEinduced endothelial damage through its antioxidant effect and modulation of the SESN2/Nrf2/GSH signaling pathway. [ABSTRACT FROM AUTHOR]

Chronic venous disease (CVD) is a proqgressive and underestimated condition related to a vicious circle established by venous reflux and endothelial inflammation, leading to vein dilation and histology distortion, including loss of media tone. Sulodexide (SDX) is a drug restoring the glycocalyx that demonstrated endothelial protection and permeability regulation, together with anti-thrombotic and anti-inflammatory roles. In the lab it also exhibited vein contractility function. The aim of the present study was to show the possible role of endothelium and nitric oxide pathway on SDXs veno-contractile effect on human saphenous veins. The remnants of great saphenous vein (GSV) segments (n = 14) were harvested during coronary artery bypass graft surgery. They were dissected as endothelium-intact (n = 8) and denuded rings (n = 6). First, a viability test was carried out in bath with Krebs-Henseleit solution to investigate a control and basal tension value. After this, cumulative doses of SDX were applied to rings and contraction values were studied in endothelium-intact phenylephrine (PheE, 6 × 10-7 M) pre-contracted vein rings. Finally, endothelium-intact PheE pre-contacted vein rings were treated by nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 10-4 M) for 10 min. Contraction protocol was applied, and contraction values were measured in cumulative doses of SDX. The same protocol was applied to endothelium-denuded vein rings to investigate the effect of SDX. Saphenous vein rings showed an increase in contraction to cumulative doses of SDX. In endothel-intact rings, KCL-induced contraction from 92.6% ± 0.3 to 112.9% ± 0.4 with cumulative SDX doses. However, SDX did not show any veno-contractile effect on endothel-denuded rings. In denuded rings contraction responses measured from 94.9% ± 0.3 to 85.2% ± 0.3 with increasing doses of SDX, indicating no significant change. Nitric oxide synthase inhibitor (L-NAME) prohibited the contraction response of the sulodexide in all dosages, indicating that the contractile function of SDX was mediated by endothelial derived nitric oxide. Results of endothel-intact and denuded rings with L-NAME showed a similar incline with denuded rings with SDX only. The results confirmed SDXs veno-contractile effect in human samples, by means of nitric oxide synthase pathways involvement.

Diabetic retinopathy (DR) is a disease that irrevocably leads to blindness, especially in the absence of proper monitoring and treatment. World statistics on its prevalence are not comforting. This pathology has always demanded and will continue to demand high attention from endocrinologists and ophthalmologists. In search of competent patient management, we have studied scientific papers on various treatment approaches with proven positive research results. We decided to analyze the drug Sulodexide, since in many studies it has proven to be a safe and effective direct anticoagulant with minimal side effects. As it turned out, Sulodexide is effective not only in relation to DR, but also in other pathologies of the fundus, which is described in this article.

Severe acute respiratory syndrome coronavirus-2 causes hyperinflammation and activation of coagulation cascade and, as a result, aggravates endothelial cell dysfunction. N-acetylcysteine and Sulodexide have been found to mitigate endothelial damage. The influence on coronary artery endothelial cells of serum collected after 4 ± 1 months from coronavirus infection was studied. The concentrations of serum samples of interleukin 6, von Willebrand Factor, tissue Plasminogen Activator, and Plasminogen Activator Inhibitor-1 were studied. The cultures with serum of patients after coronavirus infection were incubated with N-acetylcysteine and Sulodexide to estimate their potential protective role. The blood inflammatory parameters were increased in the group of cultures incubated with serum from patients after coronavirus infection. Supplementation of the serum from patients after coronavirus infection with N-acetylcysteine or Sulodexide reduced the synthesis of interleukin 6 and von Willebrand Factor. No changes in the synthesis of tissue Plasminogen Activator were observed. N-acetylcysteine reduced the synthesis of Plasminogen Activator Inhibitor-1. N-acetylcysteine and Sulodexide increased the tPA/PAI-1 ratio. N-acetylcysteine may have a role in reducing the myocardial injury occurring in the post-COVID-19 syndrome. Sulodexide can also play a protective role in post-COVID-19 patients.

Background: Degradation of the endothelial glycocalyx is critical for sepsisassociated lung injury and pulmonary vascular permeability. We investigated whether sulodexide, a precursor for the synthesis of glycosaminoglycans, plays a biological role in glycocalyx remodeling and improves endothelial barrier dysfunction in sepsis. Methods: The number of children with septic shock that were admitted to the PICU at Children's Hospital of Fudan University who enrolled in the study was 28. On days one and three after enrollment, venous blood samples were collected, and heparan sulfate, and syndecan-1 (SDC1) were assayed in the plasma. We established a cell model of glycocalyx shedding by heparinase III and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Sulodexide was administrated to prevent endothelial glycocalyx damage. Endothelial barrier function and expression of endothelialrelated proteins were determined using permeability, western blot and immunofluorescent staining. The survival rate, histopathology evaluation of lungs and wet-to-dry lung weight ratio were also evaluated. Results: We found that circulating SDC1 levels were persistently upregulated in the non-alive group on days 1 and 3 and were positively correlated with IL-6 levels. Receiver operating characteristic curve analysis showed that SDC1 could distinguish patients with mortality. We showed that SDC1-shedding caused endothelial permeability in the presence of heparinase III and sepsis conditions. Mechanistically, sulodexide (30 LSU/mL) administration markedly inhibited SDC1 shedding and prevented endothelial permeability with zonula occludens-1 (ZO-1) upregulation via NF-kB/ZO-1 pathway. In mice with LPS and CLP-induced sepsis, sulodexide (40 mg/kg) administration decreased the plasma levels of SDC1 and increased survival rate. Additionally, sulodexide alleviated lung injury and restored endothelial glycocalyx damage. Conlusions: In conclusion, our data suggest that SDC1 predicts prognosis in children with septic shock and sulodexide may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Introduction Endothelial dysfunction is frequent in patients treated with peritoneal dialysis and may lead to cardiac complications. We evaluated the effect of effluent dialysates and serum on the function of coronary artery endothelial cells (CAEC). Methods Human CAEC in in vitro culture were exposed to serum and dialysates from 24 patients treated with continuous ambulatory peritoneal dialysis (CAPD) and secretion of interleukin-6 (IL6), von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured. Modulation of the secretory activity of CAEC by Sulodexide, mixture of glycosaminoglycans: heparin sulfate and dermatan sulfate, was studied. Results Serum from CAPD patients stimulated synthesis of IL6 (+93%), vWF (+18%), and PAI-1 (+20%) and did not change t-PA secretion in CAEC. Dialysates stimulated secretion of IL6 (+89%), vWF (+29%), and PAI-1 (+31%) and did not change t-PA synthesis. Dialysates collected in 12 patients after 6 months more strongly stimulated synthesis of IL6 (+37%) and PAI-1 (+7%). Sulodexide suppressed the secretory activity of CAEC stimulated by the studied sera: IL6 (–38%), vWF (–19%), t-PA (–13%), and PAI-1 (–12%). Conclusions Serum and the dialysate from CAPD patients induce inflammatory and prothrombotic reaction in coronary arterial endothelial cells. The general pattern of the observed effects for serum and dialysates was similar but the intensity of the effects was not identical. Sulodexide reduced these effects.

