Rising incidence of thromboembolism secondary to COVID-19 has become a global concern, with several surveys reporting increased mortality rates. Thrombogenic potential of the SARS-CoV-2 virus has been hypothesised to originate from its ability to produce an exaggerated inflammatory response leading to endothelial dysfunction. Anticoagulants have remained the primary modality of treatment of thromboembolism for decades. However, there is no universal consensus regarding the timing, dosage and duration of anticoagulation in COVID-19 as well as need for postdischarge prophylaxis. This article seeks to review the present guidelines and recommendations as well as the ongoing trials on use of anticoagulants in COVID-19, identify discrepancies between all these, and provide a comprehensive strategy regarding usage of these drugs in the current pandemic.
- internal medicine
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The novel beta-coronavirus, appropriately named SARS-CoV-2 by the International Committee of Taxonomy of Viruses, belongs to a family of single-stranded RNA viruses, members of which have been recognised as causative agents of the SARS-CoV and Middle East respiratory syndrome coronavirus outbreak in 2002 and 2012, respectively.1 2 Presently, the novel COVID-19 poses a major global health crisis, having been declared a pandemic on 11 March 2020 by the WHO.
Over the past several months, an overwhelming amount of literature suggests an increased risk of thromboembolic manifestations associated with COVID-19.2 Several hypotheses have been suggested to understand the underlying pathophysiology behind development of a prothrombotic state in COVID-19 such as exaggerated inflammatory response resulting in activation of the coagulation cascade and endothelial injury.3 4 Usage of anticoagulants in COVID-19 remains an area of conjecture with no definite guidelines published to date highlighting the timing, dosage and duration of anticoagulation as well as the drug of choice. Most internationally published guidelines, based on consensus statements and expert opinions, recommend therapeutic doses of heparin only in patients diagnosed with or highly suspected of developing macrothrombi such as pulmonary embolism (PE) or deep vein thrombosis (DVT). However, these guidelines including those by CHEST, rarely address the requirement of postdischarge thromboprophylaxis.5
Anticoagulant types and uses
Anticoagulants have been the mainstay of prevention and treatment of thrombosis for decades.6 Based on their mechanisms of action, they have been classified into broad categories.
Heparin was the first true anticoagulant. Purified heparin, including unfractionated heparin (UFH) and low-molecular weight heparin (LMWH), act by promoting formation of an intermediate protease–heparin–antithrombin complex which facilitates inhibition of thrombin and activated factor X.7 It is used for prevention and treatment of macrothrombi such as DVT and PE, in patients undergoing dialysis, extracorporeal circulation and cardiovascular and orthopaedic surgeries and in candidates for invasive procedures such as percutaneous coronary intervention. Bleeding is a major disadvantage of heparin as well as thrombocytopaenia (in up to 30% of patients), alopecia, injection site reaction and hyperkalaemia.8
Historically, vitamin K antagonists such as warfarin (dicoumarol) and other coumarin derivatives were one of the earliest anticoagulants to be approved for clinical use.9 Warfarin is a competitive inhibitor of VKORC1, resulting in decreased hepatic synthesis of vitamin K-dependent clotting factors as well as Protein C and Protein S. Warfarin therapy requires close monitoring due to a narrow therapeutic window, drug interactions and wide dosing range needed for maintaining therapeutic international normalised ratio (INR).
Development of direct oral anticoagulants (DOACs) ensured a higher safety profile with greater efficacy requiring less frequent dose monitoring.10 11 These include two classes of drugs, namely direct thrombin inhibitors such as dabigatran and direct factor Xa inhibitors like apixaban, edoxaban and rivaroxaban.12 Non-bleeding adverse effects of these drugs are rare, but include severe liver injury and gastrointestinal disorders.13 A major disadvantage of new oral anticoagulants lies in the present global unavailability of specific reversal agents. While idarucizumab and andexanet alfa are two such drugs approved for use in the USA as well as EU, other reversal agents are under development.14
Fondaparinux was approved for use in the USA in 2001 as an indirect inhibitor of factor Xa, which achieves anticoagulation by binding to and activating antithrombin.15 Toxicity of fondaparinux is complicated by its long half-life.
