Thromb Haemost 2021; 121(07): 944-954
DOI: 10.1055/a-1414-5216
New Technologies, Diagnostic Tools and Drugs

Sulodexide in the Treatment of Patients with Early Stages of COVID-19: A Randomized Controlled Trial

1   Department of Vascular-Endovascular Surgery, CLINEDEM, Colonia Comercial, San Luis Rio Colorado, Sonora, México
2   Division of Vascular Surgery, Department of Surgery, Hospital General de Zona No12 Instituto Mexicano Seguro Social, San Luis Rio Colorado, Sonora, México
Joseph D. Raffetto
3   Department of Surgery, Brigham and Women's Hospital, VA Boston Healthcare System, Harvard University, Boston, Massachusetts, United States
Ana G. Hernández
4   Department of Otorhinolaryngology, CLINEDEM, Colonia Comercial, San Luis Rio Colorado, Sonora, México
Nestor Zavala
5   Hospital General de Zona No12 Instituto Mexicano Seguro Social, San Luis Rio Colorado, Sonora, México
Obed Gutiérrez
6   Department of Emergency Medicine, Hospital General de Zona No12 Instituto Mexicano Seguro Social, San Luis Rio Colorado, Sonora, México
7   Department of Emergency, Hospital General, San Luis Rio Colorado, Sonora, México
Arturo Vargas
8   Urban Outpatient Care Center, Secretaria de Salud, San Luis Rio Colorado, Sonora, México
Jorge Loustaunau
9   Department of Emergency, Hospital General de Zona No12 Instituto Mexicano Seguro Social, San Luis Rio Colorado, Sonora, México
› Author Affiliations
Funding This study was independently initiated by the lead researcher and partially funded by Alfasigma Mexico, with the latter providing the sulodexide and placebo capsules for the duration of the trial. Alfasigma did not take part in enrolling trial participants; collecting, managing, analyzing, and interpreting the data; or the decision to submit the report for publication.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce several vascular endothelial-dependent systemic complications, and sulodexide has pleiotropic actions on the vascular endothelium, which may prove beneficial. We aimed to assess the effect of sulodexide when used within 3 days of coronavirus disease 2019 (COVID-19) clinical onset. We conducted a randomized placebo-controlled outpatient trial. To be included, patients must have been at high risk for severe clinical progression. Participants received sulodexide (oral 1,000 LRU/d) or placebo for 21 days. The primary endpoint was the need for hospital care. Also assessed were patients' need for supplemental oxygen as well as D-dimer and C-reactive protein (CRP) levels, thromboembolic events, major bleeding, and mortality. A total of 243 patients were included in the per-protocol analysis from June 5 to August 30, 2020. Of these, 124 received sulodexide and 119 received a placebo. Only 17.7% of the patients in the sulodexide group required hospitalization, compared with 29.4% in the placebo group (p = 0.03). This benefit persisted in the intention-to-treat analysis (15% in sulodexide group vs. 24% with placebo [p = 0.04]). With sulodexide, fewer patients required supplemental oxygen (30 vs. 42% [p = 0.05]). After 2 weeks, fewer patients had D-dimer levels >500 ng/dL (22 vs. 47% [p < 0.01]), and patients also had lower mean CRP levels (12.5 vs. 17.8 mg/dL [p < 0.01]). There were no between-group differences in thromboembolic events, major bleeding, or mortality. Treatment of COVID-19 patients with sulodexide, when provided within 3 days of clinical onset, improved their clinical outcomes. Although the results should be confirmed, sulodexide could be valuable in an outpatient setting.


The data analyzed and presented in this study are available from the corresponding author upon reasonable request, providing that the request meets local ethical and research governance criteria. This trial is listed in the ISRCTN registry with the study ID ISRCTN59048638.

