thromboembolism secondary to COVID-19

► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ postgradmedj-2021-139923).

1Internal Medicine, RG Kar Medical College and Hospital, Kolkata, India
2Neurology, Institute of Postgraduate Medical Education and Research, Bangur Institute of Neurology, Kolkata, West Bengal, India

3Critical Care Medicine, RG Kar Medical College and Hospital, Kolkata, West Bengal, India

Correspondence to

Dr Atanu Chandra, Internal medicine, RG Kar Medical College, Kolkata, India; chandraatanu123@gmail.com

Received 8 February 2021 Revised 11 March 2021 Accepted 24 March 2021

Atanu Chandra ,1 Uddalak Chakraborty

ABSTRACT

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 in ammatory 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.

INTRODUCTION

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 Pres- ently, 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 pathophys- iology behind development of a prothrombotic state in COVID-19 such as exaggerated inflamma- tory response resulting in activation of the coagu- lation 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 postdis- charge thromboprophylaxis.5

,2 Shrestha Ghosh,1 Sugata Dasgupta3

ANTICOAGULANT TYPES AND USES

Anticoagulants have been the mainstay of preven- tion 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 dial- ysis, extracorporeal circulation and cardiovascular and orthopaedic surgeries and in candidates for invasive procedures such as percutaneous coro- nary 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 deriva- tives were one of the earliest anticoagulants to be approved for clinical use.9 Warfarin is a competi- tive 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 moni- toring.10 11 These include two classes of drugs, namely direct thrombin inhibitors such as dabig- atran and direct factor Xa inhibitors like apix- aban, 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 acti- vating 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

Anticoagulation in COVID-19: current concepts and controversies

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© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

To cite: Chandra A, Chakraborty U, Ghosh S,
et al
. Postgrad Med J Epub ahead of print: [please include Day Month Year]. doi:10.1136/ postgradmedj-2021-139923

Chandra A, et al. Postgrad Med J 2021;0:1–8. doi:10.1136/postgradmedj-2021-139923 1

  

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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 Pulmo- nary 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 vaso- pressors 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 thera- peutic 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.

1. VKA treatment should be continued for a period of at least 3 months.

2. 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 associ- ated with florid extrapulmonary manifestations.28 Most of the

severe manifestations of COVID-19 are related to an exagger- ated inflammatory response.

The preferential target of SARS-CoV-2 is respiratory epithe- lium 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 extrapul- monary 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, endothe- lial 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 pneu- monia presented primary data highlighting changes in coagu- lation 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.

Table 2 Changes in various coagulation parameters following COVID-19 in a study by Yu et al

Coagulation parameter

Survivors n=162

Non-survivors n=21

Percentage difference

PT 13.6 s 15.5 s 13.97

aPTT

41.2 s

44.8 s

8.74

Fibrinogen 4.51 g/L 5.16 g/L 14.41

d-dimer

0.61 mcg/mL

2.12 mcg/mL

247.54

FDP 4 mcg/mL 7.6 mcg/mL 90.00

AT

91%

84%

−7.69

aPTT, activated partial thromboplastin time; AT, antithrombin; FDP, brin degradation products; PT, prothombin time.

Table 1 The commonly reported extrapulmonary manifestations of COVID-19

Organ system

Manifestations

Neurologic Anosmia, cerebrovascular accident, ageusia, encephalopathy, Guillain-Barré syndrome, acute transverse myelitis

Renal

Acute kidney injury, haematuria, proteinuria

Cardiac Myocarditis, coronary artery disease, cardiogenic shock, acute cor pulmonale, stress cardiomyopathy

Gastrointestinal

Nausea/vomiting, diarrhoea, anorexia, hepatocellular injury

Endocrine Hyperglycaemic, diabetic ketoacidosis

Dermatological

Urticaria, erythematous rash, petechaie, purpura fulminans

Thromboembolism DVT, PE, catheter-related thrombosis

DVT, deep vein thrombosis; PE, pulmonary embolism.

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A study of 1561 patients with laboratory-confirmed COVID-19 by Yu and colleagues also showed significant eleva- tion 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 4.6μg/mL with a median of 1.8μg/mL. The changes in various coagulation parameters following COVID-19 in this study are described in table 2. Guan et al noted abnor- mally 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 infec- tion on the individual processes involved in the Virchow triad namely endothelial injury, stasis of blood flow and hypercoag- ulable 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 inflamma- tory response in several patients, especially those with severe diseases.4 COVID-19 has also been associated with hypervis- cosity. 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 acti- vation 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 antiphos- pholipid antibodies, notably lupus anticoagulant (LAC), and COVID-19 has been identified in multiple studies, which may also contribute to hypercoagulability. Bowles et al found pres- ence 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 devel- oping DVT according to the Padua Prediction Score.39 A French prospective cohort reported development of PE despite prophy- lactic 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 infil- tration, 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 treat- ment 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 corti- costeroids, namely dexamethasone, in combating inflammation