Background: The glomerular endothelial glycocalyx is degraded during inflammation. The glycocalyx plays a pivotal role in endothelial function and is involved in many processes including binding of chemokines and cytokines, leukocyte trafficking, and preventing proteinuria. HS-based therapeutics are a promising novel class of anti-inflammatory drugs to restore a compromised endothelial glycocalyx under inflammatory conditions. Recently, we demonstrated that treatment with HS extracted from unstimulated glomerular endothelial glycocalyx (unstimulated HSglx) reduced albuminuria during anti-GBM induced glomerulonephritis. Since endothelial HS domains are distinct in unstimulated versus inflammatory conditions, we hypothesized that 1) unstimulated HSglx, 2) LPS-stimulated HSglx, 3) the HS-mimetic fucoidan and 4) the glycosaminoglycan preparation sulodexide, which is a mixture of low molecular weight heparin and dermatan sulfate, might have different beneficial effects in experimental glomerulonephritis.Methods: The effect of unstimulated HSglx, LPS HSglx, Laminaria japonica fucoidan, or sulodexide on experimental glomerulonephritis was tested in LPS-induced glomerulonephritis in mice. Analyses included urinary albumin creatinine measurement, cytokine expression in plasma and renal cortex, and renal influx of immune cells determined by flow cytometry and immunofluorescence staining. Furthermore, the observed in vivo effects were evaluated in cultured glomerular endothelial cells and peripheral blood mononuclear cells by measuring cytokine and ICAM-1 expression levels. The ability of the compounds to inhibit heparanase activity was assessed in a heparanase activity assay.Results: Treatment of mice with LPS HSglx or sulodexide near-significantly attenuated LPS-induced proteinuria. All treatments reduced plasma MCP-1 levels, whereas only fucoidan reduced IL-6 and IL-10 plasma levels. Moreover, all treatments reversed cortical ICAM-1 mRNA expression and both fucoidan and sulodexide reversed cortical IL-6 and nephrin mRNA expression. Sulodexide decreased renal influx of CD45+ immune cells whereas renal influx of macrophages and granulocytes remained unaltered for all treatments. Although all compounds inhibited HPSE activity, fucoidan and sulodexide were the most potent inhibitors. Notably, fucoidan and sulodexide decreased LPS-induced mRNA expression of ICAM-1 and IL-6 by cultured glomerular endothelial cells.Conclusion: Our data show a potentially protective effect of glycosaminoglycans and fucoidan in experimental glomerulonephritis. Future research should be aimed at the further identification of defined HS structures that have therapeutic potential in the treatment of glomerular diseases.

Sulodexide is a heparinoid compound with wide-ranging pharmacological activities. However, the effect of sulodexide on liver fibrogenesis has not been reported. In this study, we aim to evaluate the therapeutic potential of sulodexide in mouse model of liver fibrosis and explore the underlying antifibrotic mechanisms. We found that sulodexide treatment significantly attenuated thioacetamide (TAA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis in mice. Transcriptome analysis revealed that sulodexide treatment downregulated fibrosis-related genes and liver sinusoidal endothelial cells (LSECs) capillarization-associated genes in fibrotic livers. Immunohistochemistry confirmed that the increased expression of LSEC capillarization-related genes (CD34, CD31 and Laminin) in liver fibrotic tissues was reduced by sulodexide treatment. Scanning electron microscopy showed that LSECs fenestrations were preserved upon sulodexide treatment. Quantitative real-time PCR and immunofluorescence demonstrated that the expression of mesenchymal markers was downregulated by sulodexide administration, suggesting sulodexide inhibited endothelial-mesenchymal transition of LSECs during liver fibrosis. Furthermore, sulodexide administration protected primary LSECs from endothelial dysfunction in vitro. In conclusion, sulodexide attenuated liver fibrosis in mice by restoration of differentiated LSECs, indicating that sulodexide treatment may present as a potential therapy for patients with liver fibrosis.

Introduction: Chronic venous insufficiency (CVI) is a widespread and serious social problem. The pathogenesis of the disease is multifactorial and one of the important factors in its development is inflammation. Aim: Assessment of the concentration of selected acute phase proteins: C-reactive protein (CRP) and a1 antitrypsin (AAT) in the blood serum of patients with CVI before and after treatment with Sulodexide. Material and methods: The study was carried out in 88 people, including 39 clinically healthy subjects as the reference group and 49 patients with CVI at various stages of the disease. The concentrations of CRP and AAT were determined. Results: The concentration of CRP in patients before the use of Sulodexide, compared to the results in the reference group, was statistically significantly higher. The concentration decreased significantly after the applied treatment. AAT concentration was significantly (p < 0.05) higher in the group of patients compared to the reference group. After treatment with Sulodexide, AAT concentration decreased in all study groups, which was statistically significant compared to the reference group. Conclusions: Elevated levels of acute phase proteins: CRP and AAT in patients indicate the participation of the inflammatory component in the pathogenesis of CVI. Monitoring levels of acute phase protein, especially AAT, may be useful in tracking the course of the disease, the body's response to treatment, and in making prognosis. Sulodexide, which acts mainly as an anticoagulant and profibrinolytic, also has an anti-inflammatory effect, which may contribute to the inhibition of the development of subsequent stages of CVI. [ABSTRACT FROM AUTHOR]

Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated with highly concentrated glucose solution (HG, 25 mM D-glucose) +/− sulodexide (50/5/0.5 μg/mL) or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/− sulodexide for two hours. Endothelium-dependent and endothelium-independent vasodilatation were measured by videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory, inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent responses were not affected. In the HG group, ROS formation was markedly increased in the vascular wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction. Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia-induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression. [ABSTRACT FROM AUTHOR]

Objective: Post-thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis. Elastic compression (ECS) is the common pillar for PTS prevention and treatment, while the pharmacological approach for PTS includes direct oral anticoagulants (DOACs) and venoactive drugs (VADs) for prevention and treatment, respectively. Sulodexide can be used both in long-term prevention and in the treatment of PTS. To better understand the efficacy of the main drugs used in the prevention (sulodexide or DOACs) and treatment of PTS (sulodexide or VADs), pairwise meta-analyses of observational studies and RCTs were conducted. Materials and methods: A literature search in MEDLINE, Embase, and Cochrane Library for observational studies and RCTs was performed. Incidence of PTS, reduction in PTS signs or symptoms and proportion of patients with complete venous ulcers healing were the primary outcomes for prevention and treatment of PTS, respectively. Fixed and Random effect model meta-analyses were performed. Heterogeneity and publication bias were assessed. R® software was used for the analysis. Results: 893 articles were identified during the search. 8 observational studies (6 for DOACs and 2 for sulodexide) and 2 RCTs for sulodexide, out of the 11 studies included in the qualitative synthesis, were included for the prevention and treatment of PTS, respectively. Meta-analyses of observational studies showed an overall incidence of PTS of 15% (95% CI, 11-19) for sulodexide, and a 50% reduction of PTS signs and/or symptoms for rivaroxaban compared to warfarin (OR, 0.50; 95% CI, 0.38-0.65). The overall estimate of the two sulodexide RCTs showed a significant improvement in complete ulcer healing, with an OR of 2.32 (95% CI, 1.49-3.63). Conclusions: In prevention of PTS, sulodexide and rivaroxaban showed a low incidence and reduced risk of PTS respectively, while in PTS treatment, sulodexide was significantly effective in the complete ulcers healing. These results confirm the need to move from the traditional single-pillar approach with elastic compression stockings to a more effective multi-pillar approach, tailoring the treatment to each individual patient. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is frequent in patients treated with peritoneal dialysis and may lead to cardiac complications. We evaluated the effect of effluent dialysates and serum on the function of coronary artery endothelial cells (CAEC). Human CAEC in in vitro culture were exposed to serum and dialysates from 24 patients treated with continuous ambulatory peritoneal dialysis (CAPD) and secretion of interleukin-6 (IL6), von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured. Modulation of the secretory activity of CAEC by Sulodexide, mixture of glycosaminoglycans: heparin sulfate and dermatan sulfate, was studied. Serum from CAPD patients stimulated synthesis of IL6 (+93%), vWF (+18%), and PAI-1 (+20%) and did not change t-PA secretion in CAEC. Dialysates stimulated secretion of IL6 (+89%), vWF (+29%), and PAI-1 (+31%) and did not change t-PA synthesis. Dialysates collected in 12 patients after 6 months more strongly stimulated synthesis of IL6 (+37%) and PAI-1 (+7%). Sulodexide suppressed the secretory activity of CAEC stimulated by the studied sera: IL6 (–38%), vWF (–19%), t-PA (–13%), and PAI-1 (–12%). Serum and the dialysate from CAPD patients induce inflammatory and prothrombotic reaction in coronary arterial endothelial cells. The general pattern of the observed effects for serum and dialysates was similar but the intensity of the effects was not identical. Sulodexide reduced these effects. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effects of different doses and routes of Sulodexide on leukocyte-endothelium interaction and tissue perfusion in a model of venous hypertension and low blood flow. Methods: Six weeks after venous hypertension induction, through external iliac vein ligature male hamsters (Mesocricetus auratus) received Sulodexide at 1, 2, or 4 mg/kg/day or saline (placebo) by subcutaneous or intramuscular routes during 2 or 4 weeks. After treatments, leukocyte rolling and adhesion, functional capillary density (FCD), and venular diameter were evaluated on the affected hindlimb. Results: Subcutaneous and intramuscular treatments with Sulodexide after 2 and 4 weeks, significantly reduced leukocyte rolling and adhesion and increased FCD. Sulodexide did not affect venular diameter and intramuscular treatment was more effective in reducing leukocyte adhesion than the subcutaneous one. Conclusion: This preliminary study demonstrated that Sulodexide significantly decreased leukocyte-endothelium interaction and improved tissue perfusion in hamsters subjected to venous hypertension and low blood flow. [ABSTRACT FROM AUTHOR]

