INTRODUCTION
Coronavirus disease 2019 (COVID-19) is associated with both venous and arterial thrombosis and has contributed to the need for intensive care unit (ICU) admission and increased mortality.(1) Of these, venous thromboembolic events (VTE) are more frequent than arterial thromboembolic events (ATE).(1,2) These include pulmonary emboli, with a prevalence rate of 13%–16%,(1,3,4) and deep venous thrombosis which is prevalent in almost a third of COVID-19 hospital admissions.(1,5)
The true prevalence of VTE may be underestimated since investigations such as compression ultrasound or pulmonary vascular imaging is not routinely performed for various reasons, including severity of patient illness, staff exposure concerns and lack of availability.(3) Post-mortem studies also appear to reveal a higher prevalence of VTE than clinical studies.(1)
Arterial emboli are less common (5) and the ATE described in hospitalized COVID-19 patients include myocardial infarction, stroke and arterial occlusion resulting in acute limb ischaemia.(1)
While much experience has been gathered over the last year of the pandemic with regard to the use of anticoagulation in COVID-19 patients, some questions remain unanswered. There is sufficient evidence to warrant a degree of anticoagulation in hospitalized COVID-19 patients, with clear reduction in mortality demonstrated in patients who were anticoagulated compared to those who were not anticoagulated.(6) But due to the limited availability of well-designed randomized controlled trials (RCTs) and mixed data from smaller non-randomized studies, there is controversy about prophylactic anticoagulation with regards to low, intermediate and high dosing strategies.
For enoxaparin the prophylactic dose is a subcutaneous dose of 40 mg daily. Higher intensity dosing includes intermediate dosing, which for enoxaparin is 40 mg twice a day or 1 mg/kg daily and therapeutic dosing which is generally 1 mg/kg twice a day.(7) These doses do need to be adjusted in renal failure, in patients with morbid obesity (BMI > 30) and where heparin resistance is of concern (extremes of body weight, chronic kidney disease and pregnancy).(8) There is also a paucity of data regarding an approach to post hospital discharge anticoagulation.(9,10)
This review aims to explore the current thoughts on the pathogenesis of coagulopathy in COVID-19 and the current status of anticoagulation in hospitalized patients with COVID-19.
PATHOGENESIS OF THROMBOSIS IN COVID PATIENTS
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).(11) After transmission, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE-2) receptors in the upper airways of the host. In a subset of patients at a risk of severe COVID-19, the virus replicates and migrates into the airways and enters the alveolar epithelium in the lungs. The rapid replication within the lungs may trigger a prominent immune response, resulting in the clinical features of pneumonia or acute respiratory distress syndrome.(11) Host immune response is extremely vital to prevent progression to severe and critical COVID-19.(12) There is convincing evidence that coagulopathy plays a key role in the pathogenesis of moderate-to-severe COVID-19.(13)–(15) It is clear that COVID-19-associated coagulopathy (CAC) is a distinct entity, as compared to sepsis-related coagulopathy or disseminated intravascular coagulation. CAC is thought to result from immunothrombosis and is characterized by elevated pro-inflammatory cytokines and activation of platelets, complement and the endothelium.(2) Immunothrombosis, resulting from the pro-inflammatory state coupled with a dysregulated host immune response, is characterized by an excess of immune-mediated thrombi which predominantly affect the microvasculature.(2) Microthrombi are a prominent feature in patients with severe and critical COVID-19.(2,16) Alveolar capillary microthrombi were found to be nine times more prevalent in post-mortem lung samples of those with COVID-19 compared to those with Influenza.(16)
The understanding of this multifactorial process which results from a combination of haemostasis and immune dysregulation can be simplified by examining all three components of Virchow's triad.(14) Vessel wall injury is hypothesized to occur when SARS-CoV-2 binds to ACE-2 receptors present on the endothelial cell, triggering endothelial dysfunction and impairing antithrombotic properties. A hypercoagulable state results from this pro-coagulant effect, with reduction in plasminogen activator and platelet aggregation. The pro-inflammatory state also leads to a downregulation of antithrombin 3 and protein C expression. In addition, there is an increase in levels of plasminogen activator inhibitor, fibrinogen, clotting factors and von Willebrand factor, which all lead to hypercoagulability.