What’s the evidence for therapeutic anticoagulation in severely ill patients battling the virus?
Case: A 55-year-old male presents with shortness of breath, fevers and congestion. He has a past history of hypertension and hypercholesterolemia. His vital signs include temperature 101 F, heart rate 108, respiratory rate 28, oxygen saturation 80%, and blood pressure 128/70 mm Hg. His labs reveal lymphopenia, abnormal coagulation panel and elevated D-dimer (1.7 micrograms/mL fibrinogen equivalent units [FEU], with normal < 0.5 micrograms/mL at your center). You are in the midst of the COVID-19 pandemic, and while this patient likely has COVID, what about his risk of venous thromboembolism (VTE)?
COVID-19 can cause significant mortality and morbidity. [1-4] We know about the risk of respiratory failure, but what’s the risk of VTE, and what should we do when it comes to anticoagulation?
Infection from SARS-CoV-2 causes inflammation and disrupts the normal coagulation pathway.  D-dimer and fibrinogen elevation, platelet activation, endothelial dysfunction, microvascular thrombosis and complement deposition in the alveoli/alveolar septa, and prolongation of prothrombin and thrombin times are common in seriously ill COVID-19 patients. [2,5,12,13]
Factor VIII and von Willebrand factor are also elevated. These factors reflect the severe inflammatory state of COVID-19. DIC has been associated with COVID-19, but thrombosis, rather than hemorrhage, predominates. [12, 14, 15, 23] VTE is a common complication, but there are reports of large vessel occlusion, resulting in stroke and circuit clotting in patients receiving dialysis and ECMO. [11,23] Studies of ICU patients admitted with COVID-19 suggest rates of thrombosis range from 20% to 43%. [8,9,10,11] Autopsy data of patients with COVID-19 have reported multiple pulmonary thrombi. [6,7] The most recent review of 12 consecutive autopsied COVID-19 cases in Hamburg, Germany, reported deep venous thrombosis of both legs in 7 of 12 patients in whom VTE was not suspected; PE was the direct cause of death in four. 
Emergency Department Evaluation
ED evaluation focuses on identification of COVID-19 in a suspected patient, stabilization/resuscitation if necessary, and determining disposition. Stable patients without respiratory distress, cardiac, or metabolic or hematologic abnormalities are typically discharged with follow-up recommendations. The ISTH interim guidelines provide an algorithm that includes D-dimer, prothrombin time, platelet count, and fibrinogen levels as part of the initial evaluation for patients with COVID-19.
Patients with markedly elevated D-dimer arbitrarily defined as > 3-4 times normal, prolonged prothrombin time, platelet count < 100,000, and fibrinogen > 2.0 gm/L should be considered for hospital admission for management of coagulopathy.  For patients who are discharged from the ED, the baseline hematologic parameters may be useful if the patient re-presents to the ED.
Consider VTE in patients with DVT symptoms, unexplained right ventricular dysfunction, and those with hypoxemia disproportionate to respiratory pathology. If patients do not respond to oxygen escalation (nasal cannula to non-rebreather to combination to high flow nasal cannula) and repositioning/proning, evaluate for PE.  While D-dimer elevation is common, by itself it does not warrant routine investigation for acute VTE in the absence of symptoms or other supporting information. 
There are no current recommendations on the provision of anticoagulation for patients who are not admitted to the hospital, but who are discharged from the ED with COVID-19.
One study conducted in France found that VTE occurred in 25% of 150 hospitalized patients, primarily PE. VTE developed despite anticoagulation in 70-100% with prophylactic dosing and 30-56% with therapeutic dosing. Other studies have found VTE in approximately 80% of ICU patients and 15% of non-ICU patients. [11, 23, 24]
A recent report from New York, including 2,773 hospitalized patients, found that 63% of non-anticoagulated or prophylaxis dose anticoagulated patients died, and 29% treated with treatment anticoagulation dose survived. However, the data suffer from weak reporting methodology.  There was no difference between the two groups in bleeding (2-3%). While there are some limitations to the available data, the current evidence supports anticoagulation for all admitted patients.