Selection of the ideal anticoagulant for any disease takes into account various patient-specific factors such as the underlying thromboembolic state, for example ischaemic stroke or atrial fibrillation, as well as acceptable bleeding risk and presence of co-morbidities such as hepatic or renal disease.16
Role of anticoagulants in PE
Acute PE has a mortality rate as high as 30% in the first month, with up to 30% survivors experiencing recurrence or chronic disabilities.17 18 With an annual incidence rate ranging from 0.2 to 0.8/1000, PE has been hypothesised to have multifactorial etiologies.19–21
Acute PE warrants mandatory risk stratification to determine appropriate therapeutic intervention. Models such as the Pulmonary Embolism Severity Index (PESI) and the simplified-PESI (sPESI) risk prediction scores provide a tool for identification of low-risk and high-risk patients.22 According to ESC guidelines, treatment of high-risk acute PE includes early oxygenation in the form of ventilation if required, ensuring haemodynamic stability, and management of right heart failure, including need for vasopressors and advanced life support in severe cases.23
The CHEST guidelines provide specific recommendations regarding choice of anticoagulant with respect to phase of VTE treatment.24 In the acute phase, administration of rapidly acting parenteral anticoagulant such as UFH, LMWH or fondaparinux is advocated. LMWH and fondaparinux are preferred over UFH due to a lower risk of bleeding. DOAC such as apixaban is also approved for the acute treatment of DVT and PE.25
Vitamin K antagonists (VKA) with a recommended therapeutic INR range of 2 to 3 (target INR 2.5) or DOAC such as dabigatran or rivaroxaban are preferred for long term (beyond 10 days) and extended duration of treatment of PE lasting beyond 3 months.23 24 Several key clinical trials evaluating VKA for secondary prophylaxis conclude the following.
VKA treatment should be continued for a period of at least 3 months.
Risk of recurrence of VTE following shorter duration of prophylaxis (3–6 months) is greater compared with a longer duration of 12–24 months.
Fernandes et al estimated that extended anticoagulation can reduce risk of recurrence of VTE by up to 95%.26 However, such a benefit is offset by an increased risk of bleeding.
Disease spectrum of COVID-19
The clinical manifestations of COVID-19 is associated with a broad spectrum of clinical respiratory illness, ranging from mild variety of upper respiratory tract infection to the severe form of disease such as, severe life-threatening pneumonia, acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and death in a substantial proportion of patients.27 Apart from the characteristic respiratory illness, it has also seen to be associated with florid extrapulmonary manifestations.28 Most of the severe manifestations of COVID-19 are related to an exaggerated inflammatory response.
The preferential target of SARS-CoV-2 is respiratory epithelium where it mainly enters through the angiotensin-converting enzyme 2 (ACE2) receptor into host cells.29 Type-2 pneumocytes account for about 83% of the ACE2-expressing cells of the lung. It is also expressed in heart, vasculature, brain, gut and kidneys, which may be responsible for the pathogenesis of the extrapulmonary manifestations. Infection with SARS-CoV-2 causes downregulation of ACE2, thereby increasing the vulnerability to the damaging effects to angiotensin 2 (mainly by oxidative stress and inflammation). Exaggerated and dysregulated immune response, dysfunction of the ACE2 mediated pathways, endothelial damage with thromboinflammation and direct tissue damage by viral particles are the possible mechanisms of SARS-CoV-2 mediated extrapulmonary manifestations.28 The commonly reported extrapulmonary manifestations of COVID-19 are described in table 1.