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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

Several international guidelines have been formulated on the use of anticoagulation in COVID-19. Some of the salient guide- lines and respective recommendations have been tabulated in table 4.5 50–55

ANTICOAGULANTS IN COVID—THE PRESENT CONSENSUS

To the best of our knowledge, no single RCT or a large depend- able 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

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Table 3 Ongoing RCTs on role of anticoagulation in COVID-19

Name

Identi er

Location

Type of study

Active comparator

Intervention/ treatment arm

Primary outcome

Phase of trial

Anticoagulation in patients suffering from COVID-19 (the ANTI- CO Trial)

NCT04445935

Hamad Medical Corporation, Qatar, Doha

Triple-blinded RCT

Standard anticoagulation with LMWH/UFH

Intravenous bivalirudin according to the institutional HIT protocol.

P/F ratio (time 4 frame: 3 days of intervention).

Anticoagulation in critically ill patients with COVID-19 (the IMPACT Trial)

NCT04406389

Weill Cornell Medicine New York, USA

Open-labelled RCT

Intermediate dose prophylaxis drug: enoxaparin, UFH, fondaparinux

Therapeutic dose anticoagulation drug: enoxaparin, UFH, fondaparinux, argatroban.

30-Day mortality.

4

Coagulopathy of COVID-19: a pragmatic RCT of therapeutic anticoagulation vs standard care

NCT04362085

St. Michael’s Hospital, Toronto, Canada

Two arm, parallel, pragmatic, multicentre, open-label RCT

Standard Care LMWH, UFH fondaparinux at thromboprophylactic doses for acutely ill hospitalised medical patients

Therapeutic anticoagulation LMWH or UFH (high-dose nomogram) will be administered until discharged from hospital, 28 days or death.

ICU admission, non- 3 invasive positive pressure ventilation, invasive mechanical ventilation, all-cause death (yes/no) up to

28 days.

FREEDOM COVID-19 anticoagulation strategy

NCT04512079

· Icahn School
of Medicine at Mount Sinai New York, New York, USA

Prospective, multicentre, open label, randomised controlled comparative safety and effectiveness trial

1. Prophylactic enoxaparin. 2. Full-dose enoxaparin

Apixaban (5 mg every 12 hours; 2.5 mg every 12 hours for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL).

Time to rst events Number of in-hospital rate of BARC 3 or 5 (time frame for both: 30 days).

4

Intermediate or prophylactic-dose anticoagulation for venous or arterial TE in severe COVID-19

NCT04367831

Columbia University Medical Center New York, New York, USA

Single-blind parallel RCT Prophylactic dose anticoagulation with

enoxaparin, UFH.

Intermediate-dose anticoagulation with UFH infusion or enoxaparin intermediate dose.

Total number 4 of patients with clinically relevant venous or arterial thrombotic events

in ICU (time frame: discharge from ICU or 30 days).

Full anticoagulation vs prophylaxis in COVID-19: COALIZAO ACTION Trial

NCT04394377

Bahia, Brazil

Single-blinded parallel, multicentric RCT

Usual standard of care with prophylactic dose of enoxaparin

Rivaroxaban 20 mg/ day followed by enoxaparin/UFH when needed.

Mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days.

4

Tenecteplase in patients with COVID-19

NCT04505592

Mount Sinai Hospital New York, USA

Placebo-controlled, double-blind, RCT

Placebo control

Tenecteplase

Number of 2 participants free of respiratory failure Number of

occurrences of bleeding (time frame for both: 28 days).

Antithrombotics for adults hospitalised With COVID-19 (ACTIV-4)

NCT04505774

NYU Langone New York, New York, USA

Multicentre, adaptive, randomised controlled platform trial

Prophylactic dose anticoagulation heparin standard of care

Therapeutic dose anticoagulation increased dose of heparin above standard of care.

21-Day organ support (respiratory or vasopressor) free days.

4

Preventing COVID-19 complications with low-dose and high- dose anticoagulation

NCT04345848

Switzerland

Open-label RCT

Prophylactic doses of enoxaparin or UFH. If in intensive care augmented thromboprophylaxis

Therapeutic doses
of enoxaparin or intravenous UFH, from admission until the end of hospital stay or clinical recovery.

Composite outcome 4 of arterial or venous thrombosis, DIC and all-cause mortality

(time frame: 30 days).

Full-dose heparin
vs prophylactic or intermediate dose heparin in high-risk patients with COVID-19

NCT04401293

New York, USA

Open-label multicentre randomised active control trial

Prophylactic/intermediate dose LMWH or UFH therapy

Full-dose LMWH anticoagulation therapy.

