Review Postgrad Med J: first published as 10.1136/postgradmedj-2021-139923 on 13 April 2021. Downloaded from Anticoagulation in COVID-19: current concepts and controversies Atanu Chandra ,1 Uddalak Chakraborty ,2 Shrestha Ghosh,1 Sugata Dasgupta3 ► Additional material is ABSTRACT ANTICOAGULANT TYPES AND USES published online only. To view Rising incidence of thromboembolism secondary Anticoagulants have been the mainstay of preven- please visit the journal online 6 (http:// dx. doi. org/ 10. 1136/ to COVID-19 has become a global concern, with tion and treatment of thrombosis for decades. postgradmedj- 2021- 139923). several surveys reporting increased mortality rates. Based on their mechanisms of action, they have Thrombogenic potential of the SARS-CoV -2 virus been classified into broad categories. 1 Internal Medicine, RG Kar has been hypothesised to originate from its ability Heparin was the first true anticoagulant. Purified Medical College and Hospital, heparin, including unfractionated heparin (UFH) Kolkata, India to produce an exaggerated inflammatory response 2Neurology, Institute of leading to endothelial dysfunction. Anticoagulants and low- molecular weight heparin (LMWH), act by Postgraduate Medical Education have remained the primary modality of treatment of promoting formation of an intermediate protease– and Research, Bangur Institute thromboembolism for decades. However, there is no heparin–antithrombin complex which facilitates of Neurology, Kolkata, West inhibition of thrombin and activated factor X.7 It is Bengal, India universal consensus regarding the timing, dosage and 3Critical Care Medicine, RG Kar duration of anticoagulation in COVID-19 as well as used for prevention and treatment of macrothrombi Medical College and Hospital, need for postdischarge prophylaxis. This article seeks to such as DVT and PE, in patients undergoing dial- Kolkata, West Bengal, India review the present guidelines and recommendations as ysis, extracorporeal circulation and cardiovascular well as the ongoing trials on use of anticoagulants in and orthopaedic surgeries and in candidates for Correspondence to COVID-19, identify discrepancies between all these, and invasive procedures such as percutaneous coro- Dr Atanu Chandra, Internal nary intervention. Bleeding is a major disadvantage medicine, RG Kar Medical provide a comprehensive strategy regarding usage of College, Kolkata, India; these drugs in the current pandemic. of heparin as well as thrombocytopaenia (in up to chandraatanu123@ gmail. com 30% of patients), alopecia, injection site reaction and hyperkalaemia.8 Received 8 February 2021 Historically, vitamin K antagonists such as Revised 11 March 2021 warfarin (dicoumarol) and other coumarin deriva- INTRODUCTION Accepted 24 March 2021 tives were one of the earliest anticoagulants to be The novel beta- coronavirus, appropriately named approved for clinical use.9 Warfarin is a competi- SARS- CoV-2 by the International Committee of tive inhibitor of VKORC1, resulting in decreased Taxonomy of Viruses, belongs to a family of single- hepatic synthesis of vitamin K-dependent clotting stranded RNA viruses, members of which have been factors as well as Protein C and Protein S. Warfarin recognised as causative agents of the SARS-CoV therapy requires close monitoring due to a narrow and Middle East respiratory syndrome coronavirus http://pmj.bmj.com/ 1 2 therapeutic window, drug interactions and wide outbreak in 2002 and 2012, respectively. Pres- dosing range needed for maintaining therapeutic ently, the novel COVID-19 poses a major global international normalised ratio (INR). health crisis, having been declared a pandemic on Development of direct oral anticoagulants 11 March 2020 by the WHO. (DOACs) ensured a higher safety profile with Over the past several months, an overwhelming greater efficacy requiring less frequent dose moni- amount of literature suggests an increased risk toring.10 11 These include two classes of drugs, of thromboembolic manifestations associated namely direct thrombin inhibitors such as dabig- on September 26, 2021 by guest. Protected copyright. 