COVID-19’DA ANTİKOAGÜLAN TEDAVİ

Year 2021, , 37 - 45, 01.05.2021

Demircan Özbalcı

https://doi.org/10.17343/sdutfd.899521

Abstract

COVID-19’da birçok organın tutulumu olmakla birlikte, en sık mortalite ve morbidite sebebi ARDS ve trombozlardır. Şiddetli tromboinflamasyon, yaygın damar içi pıhtılaşma sendromu ve bunların sonucu olarak görülen tromboz riskinden dolayı, COVID-19’da antikoagülan tedavi, standart tedavi olarak yerini almıştır. D-Dimer yüksekliği, COVID-19 koagülopatisinin en önemli belirtecidir. Düşük molekül ağırlıklı heparin (DMAH) COVID-19’da ilk akla gelen antikoagülan ajandır. Hemen hemen tüm klinik durumlarda ilk seçenektir. Warfarin kullanımı önerilmezken, direkt oral antikoagülanlar, aspirin ve P2Y12 inhibitörlerinin etkileri üzerine daha net kanıtlar gerekmektedir. Bu derlemede, COVID-19 hastalarında antikoagülan profilaksi ve tedavi endikasyonları ile bu tedavilerin süresi yanı sıra, bu hastaların takibinde, hastalık birliktelik gösteren klinik durumların tedavisi de son kılavuzların önerileri doğrultusunda anlatılacaktır.

Keywords

COVID-19, D-Dimer, Düşük Molekül Ağırlıklı Heparin, Antikoagülan Ajanlar

Supporting Institution

Yok

Project Number

Yok

Thanks

Değerli hocam Füsun Zeynep Akçam'a bu yazının hazırlanmasındaki katkısından dolayı teşekkür ediyorum.

ANTICOAGULANT THERAPY IN COVID-19

Abstract

Although many organs are involved in COVID-19, the most common causes of mortality and morbidity are ARDS and thrombosis. Anticoagulant therapy has become as a standard treatment in COVID-19 due to severe thromboinflammation, diffuse intravascular coagulation syndrome and the risk of thrombosis seen as a result. Elevation of D-dimer is the most important marker of COVID-19 coagulopathy. Low molecular weight heparin (LMWH) is the first choice in almost all clinical situations. While the use of warfarin is not recommended, clearer evidence is needed on the effects of direct oral anticoagulants, aspirin and P2Y12 inhibitors. In this review, anticoagulant prophylaxis and treatment indications in COVID-19 patients and the duration of these treatments, as well as the treatment of clinical conditions associated with the disease in the follow-up of these patients will be explained in line with the recommendations of the latest guidelines.

