Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease 2019

CHEST Guideline and Expert Panel Report

      Background

      Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE. This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.

      Methods

      A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.

      Results

      The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.

      Conclusions

      The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.

      Key Words

      Abbreviations:

      aPTT (acketivated partial thromboplastin time), CHEST (American College of Chest Physicians), COVID-19 (coronavirus disease 2019), DIC (disseminated intravascular coagulation), DOAC (direct oral anticoagulant), LMWH (low-molecular-weight heparin), PE (pulmonary embolism), PICO (Population, Intervention, Comparator, Outcome), RR (relative risk), SIC (sepsis-induced coagulopathy), UFH (unfractionated heparin)

      Summary of Recommendations

      1. In the absence of a contraindication, in acutely ill hospitalized patients with COVID-19, we suggest anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis.
      2. In the absence of a contraindication, in critically ill patients with COVID-19, we recommend anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis.
      3. In acutely ill hospitalized patients with COVID-19, we suggest anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH) or fondaparinux over anticoagulant thromboprophylaxis with unfractionated heparin (UFH); and we recommend anticoagulant thromboprophylaxis with LMWH, fondaparinux or UFH over anticoagulant thromboprophylaxis with a direct oral anticoagulant (DOAC).
      Remarks: The panel favors LMWH and fondaparinux over UFH to limit staff exposure. The panel cautions against the use of DOACs in these patients secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be receiving concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and thus bleeding risk associated with the DOACs.
      4. In critically ill patients with COVID-19, we suggest anticoagulant thromboprophylaxis with LMWH over anticoagulant thromboprophylaxis with UFH; and we recommend anticoagulant thromboprophylaxis with LMWH or UFH over anticoagulant thromboprophylaxis with fondaparinux or a DOAC.
      Remarks: The panel favors LMWH over UFH to limit staff exposure. The panel strongly cautions against the use of DOACs in critically ill patients secondary to their hemodynamic instability, the high likelihood of drug-drug interactions, and the high incidence of acute kidney injury in these patients. In addition, there is a lack of evidence for anticoagulant thromboprophylaxis even in non-COVID critically ill patients.
      5. In critically ill or acutely ill hospitalized patients with COVID-19, we recommend against the use of antiplatelet agents for VTE prevention.
      6. In acutely ill hospitalized patients with COVID-19, we recommend current standard dose anticoagulant thromboprophylaxis over intermediate (LMWH BID or increased weight-based dosing) or full treatment dosing, per existing guidelines.
      Remarks: Although there has been some concern for increased risk of VTE in hospitalized COVID-19 patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials.
      7. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis over intermediate (LMWH BID or increased weight-based dosing) or full treatment dosing, per existing guidelines.
      Remarks: Although there is anecdotal and observational data that suggest an increased VTE risk in critically ill patients with COVID-19, it is not clear if the most severely ill COVID-19 patients occupy a different level of risk for VTE than other severely ill nonsurgical, medical ICU patients. There is also insufficient data regarding bleeding risk in this population, and given severity of illness, it may be just as likely that critically ill COVID-19 patients are at high risk of adverse bleeding complications. Finally, it is not clear that this population has a higher risk of VTE when treated with standard doses of anticoagulant thromboprophylaxis per existing guidelines.
      8. In patients with COVID-19, we recommend inpatient thromboprophylaxis only over inpatient plus extended thromboprophylaxis after hospital discharge.
      Remarks: Extended thromboprophylaxis in patients with COVID-19 at low risk of bleeding should be considered, if emerging data on the post-discharge risk of VTE and bleeding indicate a net benefit of such prophylaxis. See text for assumptions indicating net benefit.
      9. In critically ill patients with COVID-19, we suggest against the addition of mechanical prophylaxis to pharmacological thromboprophylaxis.
      Remarks: Although there is no evidence supporting the combination of mechanical and pharmacological thromboprophylaxis for patients with COVID-19 who are critically ill, it is not likely that adding mechanical prophylaxis in this population would cause major harm. We recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis.
      10. In critically ill patients with COVID-19 who have a contraindication to pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis.
      11. In critically ill COVID-19 patients, we suggest against routine ultrasound screening for the detection of asymptomatic DVT.
      Remarks: Although we suggest against a routine screening ultrasound for critically ill COVID-19 patients, we note that clinicians should have a low threshold for performing ultrasound in patients with a reasonable degree of clinical suspicion for VTE. Lower extremity ultrasound should also be part of point of care ultrasound, particularly in situations like unexplained right ventricular dysfunction, unexplained/refractory hypoxemia or in patients with suspected PE who are unable to undergo a diagnostic study (ie, unstable for transport or advanced renal failure). It should be noted that even if clot is not visualized on lower extremity ultrasound, pulmonary embolism is not fully excluded.
      12. For acutely ill hospitalized COVID-19 patients with proximal DVT or pulmonary embolism (PE), we suggest initial parenteral anticoagulation with therapeutic weight adjusted LMWH or IV UFH. The use of LWMH will limit staff exposure and avoid the potential for heparin pseudo-resistance. In patients without any drug-to-drug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. Dabigatran and edoxaban can be used after initial parenteral anticoagulation. Vitamin K antagonist therapy can be used after overlap with initial parenteral anticoagulation.
      Remarks: The panel has downgraded the most recent CHEST recommendation regarding the use of oral anticoagulants in patients hospitalized with COVID-19 secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the DOACs. Thus LMWH or UFH are favored over oral anticoagulants.
      13. For outpatient COVID 19 patients with proximal DVT or PE and no drug-to-drug interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. Initial parenteral anticoagulation is needed before dabigatran and edoxaban. For patients who are not treated with a DOAC, we suggest vitamin K antagonists over LMWH (for patient convenience and comfort). Parenteral anticoagulation needs to be overlapped with vitamin K antagonists.
      14. In critically ill COVID-19 patients with proximal DVT or PE, we suggest parenteral over oral anticoagulant therapy. In critically ill COVID-19 patients with proximal DVT or PE who are treated with parenteral anticoagulation, we suggest LMWH or fondaparinux over UFH.
      Remarks: UFH might be preferred over LMWH or fondaparinux in patients at high bleeding risk (including those with severe renal failure), or in those with overt or imminent hemodynamic decompensation due to PE, in whom primary reperfusion treatment may be necessary. The decision to use UFH should be balanced with the risks associated with extra staff exposure and issues with heparin resistance as above.
      15. For COVID 19 patients with proximal DVT or PE, we recommend anticoagulation therapy for a minimum duration of three months.
      16. In most patients with COVID-19 and acute, objectively confirmed PE not associated with hypotension (systolic BP < 90 mm Hg or BP drop of ≥ 40 mm Hg lasting longer than 15 minutes), we recommend against systemic thrombolytic therapy.
      Remarks: Please see statement 18 for the select patients that may require systemic thrombolysis.
      17. In patients with COVID-19 and both acute, objectively confirmed PE and hypotension (systolic BP < 90 mm Hg) or signs of obstructive shock due to PE, and who are not at high risk of bleeding, we suggest systemically administered thrombolytics over no such therapy.
      18. In patients with COVID-19 and acute PE with cardiopulmonary deterioration due to PE (progressive increase in heart rate, a decrease in systolic BP which remains >90 mm Hg, an increase in jugular venous pressure, worsening gas exchange, signs of shock [eg, cold sweaty skin, reduced urine output, confusion], progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers) after initiation of anticoagulant therapy who have not yet developed hypotension and who have a low risk of bleeding, we suggest systemic thrombolytic therapy over no such therapy.
      19. We recommend against the use of any advanced therapies (systemic thrombolysis, catheter-directed thrombolysis or thrombectomy) for most patients without objectively confirmed VTE.
      Remarks: Thrombolysis may be considered in select patients when cardiac arrest is suspected to be caused by PE and imaging is not obtainable. We would suggest that providers consider the differential of RV strain (preexisting pulmonary hypertension, high positive end-expiratory pressure, severe ARDS) before entertaining the use of empiric thrombolysis.
      20. In those patients with COVID-19 receiving thrombolytic therapy, we suggest systemic thrombolysis using a peripheral vein over catheter directed thrombolysis.
      21. In patients with COVID-19 and recurrent VTE despite anticoagulation with therapeutic weight adjusted LMWH (and documented compliance), we suggest increasing the dose of LMWH by 25% to 30%.
      22. In patients with COVID-19 and recurrent VTE despite anticoagulation with apixaban, dabigatran, rivaroxaban or edoxaban (and documented compliance), or vitamin K antagonist therapy (in the therapeutic range) we suggest switching treatment to therapeutic weight-adjusted LMWH.