Supplementary Material

Publication History

Received: 26 December 2020

Accepted: 05 March 2021

Accepted Manuscript online:
07 March 2021

Article published online:
09 May 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 World Health Organization. COVID-19 early epidemiologic and clinical investigations for public health. Accessed April 15, 2020 at:
  • 2 Dawood FS, Ricks P, Njie GJ. et al. Observations of the global epidemiology of COVID-19 from the prepandemic period using web-based surveillance: a cross-sectional analysis. Lancet Infect Dis 2020; 20 (11) 1255-1262
  • 3 COVID-19 Mexico. Datos generales: casos confirmados. Secretaria de Salud. Gobierno de Mexico. . Accessed June 7, 2020 at:
  • 4 Schutte AE, Harrison DG. Immunity, inflammation and the vasculature in the COVID-19 era. J Hypertens 2020; 38 (09) 1701-1702
  • 5 Gencer S, Lacy M, Atzler D, van der Vorst EPC, Döring Y, Weber C. Immunoinflammatory, thrombohaemostatic, and cardiovascular mechanisms in COVID-19. Thromb Haemost 2020; 120 (12) 1629-1641
  • 6 Campbel C, Kahwash K. Microvascular thrombi in COVID-19. American College Cardiology, 25 January 2021 [Online]. Accessed January 29, 2021 at:
  • 7 Carsana L, Sonzogni A, Nasr A. et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20 (10) 1135-1140
  • 8 Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368 (6490): 473-474
  • 9 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
  • 10 Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol 2015; 80 (03) 389-402
  • 11 McGurnaghan SJ, Weir A, Bishop J. et al; Public Health Scotland COVID-19 Health Protection Study Group, Scottish Diabetes Research Network Epidemiology Group. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland. Lancet Diabetes Endocrinol 2021; 9 (02) 82-93
  • 12 Evans PC, Rainger GE, Mason JC. et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res 2020; 116 (14) 2177-2184
  • 13 Masola V, Zaza G, Onisto M, Lupo A, Gambaro G. Glycosaminoglycans, proteoglycans and sulodexide and the endothelium: biological roles and pharmacological effects. Int Angiol 2014; 33 (03) 243-254
  • 14 Li T, Liu X, Zhao Z, Ni L, Liu C. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget 2017; 8 (53) 91350-91361
  • 15 Coccheri S, Mannello F. Development and use of sulodexide in vascular diseases: implications for treatment. Drug Des Devel Ther 2013; 8: 49-65
  • 16 Zielinski A, Zabel M, Wysocka T, Urbanek T, Suminska K. Sulodexide activates glycocalyx restorations in patients with chronic venous disease. Vasc Insight Nautilus 2019; 1: 17-18
  • 17 Mannello F, Ligi D, Canale M, Raffetto JD. Sulodexide down-regulates the release of cytokines, chemokines, and leukocyte colony stimulating factors from human macrophages: role of glycosaminoglycans in inflammatory pathways of chronic venous disease. Curr Vasc Pharmacol 2014; 12 (01) 173-185
  • 18 Matta P, Manello F, Ferrari P, Augus G. Vascular pathologies and inflammation: The anti-inflammatory properties of sulodexide. Ital J Vasc Endovasc Surg 2012; 2 (03) 1-7
  • 19 Pompilio G, Integlia D, Raffetto J, Palareti G. Comparative efficacy and safety of sulodexide and other extended anticoagulation treatments for prevention of recurrent venous thromboembolism: a Bayesian network meta-analysis. TH Open 2020; 4 (02) e80-e93
  • 20 Billett HH, Reyes-Gil M, Szymanski J. et al. Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality. Thromb Haemost 2020; 120 (12) 1691-1699
  • 21 Drouet L, Harenberg J, Torri G. The multiple faces of heparin: opportunities in COVID-19 infection and beyond. Thromb Haemost 2020; 120 (10) 1347-1350
  • 22 Harenberg J, Bauersachs R, Ageno W. Does chronic treatment with oral anticoagulants ameliorate the clinical course of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection in Coronavirus disease 2019 (COVID-19)?. Semin Thromb Hemost 2020; DOI: 10.1055/s-0040-1715091.
  • 23 Duvignaud A, Lhomme E, Pistone T. et al; COVERAGE study group. Home treatment of older people with symptomatic SARS-CoV-2 infection (COVID-19): a structured summary of a study protocol for a multi-arm multi-stage (MAMS) randomized trial to evaluate the efficacy and tolerability of several experimental treatments to reduce the risk of hospitalisation or death in outpatients aged 65 years or older (COVERAGE trial). Trials 2020; 21 (01) 846