Keywords

COVID-19, D-Dimer, Low Molecular Weight Heparin, Anticoagulant Agents

Project Number

Yok

References

• 1- 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 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID: PMC7159299.
• 2- Magrone T, Magrone M, Jirillo E. Focus on Receptors for Coronaviruses with Special Reference to Angiotensin- Converting Enzyme 2 as a Potential Drug Target - A Perspective. Endocr Metab Immune Disord Drug Targets. 2020;20(6):807-811. doi: 10.2174/1871530320666200427112902. PMID: 32338224.
• 3- Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24. Erratum in: Lancet Respir Med. 2020 Apr;8(4):e26. PMID: 32105632; PMCID: PMC7102538.
• 4- Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-1474. doi: 10.1161/CIRCRESAHA.120.317015. Epub 2020 Apr 8. PMID: 32264791; PMCID: PMC7188049.
• 5- Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. PMID: 32007143; PMCID: PMC7135076.
• 6- Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. PMID: 32031570; PMCID: PMC7042881.
• 7- 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 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28. PMID: 32109013; PMCID: PMC7092819.
• 8- Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620938149. doi: 10.1177/1076029620938149. PMID: 32677459; PMCID: PMC7370334.
• 9- 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 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. PMID: 32171076; PMCID: PMC7270627.
• 10- Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. PMID: 32007143; PMCID: PMC7135076.
• 11- Xu JF, Wang L, Zhao L, Li F, Liu J, Zhang L, et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. Research Sqare. 2020. doi:10.21203/rs.3.rs-18340/v1
• 12- Chen J, Wang X, Zhang S, Lin B, Wu X, Wang Y, et al. Characteristics of Acute Pulmonary Embolism in Patients With COVID-19 Associated Pneumonia From the City of Wuhan. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620936772. doi: 10.1177/1076029620936772. PMID: 32726134; PMCID: PMC7391435.
• 13- Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-1424.
• 14- 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 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10. PMID: 32291094; PMCID: PMC7146714.
• 15- Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):e38. doi: 10.1056/NEJMc2007575. Epub 2020 Apr 8. PMID: 32268022; PMCID: PMC7161262.
• 16- Ho FK, Man KKS, Toschner M, Celis-Morales C, Wong ICK, Sattar Net al. COVID-19 infection and subsequent thromboembolism: A self-controlled case series analysis of a population cohort: https://doi.org/10.1101/2021.02.02.21251043
• 17- Fox SE, Fox SE, Akmatbekov A, Harbert JL, Li G, Brown QJ, et al. Pulmonary and cardiac pathology in COVID-19: the first autopsy series from New Orleans. Chemrxiv Pre Print. 2020.
• 18- Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020 Aug 6;383(6):590-592. doi: 10.1056/NEJMc2011400. Epub 2020 May 13. PMID: 32402155; PMCID: PMC7240771.
• 19- Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 May 2;395(10234):1417-1418. doi: 10.1016/S0140-6736(20)30937-5. Epub 2020 Apr 21. PMID: 32325026; PMCID: PMC7172722.
• 20- Nazy I, Jevtic SD, Moore JC, Huynh A, Smith JW, Kelton JG, et al. Platelet-activating immune complexes identified in critically ill COVID-19 patients suspected of heparin-induced thrombocytopenia. J Thromb Haemost. 2021 Feb 27. doi: 10.1111/jth.15283. Epub ahead of print. PMID: 33639037.
• 21- Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620938149. doi: 10.1177/1076029620938149. PMID: 32677459; PMCID: PMC7370334.
• 22- Li J, Li Y, Yang B, Wang H, Li L. Low-molecular-weight heparin treatment for acute lung injury/acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. Int J Clin Ex Med 2018;11(02):414–422
• 23- Langer F, Kluge S, Klamroth R, Oldenburg J. Coagulopathy in COVID-19 and Its Implication for Safe and Efficacious Thromboprophylaxis. Hamostaseologie. 2020 Aug;40(3):264-269. doi: 10.1055/a-1178-3551. Epub 2020 Jun 4. PMID: 32498097; PMCID: PMC7416221.
• 24- Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, Merouani K. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020 Jul;18(7):1743-1746. doi: 10.1111/jth.14869. Epub 2020 May 27. PMID: 32320517; PMCID: PMC7264774.
• 25- Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020 Jul 23;136(4):489-500. doi: 10.1182/blood.2020006520. PMID: 32492712; PMCID: PMC7378457.
