Hypercoagulopathy in Severe COVID-19: Implications for Acute Care

Abstract

COVID-19 was first described in late 2019 and has since developed into a pandemic affecting more than 21 million people worldwide. Of particular relevance for acute care is the occurrence of COVID-19-associated coagulopathy (CAC), which is characterised by hypercoagulability, immunothrombosis and venous thromboembolism, and contributes to hypoxia in a significant proportion of patients. This review describes diagnosis and treatment of CAC in the emergency department and in intensive care. We summarise the pathological mechanisms and common complications of CAC such as pulmonary thrombosis and venous thromboembolic events and discuss current strategies for thromboprophylaxis and therapeutic anti-coagulation in the acute care setting.

Fig. 1

Overview of pathological mechanisms underlying COVID-19 infection, immune activation and coagulopathy. SARS-CoV-2 has been found within epithelial and endothelial cells, which it enters by binding to CD147 receptors and ACE2 receptors with the assistance of type 2 transmembrane serine protease (TMPRSS2). Heparan sulphate interacts with the SARS-CoV-2 spike glycoprotein adjacent to ACE2R to facilitate binding. Unfractionated heparin binds to the spike protein and blocks this interaction in vitro, whereas low molecular weight heparins (LMWHs) such as enoxaparin and dalteparin are less effective. SARS-CoV-2 replicates within the cell before copies are released. Damage-associated molecular pathogens (DAMPs) are presented by infected cells and pyroptosis triggers an immune response, which results in the recruitment and activation of neutrophils, monocytes and macrophages and the release of cytokines, activation of complement and the production of neutrophil extracellular traps (NETs). Unfractionated heparin counteracts cytokine production, complement activation and NETosis, in addition to reducing other pro-inflammatory molecules. Activation of the immune system also activates the coagulation system, leading to increased thrombin generation. Vascular endothelial injury contributes to thrombin generation and hypercoagulability. High levels of fibrinogen in the presence of raised D-dimer levels indicate a hypofibrinolytic state. ACE2, angiotensin converting enzyme 2; ACE2R, angiotensin converting enzyme 2 receptor; CD147, cluster of differentiation 147 receptor; DAMPs: damage-associated molecular pathogens; NET, neutrophil extracellular trap; TMPRSS2, transmembrane serine protease 2; UFH, unfractionated heparin.

Fig. 2

Proposed scheme for anticoagulation in critically ill patients with COVID-19 based on existing guidelines and evidence. ( A ) Different dosing regimens exist for intermediate dose thromboprophylaxis, depending on the type of LMWH used: Fixed dose: 40 mg BD enoxaparin or 5000 units BD dalteparin or 4500 units BD tinzaparin, weight-based dose: 0.5 mg/kg BD enoxaparin, 50 units/kg BD tinzaparin, reduced dose in renal impairment (e.g. CrCl < 30 mL/min): 40 mg OD or 20 mg BD enoxaparin, 5000 units BD or TDS s.c. UFH. For extremes of body weight (< 50 kg or > 100 kg) dosing based on actual body weight is recommended. ( B ) Target range of anti-FXa levels: intermediate thromboprophylaxis with LMWH: 0.2–0.4 units/mL, therapeutic anticoagulation with LMWH 0.6–1.0 units/mL and therapeutic anti-coagulation with UFH 0.3–0.7 units/mL. ( C ) APTT ratio target range depends on reagents used and varies, local guidance should be used. APTT, activated partial thromboplastin time; BD: twice daily; BMI, body mass index; CPAP, continuous positive airway pressure; CrCl, creatinine clearance; CTPA, computed tomography pulmonary angiogram; ED, emergency department; i.v., intravenous; LMWH, low molecular weight heparin; NIV, non-invasive ventilation; OD, once daily; PE, pulmonary embolism; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; RRT, renal replacement therapy; s.c., subcutaneous; TDS, three times daily; UFH, unfractionated heparin; VTE, venous thromboembolism.