  • 24 Cao R-N, Tang L, Xia Z-Y, Xia R. Endothelial glycocalyx as a potential theriapeutic target in organ injuries. Chin Med J (Engl) 2019; 132 (08) 963-975
  • 25 Kaur S, Tripathi DM, Yadav A. The enigma of endothelium in COVID-19. Front Physiol 2020; 11: 989
  • 26 IMSS. Calculadora de complicacion de salud por COVID-19. Gobierno de Mexico: IMSS; . Accessed June 6, 2020 at:
  • 27 González Ochoa A. Sulodexide and phlebotonics in the treatment of venous ulcer. Int Angiol 2017; 36 (01) 82-87
  • 28 Andreozzi GM, Bignamini AA, Davì G. et al; SURVET Study Investigators. Sulodexide for the prevention of recurrent venous thromboembolism: the sulodexide in secondary prevention of recurrent deep vein thrombosis (SURVET) study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation 2015; 132 (20) 1891-1897
  • 29 Lineamientos para la atencion de pacientes con COVID-19. Gobierno de Mexico:; . Accessed February 15, 2021. Accessed 2021 at:
  • 30 Algoritmos interinos para la atencion del COVID-19. Instituto Mexicano Seguro Social; . Accessed 2020 at:
  • 31 Gonzalez Ochoa AJ, Carrillo J, Manríquez D, Manrique F, Vazquez AN. Reducing hyperpigmentation after sclerotherapy: a randomized clinical trial. J Vasc Surg Venous Lymphat Disord 2021; 9 (01) 154-162
  • 32 Froldi G, Dorigo P. Endothelial dysfunction in coronavirus disease 2019 (COVID-19): gender and age influences. Med Hypotheses 2020; 144 (110015): 110015
  • 33 Jarzabek K, Gabryel B, Urbanek T. Sulodexide in the treatment of vascular disease: its therapeutic action on the endothelium. Phlebol Rev. 2016; 4: 51-59
  • 34 Ciszewicz M, Polubinska A, Antoniewicz A, Suminska-Jasinska K, Breborowicz A. Sulodexide suppresses inflammation in human endothelial cells and prevents glucose cytotoxicity. Transl Res 2009; 153 (03) 118-123
  • 35 Wise J. Covid-19: study reveals six clusters of symptoms that could be used as a clinical prediction tool. BMJ 2020; 370: m2911
  • 36 Chen J, Qi T, Liu L. et al. Clinical progression of patients with COVID-19 in Shanghai, China. J Infect 2020; 80 (05) e1-e6
  • 37 Mannello F, Medda V, Ligi D, Raffetto JD. Glycosaminoglycan sulodexide inhibition of MMP-9 gelatinase secretion and activity: possible pharmacological role against collagen degradation in vascular chronic diseases. Curr Vasc Pharmacol 2013; 11 (03) 354-365
  • 38 Urbanek T, Zbigniew K, Begier-Krasińska B, Baum E, Bręborowicz A. Sulodexide suppresses inflammation in patients with chronic venous insufficiency. Int Angiol 2015; 34 (06) 589-596
  • 39 Marchandot B, Trimaille A, Curtiaud A. et al. Staging severity of COVID-19 according to hemostatic abnormalities (CAHA score). Thromb Haemost 2020; 120 (12) 1716-1719
  • 40 Wu C, Chen X, Cai Y. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180 (07) 934-943
  • 41 Valerio L, Ferrazzi P, Sacco C. et al; Humanitas COVID-19 Task Force. Course of D-dimer and C-reactive protein levels in survivors and nonsurvivors with COVID-19 pneumonia: a retrospective analysis of 577 patients. Thromb Haemost 2021; 121 (01) 98-101
  • 42 Yao Y, Cao J, Wang Q. et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care 2020; 8 (01) 49
  • 43 Ranucci M, Ballotta A, Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18 (07) 1747-1751
  • 44 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
  • 45 Gerotziafas GT, Catalano M, Colgan M-P. et al; Scientific Reviewer Committee. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; 120 (12) 1597-1628
  • 46 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
  • 47 Połubińska A, Staniszewski R, Baum E, Sumińska-Jasińska K, Bręborowicz A. Sulodexide modifies intravascular homeostasis what affects function of the endothelium. Adv Med Sci 2013; 58 (02) 304-310
  • 48 Fröhlich GM, Jeschke E, Eichler U. et al. Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany. Clin Res Cardiol 2021; DOI: 10.1007/s00392-020-01783-x.
  • 49 Malik SUF, Chowdhury PA, Hakim A, Islam MS, Alam MJ, Azad AK. Blood biochemical parameters for assessment of COVID-19 in diabetic and non-diabetic subjects: a cross-sectional study. Int J Environ Health Res 2021; DOI: 10.1080/09603123.2021.1879741.