Composite
outcome of arterial thromboembolic events, VTE events and all-cause mortality at day 30 ± 2 days.

3

BARC, Bleeding Academic Research Consortium; ICU, intensive care unit; LMWH, low-molecular weight heparin; P/F ratio, PaO2/FiO2 ratio; RCT, randomised control trial; UFH, unfractionated heparin; VTE, venous thromboembolism.

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Table 4 Current guidelines and recommendations on use of anticoagulation in COVID-19

Guideline

Consideration of therapeutic anticoagulation

Duration of therapeutic anticoagulation

Consideration of thrombolysis

Monitoring of patients receiving therapeutic anticoagulation

Termination of anticoagulation

Mechanical thromboprophylaxis

CDC50 Clinically suspected thromboembolic events

or high suspicion despite of normal imaging ndings.

No mention

Inconclusive data. In pregnancy with acute PE and haemodynamic instability, thrombolysis may be used

As per standard care in patients without COVID-19.

Active bleeding severe thrombocytopaenia.

No mention

ISTH-IG51

No recommendations

No mention

No mention

No mention

Active bleeding or platelets <25 × 109/L.

No mention

ACF52

Clinically suspected thromboembolic events or high suspicion despite of normal imaging ndings.

3 Months course for patients initiated
on anticoagulation during hospitalisation (except in recent bleeding or high bleeding risk).

STEMI, acute ischaemic stroke, or high-risk massive PE with haemodynamic instability.

Monitor anti-Xa levels in UFH. Monitor anti- Xa or PTT in patients with normal baseline PTT levels and no heparin resistance (> 35 000 u heparin over 24 hours).

Active bleeding
or profound thrombocytopaenia

Intermittent pneumatic compression if contraindication to pharmacological thromboprophylaxis. Both mechanical and pharmacological thromboprophylaxis in critically ill patients if no contraindication.

ASH53

Increasing the intensity of anticoagulation regimen or change anticoagulants in patients with recurrent thrombosis of catheters and extracorporeal circuits (ie, ECMO, CRRT) on prophylactic anticoagulation regimens.

No mention

No mention

Anti-Xa monitoring of UFH.

Active bleeding and platelet count < 25
× 109/L or brinogen <0.5 g/L. Therapeutic anticoagulation may need to be held if platelet count <30–50 × 109/L or brinogen <1.0 g/L.

Mechanical thromboprophylaxis when pharmacological thromboprophylaxis is contraindicated.

SCC-ISTH54

Therapeutic anticoagulation not
to be considered for primary prevention. Increased intensity of anticoagulation regimen can be considered
in patients without con rmed VTE or PE
but have deteriorating pulmonary status or ARDS.

Minimum 3 months

No mention

No speci c recommendations.

No speci c recommendations.

Mechanical thromboprophylaxis if pharmacological therapy contraindicated.

ACC55

Therapeutic anticoagulation in VTE. Haemodynamically stable patients with submassive PE.

No mention

Systemic brinolysis is indicated for haemodynamically high-risk PE.

No mention

Suspected or con rmed DIC without overt bleeding.

Mechanical thromboprophylaxis considered in immobilised patients if pharmacological prophylaxis is contraindicated.

ACCP5 PE or proximal DVT Minimum 3 months No mention Anti-Xa levels in all patients receiving

UFH given potential of heparin resistance.

No mention

Mechanical thromboprophylaxis
in critically ill patients who have a contraindication to pharmacological thromboprophylaxis.

ACC, American College of Cardiology; ACCP, American College of Chest Physicians; ACF, Anticoagulation Forum; ARDS, acute respiratory distress syndrome; ASH, American Society of Hematology; CDC, Centers for Disease Control and Prevention; CRRT, continuous renal replacement therapy; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; ISTH-IG, International Society of Thrombosis and Hemostasis Interim Guidance; PE, pulmonary embolism; PTT, partial thromboplastin time; SCC-ISTH, Scienti c and Standardization Committee of ISTH; STEMI, ST elevation myocardial infarction; UFH, unfractionated heparin.

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 diffi- cult 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

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assessment. d-dimer may be useful in investigating a possible acute VTE/PE in patients who develop new or worsening breath- lessness. 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 effi- cacy of prophylactic and therapeutic anticoagulation in critically ill ventilated patients with high d-dimer level (>1000μg/L).59 They showed significant improvement in the oxygenation in the

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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 acti- vator (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:

1. Parenteral anticoagulants are indicated in any acutely ill hos-
pitalised patients. Hence, it is indicated in moderate, severe
and critical disease.

2. LMWH/fondaparinaux is preferred over UFH, due to lesser
patient contact of healthcare staff and no need of aPTT mon-
itoring (necessitating patient contacts).