Coagulation abnormalities in COVID-19
Though respiratory manifestations are the hallmark of the disease, over the past several months, an overwhelming amount of literature suggests that COVID-19, caused by SARS-CoV-2, is associated with several coagulation abnormalities which may be responsible for thrombotic manifestations related to this disease such as venous thromboembolism (VTE) and PE.2
Tang et al in a study of 183 patients of COVID-19 pneumonia presented primary data highlighting changes in coagulation parameters among survivors and non-survivors.30 After secondary analysis of this data, we have noted drastic increases in prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, d-dimer and fibrin degradation products (FDP) and a sharp decline in antithrombin levels among non-survivors as compared with survivors. The changes have been formulated into a table 2.
A study of 1561 patients with laboratory-confirmed COVID-19 by Yu and colleagues also showed significant elevation of coagulation parameters.31 The study reported a 260.00% increase in d-dimer in patients of severe disease, with levels ranging from 0.9 to 4.6 µg/mL with a median of 1.8 µg/mL. The changes in various coagulation parameters following COVID-19 in this study are described in table 2. Guan et al noted abnormally increased d-dimer levels in 260 (46.4%) of 560 cases with a prevalence of 43% and 60% in non-severe and critically ill intensive care unit (ICU) patients respectively.32
The exact mechanism of coagulation dysfunction in patients with COVID-19 is unknown. The SARS-CoV-2 does not have any intrinsic procoagulant activity. Several hypotheses have been suggested to understand the underlying pathophysiology behind development of a prothrombotic state in COVID-19.33 One possible explanation studies the effect of SARS-CoV-2 infection on the individual processes involved in the Virchow triad namely endothelial injury, stasis of blood flow and hypercoagulable state.3
The thrombogenic potential of this virus is mainly attributed to the combined effect of the profound inflammatory response along with thromboinflammation and endothelial damage. Novel coronavirus is reported to cause endothelial dysfunction by an ACE2-mediated pathway with an exaggerated inflammatory response in several patients, especially those with severe diseases.4 COVID-19 has also been associated with hyperviscosity. In a study by Maier et al, all 15 patients evaluated showed plasma viscosity greater than 95% of normal.34 Inhibition of plasminogen system, platelet dysfunction and complement activation in COVID-19 are some of the other factors responsible for development of a hypercoagulable state. Use of central venous catheters and mechanical ventilation along with prolonged immobilisation in critically ill patients may act as additional risk factors for thromboembolism (TE).35
A possible association between development of antiphospholipid antibodies, notably lupus anticoagulant (LAC), and COVID-19 has been identified in multiple studies, which may also contribute to hypercoagulability. Bowles et al found presence of LAC in 31 of 34 diagnosed patients with elevated aPTT.36 Harzallah et al further reported 25 LAC positive cases out of 56 patients in an independent study based in Mulhouse, France.37
Incidence of TE has been reported in about 20%–30% of patients in a few studies, whereas some other studies have reported this to be as high as 70%.38 A study from China predicted that upto 40% of patients had a higher risk of developing DVT according to the Padua Prediction Score.39 A French prospective cohort reported development of PE despite prophylactic anticoagulation in 16.7% of patients.40 A Dutch study reported an incidence of VTE of 27% despite prophylaxis.41 An Italian study found a VTE rate of 22.2%.42
The evidence of vasculopathy and thrombosis has also been seen in several reports of autopsy lung tissue in patients died of severe disease. Ackermann et al examined seven lung samples from patients died of severe COVID-19 and found that, apart from the diffuse alveolar damage and perivascular T-cell infiltration, there was severe endothelial damage and enhanced angiogenesis along with widespread thrombosis in pulmonary vasculature.43
A weak association may also be present between current treatment modalities for COVID-19 and blood coagulation. However, evidence in this field is severely lacking. Corticosteroids have been known to result in an increased VTE risk. However, the RECOVERY trial has greatly advocated use of low-dose corticosteroids, namely dexamethasone, in combating inflammation and ‘cytokine storm’ secondary to SARS-CoV-2 infection.44 The possible mechanism suggested is a decrease in fibrinogen and procoagulant factors with an increase in anticoagulant factors. A few studies have also tried to evaluate procoagulant effects of remdesivir. In a study by Grein et al, 3 (5.66%) out of 53 patients diagnosed with COVID-19 developed DVT following administration of remdesivir.45 However, greater understanding in this regard is warranted.