• 26- Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 Aug;18(8):1995-2002. doi: 10.1111/jth.14888. Epub 2020 Jul 27. PMID: 32369666; PMCID: PMC7497052.
• 27- Bikdeli B, Madhavan MV, Gupta A, Jimenez D, Burton JR, Der Nigoghossian C, et al. Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research. Thromb Haemost. 2020 Jul;120(7):1004-1024. doi: 10.1055/s-0040-1713152. Epub 2020 May 30. PMID: 32473596; PMCID: PMC7516364.
• 28- Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019 Jun;94(6):697-709. doi: 10.1002/ajh.25475. Epub 2019 Apr 16. PMID: 30916798.
• 29- Marcos-Jubilar M, García Erce JA, Martínez-Calle N, Páramo JA, Martínez Virto A, Quintana-Díaz M. Safety and effectiveness of a prothrombin complex concentrate in approved and off-label indications. Transfus Med. 2019 Aug;29(4):268-274. doi: 10.1111/tme.12621. Epub 2019 Jul 25. PMID: 31347218.
• 30- van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010 Jun;103(6):1116-27. doi: 10.1160/TH09-11-0758. Epub 2010 Mar 29. PMID: 20352166.
• 31- Dou H, Song A, Jia S, Zhang L. Heparinoids Danaparoid and Sulodexide as clinically used drugs. Prog Mol Biol Transl Sci. 2019;163:55-74. doi: 10.1016/bs.pmbts.2019.02.005. Epub 2019 Mar 21. PMID: 31030761.
• 32- Burgess JK, Chong BH. The platelet proaggregating and potentiating effects of unfractionated heparin, low molecular weight heparin and heparinoid in intensive care patients and healthy controls. Eur J Haematol. 1997 Apr;58(4):279-85. doi: 10.1111/j.1600-0609.1997.tb01667.x. PMID: 9186540.
• 33- Hagiwara S, Iwasaka H, Hidaka S, Hishiyama S, Noguchi T. Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats. Crit Care. 2008;12(2):R43. doi: 10.1186/cc6851. Epub 2008 Apr 2. PMID: 18380908; PMCID: PMC2447588.
• 34- Juschten J, Tuinman PR, Juffermans NP, Dixon B, Levi M, Schultz MJ. Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies. Ann Transl Med. 2017 Nov;5(22):444. doi: 10.21037/atm.2017.08.23. PMID: 29264361; PMCID: PMC5721225.
• 35- Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost. 2020 Jul;18(7):1548-1555. doi: 10.1111/jth.14872. Epub 2020 Jun 3. PMID: 32329246; PMCID: PMC7264738.
• 36- Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006 Dec;116(12):3211-9. doi: 10.1172/JCI29499. PMID: 17143330; PMCID: PMC1679711.
• 37- Looney MR, Nguyen JX, Hu Y, Van Ziffle JA, Lowell CA, Matthay MA. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest. 2009 Nov;119(11):3450-61. doi: 10.1172/JCI38432. Epub 2009 Oct 5. PMID: 19809160; PMCID: PMC2769181.
• 38- Wang L, Li H, Gu X, Wang Z, Liu S, Chen L. Effect of Antiplatelet Therapy on Acute Respiratory Distress Syndrome and Mortality in Critically Ill Patients: A Meta-Analysis. PLoS One. 2016 May 16;11(5):e0154754. doi: 10.1371/journal.pone.0154754. PMID: 27182704; PMCID: PMC4868259.
• 39- Boyle AJ, Di Gangi S, Hamid UI, Mottram LJ, McNamee L, White G, et al. Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis. Crit Care. 2015 Mar 23;19(1):109. doi: 10.1186/s13054-015-0846-4. PMID: 25887566; PMCID: PMC4371625.
• 40- Chen W, Janz DR, Bastarache JA, May AK, O'Neal HR Jr, Bernard GR, et al. Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis. Crit Care Med. 2015 Apr;43(4):801-7. doi: 10.1097/CCM.0000000000000789. PMID: 25559436; PMCID: PMC4359645.
• 41- Panka BA, de Grooth HJ, Spoelstra-de Man AM, Looney MR, Tuinman PR. Prevention or Treatment of Ards With Aspirin: A Review of Preclinical Models and Meta-Analysis of Clinical Studies. Shock. 2017 Jan;47(1):13-21. doi: 10.1097/SHK.0000000000000745. PMID: 27984533; PMCID: PMC5175412.
• 42- Kor DJ, Carter RE, Park PK, Festic E, Banner-Goodspeed VM, Hinds R, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial. JAMA. 2016 Jun 14;315(22):2406-14. doi: 10.1001/jama.2016.6330. Erratum in: JAMA. 2016 Sep 13;316(10):1116. PMID: 27179988; PMCID: PMC5450939.
• 43- Osborne TF, Veigulis ZP, Arreola DM, Mahajan SM, Röösli E, Curtin CM. Association of mortality and aspirin prescription for COVID-19 patients at the Veterans Health Administration. PLoS One. 2021 Feb 11;16(2):e0246825. doi: 10.1371/journal.pone.0246825. PMID: 33571280; PMCID: PMC7877611.
• 44- Meizlish ML, Goshua G, Liu Y, Fine R, Amin K, Chang E, et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis. Am J Hematol. 2021 Jan 21. doi: 10.1002/ajh.26102. Epub ahead of print. PMID: 33476420.
• 45- Chow JH, Khanna AK, Kethireddy S, Yamane D, Levine A, Jackson AM, et al. Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19. Anesth Analg. 2020 Oct 21. doi: 10.1213/ANE.0000000000005292. Epub ahead of print. PMID: 33093359.