3. Enoxaparin is the most preferred LMWH.

4. Dosing of anticoagulation:

i. Moderate disease (standard risk patient): standard weight-adjusted prophylactic dose (eg, enoxaparin 40 mg once daily for a 70kg adult with CrCl >30mL/min).

ii. 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 40mg two times per day for a 70kg adult with CrCl >30mL/ min).

iii. Diagnosed/highly suspected macrothrombosis (PE/DVT): therapeutic dose (enoxaparin 1 mg/kg 12 hourly subcuta- neous or 1.5mg/kg subcutaneously once daily).

iv. 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 Amer- ican 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 anticoagula- tion should be individualised. Based on present recommendations as well as past and ongoing trials regarding usage of anticoag- ulants, 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:

1. Modified IMPROVE VTE (MIV) score (table 5) ≥4

2. MIV ≥2 with a d-dimer value >2 times the upper limit of
normal range

3. Age ≥75 years

6

4. Age >60 years with a d-dimer value >2 times the upper limit of normal range

5. 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 (10mg once a day), betrixaban (160mg on the first day followed by 80mg 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 2.5mg two times per day may be used. At eGFR <15mL/min and patients with ESRD on dialysis, it is preferably better to avoid DOACs. The FDA has approved apixaban 2.5mg 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

Table 5 Modi ed IMPROVE VTE risk score

VTE risk factor

VTE risk score

Previous VTE 3

Known thrombophilia

2

Current lower limb paralysis or paresis 2

History of cancer

2

ICU/CCU stay 1

Complete immobilisation ≥1 day

1

Age ≥60 years 1

CCU, critical care units; ICU, intensive care unit; IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; VTE, venous thromboembolism.

Main messages

►  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 insuf ciency?

Chandra A, et al. Postgrad Med J 2021;0:1–8. doi:10.1136/postgradmedj-2021-139923

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Review

eGFR <15mL/min, avoiding administration of these drugs in such a clinical scenario may be wise.

Regarding duration, the FDA recommends use of rivaroxaban (10mg daily) for 31 to 39 days and betrixaban (160mg on the first day followed by 80mg 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 14–30days for thromboprophylaxis.54

CONCLUSION

Increased mortality secondary to COVID-19 has necessitated need for definitive guidelines addressing timing, choice, dura- tion 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 knowl- edge 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 strate- gies 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.

Contributors AC, UC and SG prepared the manuscript with adequate planning and execution. SD contributed to review of literature, critical revision of content and nal 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 speci c grant for this research from any funding agency in the public, commercial or not-for-pro t sectors.

Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.

This article is made freely available for use in accordance with BMJ’s website
terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

ORCID iDs

Atanu Chandra http://orcid.org/0000-0002-3809-8926 Uddalak Chakraborty http://orcid.org/0000-0002-1691-6289

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Key references

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Self assessment questions

1. Which of the following are extrapulmonary manifestations of COVID-19?
a. Myocarditis
b. Acute kidney injury c. Endocarditis
d. Encephalopathy
e. Hypoglycaemic

2. COVID-19 contributes to coagulopathy by all of the following mechanisms except?
a. In ammation producing endothelial damage
b. Platelet dysfunction
c. Activation of Factor X
d. Complement activation

3. Which of the following anticoagulants are preferred in
patients with COVID-19 with renal insuf ciency? a. UFH
b. Fondaparinux
c. Enoxaparin
d. Warfarin
e. Rivaroxaban

4. Which of the following anticoagulants are preferred for
postdischarge prophylaxis of COVID-19 patients? a. Fondaparinux
b. Enoxaparin
c. Warfarin
d. Rivaroxaban
e. Apixaban

5. Which factors should be considered before prescribing
postdischarge prophylaxis in patients with COVID-19? a. Previous VTE
b. Known thrombophilia
c. Immobilisation
d. d-dimer level
e. Presence of secondary bacterial infection

Chandra A, et al. Postgrad Med J 2021;0:1–8. doi:10.1136/postgradmedj-2021-139923

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Postgrad Med J: first published as 10.1136/postgradmedj-2021-139923 on 13 April 2021. Downloaded from http://pmj.bmj.com/ on May 13, 2021 at India:BMJ-PG Sponsored. Protected by copyright.

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Answers

1. a. True b. True c. False d. True e. False 2. a. False b. False c. True d. False
3. a. False b. False c. True d. True e. False 4. a. False b. False c. False d. True e. True 5. a. True b. True c. True d. True e. False

Chandra A, et al. Postgrad Med J 2021;0:1–8. doi:10.1136/postgradmedj-2021-139923

Postgrad Med J: first published as 10.1136/postgradmedj-2021-139923 on 13 April 2021. Downloaded from http://pmj.bmj.com/ on May 13, 2021 at India:BMJ-PG Sponsored. Protected by copyright.

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