If VTE is present or suspected based on clinical evaluation, provide full treatment dose anticoagulation. Those with deterioration or massive PE can be managed with systemic or catheter-directed fibrinolysis. 
Anticoagulation recommendations may vary based on institution or agency. All admitted patients should receive anticoagulation, considering the patient’s bleeding risk factors. The HAS-BLED score can help determine bleeding risk (available on MDCalc at https://www.mdcalc.com/has-bled-score-major-bleeding-risk).  General anticoagulation recommendations for COVID-19 patients include the following: [5, 17, 18, 23]
- Full intensity anticoagulation (confirmed or suspected VTE that are too ill or unstable for any confirmation, atrial fibrillation, mechanical heart valves, etc.): Enoxaparin 1 mg/kg q 12 hr (check renal function) or UFH 80 U/kg bolus, then 18U/kg/hr
- Intermediate-intensity anticoagulation (only risk factor very high D-dimer): Enoxaparin 0.5mg/kg q 12 hr (check renal function) or UFH 60U/kg bolus, then 12U/kg/hr or follow institutional recommendations
- All patients without indication for full dose anticoagulation: follow institution’s recommendation for prophylactic dosing
- Patients that were admitted to the hospital with, or for, COVID-19, may be continued on apixaban or rivaroxaban for about 30-45 days until full mobility. 
There is strong evidence for therapeutic anticoagulation in severely ill patients with COVID-19. The ISTH and JACC recommend prophylactic anticoagulation for non-ICU-admitted patients, and those with markedly elevated D-dimer levels. Follow your institutional guidelines for specific agent and dosing regimens. For patients who return to the ED after hospitalization for, or with, COVID, expect continuation of oral anticoagulants for at least 30 days.
- Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
- Zhou F, Yu T, Du R et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 2020 Mar 28;395(10229):1054-1062.
- Wang D, Hu B, Hu C et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. 2020 Feb 7. doi: 10.1001/jama.2020.1585. [Epub ahead of print]
- Yang X, Yu Y, Xu J et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020.
- Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up. JACC April 15, 2020. [Epub Ahead of Print] PMID 32311448
- Fox SE, Akmatbekov A, Harbert JL, et al. Pulmonary and Cardiac Pathology in COVID-19: The First Autopsy Series from New Orleans. Chemrxiv Pre-Print 2020.
- Dolhnikoff M,Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020 Apr 15. doi: 10.1111/jth.14844.
- Cui S,Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severenovel coronavirus pneumonia. J Thromb Haemost. 2020 Apr 9. doi: 10.1111/jth.14830. [Epub ahead of print]
- Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of Thrombotic Complications in Critically Ill ICU Patients with COVID-19. Thrombosis Research. [Epub Ahead of Print]
- Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: an urgent call for ultrasound screening [published online ahead of print, 2020 Apr 22].Intensive Care Med. 2020;1‐3. doi:10.1007/s00134-020-06040-3
- Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Medicine (2020); DOI: 10.1007/s00134-020-06062-x https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf
- Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844‐847.
- Zhang L,Yan X, Fan Q, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020 Apr 19. doi: 10.1111/jth.14859. [Epub ahead of print]
- Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Br J Haematol 2009;145:24-33.
- Tang N,Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099.
- Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. Journal of Thrombosis and Haemostasis 2020. [Epub Ahead of Print].
- World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance 28 January 2020. Accessible at: https://www.who.int/docs/defaultsource/coronaviruse/clinical-management-of-novel-cov.pdf.
- Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. JACC. 2020. doi: https://doi.org/10.1016/j.jacc.2020.05.001.
- Pisters R,Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. 2010 Nov;138(5):1093-100.
- Wichmann D, Sperhake JP, Lutgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Annals Internal Medicine. https://doi.org/10.7326/M20-2003
- Moll, Stephan.’COVID-19 Coagulopathy: What is the PE and DVT Risk. How Should We Optimize the Anticoagulation Therapy Algorithm’ VuMed May 2020 and clotconnect.org
- Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi:10.1111/jth.14869