• 2D-LC-MS was firstly applied to analyze Sulodexide, a mixture of polysaccharides. • A novel in-source acid-induced MS was developed for online polysaccharide analysis. • Three components were observed and identified from Sulodexide. • The three components in Sulodexide were collected and analyzed offline. • The three components in Sulodexide were confirmed as HS-like, HP-like and DS. Sulodexide, a heparinoid medicine, is wildly used in clinic for prophylaxis and treatment of thromboembolic diseases and diabetic nephropathy. Despite its widespread use, the structure of Sulodexide remains poorly understood. It consists of various polysaccharides characterized by differing sugar compositions, linkages, and sulfonation patterns, yet they share common features such as strong hydrophilicity, high native charges, and considerable polydispersity, posing significant challenges for conventional chromatographic and online mass spectrometry (MS) characterization. In this work, a novel analytical method combining multiple-heart cut 2D-LC and in-source acid-induced dissociation (inAID) MS was developed. Three polysaccharides in Sulodexide were separated by high efficient strong-anion-exchange chromatography, followed by desalting with the second dimensional size-exclusion chromatography before MS. A novel MS strategy employing inAID technique was utilized for online analysis, leading to the initial identification of Sulodexide polysaccharide components. The results were validated through disaccharide composition analysis of those three polysaccharide components after offline preparation. This advanced strategy, merging various techniques, enable a comprehensive structural elucidation of such complex drugs and provides a viable tool for potential routine analysis of complex biomolecules. [ABSTRACT FROM AUTHOR]

The article presents an overview of publications describing the mechanisms of the development of the pathological process in patients infected with SARS-CoV-2 coronavirus. The authors analysed publications showing that damage to the endothelium and endothelial glycocalyx is the main factor influencing the development of coronavirus COVID-19 infection. It is the endothelium inflammation caused by a virus that leads to the dysfunction of the vascular system and the development of coagulopathy. Using scanning electron microscopy and flow cytofluorimetry, we showed that patients with COVID-19 of moderate severity (CT2) had significant desquamation of endothelial cells (concentration of circulating endothelial cells (CEC) in blood is 300-400 cells/ml whereas the normal range is no more than 10 cells/ ml). Such desquamation should cause exposure of the pro-inflammatory and thrombogenic subendothelial matrix, which, as a results, leads to the development of thrombotic disorders of the circulatory system. Therefore, it is only natural to try to counteract disease progression by protecting the endothelial glycocalyx from damage. Sulodexide, a mixture of fast-moving heparin fraction (80%) and the glycocalyx element dermatan sulfate (20%) obtained from the mucous membrane of the small intestine of pigs, is very promising in this regard. This drug can significantly reduce the inflammatory process, protect the glycocalyx and endothelium from damage, resulting in lowering the degree of thrombus formation in patients with coronavirus COVID-19 infection, which relieves the course of the disease and improves its outcome. The experimental data presented in the review, although obtained in not large enough population of patients, allow us to consider sulodexide a promising drug that protects the endothelium and suppresses thrombosis in COVID-19.

Sulodexide (SDX), a purified glycosaminoglycan mixture used to treat vascular diseases, has been reported to exert endothelial protective effects against ischemic injury. However, the mechanisms underlying these effects remain to be fully elucidated. The emerging evidence indicated that a relatively high intracellular concentration of reduced glutathione (GSH) and a maintenance of the redox environment participate in the endothelial cell survival during ischemia. Therefore, the aim of the present study was to examine the hypothesis that SDX alleviates oxygen–glucose deprivation (OGD)-induced human umbilical endothelial cells' (HUVECs) injury, which serves as the in vitro model of ischemia, by affecting the redox state of the GSH: glutathione disulfide (GSSG) pool. The cellular GSH, GSSG and total glutathione (tGSH) concentrations were measured by colorimetric method and the redox potential (ΔEh) of the GSSG/2GSH couple was calculated, using the Nernst equation. Furthermore, the levels of the glutamate–cysteine ligase catalytic subunit (GCLc) and the glutathione synthetase (GSS) proteins, a key enzyme for de novo GSH synthesis, were determined using enzyme-linked immunoassay (ELISA). We demonstrated that the SDX treatment in OGD conditions significantly elevated the intracellular GSH, enhanced the GSH:GSSG ratio, shifting the redox potential to a more pro-reducing status. Furthermore, SDX increased the levels of both GCLc and GSS. The results show that SDX protects the human endothelial cells against ischemic stress by affecting the GSH levels and cellular redox state. These changes suggest that the reduction in the ischemia-induced vascular endothelial cell injury through repressing apoptosis and oxidative stress associated with SDX treatment may be due to an increase in GSH synthesis and modulation of the GSH redox system. [ABSTRACT FROM AUTHOR]