Mortality secondary to coagulopathy in COVID-19
The incidence of TE in COVID-19 varies widely in different published reports. The strength of association between the mortality in patients with COVID-19 and TE is also a matter of debate. The thromboembolic manifestations are seen to be related to an increased mortality and morbidity in patients with COVID-19 in several studies.
A study by Zhang et al showed a higher mortality in patients with COVID-19 with TE.46 Another study conducted by Tang et al revealed significantly higher levels of d‐dimer and FDPs at the time of admission among the non-survivor group, thereby indicating poorer prognosis in patients with novel coronavirus pneumonia with coagulopathy.47 A meta-analysis conducted by Malas et al reported an overall arterial thromboembolism (ATE) rate of 2%, VTE rate of 21%, DVT rate of 20% and PE rate of 13% among SARS-COV-2 infected individuals. The rate of ATE, VTE, DVT and PE were 5%, 31%, 28% and 19%, respectively in case of ICU patients.38 They also reported that the odds of mortality were significantly increased by TE (as high as 74%).
In contrast, a study by Hippensteel et al found no significant difference in mortality among the critically ill patients, though they found a higher prevalence of VTE in critically ill patients with COVID-19.48
However, as all the patients with COVID-19 are not routinely screened for PE, therefore the reported incidence and mortality secondary to it, may differ from the reported figures.
Trials and guidelines
The ongoing randomised control trials (RCTs) are yet to provide concrete evidence on definitive role of anticoagulation in COVID-19, though results are promising. The ongoing RCTs have been elaborated in table 3.49
Anticoagulants in COVID—the present consensus
To the best of our knowledge, no single RCT or a large dependable observational study has neither been completed nor published highlighting the timing, dosage, choice and duration of anticoagulation in patients with COVID-19. All RCTs are ongoing.49 The guidelines, published internationally until, are based on consensus statements and expert opinions only. Some of these guidelines clearly mention the percentage of experts in the panel agreeing to a certain recommendation and the percentage recommending otherwise.56 57
Thus, a current dearth of useful strategy concerning use of anticoagulants in COVID-19 exists. This grey area is still evolving and, hence, clinical judgement is necessary on case to case basis. The main limitation of available guidelines lies in recognising COVID-19 as a cause of microthrombi, leading to worsening prognosis of patients, but being unable to provide consensus statements or guidelines to appropriately address this issue. All the guidelines recommend heparin in therapeutic doses only in diagnosed or highly suspected macrothrombi (PE/DVT), while ignoring the issue of undiagnosable microthrombi. There is no separate scoring system to assess VTE risk on admission specific to COVID-19. Although significantly elevated levels of d-dimer are more likely to be associated with VTE, it is difficult at this point to identify the threshold that can only be used to diagnose thrombus non-invasively.58 Rather, the decision for further diagnostic imaging should be based on overall clinical assessment. d-dimer may be useful in investigating a possible acute VTE/PE in patients who develop new or worsening breathlessness. However, it has been universally accepted that although a high d-dimer level is a proven poor prognostic factor, it should not guide anticoagulant dosage or escalation. A single-centre randomised trial (n=20) was performed to compare the efficacy of prophylactic and therapeutic anticoagulation in critically ill ventilated patients with high d-dimer level (>1000 µg/L).59 They showed significant improvement in the oxygenation in the therapeutic anticoagulation group, though no difference was observed among both the arms regarding in-hospital or 28-day mortality.