(14) Haemostasis and the immune system are interconnected with the innate immune response (monocytes, macrophages and neutrophils) being a key feature of immunothrombosis. When the immune response is dysregulated, there is uncontrolled release of cytokines, including interleukin (IL)-6, interferon gamma and IL-2, which aids in platelet production leading to a pro-thrombotic state. IL-2 specifically attracts neutrophils, which contribute to the formation of thromboses at the site of infection. This predisposes to the formation of neutrophil extracellular traps (NET). The defence mechanism called NETosis plays a role in the pathophysiology of VTE.(2) Venous stasis may result from multiple other factors, including limited mobility due to illness severity, fatigue, hypoxia and heart failure from myocardial dysfunction.(14)
While advances have been made in understanding of the pathogenesis of CAC, more evidence is needed to guide appropriate treatment, specifically treatment targeting the immunopathogenesis of coagulopathy in COVID-19.
INDICATIONS FOR ANTICOAGULATION IN HOSPITALIZED PATIENTS WITH COVID-19
Prophylactic anticoagulation
All patients admitted to hospital with COVID-19, who do not have any indication for therapeutic anticoagulation, should be prescribed anticoagulation for VTE prophylaxis, provided that there are no contraindications.(7,17) The agent of choice is low molecular weight heparin (LMWH), enoxaparin. In addition to inhibition of a hypercoagulable state, LMWH has also been found to have anti-inflammatory effects in patients infected with COVID-19, through an inhibition of release of cytokines such as IL-6, and an attenuation of IL-6 biological activity.(18) The use of anticoagulants in COVID-19 patients has been strongly associated with significant reduction in mortality, and for those who did not survive, there was a delay in death.(6) The largest benefit was observed in patients with more severe disease such as those who needed high amounts of oxygen support with non-invasive and invasive mechanical ventilation.(19,20) While the indication for anticoagulation is clear, there remains controversy regarding the optimal dosing strategy, and specifically whether prophylactic high or low intensity dosing of heparin is most efficient at preventing thrombosis.
Prophylactic (low) dose vs. intermediate/therapeutic (high) dose strategies
In an international survey conducted by Rosovsky et al. in 2020, 500 physicians from 41 countries responded to questions about the type of anticoagulation and dosing strategies.(21) About 78% were in agreement with the prescription of prophylactic anticoagulation for all hospitalized patients with COVID-19, with the drugs of choice being LMWH or unfractionated heparin (UFH). The preferred dose at which the anticoagulants were used for prophylaxis purposes varied significantly among physicians.(21) An intermediate dose of anticoagulation has been recommended by the Enhanced dose THRomboprophylaxis in Admissions (ETHRA) study, as this was associated with a better prognosis without causing any major bleeding.(22) This recommendation was also supported by other studies, which suggested that the higher doses (intermediate to therapeutic level doses) were more effective in the prevention of VTE and reduction in mortality without increased risk of bleeding.(9,10,23)
However, the results from recent RCTs do not support the routine administration of these higher doses of UFH.(24)–(26) First, the INSPIRATION trial compared standard prophylaxis dose to intermediate dose enoxaparin regimen in 600 adult patients admitted to the ICU. This study showed no difference in thrombotic events or mortality at 30 days.(24) The second RCT, which was a multiplatform RCT that harmonized the protocols of the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community Acquired Pneumonia, Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 Antithrombotics Inpatient platform trial and the Antithrombotic Therapy to Ameliorate Complications of COVID-19 trials, is currently published as two preprints which have not yet been peer-reviewed at the time of submission of this review.(25,26) In critically ill patients, there was no improvement in hospital survival in patients given therapeutic anticoagulation in the ICU compared to prophylaxis doses.(25) In patients who were admitted to hospital, but not in the ICU, there was a marginal benefit of therapeutic doses over prophylactic doses, which became more impactful in those patients with d-dimer levels >2 times the upper limit of normal. These patients tended to be older with comorbidities, and these risk factors could possibly be used as a surrogate in settings where d-dimer monitoring is not routinely available.(26)