Objective: Inflammation and endothelial dysfunction are important venous changes in patients with chronic venous disease (CVD). The use of the venoactive drugs remains an important treatment modality for patients with CVD, reducing the severity of the CVD-related symptoms and swelling but also reducing inflammation and protecting endothelial cells. In this research, the effects of the serum obtained from patients with CVD before and after sulodexide treatment were evaluated for in vivo and in vitro inflammatory markers and endothelial cell function., Methods: Inflammatory markers (IL-6, matrix metalloproteinase-9 [MMP-9], vascular cell adhesion molecule-1 [VCAM-1], and von Willebrand factor [vWF]) from the incompetent great saphenous veins (GSVs) and from the systemic venous circulation were studied in 10 patients with CVD (C2s) before and after 2 months of sulodexide (2 × 500 lipasemic units/d) therapy. Serum obtained from the vein blood before and after sulodexide treatment was evaluated for in vitro cultured human umbilical vein endothelial cell function., Results: The serum collected from lower leg incompetent GSVs had significantly elevated levels of VCAM-1 (+29%, P < .001) compared with the serum from the systemic circulation. Endothelial cells exposed to the serum from the incompetent lower leg veins of the untreated CVD patients demonstrated higher stimulated synthesis of MMP-9 (+17%, P < .01), as well as increased markers of senescence (prolongation of population doubling time, β-galactosidase activity, and expression of p21 and p53 genes). CVD serum-induced senescent endothelial cells had a higher expression of genes regulating IL-6, MMP-9, VCAM-1, and vWF synthesis. The overall proinflammatory effect on endothelial cells by the serum collected from the incompetent GSVs was stronger as compared with the serum from the systemic circulation. Serum collected from the veins after sulodexide treatment caused lower levels of endothelial cell inflammatory markers as well as respective gene expression than serum obtained at the beginning of the study (before sulodexide treatment). Sulodexide application also reduced the inflammatory secretory activity of the senescent endothelial cells. Sulodexide treatment resulted in the decrease of the majority of the studied inflammatory parameters in both lower limb incompetent vein and systemic blood., Conclusions: In patients with CVD, there are significant differences between circulating inflammatory markers analyzed from the lower leg incompetent GSV segments compared with the systemic circulation, indicating a higher inflammatory condition in CVD. Treatment with sulodexide reduces the proinflammatory and endothelial cell activation properties of the serum from patients with CVD., Clinical Relevance: The study documented the significant proinflammatory human vascular endothelial cell activation when exposed to the serum collected from the varicose veins as compared with the serum from the systemic circulation in patients with chronic venous disease (CVD). The inflammatory marker expression, endothelial dysfunction, and endothelial cell senescence transformation can be successfully controlled and downregulated by patients' exposure to the glycosaminoglycan (sulodexide) treatment. Further studies are needed to confirm if glycosaminoglycan application can prevent further CVD clinical progression due to potential CVD-related pathological processes' modulation and their downregulation., Competing Interests: Disclosures A.Z. received funds for educative lectures supported by AlfaSigma Company. K.S.-J. is an employee of AlfaSigma Poland. R.A.K. was partly supported by a grant from the National Heart, Lung, and Blood Institute, United States (HL147889-01A1). T.U. has been paid a consulting fee by AlfaSigma Company and is on their speakers’ bureau. The remaining authors report no conflicts., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Endothelial dysfunction is a valued part in the pathogenesis of many diseases and conditions including the active phase of COVID-19 and postcovid syndrome. The review presents both the viral and autoimmune pathways for endothelial and glycocalyx lesions and the clinical impacts of such a lesion in comorbid patients. Both endothelium and glycocalyx affected by the SARS-CoV-2 virus are considered as the main goal for therapy in outpatient patients and patients with postcovid syndrome. The glycosaminoglycans belonged natural components of vascular wall seem appropriate pathogenetically in order to recovery the endothelial barrier. The review demonstrates the advantages and limitations of using sulodexide in patients with COVID-19. This article presents a clinical case of a patient with confirmed COVID-19 of moderate severity, with the presence of risk factors for thrombosis, who developed a post-covid syndrome, a heterogeneous symptom complex that developed after the acute phase of COVID-19 infection. The post-covid period was marked by symptoms of rapid fatigue, tachycardia, shortness of breath. By day 25-26, itching and red rash appeared, and there was moderate swelling of the shins and feet of both lower extremities. Taking into account the clinical picture and laboratory findings, a decision was made to cancel the previously prescribed low-molecularweight heparin and prescribe sulodexide at a dose of 500 LU 2 times a day for a course of 28 days. On the 4th-5th day after the start of treatment there was a decrease in the area of skin rash, cessation of itching, almost complete disappearance of the cutaneous vascular pattern and reduction in the severity of edema. This clinical case demonstrates endothelial damage caused by COVID-19, which makes it advisable to use angioprotective drugs.

Obstructive jaundice is a complex pathology that significantly complicates surgical interventions and is accompanied by a number of negative consequences. In connection with the danger of obstructive jaundice, it is very important to timely identify the severity of this condition and take appropriate measures to treat the patient. To date, methods for predicting the risk of postoperative complications in obstructive jaundice are being actively developed, and methods for treating this pathology are being developed. In this study, we studied the biochemical parameters of the functional state of the liver of dogs with simulated obstructive jaundice with different treatment regimens. 3 experimental groups were formed. Control dogs received no treatment. The dogs of the second group underwent decompression of the biliary tract without control of the rate of bile outflow. In animals of the third group, decompression of the biliary tract was carried out and the rate of bile outflow was controlled. As therapy, dogs of this experimental group received Cytoflavin (0.28 ml / kg body weight) and sulodexide (1 ml / kg body weight) under conditions of moderate hypothermia. All animals underwent laparotomy with puncture of the gallbladder and subsequent introduction of a catheter through the cystic duct into the common bile duct. Blood from the portal vein and lymph from the main lymphatic were taken for the analysis of the following biochemical parameters: direct bilirubin, C-reactive protein, alanine aminotransferase, gammaglutamyl transferase and glucose. The concentration of the listed indicators of the functional state of the liver was assessed at different times after the simulation of obstructive jaundice. The results of the study showed that in dogs of all groups, one day after modeling obstructive jaundice, biochemical parameters significantly increase both in the blood of the portal vein and in the lymph of the thoracic lymphatic duct, which is associated with a violation of the functional state of the liver. In animals in which the rate of bile outflow was not controlled, biochemical parameters remained at a high level, which reflected the development of liver failure and reperfusion syndrome. After administration of cytoflavin and sulodexide in moderate hypothermia, dogs showed a decrease in the concentration of biochemical parameters to the control level, which characterizes the normalization of the functional state of the liver. In general, the proposed treatment regimen has shown high efficiency and can be used to correct post-decompression liver dysfunction in dogs with obstructive jaundice. The results of the study are valuable for the development of methods for treating patients with obstructive jaundice and preventing the development of postoperative complications. This article can be informative for specialists in the field of surgery and anesthesiology who are involved in the correction of postoperative complications in patients with obstructive jaundice.

Introduction. The problem of care for patients with trophic venous ulcers remains an urgent medical and social problem, which has been aggravated again against the background of the COVID-19 pandemic in 2020-2021. As is now known, after a COVID-19 viral infection, most patients with cardiovascular diseases experience a significant exacerbation of these ailments. This is also true for postthrombotic lower extremity disease (PTD). Many patients with edematous or edematous-painful forms of PTB after COVID-19-associated pneumonia experience formation of trophic ulcers of the distal parts of the lower extremities.Aim. To study characteristic features of the course of ulcerative process in PTB in patients after COVID-19-associated pneumonia and to search safe and effective means, accelerating wound epithelialization in such patients.Material and methods. Efficiency of sulodexide use in conservative therapy of 16 patients with PTB, in whom trophic defects (venous ulcers) of the lower third of the shin and foot first appeared after pneumonia due to SARS-CoV-2 infection, was evaluated. At the same time, trophic ulcers were highly resistant to conventional therapy aimed at their healing. All 16 patients were unable to achieve epithelialization more than one month after the occurrence of trophic ulcers. Results. According to the results of this study it was found that the use of sulodexide as an angiotropic agent having, among other things, anti-inflammatory effect on the vessel wall in patients with trophic ulcers formed after COVID-19-associated pneumonia is justified.Conclusions. The treatment of trophic defects of the lower limbs in patients with PTB after COVID-19-associated pneumonia has a number of regular features. Sulodexide showed high efficacy as an angiotropic agent, whose pharmacological properties are adequate to the pathogenesis of trophic ulcers taking into account the course of infection caused by SARS-CoV-2.