Two small case series, one from All India Institute of Medical Sciences (AIIMS), Rishikesh, and another from abroad, have been successful in using recombinant tissue plasminogen activator (rTPA) in refractory hypoxaemia in ARDS (even in cases without a CT pulmonary angiography diagnosed PE).60 However, no consensus guideline has supported this endeavour so far. RCT on use of rTPA is ongoing. Thus, there is huge scope for clinician’s judgement while escalating anticoagulant dosing till more data are available.
As of now, after considering all expert opinion and consensus statements, we have come to the following conclusions:
Parenteral anticoagulants are indicated in any acutely ill hospitalised patients. Hence, it is indicated in moderate, severe and critical disease.
LMWH/fondaparinaux is preferred over UFH, due to lesser patient contact of healthcare staff and no need of aPTT monitoring (necessitating patient contacts).
Enoxaparin is the most preferred LMWH.
Dosing of anticoagulation:
Moderate disease (standard risk patient): standard weight-adjusted prophylactic dose (eg, enoxaparin 40 mg once daily for a 70 kg adult with CrCl >30 mL/min).
Severe and critical disease (high-risk patient: requiring invasive ventilation/continuous positive airway pressure (CPAP)/non-invasive ventilation (NIV)/high-flow nasal oxygen): intermediate dose LMWH (enoxaparin 40 mg two times per day for a 70 kg adult with CrCl >30 mL/min).
Diagnosed/highly suspected macrothrombosis (PE/DVT): therapeutic dose (enoxaparin 1 mg/kg 12 hourly subcutaneous or 1.5 mg/kg subcutaneously once daily).
Renal insufficiency: enoxaparin with dose reduction is the preferred over other LMWH drugs/fondaparinaux. UFH with aPTT monitoring indicated at eGFR <15 mL/min.
Post discharge prophylaxis in COVID-19
Postdischarge thromboprophylaxis following COVID-19 remains an issue of much debate. Routine administration of oral anticoagulants in all patients with COVID-19 at the time of discharge is not recommended. The American College of Chest Physicians guidelines published in CHEST as well as the American College of Cardiology guidelines published in the Journal of the American College of Cardiology (JACC) do not elucidate on postdischarge thromboprophylaxis.5 55
The CHEST consensus statement clearly refutes it due to lack of evidence. However, NIH guidelines, updated on 11 February, as well as ISTH guidelines, BTS guidelines and SIGN (Scottish guidelines) mention post discharge thromboprophylaxis, based on expert opinion.50 51 61 62
Decisions regarding postdischarge prophylactic anticoagulation should be individualised. Based on present recommendations as well as past and ongoing trials regarding usage of anticoagulants, we can conclude that patients with moderate to severe disease and fulfilling any one of the following criteria would be the ideal candidates for postdischarge thromboprophylaxis50:
Modified IMPROVE VTE (MIV) score (table 5) ≥4
MIV ≥2 with a d-dimer value >2 times the upper limit of normal range
Age ≥75 years
Age >60 years with a d-dimer value >2 times the upper limit of normal range
Age 40–60 years with a d-dimer value >2 times the upper limit of normal range and history of VTE or with diagnosed malignancy
Candidates, thus, selected should be assessed for VTE risk using the MIV score.63 This can be counter balanced against bleeding risk by the VTE BLEED or HASBLED score. If no bleeding risk is ascertained, patient can be discharged on postdischarge prophylaxis. There is no role of routine measurement of d-dimer during postdischarge follow-up. DOACs do not require INR monitoring and, hence, are preferred over VKAs in this regard. Preferred DOACs include rivaroxaban (10 mg once a day), betrixaban (160 mg on the first day followed by 80 mg once a day) and apixaban (2.5 mg two times per day) as per studies.63 64
In renal insufficiency, warfarin is preferred over DOACs with INR monitoring. However, at eGFR 30–15 mL/min, apixaban 2.5 mg two times per day may be used. At eGFR <15 mL/min and patients with ESRD on dialysis, it is preferably better to avoid DOACs. The FDA has approved apixaban 2.5 mg two times per day at eGFR <15 mL/min and 5 mg two times per day in patients with ESRD on dialysis since it is partially dialysable. However, as European guidelines negate usage of DOACs at eGFR <15 mL/min, avoiding administration of these drugs in such a clinical scenario may be wise.