LMWH, and specifically enoxaparin, is generally the preferred agent due to ease of dosing, given once daily or twice daily if the higher dose strategy is used, followed by UFH. If there is a concern of heparin-induced thrombosis, fondaparinux is a viable alternative agent.(9) The use of direct oral anticoagulants (DOACs) is limited because of potential drug interactions, the inability of oral intake in critically ill patients and mixed results in observational studies.(9) In a study by Billett et al., outcomes were analysed in a cohort of 3625 patients with COVID-19 for the prophylactic and therapeutic use of apixaban. A significant decline in mortality (OR 0.46, P = 0.001) was reported, but it was not superior to mortality decline in those who received enoxaparin (OR 0.49, P = 0.001).(27) Another study by Flam et al., a multicentre cohort of 103,703 patients with COVID-19, found that the use of DOACs was not associated with reduction in mortality.(28)
Higher doses for prophylactic therapy
Higher doses (intermediate to therapeutic level) have been recommended for patients with evidence of severe disease or those with risk factors for more severe disease such as those with obesity, diabetes mellitus, hypertension and advanced age. Deranged coagulation markers such as elevated d-dimer, prothrombin time and FDPs were observed in patients with severe disease, and this led to a suggestion that measuring these could be used as a guide in choosing the appropriate dose of anticoagulation.(29)
However, there needs to be caution with the use of higher doses for prophylaxis as they have been associated with a higher risk of bleeding. This was demonstrated in a systematic review and meta-analysis, which was performed to evaluate the use of anticoagulation and in-hospital mortality from COVID-19.(30) Seventeen studies (N = 17,833) were aggregated in the meta-analysis. Pooled odds ratios of in-hospital mortality and bleeding were estimated, comparing the adverse outcomes among the intermediate-to therapeutic, prophylactic dose and no anticoagulation use. The odds of mortality between those who did not receive anticoagulation and those who received higher doses were similar, but lower in the prophylactic dose group. An increased risk of mortality and bleeding with the higher doses was demonstrated.(30) Another single-centre retrospective analysis was also in agreement with these findings, where the therapeutic level dose of anticoagulation for the prevention of VTE conferred a higher risk of bleeding and mortality.(31)
Therapeutic anticoagulation
Therapeutic dose anticoagulation must be given to patients with confirmed VTE, if there is a high suspicion of VTE or in non-critically ill patients at higher risk of VTE (d-dimer > 2 × upper limit of normal (ULN), the presence of comorbidities or older age). Other indications for therapeutic doses include patients with atrial fibrillation, mechanical heart valves or a long-term prevention of secondary VTE.(15) Unless contraindicated, LMWH is the most frequently used anticoagulant and is preferred over DOACs for admitted patients. It is readily available, easy to administer and familiar to staff. Where indications for thrombolysis exist, for example an acute myocardial infarction, acute cerebrovascular accident or acute pulmonary embolism with haemodynamic instability, thrombolytic agents such as tissue plasminogen activator or streptokinase should be administered.(10)
There is currently no evidence of survival benefit, but there is an increased risk of bleeding when using therapeutic doses of anticoagulation for prophylaxis of VTE in the ICU setting.(25) Reasons for the lack of benefit are that therapeutic doses may be insufficient to influence the thrombo-inflammation and organ injury seen in advanced disease.(26) Heparin resistance is a distinct entity seen in COVID-19 patients, especially in the critical care setting.(32) Heparin resistance is defined as the need for unusually high heparin doses to achieve a target-activated partial thromboplastin time or anti-factor Xa level.(33) Anti-factor Xa monitoring should be considered in critically ill patients where therapeutic heparin is indicated (32) or may be considered in scenarios where heparin resistance is of concern (extremes of body weight, chronic kidney disease and pregnancy).(8)
DURATION OF PROPHYLACTIC ANTICOAGULATION AFTER HOSPITAL DISCHARGE
The risk of hospital-associated VTE is thought to persist up to 6 weeks post discharge in medically ill patients, especially those who required admission to ICU. In an observational retrospective study, the rate of symptomatic VTE and subsequently confirmed on imaging was 2.6% at 42 days after hospital discharge with COVID-19.(34) Based on this, an extended prophylactic anticoagulation regimen with LMWH or DOACs has been suggested.