Raynaud's phenomenon is a painful vascular condition in which abnormal vasoconstriction of the digital arteries causes blanching of the skin. The treatment approach can vary depending on the underlying cause of disease. Raynaud's phenomenon can present as a primary symptom, in which there is no evidence of underlying disease, or secondary to a range of medical conditions or therapies. Systemic sclerosis is one of the most frequent causes of secondary Raynaud's phenomenon; its appearance may occur long before other signs and symptoms. Timely, accurate identification of secondary Raynaud's phenomenon may accelerate a final diagnosis and positively alter prognosis. Capillaroscopy is fundamental in the diagnosis and differentiation of primary and secondary Raynaud's phenomenon. It is helpful in the very early stages of systemic sclerosis, along with its role in disease monitoring. An extensive range of pharmacotherapies with various routes of administration are available for Raynaud's phenomenon but a standardized therapeutic plan is still lacking. This review provides insight into recent advances in the understanding of Raynaud's phenomenon pathophysiology, diagnostic methods, and treatment approaches. [ABSTRACT FROM AUTHOR]

Background. Despite the fact that COVID-19 usually manifests with severe pneumonia, there is a growing body of evidence that life-threatening multiorgan damage is caused by vascular and hemostatic abnormalities. Since there is no established therapy, assessing antithrombotics is indeed important. Sulodexide, a compound derived from porcine intestinal mucosa is a mixture of fast-moving heparin fraction (80%) and dermatan sulfate (20%), is approved in Europe and currently in trials for COVID-19 indication. Methods. This single-center, prospective, observational study included 28 patients with mild COVID-19 hospitalized in the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Patients in the control group (n = 14) were treated using routine therapy according to current guidelines, while patients in the experimental group (n = 14) had the routine treatment supplemented with daily intravenous injections of sulodexide in 600-unit doses. Scanning electron microscopy was utilized to examine the blood specimens derived from the cubital vein at admission and at 10 days after hospitalization, which was approximately the average duration of patients' treatment in the hospital (11.6 ± 0.4 days). Results. Sulodexide significantly (by 40%) diminished the score of circulating endothelial cells, potentially indicating its antiviral endothelium-protective properties. It also prevented the extra activation of the platelets and the formation of erythrocytic sludges. Among patients in the control group, the share of activated platelets rose from 37 ± 5% to 45 ± 6% (p = 0.04) over the course of the study period, whereas among patients in the experimental group, the share of activated platelets remained practically unchanged (43 ± 6% vs. 38 ± 4%, p = 0.22). The score of erythrocytic sludges in the control group remained practically the same (4.8 ± 1.1 at admission vs. 3.9 ± 0.9 after 10 days, p = 0.67), whereas in the experimental group, it significantly decreased (from 5.7 ± 1.7 to 2.4 ± 0.9, p = 0.03). Conclusions. Sulodexide is able to defend endothelium, normalize blood, and, seemingly, prevent thrombosis. Therefore, it may be considered as a promising and effective agent for the treatment of patients with mild COVID-19. Broader randomized trials are needed to assess whether the observed findings will transform into sustained long-term clinical benefit. [ABSTRACT FROM AUTHOR]

Since the beginning of the COVID-19 pandemic, there has been an urgent need to find effective treatment. It is widely known that virus attacks and damages mostly the lungs, but also infect vascular endothelial cells. Therefore, the protection of the endothelium is a promising target in the therapy of COVID-19 and its complications. In this review article, we focused on several groups of drugs with potential to protect the endothelium. The most promising ones are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, drugs targeting angiotensin-converting enzyme 2, heparins, sulodexide, acetylsalicylic acid, statins, tocilizumab, baricitinib, and defibrotide. Although the short period of trials and the lack of data necessitate further research, endothelial protection remains a promising target for COVID-19 therapy. [ABSTRACT FROM AUTHOR]

Low attention has generally been dedicated to the influence of clinical presentation, extent of venous thrombosis and presence of residual vein obstruction (RVO) on the decision about the duration of secondary prophylaxis after a first venous thromboembolism (VTE). This study aimed at investigating the role of the mentioned VTE characteristics on the therapeutic decision using the information collected in the international, prospective, observational WHITE study. 1240 patients were recruited by 79 clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). 35 patients had as index event a pulmonary embolism (PE) without a deep vein thrombosis (DVT), and all continued anticoagulation. We focused on the 1205 subjects with DVT. The treatment decision differed among countries; altogether, more than 85% of patients with proximal (with or without distal) DVT continued a prophylactic treatment with anticoagulants, or antithrombotics; 34% of patients with isolated distal DVT stopped treatment, and more than 85% of patients with a PE associated to a DVT continued treatment. At multivariable analysis, the presence of proximal DVT, signs of post-thrombotic syndrome (PTS), residual vein obstruction (RVO), maintenance <180 days and concomitant diseases was associated with increased probability to continue secondary prophylaxis. The presentation as proximal DVT (with or without PE) or isolated PE influenced the treating physicians' decision in favor of extension of secondary prophylaxis, together with the presence of concomitant diseases and local conditions which may increase the risk of post-thrombotic syndrome. • Optimal duration of treatment after venous thromboembolism remains uncertain. • The role of the nature (unprovoked or provoked) of the events is still debated. • We assessed the physicians' decision in seven countries with important differences. • Secondary prophylaxis was preferred in cases guessed at high risk for recurrences. • Higher risk was attributed to proximal DVT, residual thrombi, concomitant diseases. [ABSTRACT FROM AUTHOR]

Background. The adverse impact of chronic hyperglycaemia on vascular wall in diabetes mellitus includes endothelial dysfunction with subsequent development of diabetic microangiopathy. Microangiopathy can be corrected via adequate glycaemic control for establishing a target level of glycated haemoglobin. Considering a multiplex nature of metabolic and vascular regulation, a comprehensive approach is required for simultaneous correction of rheological disorders, hypercoagulation and endothelial dysfunction.Objectives. Estimation of vascular factors (von Willebrand factor, desquamated endothelium, antithrombin III, protein C, VEGF) and capillaroscopic patterns in therapy for type 1 diabetes with methylethylpyridinol in comparison with sulodexide.Methods. A total of 89 patients with type 1 diabetes were examined and separated by two cohorts: 42 patients receiving sulodexide (cohort 1) and 47 patients receiving methylethylpyridinol (cohort 2). Therapy duration was 14 days. Both cohorts were estimated pre- and post-treatment endothelial conditions (activity of von Willebrand factor, VEGF, desquamated endothelial cell count), anticoagulant indicators (activity of antithrombin III, protein C) and had capillaroscopy with functional test and oximetry.Results. Diabetes patients in pre-treatment exhibited signs of endothelial dysfunction, reduced blood anticoagulant protection and capillary constriction. Both cohorts in post-treatment showed the significantly reduced von Willebrand factor, VEGF activity and desquamated endothelial cell count. The anticoagulant system revealed positive dynamics; capillaroscopy reported limiting of the capillary transition zonal diameter and a certain improvement in functional performance.Conclusion. Patients with type 1 diabetes were revealed with endothelial dysfunction and an increased blood procoagulant activity. Both sulodexide and methylethylpyridinol treatments improved endothelial dysfunction and anticoagulant blood protection. Both preparations can be used for complex microangiopathy correction in patients with

ObjectiveNon-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19.Approach and ResultsWe conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10−3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10−3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57– 0.75], p = 0.001 and AUC = 0.60, CI [0.51– 0.69], p = 0.03, respectively).ConclusionSulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.