Regarding duration, the FDA recommends use of rivaroxaban (10 mg daily) for 31 to 39 days and betrixaban (160 mg on the first day followed by 80 mg once a day) for 35 to 42 days.50 ACC suggested extended thromboprophylaxis with LMWH or DOACs for a maximum period of 45 days in case of high risk for VTE such as, d-dimer level of more than two times the upper limit of normal or presence of active cancer.55 The SCC-ISTH suggests duration of 14–30 days for thromboprophylaxis.54
Increased mortality secondary to COVID-19 has necessitated need for definitive guidelines addressing timing, choice, duration and dosage of anticoagulation in patients diagnosed with the novel coronavirus. As most RCTs as well as observational studies are ongoing with multiple conflicting guidelines, a concrete strategy is yet to be devised. Most clinicians have resorted to individual bias in treatment of patients with anticoagulants, with decisions varying case to case as per individual patient profile. After thorough research of existing protocols, current knowledge and ongoing trials, we have identified areas of information deficiency pertaining to usage of anticoagulants in management of COVID-19 and attempted to condense all available strategies to formulate a single guideline to direct anticoagulation treatment. We recommend anticoagulation with enoxaparin in moderate to severe cases of COVID-19 along with postdischarge prophylaxis to prevent possible undiagnosed microthrombi with DOACs such as rivaroxaban and apixaban. We encourage further research on the aforementioned conclusions drawn and recommendations made by us to help in the better treatment of mankind during this pandemic.
VTE secondary to COVID-19 has resulted in higher mortality.
A vast majority of patients present with undiagnosed thromboembolism following COVID-19.
Anticoagulation in moderate to severe and critical cases of COVID-19 is advisable.
Enoxaparin is the preferred low-molecular weight heparin for anticoagulation in acute phase of venous thromboembolism.
Postdischarge prophylaxis may be considered in patients with high risk of thromboembolic events after assessing the bleeding risk.
Rivaroxaban and apixaban are preferred for post discharge prophylaxis.
Current research questions
Should postdischarge prophylaxis with anticoagulants be recommended in all hospitalised patients of COVID-19?
If yes, what should be the duration of such prophylaxis?
Should direct oral anticoagulants be used in patients of COVID-19 with renal insufficiency?
Miesbach W, Makris M. COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation. Clin Appl Thromb Hemost 2020;26:1076029620938149.
Kearon C, Akl EA, Comerota AJ, et al. Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S–96S.
Gupta A, Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26(7):1017–32. doi: 10.1038/s41591-020-0968-3.
Flaczyk A, Rosovsky RP, Reed CT, et al. Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations. Crit Care. 2020;24(1):559. doi: 10.1186/s13054-020-03273-y.
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/.
Self assessment questions
Which of the following are extrapulmonary manifestations of COVID-19?
Acute kidney injury
COVID-19 contributes to coagulopathy by all of the following mechanisms except?
Inflammation producing endothelial damage
Activation of Factor X
Which of the following anticoagulants are preferred in patients with COVID-19 with renal insufficiency?
Which of the following anticoagulants are preferred for postdischarge prophylaxis of COVID-19 patients?
Which factors should be considered before prescribing postdischarge prophylaxis in patients with COVID-19?
Presence of secondary bacterial infection
a. True b. True c. False d. True e. False
a. False b. False c. True d. False
a. False b. False c. True d. True e. False
a. False b. False c. False d. True e. True
a. True b. True c. True d. True e. False
Contributors AC, UC and SG prepared the manuscript with adequate planning and execution. SD contributed to review of literature, critical revision of content and final approval of manuscript. All authors are in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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