• 46- Sahai A, Bhandari R, Koupenova M, Freedman J, Godwin M, McIntyre T, et al. SARS-CoV-2 Receptors are Expressed on Human Platelets and the Effect of Aspirin on Clinical Outcomes in COVID-19 Patients. Res Sq [Preprint]. 2020 Dec 23:rs.3.rs-119031. doi: 10.21203/rs.3.rs-119031/v1. PMID: 33398263; PMCID: PMC7781327.
• 47- Salah HM, Mehta JL. Meta-Analysis of the Effect of Aspirin on Mortality in COVID-19. Am J Cardiol. 2021 Mar 1;142:158-159. doi: 10.1016/j.amjcard.2020.12.073. Epub 2021 Jan 6. PMID: 33417877; PMCID: PMC7834714.
• 48- Tonew E, Indulen MK, Dzeguze DR. Antiviral action of dipyridamole and its derivatives against influenza virus A. Acta Virol. 1982 May;26(3):125-9. PMID: 6127012.
• 49- Liu X, Li Z, Liu S, Sun J, Chen Z, Jiang M, et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharm Sin B. 2020 Jul;10(7):1205-1215. doi: 10.1016/j.apsb.2020.04.008. Epub 2020 Apr 20. PMID: 32318327; PMCID: PMC7169892.
• 50- Liu X, Li Z, Liu S, Sun J, Chen Z, Jiang M, et al. Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction. Acta Pharmaceutica Sinica B, Volume 10, Issue 7, 2020, pages 1205-1215, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2020.04.008.
• 51- Gross AK, Dunn SP, Feola DJ, Martin CA, Charnigo R, Li Z, et al. Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness. J Thromb Thrombolysis. 2013 Feb;35(2):147-54. doi: 10.1007/s11239-012-0833-4. PMID: 23124575; PMCID: PMC3732820.
• 52- Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets. 2014;25(7):517-25. doi: 10.3109/09537104.2013.842965. Epub 2013 Oct 15. PMID: 24127651; PMCID: PMC4220996.
• 53- Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, et al. Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia. JACC Basic Transl Sci. 2018 Aug 28;3(4):435-449. doi: 10.1016/j.jacbts.2018.05.005. PMID: 30175268; PMCID: PMC6115703.
• 54- Aungraheeta R, Conibear A, Butler M, Kelly E, Nylander S, Mumford A, et al. Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor. Blood. 2016 Dec 8;128(23):2717-2728. doi: 10.1182/blood-2016-03-707844. Epub 2016 Sep 30. PMID: 27694321; PMCID: PMC5161012.
• 55- Lancellotti P, Musumeci L, Jacques N, Servais L, Goffin E, Pirotte B, et al. Antibacterial Activity of Ticagrelor in Conventional Antiplatelet Dosages Against Antibiotic-Resistant Gram-Positive Bacteria. JAMA Cardiol. 2019 Jun 1;4(6):596-599. doi: 10.1001/jamacardio.2019.1189. PMID: 31066863; PMCID: PMC6506905.
• 56- Watson RA, Johnson DM, Dharia RN, Merli GJ, Doherty JU. Anti-coagulant and anti-platelet therapy in the COVID-19 patient: a best practices quality initiative across a large health system. Hosp Pract (1995). 2020 Oct;48(4):169-179. doi: 10.1080/21548331.2020.1772639. Epub 2020 Jun 9. PMID: 32429774; PMCID: PMC7441801.
• 57- Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID: 30883055.
• 58- Szerlip M, Anwaruddin S, Aronow HD, Cohen MG, Daniels MJ, Dehghani P, et al. Considerations for cardiac catheterization laboratory procedures during the COVID-19 pandemic perspectives from the Society for Cardiovascular Angiography and Interventions Emerging Leader Mentorship (SCAI ELM) Members and Graduates. Catheter Cardiovasc Interv. 2020 Sep 1;96(3):586-597. doi: 10.1002/ccd.28887. Epub 2020 Apr 21. PMID: 32212409.
• 59- Mahmud E, Dauerman HL, Welt FGP, Messenger JC, Rao SV, Grines C, et al. Management of Acute Myocardial Infarction During the COVID-19 Pandemic: A Position Statement From the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP). J Am Coll Cardiol. 2020 Sep 15;76(11):1375-1384. doi: 10.1016/j.jacc.2020.04.039. Epub 2020 Apr 21. PMID: 32330544; PMCID: PMC7173829.
• 60- Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139-e228. doi: 10.1016/j.jacc.2014.09.017. Epub 2014 Sep 23. Erratum in: J Am Coll Cardiol. 2014 Dec 23;64(24):2713-4. Dosage error in article text. PMID: 25260718.
• 61- Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19. PMID: 24251359.
• 62- TC. Sağlık Bakanlığı COVID-19 Rehberi- Antisitokin-Antiinflamatuar Tedaviler, Koagülopati Yönetimi 07.11.2020. https://covid19.saglik.gov.tr/TR-66341/antisitokin-antiinflamatuar-tedaviler-koagulopati-yonetimi.html
• 63- The Remap-cap, Actıv-4a, and Attacc Investigators. Therapeutic anticoagulation in critically ill patients with covid-19 – preliminary report. Medrxiv https://doi.org/10.1101/2021.03.10.21252749