The decision on treatment after a first venous thromboembolism (VTE) to prevent recurrences may be influenced by many factors. The prospective, observational, WHITE study aimed to analyze how this issue was tackled in every-day clinical practice in various countries, which have sensibly different socio-economic conditions and healthcare systems. Doctors active in 79 Internal or Vascular clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia) enrolled VTE patients after the maintenance treatment phase. The present report analyzed information, collected in the central database, regarding the baseline characteristics, index events, type and duration of anticoagulant therapy and decision on post-maintenance treatment. From April 2018 to December 2020, 1240 patients were enrolled, 58% with an unprovoked index event. Direct oral anticoagulants (DOACs) were used in > 85% of all cases in China, Poland, Portugal, Russia and Czechia, in 52% in Slovakia and in no patient in Tunisia. The maintenance anticoagulation lasted in average approximately 6 months. Altogether, anticoagulation was stopped in 20%, extended in about 50%, regardless of whether the event was unprovoked or provoked and shifted to antithrombotics (mainly sulodexide or aspirin) in the remaining patients. In conclusion, some differences in VTE patient management were found between countries. The provoked/unprovoked nature of the index event, instead, was not the prevalent criterion to drive the decision on extension of anticoagulation, without large variations between countries. DOACs were the most widely used anticoagulant drugs, whereas > 25% of patients received antithrombotic drugs instead of anticoagulants as extended treatment. [ABSTRACT FROM AUTHOR]

Background. Despite the progress in the diagnostics of microvascular angina (МА) there is no effective pathogenetic therapy.Aim. To study the effect of trimetazidine and sulodexide as a part of drug therapy on clinical manifestations, exercise tolerance, quality of life, myocardial perfusion and endothelial function in patients with MA.Material and methods. Patients with MA (n=90) were included into the study and randomized into 3 groups. Patients of the first group (control; n=30) received standard antianginal therapy. The second group (treatment group; n=30) received standard therapy and sulodexide (1 ampoule of 600 IU intramuscularly for 10 days, then 1 capsule of 250 IU, 2 times a day). Patients of the third group (treatment group; n=30) received standard therapy and trimetazidine with modified release 35 mg 2 times a day. Evaluation of angina symptoms and quality of life by the Seattle Questionnaire, stress (treadmill) test, positron emission tomography (baseline, adenosine test, cold-pressor test), peripheral arterial tonometry were performed at baseline and 3 months after starting treatment.Results. After 3 months of treatment a significant improvement in symptoms, quality of life and results of stress-test were observed only among patients of treatment groups, most pronounced in the 3rd group. Patients of this group showed an increase in myocardial blood flow >25% according to positron emission tomography (from 86.2±29.7 to 129.5±41.0 ml/100g/min, p

The implementation of the reproductive function is one of the main components of women’s quality of life. Despite significant progress in the treatment of infertility and prevention of reproductive losses, these problems are still relevant. It is also important to timely diagnose various pathological processes in order to determine the tactics of preparing women for pregnancy and its further management, taking into account the pathogenetic characteristics of diseases. Various attempts have been made to optimize both diagnostic and therapeutic approaches. Special attention is paid to identifying risk groups and ensuring the most effective preparation for pregnancy, taking into account possible risk factors for adverse outcomes. Adequate diagnostics of background pathology and the use of proven effective methods of pregravid preparation can significantly improve pregnancy outcomes. Peculiarities of the vascular system functioning may affect both the life of the woman in general and the outcome of pregnancy. Endothelial dysfunction is a component of pathogenesis of many nosologies (diabetes mellitus, chronic venous disease, hypertension, autoimmune pathology, etc.). Restoration of vascular endothelial dysfunction and, as a consequence, prevention of probable vascular complications is one of the new goals in the preventive approach to pregnancy. The promising center of this approach is considered to be the drug sulodexide. The three main effects of this drug – antithrombotic, anti-inflammatory and defensive in relation to endothelium – provide a significant increase in pregnancy preparation possibilities in many nosologies. This review presents its main features and areas of use.

Dementia is a syndrome of acquired intellectual deficit resulting in significant impairment of social or occupational functioning. Vascular dementia (VaD) is the second most common causes of dementia after Alzheimer’s disease, causing around 15% of cases. However, unlike Alzheimer’s disease an involvement of the cerebral cholinergic system in the pathophysiology of VaD has been hypothesized and there is no standard treatment. In the Vascular Dementia Italian Sulodexide Study (VA.D.I.S.S.) the positive results obtained with the sulodexide are worthy of note. In this study 40 elderly subjects with recent onset (less than 9 month) slight to moderate mental deterioration due to vascular origin were observed for nine months during oral treatment with sulodexide and choline alphoscerate with the aim of analyzing whether therapeutic effects can be enhanced. These preliminary results suggest that the additional therapy of choline alphoscerate with sulodexide represents a way to increase the beneficial effects of cholinergic therapies in the VaD and improve all the different examinate score: mini mental state evaluation (MMSE), basic activities of daily living (ADL), instrumental activities of daily living (IADL).

Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated with highly concentrated glucose solution (HG, 25 mM D-glucose) +/− sulodexide (50/5/0.5 μg/mL) or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/− sulodexide for two hours. Endothelium-dependent and endothelium-independent vasodilatation were measured by videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory, inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent responses were not affected. In the HG group, ROS formation was markedly increased in the vascular wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction. Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia-induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression.

Objective: To evaluate the efficacy of Sulodexide in treating idiopathic membranous nephropathy (IMN) in the Chinese population., Methods: We systematically reviewed all eligible randomized clinical trials (RCTs) conducted in China that investigated the effects of Sulodexide on IMN. Three RCTs published between 2013 and 2022 were included, encompassing a total of 146 patients. The primary outcomes evaluated were changes in urine total protein (UTP), serum albumin (ALB), cholesterol (CHOL), and fibrinogen (FIB) levels., Results: Statistically significant differences were observed in the Sulodexide treatment group compared to the control group for the following parameters: reduction in UTP and CHOL, increase in ALB, and reduction in FIB levels., Conclusion: Sulodexide, when combined with conventional therapy, effectively reduces UTP and CHOL levels, decreases FIB levels, and increases ALB in Chinese patients with IMN., Competing Interests: None., (AJTR Copyright © 2024.)

A recently published bibliographic analysis supported the usefulness of sulodexide to diminish micro and macroalbuminuria in diabetic nephropathy. This paper discusses the biological effects of sulodexide in reducing diabetic nephropathy, namely: glycocalyx restoration, improvement of endothelial functioning, recovering of heparan sulfate in the glomerular filtration membrane, decreasing of inflammatory mediators and regulation of fibrosis mediators. [ABSTRACT FROM AUTHOR]

Objective. To study the impact of sulodexide on the healing process of trophic ulcers of the mixed genesis in the lower extremities. Materials and methods. Analysis of the medical cards data was done for 105 patients, who in 2015 - 2019 yrs have had treated the trophic ulcers of the mixed genesis of the ankles in Department of Vascular Surgery of the Poltava Regional Clinical Hospital. The causes of development of trophic ulcers were confirmed by data of ultrasonographic color angioscanning of the lower extremities and pelvis with measurement of the ankle-brachial pressure index and arteriography. All the patients did not accepted the proposal for performing of correcting and restoration surgical treatment on the lower extremities vessels. Depending on the treatment prescribed the patients were divided into two groups. Into the Group I (comparative) 53 (50.5%) patients were included, who obtained a casual conservative treatment, directed to improvement of the lower extremities blood supply, as well as the blood rheological properties, which included venotonic, analgesic, antibacterial preparations and local treatment, depending on the wound process stage. Into the Group II (the main) 52 (49.5%) patients were included, who on the background of typical treatment have obtained sulodexide in a dose 600 LU (lipoproteidlipase units) on 200 ml of physiological solution of sodium chloride up to 15 days long with subsequent therapy in the dose of 1 capsule twice a day (500 LU) during up to 60 days. In the Group I there were 32 (60.4%) men and 21 (39.6%) women, and in the Group II – 30 (57.7%) men and 22 (42.3%) women. Average age of patients in the Group I have constituted (65.8 ± 4.38), and in the Group II – (66.2 ± 5.04) yrs old. The pain intensity in accordance to the ten-point numerical rating scale was checked before the treatment beginning, in 7 and 14 - 15 days, the trophic ulcers square was measured, local temperature of the patient’s body, pН-metry and cytological investigations of the wounds exudate were done in all the patients before the treatment. Besides this, 38 (71.7%) patients of the comparison group and 40 (76.9%) patients of the main group were followed during 90 - 120 days after leaving a stationary. Results. In the patients, who have obtained sulodexide additionally, reparative processes in the trophic ulcers regions of the lower extremities have become accelerated, the pain syndrome have been lowered rapidly, the water index normalized, the blood supply improved, the ankle-brachial index enhanced, a local temperature raised, cytological picture of the wound exudate improved, what promoted more rapid healing of ulcers and reduction of the stationary stay duration. During the planned visits of the patients in 90 - 120 days a complete healing of trophic ulcers of the lower extremities in 31 (77.5%) patients of the main group and in 24 (63.2%) patients of the comparison group was proved. Conclusion. Application of sulodexide in the treatment dosage is expedient to include into complex of treatment for trophic ulcers of the mixed origin in the lower extremities.