Post discharge anticoagulation, however, is currently not routinely recommended for all patients.(35) Exceptions are patients with confirmed VTE where anticoagulation should be continued for 3–6 months. International guidelines recommend VTE prophylaxis use for up to 4 weeks after discharge in patients deemed to be at high risk for VTE. High-risk patients include those with advanced age (>70 years), prolonged ICU stay, severe immobility, underlying malignancy and previous history of VTE.(36) The preferred drug of choice is enoxaparin or DOACs (rivaroxaban or betrixaban). The risk of bleeding needs to be assessed prior to prescribing prophylactic anticoagulation at discharge. The highest risk of bleeding has been reported in those on antiplatelet or oral anticoagulation before admission, those with advanced age (>70 years) and those who received therapeutic level doses of anticoagulation for prophylaxis during admission.(34) Uncertainty still remains regarding optimal therapy for VTE prophylaxis after hospital discharge in patients with COVID-19, and there is a need for large RCTs to explore this further.
CURRENT AVAILABLE RECOMMENDATIONS
The COVID-19 treatment guidelines as per the National Institute of Health, last updated in February 2021, recommend the use of a standard prophylactic dose of LMWH in COVID-19 patients. This is on the basis that there is insufficient data regarding the use of intermediate to therapeutic doses. These guidelines also make a recommendation for the use of the same dose in pregnant and lactating individuals with severe COVID-19. However, specialized care is needed during delivery similar to that given to pregnant patients on heparin for another indication without COVID-19.(35)
The South African National Department of Health released a rapid review in June 2020 regarding the optimal dose of anticoagulation for the prevention of venous thromboembolism in patients with COVID-19. The evidence regarding the appropriate dosing of anticoagulation was still scanty at the time of the review. However, the recommendation was the use of a standard prophylactic dose of LMWH, similar to the international guideline.(17)
Apart from the national guidelines, there are no published South African data on effective anticoagulation in COVID-19 patients. Although the published evidence is not conclusive, the higher dose strategy (therapeutic doses) in patients at a higher risk of severe disease (higher d-dimer levels, obesity and other metabolic comorbidities) may be considered in non-critically ill hospitalized patients.
CONCLUSION
Coagulopathy in COVID-19 patients contributes to a severity of disease and mortality. The pathogenesis of thrombosis remains multifactorial, with all three factors of Virchow's triad contributing to thrombosis. Immunothrombosis plays a role in severe COVID-19, and further research is needed to delineate optimal therapeutic strategies targeting immune dysregulation. Anticoagulation is indicated in all patients who are hospitalized with COVID-19. The preferred agent is LMWH, at prophylactic doses, unless there are clear indications for therapeutic doses. These include confirmed or suspected VTE, and non-critically ill patients at higher risk of VTE (d-dimer > 2 × ULN, the presence of comorbidities or older age). There is no evidence for additional antiplatelet therapy, unless otherwise indicated. The results of ongoing randomized clinical trials are awaited and may provide further clarity on optimal anticoagulation strategies.
Authors’ contributions: AP and NM contributed equally to the final manuscript.
