The safety of fondaparinux, enoxaparin, and unfractionated heparin in COVID-19 patients

  • Siti Aulia Musyrifah Master of Clinical Pharmacy Program, Faculty of Pharmacy, Universitas Gadjah Mada Yogyakarta, Indonesia
  • Agung Endro Nugroho
  • Fita Rahmawati 2Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada Yogyakarta, Indonesia
Keywords: fondaparinux, enoxaparin, unfractionated heparin, safety, COVID-19


The coagulopathy, a hematological disorder affecting blood clotting, carries an elevated risk of thrombosis and mortality in COVID-19 patients. Fondaparinux, enoxaparin, and unfractionated heparin (UFH) are potential treatments for reducing coagulopathy in COVID-19 patients. Nonetheless, anticoagulant administration increases the risk of bleeding-related adverse effects. This study aimed to evaluate the safety profile of fondaparinux, enoxaparin, and UFH in COVID-19 patients. The safety was evaluated based on the prevalence of major and minor bleeding events from the data of medical records collected retrospectively from October 2022 to December 2021 at Kediri District Hospital. The Chi-square analysis and multiple logistic regression were employed to establish associations between variables. Out of the 315 patients who meet the inclusion criteria, 35 patients (11.1%) exhibited bleeding, 11 patients (3.5%) experienced major bleeding, while 24 patients (7.6%) encountered minor bleeding. No significantly different in bleeding events both major and minor bleeding among the groups receiving fondaparinux, enoxaparin, and UFH were observed (p> 0.05). The UFH emerged as the most common anticoagulant associated with bleeding incidents. The multivariate analysis revealed that age ≥ 60 yr and concomitant medication with ketorolac influenced bleeding incidence. The monitoring of bleeding events on the use of anticoagulants is necessary.


Zhu H, Wei L, Niu P. The novel coronavirus outbreak in Wuhan, China. Glob Health Res Policy 2020; 5(1):6.

World Health Organization. Living guidance for clinical management of COVID-19: living guidance. Published November 23, 2021. Accessed June 5, 2023.

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18):1708-20.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-62.

Campbell CM, Kahwash R. Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? Circulation 2020; 141(22):1739-41.

Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395(10234):1417-8.

Fan BE, Chong VCL, Chan SSW, Lim GH, Lim KGE, Tan GB, et al. Hematologic parameters in patients with COVID-19 infection. Am J Hematol 2020; 95(6):E131-4.

Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol 2020; 92(10):1733-4.

Yang X, Yang Q, Wang Y, Wu Y, Xu J, Yu Y, et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020; 18(6):1469-72.

Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191:145-7.

Haswan D, Yasin NM, Pinzon RT. Perbandingan efektivitas dan keamanan penggunaan direct oral anticoagulants (rivaroxaban, edoxaban) dan low molecular weight heparin (enoxaparin) pada pasien COVID-19 di Rumah Sakit Bethesda, Yogyakarta. [Thesis]. Yogyakarta: Universitas Gadjah Mada; 2022.

Adrian LH, Hutomo SA, Negari ADS. Efficacy and safety of fondaparinux versus unfractionated heparin in patients hospitalised with severe COVID-19 pneumonia and coagulopathy: a randomised, open-label clinical trial. Eur Heart J 2022; 43(Supplement_1):ehab849.169.

Saeed K, Áinle FN. Standardizing definitions for bleeding events in studies including pregnant women: a call to action. Res Pract Thromb Haemost 2022; 6(7):e12822.

Simard C, Gerstein L, Cafaro T, Filion KB, Douros A, Malhame I, et al. Bleeding in women with venous thromboembolism during pregnancy: a systematic review of the literature. Res Pract Thromb Haemost 2022; 6(6):e12801.

Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3(4):692-4.

Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13(11):2119-26.

Pawlowski C, Venkatakrishnan AJ, Kirkup C, Berner G, Puranik A, O'Horo JC, et al. Enoxaparin is associated with lower rates of mortality than unfractionated heparin in hospitalized COVID-19 patients. EClinicalMedicine 2021; 33:100774.

Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl):e24S-e43S.

Russo V, Cardillo G, Viggiano GV, Mangiacapra S, Cavalli A, Fontanella A, et al. Fondaparinux use in patients with COVID-19: a preliminary multicenter real-world experience. J Cardiovasc Pharmacol 2020; 76(4):369-71.

Hirsh J, Anand SS, Halperin JL, Fuster V. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol 2001; 21(7):1094-6.

Liu Z, Ji S, Sheng J, Wang F. Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discov Ther 2014; 8(1):1-10.


Fareed J, Hoppensteadt D, Walenga J, Iqbal O, Ma Q, Jeske W, et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin. Clin Pharmacokinet 2003; 42(12):1043-57.

Demelo‐Rodriguez P, Farfán‐Sedano AI, Pedrajas JM, Llamas P, Sigüenza P, Jaras MJ, et al. Bleeding risk in hospitalized patients with COVID‐19 receiving intermediate‐ or therapeutic doses of thromboprophylaxis. J Thromb Haemost 2021; 19(8):1981-9.

Sadeghipour P, Talasaz AH, Rashidi F, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION Randomized Clinical Trial. JAMA 2021; 325(16):1620-30.

Lopes RD, de Baros E Silva PGM, Furtado RHM, Macedo AVS, Bronhara B, Damiani LP, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet 2021; 397(10291):2253-63.

Nakamura J, Tsujino I, Yachi S, Takeyama M, Nishimoto Y, Konno S, et al. Incidence, risk factors, and clinical impact of major bleeding in hospitalized patients with COVID-19: a sub-analysis of the CLOT-COVID Study. Thromb J 2022; 20(1):53.

Mauro A, De Grazia F, Lenti MV, Penagini R, Frego R, Ardizzone S, et al. Upper gastrointestinal bleeding in COVID-19 inpatients: Incidence and management in a multicenter experience from Northern Italy. Clin Res Hepatol Gastroenterol 2021; 45(3):101521.

Medscape. Drug interactions checker - medscape drug reference database. Published 2023. Accessed June 26, 2023.