Background/objectives: Recent data suggest a role for heparanase in several proteinuric conditions. An increased glomerular heparanase expression is associated with loss of heparan sulfate in the glomerular basement membrane (GBM). The aim of the present study was to investigate the renal effects of heparanase inhibition in a diabetic experimental model.

Background/Aims: Thromboembolic episodes are a frequent problem in end stage renal failure patients. The pathomechanism of the disorder is complex, including bioincompatibility of renal replacement therapy, endothelial dysfunction, increased blood level of procoagulant factors and uremic toxins. We studied changes in the functional properties of venous endothelial cells (VEC) in the presence of uremic serum and evaluated their possible modulation by N-acetylcysteine (NAC) or sulodexide (SUL). Methods: Serum samples from 12 uremic patients treated with hemodialysis were studied ex vivo on in vitro cultured VEC. In separate experiments, NAC 1 mmol/L or SUL 0.5 LRU/mL were added to uremic serum samples. Both changes in the gene expression and secretory activity of VEC were studied. Results: Uremic serum increased the expression of the following genes: IL6 +97%, p < 0.002; VEGF +28%, p < 0.002; vWF +47%, p < 0.002; PECAM +76%, p < 0.002; ICAM-1 +275%, p < 0.002; t-PA +96%, p < 0.002. Changes in gene expression were reflected by the increased secretory activity of VEC treated with the uremic serum. Exposure of VEC to uremic serum supplemented with NAC or SUL resulted in weaker stimulation of the studied genes’ expression. Also, secretion of the studied solutes, with the exception of ICAM-1, was reduced in the presence of NAC: IL6 –34%, p < 0.01; VEGF –40%, p < 0.005; vWF –25%, p < 0.001; t-PA –47%, p < 0.01, and MMP9 –37%, p < 0.001. SUL reduced the uremic serum-induced secretion of all solutes: IL6 –24%, p < 0.05; ICAM-1 –43%, p < 0.01; VEGF –38%, p < 0.01; vWF –23%, p < 0.01; t-PA –49%, p < 0.01, and MMP9 –25%, p < 0.05. Conclusions: Uremic serum induces prothrombotic changes in VEC, which may cause a predisposition to thrombotic disorders in patients with renal failure. NAC and SUL reduce the effects of the uremic serum in VEC, which suggests their potential therapeutic application in uremic patients.

Aim of the study. To evaluate the clinical efficacy of sulodexide in the daily dosage of 500 LSU in patients with chronic lower limb vein diseases of clinical classes C1-C3 according to CEAP.Patients and methods. This study included 35 patients with chronic C1-C3 CEAP lower limb vein disease who took 500 LSU of Sulodexide for 90 days. In order to evaluate the effectiveness of the treatment we used: a questionnaire to assess the quality of patient’s life with chronic venous insufficiency CIVIQ 20; visually – analogue scale of pain assessment VAS; clinical scale of venous diseases VCSS severity assessment; measuring the circumference of the limbs on the hip and shin.Results of the study. The study was completed by 32 patients. As a result of the performed treatment the convulsive syndrome in calf muscles completely regressed, though on the first visit it was registered in 22,4% of patients (p = 0,0481), the frequency of complaints about severity and fatigue in the lower limbs at static loads decreased significantly from 28,1% to 9,6% (p = 0,2414). The circumference of the femur in the middle third of the limb decreased from 53.7 cm to 51.1 cm (p

Sulodexide is a highly purified mixture of glycosaminoglycans composed of fast mobility heparin (80%) and dermatan sulfate (20%). Glycosaminoglycans constitute a group of heteropolysaccharides consisting of repeating disaccharide units, which contain amino sugar combined with uronic acid or a hexose. Glycosaminoglycans build glycocalyx covering endothelium of blood vessels, and thus, play an important role in vascular homeostasis. Multi-directional activity of sulodexide including antithrombotic, fibrinolytic, anti-aggregation, anti-inflammatory, anti-proliferative, and anti-oxidative qualities, as well as a high safety profile have allowed using the drug in numerous entities. Advantageous results of sulodexide therapy are observed in diseases involving endothelial damage, prothrombotic or inflammatory states. Thanks to its pleiotropic effects, sulodexide can be also applied in treatment of skin diseases.

Sulodexide (SDX), a purified glycosaminoglycan mixture used to treat vascular diseases, has been reported to exert endothelial protective effects against ischemic injury. However, the mechanisms underlying these effects remain to be fully elucidated. The emerging evidence indicated that a relatively high intracellular concentration of reduced glutathione (GSH) and a maintenance of the redox environment participate in the endothelial cell survival during ischemia. Therefore, the aim of the present study was to examine the hypothesis that SDX alleviates oxygen–glucose deprivation (OGD)-induced human umbilical endothelial cells’ (HUVECs) injury, which serves as the in vitro model of ischemia, by affecting the redox state of the GSH: glutathione disulfide (GSSG) pool. The cellular GSH, GSSG and total glutathione (tGSH) concentrations were measured by colorimetric method and the redox potential (ΔEh) of the GSSG/2GSH couple was calculated, using the Nernst equation. Furthermore, the levels of the glutamate–cysteine ligase catalytic subunit (GCLc) and the glutathione synthetase (GSS) proteins, a key enzyme for de novo GSH synthesis, were determined using enzyme-linked immunoassay (ELISA). We demonstrated that the SDX treatment in OGD conditions significantly elevated the intracellular GSH, enhanced the GSH:GSSG ratio, shifting the redox potential to a more pro-reducing status. Furthermore, SDX increased the levels of both GCLc and GSS. The results show that SDX protects the human endothelial cells against ischemic stress by affecting the GSH levels and cellular redox state. These changes suggest that the reduction in the ischemia-induced vascular endothelial cell injury through repressing apoptosis and oxidative stress associated with SDX treatment may be due to an increase in GSH synthesis and modulation of the GSH redox system.

The article is devoted to the incidence and severity of post-thrombotic syndrome (PTS), the odds ratio (OR) of PTS development in patients with previous proximal deep vein thrombosis (DVT) against the background of prolonged antithrombotic warfarin and sulodexide (SD) therapy (ATT) with due account for safety and development of clinically significant bleeding (CSB) during the year. A total of 130 patients aged 18 to 69 years with acute proximal DVT were enrolled in the comparative prospective study. Group I included 64 patients (31 men and 33 women), who received vitamin K antagonists (warfarin) therapy. Group II included 66 patients (37 men and 29 women), who received sulodexide in 3 months after completing a course of standard ACT (heparins in the acute period with the transition to AVK). The studied parameters included OR, incidence and severity of PTS in patients according to the Villalta scale, and the incidence rate of PTS against the background of prolonged warfarin and sulodexide ATT in 12 months’ time. It was established that the prolonged sulodexide ATT within one year after completing a course of standard ACT in patients with proximal DVT reduced the development of clinical signs of PTS by 22.2% compared to the standard warfarin therapy. At the same time, there is a lower incidence of severe forms of PTS in patients, who underwent proximal venous thrombosis, 17.8% against the background of sulodexide treatment. Thus, the prolonged sulodexide ATT is associated with a 1.7-fold decrease in the risk of the development of both PTS and its severe forms. Therefore, the prolonged use of sulodexide for one year in patients, who underwent proximal DVT, provides an alternative to warfarin and is associated with a lower incidence of PTS, including its severe forms. The prolonged sulodexide ATT is safe and does not cause the development of clinically significant hemorrhagic complications during the year.

