covid-19

Use of Anticoagulation in Patients with COVID-19 Infection

In Medical Concepts by Johnny HuangLeave a Comment

Introduction

The novel coronavirus, known as COVID-19, was originally reported in a cluster of pneumonia cases in Wuhan (China) near the end of 2019​1​. Over the next 6 months, COVID-19 has emerged as the world’s newest pandemic disease with over 7 million cases worldwide​1​. The clinical presentation of COVID-19 is broad and classically involves fever, cough, dyspnea, malaise, and bilateral infiltrates on chest imaging. Less typical symptoms including diarrhea, myalgia, confusion, anosmia, and ageusia were also reported in the literature​2​. In terms of investigations, patients with COVID-19 infection may have lymphopenia, elevated lactate dehydrogenase level, and elevated inflammatory markers such as ferritin or C-reactive protein​3​. There has been increasing evidence that suggested COVID-19 is an endothelial disease with pro-thrombotic properties​4​. This article aims to discuss the hypercoagulability of COVID-19 infection and management of patients without evidence of venous thromboembolism (VTE).

Pathogenesis of COVID-19 Hypercoagulability

The pathogenesis of COVID-19-associated hypercoagulability is not fully understood. Several studies proposed mechanisms where COVID-19 directly invades endothelial cells or indirectly causes cell injury via a cytokinetic inflammatory response or complement reactivation​4​. Patients with severe COVID-19 infection were found to have elevated fibrinogen and D-dimer levels​5,6​, though it was unclear whether this reflects hypercoagulability or an underlying inflammatory condition such as sepsis. Several studies showed that elevated D-dimer was associated with poor outcomes and prognosis in admitted patients with COVID-19 infection​7,8​. In contrast to disseminated intravascular coagulation that involves bleeding and reduced fibrinogen levels, the distinguishing feature of COVID-19 pertains to thrombosis formation and inflammation without significant consumption of coagulation markers​5​. A case-series study showed an increased risk for VTE, mostly pulmonary embolism, among intensive care unit (ICU) patients with COVID-19-associated acute respiratory distress syndrome (ARDS) than those with non-COVID-19 ARDS, despite being on prophylactic anticoagulation​9​. Similar studies showed an incidence of VTE up to 30% within 7 days of admission among critically ill COVID-19 patients​10–12​.

Evidence of Anticoagulation in Patients with COVID-19 Infection

The management of COVID-19-associated hypercoagulability is evolving and challenging. According to the International Society on Thrombosis and Hemostasis, all patients admitted to the hospital with medical and surgical concerns should receive standard VTE prophylaxis, unless contraindicated​13​. Low molecular weight or unfractionated heparin have been the main choice of therapy due to their shorter half lives. On top of its anticoagulation properties, heparin was noted to down-regulate interleukin-6 and its associated cytokinetic effects in a pre-clinical study​14​. However, the clinical utility of anticoagulation in COVID-19 patients without evidence of VTE was limited, especially in the outpatient setting. It was noted that therapeutic dose of anticoagulation should be considered for critically ill inpatients in the absence of VTE​15​. An early study in China showed that the use of therapeutic anticoagulation was associated with reduced 28-day mortality (40.0 vs 64.2%) in a subgroup of 97 COVID-19 patients with sepsis-induced coagulopathy or significantly elevated D-dimer​15​. More recently, a retrospective study of 2,773 inpatients, of which 786 received therapeutic anticoagulation, showed that the use of therapeutic anticoagulation was associated with improved in-hospital mortality among intubated patients (29.1% vs 62.7%), after adjusting for multiple confounders​16​. However, patients who were fully anticoagulated were more likely to require mechanical ventilation than those without (29.8% vs 8.1%, p<0.001).

The Management of COVID-19 Hypercoagulability in the Emergency Department

Given the limited evidence, the practical management of COVID-19 hypercoagulability varies amongst centers and practitioners. The decision to initiate prophylactic or therapeutic anticoagulation should be based on numerous factors including patient hemodynamic status, need for respiratory support, and laboratory investigations such as D-dimer and fibrinogen levels. All patients admitted with moderate COVID-19 infection should receive a weight-adjusted prophylactic anticoagulation (refer to Figure 1 for dosing regimen), unless contraindicated​17​. Although controversial, COVID-19 patients who are hemodynamically unstable, with any signs of thrombosis, or signs of end-organ damage (e.g. on renal replacement therapy) may have a low threshold to receive therapeutic anticoagulation (refer to Figure 1 for inpatient anticoagulation algorithm)​18​. There is insufficient data to support the use of thrombolytics (e.g. tissue plasminogen activator) in critically ill patients with COVID-19 infection​19​. In patients with complex co-morbidities and abnormal coagulation panels, the thrombosis team may be consulted prior to initiation or augmentation of anticoagulation therapy. For patients with COVID-19 infection but hospitalization is not warranted, the use of anticoagulation is controversial in the absence of VTE due to very limited evidence. The National Institute of Health recommended against the use of prophylactic anticoagulation in outpatients unless there are other indications​17​. Currently there are no published randomized control trials to support the outpatient use of prophylactic anticoagulation.

Table 1. Prophylactic and therapeutic venous thromboembolism anticoagulation dosing guidelines, modified from the Massachusetts General Hospital. UFH: unfractionated heparin.

Conclusion

In summary, COVID-19 is the newest emergent pandemic disease with unique hypercoagulable properties and multi-organ involvement including the respiratory system. Despite the study limitations, the current evidence recommends for prophylactic dose of anticoagulation for patients admitted with moderate COVID-19 infection without clinical findings of VTE, unless contraindicated. An observational study showed that therapeutic anticoagulation was associated with improved hospital survival within a selected population of critically ill patients. Patients with COVID-19 infection who do not require hospitalization should not receive prophylactic anticoagulation due to insufficient data. As more studies and trials unfold, emergency physicians should be vigilant for new developing guidelines to shape their clinical practice.

Figure 1. Anticoagulation Algorithm for Patients Admitted with COVID-19 Infection at the University Health System (US). DVT: deep venous thrombosis, SIC: sepsis-induced coagulopathy, CrCL: creatinine clearance, TBW: total body weight.

References

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Review with the Expert

Dr. de Wit is an Emergency Medicine/Thrombosis physician, researcher, and educator. She received dual specialty training in Internal Medicine and Emergency Medicine in the UK. At the McMaster University, Dr. de Wit remains actively involved in research on the diagnosis of venous thromboembolism and coagulopathy.

Dr. Kerstin de Wit
Emergency Medicine and Thrombosis Physician, Hamilton Health Sciences
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Johnny Huang

Johnny Huang

Johnny is a family medicine resident at McMaster University. He's interested in medical education and health services research around EM. Outside of work, His hobbies include traveling and various sports/analytics.
Johnny Huang

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Kevin Junghwan Dong

Kevin Junghwan Dong

Kevin Dong is an Emergency Medicine physician in Hamilton, Ontario. His interests include medical education, mentorship, and producing video/podcasts. He completed the Digital Scholar Fellowship in 2019 and he is currently the CanadiEM Director of Multimedia.