2 with COVID-19. Several hypotheses have been atran and direct factor Xa inhibitors like apix- suggested to understand the underlying pathophys- aban, edoxaban and rivaroxaban.12 Non- bleeding iology behind development of a prothrombotic adverse effects of these drugs are rare, but include state in COVID-19 such as exaggerated inflamma- severe liver injury and gastrointestinal disorders.13 tory response resulting in activation of the coagu- A major disadvantage of new oral anticoagulants 3 4 lation cascade and endothelial injury. Usage of lies in the present global unavailability of specific anticoagulants in COVID-19 remains an area of reversal agents. While idarucizumab and andexanet conjecture with no definite guidelines published to alfa are two such drugs approved for use in the © Author(s) (or their date highlighting the timing, dosage and duration USA as well as EU, other reversal agents are under employer(s)) 2021. No of anticoagulation as well as the drug of choice. development.14 commercial re- use. See rights Most internationally published guidelines, based Fondaparinux was approved for use in the USA and permissions. Published on consensus statements and expert opinions, by BMJ. in 2001 as an indirect inhibitor of factor Xa, which recommend therapeutic doses of heparin only achieves anticoagulation by binding to and acti- To cite: Chandra A, in patients diagnosed with or highly suspected vating antithrombin.15 Toxicity of fondaparinux is Chakraborty U, Ghosh S, of developing macrothrombi such as pulmonary complicated by its long half- life. et al. Postgrad Med J Epub ahead of print: [please embolism (PE) or deep vein thrombosis (DVT). Selection of the ideal anticoagulant for any disease include Day Month Year]. However, these guidelines including those by takes into account various patient- specific factors doi:10.1136/ CHEST, rarely address the requirement of postdis- such as the underlying thromboembolic state, for postgradmedj-2021-139923 charge thromboprophylaxis.5 example ischaemic stroke or atrial fibrillation, as Chandra A, et al. Postgrad Med J 2021;0:1–8. doi:10.1136/postgradmedj-2021-139923 1 Review Postgrad Med J: first published as 10.1136/postgradmedj-2021-139923 on 13 April 2021. Downloaded from well as acceptable bleeding risk and presence of co-morbidities Table 2 Changes in various coagulation parameters following such as hepatic or renal disease.16 COVID-19 in a study by Yu et al Coagulation Survivors Non- survivors Percentage ROLE OF ANTICOAGULANTS IN PE parameter n=162 n=21 difference Acute PE has a mortality rate as high as 30% in the first month, PT 13.6 s 15.5 s 13.97 with up to 30% survivors experiencing recurrence or chronic aPTT 41.2 s 44.8 s 8.74 disabilities.17 18 With an annual incidence rate ranging from 0.2 Fibrinogen 4.51 g/L 5.16 g/L 14.41 to 0.8/1000, PE has been hypothesised to have multifactorial D- dimer 0.61 mcg/mL 2.12 mcg/mL 247.54 etiologies.19–21 FDP 4 mcg/mL 7.6 mcg/mL 90.00 Acute PE warrants mandatory risk stratification to determine AT 91% 84% −7.69 appropriate therapeutic intervention. Models such as the Pulmo- nary Embolism Severity Index (PESI) and the simplified- PESI aPTT, activated partial thromboplastin time; AT, antithrombin; FDP, fibrin (sPESI) risk prediction scores provide a tool for identification of degradation products; PT, prothombin time. low- risk and high- risk patients.22 According to ESC guidelines, treatment of high- risk acute PE includes early oxygenation in the severe manifestations of COVID-19 are related to an exagger- form of ventilation if required, ensuring haemodynamic stability, ated inflammatory response. and management of right heart failure, including need for vaso- The preferential target of SARS- CoV-2 is respiratory epithe- pressors and advanced life support in severe cases.23 lium where it mainly enters through the angiotensin-converting The CHEST guidelines provide specific recommendations enzyme 2 (ACE2) receptor into host cells.29 Type-2 pneumocytes regarding choice of anticoagulant with respect to phase of VTE account for about 83% of the ACE2- expressing cells of the lung. treatment.24 In the acute phase, administration of rapidly acting It is also expressed in heart, vasculature, brain, gut and kidneys, parenteral anticoagulant such as UFH, LMWH or fondaparinux which may be responsible for the pathogenesis of the extrapul- is advocated. LMWH and fondaparinux are preferred over UFH monary manifestations. Infection with SARS-CoV -2 causes due to a lower risk of bleeding. DOAC such as apixaban is also downregulation of ACE2, thereby increasing the vulnerability approved for the acute treatment of DVT and PE.25 to the damaging effects to angiotensin 2 (mainly by oxidative Vitamin K antagonists (VKA) with a recommended thera- stress and inflammation). Exaggerated and dysregulated immune peutic INR range of 2 to 3 (target INR 2.5) or DOAC such as response, dysfunction of the ACE2 mediated pathways, endothe- dabigatran or rivaroxaban are preferred for long term (beyond lial damage with thromboinflammation and direct tissue damage 10 days) and extended duration of treatment of PE lasting by viral particles are the possible mechanisms of SARS-CoV -2 beyond 3 months.23 24 Several key clinical trials evaluating VKA mediated extrapulmonary manifestations.28 The commonly for secondary prophylaxis conclude the following. reported extrapulmonary manifestations of COVID-19 are