BACKGROUND: Although the number of vascular surgeries performed is increasing, the incidence of complications associated with this surgery has not improved and re-operations are frequently required. Thrombosis in a vessel is the most hazardous postoperative complication. OBJECTIVE: The aim of this study was to evaluate the anti-thrombotic and anti-inflammatory effects of sulodexide compared to aspirin in a rat model. METHODS: We divided the animals into three groups (sham (saline), aspirin, and sulodexide). The abdominal aorta was surgically opened and closed, primarily with 8/0 Prolene sutures. Postoperatively, saline, aspirin, or sulodexide was administered by oral gavage for 14 days to the rats. The degree of neovascularization, thrombus, calcification, inflammatory infiltrates, and fibrosis were analyzed histopathologically by hematoxylin and eosin staining. RESULTS: There was no significant difference in the incidence of postoperative thrombogenesis, but less calcification and inflammatory infiltrates were observed in the sulodexide group compared to the aspirin group. Histopathologic score revealed less infiltration of inflammatory cells and mild calcification for the sulodexide group (0.17±0.41 and 1.33±0.52, respectively) compared to the aspirin group (0.67±0.52 and 1.67±0.52, respectively) at days 14. CONCLUSIONS: This study offers the possibility that sulodexide could be used as an aspirin substitute for the postoperative management of vascular patients, with low gastrointestinal discomfort. In addition, it may also offer reduced postoperative calcification and inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Micro- and macrovascular complications of diabetes are leading morbidities in the world population. They are responsible not only for increased mortality but also severe disabilities, which jeopardize quality of life (e.g., blindness, walking limitations, and renal failure requiring dialysis). The new antidiabetic agents (e.g., glucagon-like peptide 1 receptor agonists and sodium–glucose cotransporter inhibitors) are increasingly recognized as breakthrough agents in the treatment of diabetes and prevention of diabetic complications. However, drugs effective in preventing and treating diabetic disabilities are still needed and sulodexide could be one of those able to address the unmet clinical needs of the new antidiabetic agents. Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal. We also manually searched potentially relevant journals, conference proceedings, and journal supplements. Any study monitoring any effect of sulodexide in subjects with diabetes, in relation to renal, vascular, and ocular complication, was considered. Treatment effects were estimated using standardized mean differences (SMDs), mean differences (MDs), and risk ratios (RRs), as appropriate. We calculated 95% confidence interval (CIs) and heterogeneity (Q, tau, and I2). Results: The search found 45 studies with 2817 participants (mean age 57 years; 63% male). The 26 randomized controlled studies included 2074 participants (mean age 58.8 years; 66% male). Sulodexide reduced the impact of diabetic retinopathy; increased the pain-free and maximal walking distance in peripheral arterial disease; accelerated the healing of diabetes-associated trophic ulcers; and decreased the rate of albumin excretion in subjects with nephropathy. The risk of adverse events (AEs) was not different between sulodexide and controls. Conclusion: Sulodexide has a beneficial effect on the ocular, peripheral arterial disease, trophic ulcers, and renal complications of diabetes without increasing the risk of AEs. [ABSTRACT FROM AUTHOR]

The protective effect on the vascular endothelium, downregulation of the inflammatory reaction, inhibition of the metalloproteinase expression and free radical production, as well as several other pluripotential proprieties of glycosaminoglycans open new perspectives in the effective treatment of the venous, arterial and microcirculation diseases. In the paper, an overview of the current knowledge concerning vasoprotective effects of the glycosaminoglycans is discussed, including beneficial effects on the chronic venous disease (CVD) as well as vascular complications of diabetes. According to the laboratory, as well as clinical study results, the biological proprieties as well as clinical efficacy, position currently sulodexide among the venoactive drugs. The clinical efficacy concerning the CVD symptom reduction, leg swelling decrease, as well as venous leg ulcer healing improvement corresponds with the basic science study results and data about the sulodexide influence on the several processes related to the CVD and its complication occurrence. Vasoprotective effect of the glycosaminoglycans related to the high affinity of the drug to the vascular endothelium as well as to the possibility of the microcirculation homeostasis control recovery were also documented in other clinical conditions such as diabetic nephropaty and retinopathy. According to the literature, discussed in the current publication, an influence of sulodexide on the intermittent claudication distance in the PAOD patients should be mentioned, together with several other potential clinical conditions where the clinically beneficial effect of the glycosaminoglycans can be expected. [ABSTRACT FROM AUTHOR]

Background: International guidelines recommend at least three months anticoagulation in all patients after acute venous thromboembolism (VTE) and suggest those with unprovoked events be considered for indefinite anticoagulation if the risk of recurrence is high and the risk of bleeding during treatment non-high. Other authors have recently argued against using a dichotomy unprovoked/provoked events to decide on anticoagulation duration and suggest instead using overall risk factors present in each patient as the basis for deciding. Aim: This sub-analysis of the WHITE study aimed at assessing the reasons for the treatment decisions taken by doctors in different countries. Results: 1240 patients were recruited in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). Anticoagulation was extended in 51.7% and 49.3% of patients with unprovoked or provoked events (n.s.); stopped in 15.4% versus 28.9% (P <.0001), and changed to antithrombotic drugs (sulodexide or aspirin) in 32.9% versus 21.8% (P <.0001). In the 430 subjects with isolated distal deep vein thrombosis (IDDVT) anticoagulation was stopped in 34.4%, continued in 37.0% (mainly those with post-thrombotic syndrome [PTS]) and switched to antithrombotics in the balance. High risk of recurrence was the most prevalent reason (>83% of cases) given to continue anticoagulation, regardless of nature and site of the index events, followed by risk of bleeding and presence of PTS signs. Conclusion: On average, attending physicians estimated the risk of recurrence in real life conditions, and the consequent therapeutic decision, using all the information available, not limiting to the location or nature of the index event. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications. [ABSTRACT FROM AUTHOR]

Objective This network meta-analysis (NMA) assesses the clinical comparative efficacy and safety of sulodexide versus direct-acting oral anticoagulants (DOACs), vitamin K antagonist (VKA), and aspirin in patients with an unprovoked venous thromboembolism (VTE). Methods We conducted a literature search in MEDLINE, Embase, and Cochrane Library using both randomized controlled trials (RCTs) and observational studies. Reduction in recurrent deep venous thrombosis (r-DVT), pulmonary embolism (PE), major bleeding (MB), clinically relevant nonmajor bleeding (CRNMB) were the primary efficacy and safety outcomes. Other secondary end points were also included. We performed a fixed, random effects, and hierarchical models Bayesian NMA for each outcome. Results We identified 18 RCTs and seven observational studies. Random models showed sulodexide is the best treatment compared with DOACs, VKA, and aspirin at reducing the risk of CRNMB, for preventing death from any cause, and VTE/PE/myocardial infarction (MI)/stroke with 0.47, 0.81, and 0.65 probabilities, respectively. In the random model sulodexide was the best treatment for reducing the risk of MB with a 0.50 probability and hierarchical model that confirmed favorable results. Random and hierarchical models showed sulodexide and DOACs to be the best treatments for reducing PE risk. Sulodexide was more effective than aspirin for reducing r-DVT with 0.12 and less of 0.0001 probabilities, respectively. Conclusion Sulodexide is more effective for reducing MB and CRNMB, for preventing deaths from any cause, and from VTE/PE/MI/stroke, than other treatments, for both random and hierarchical models. Sulodexide showed to be more effective than aspirin in reducing the risk of r-DVT and PE. Sulodexide's reduction in bleeding while protecting from recurrent DVT risk makes this therapeutic option an important alternative for extended anticoagulation treatment.