      Background

      In late December 2019, a novel beta coronavirus, the severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19), was identified. It was officially declared a pandemic by the World Health Organization in March 2020.

      Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19 [published online ahead of print April 18, 2020]. Am J Emerg Med. https://doi.org/10.1016/j.ajem.2020.04.048.

      Emerging evidence shows that severe COVID-19 can be complicated by coagulopathy. In the most severe cases, this manifests as disseminated intravascular coagulation (DIC), which is a pro-thrombotic condition with a high risk of VTE.
      • Lillicrap D.
      Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia.
      The presence of DIC in these patients has been found to be a strong predictor of mortality. In a retrospective review of 183 consecutive patients with COVID-19 at a single institution, Tang et al
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      noted that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of overt DIC (as defined by the validated International Society on Thrombosis and Haemostasis DIC score). The literature also demonstrates that many patients with COVID-19 have highly abnormal D-dimer levels, which were also prognostic. The incidence of VTE in COVID-19 patients is not well defined, but early reports suggest it may be higher than in non-COVID hospitalized patients with similar degrees of illness, even in the presence of prophylactic anticoagulation.
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      • 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.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].

      Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study [published online ahead of print May 6, 2020]. Ann Intern Med. https://doi.org/10.7326/M20-2003.

      The mechanism for this is likely multifactorial. In fact, it could be argued that the lungs of patients with COVID-19 exhibit all components of Virchow’s triad: hypercoagulable state, endothelial injury, and stasis of blood flow. High plasma levels of several proinflammatory cytokines (IL-2, IL-7, granulocyte colony-stimulating factor, IP10, MCP1, MIP1A, and tumor necrosis factor-α) have been observed in COVID-19 patients admitted to the ICU.
      • Lillicrap D.
      Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia.
      As in other critical illnesses, this systemic cytokine storm triggers the coagulation system and a hypercoagulable state. There is also evidence of significant endothelial injury, as evidenced by reports of significantly elevated von Willebrand factor and Factor VIII levels.
      • Escher R.
      • Breakey N.
      • Lämmle B.
      Severe COVID-19 infection associated with endothelial activation.
      Finally, severe COVID-19 is manifested as severe ARDS. Current evidence-based guidelines recommend positive-pressure ventilation with high levels of positive end-expiratory pressure and fluid restriction,
      Coronavirus Disease 2019 (COVID-19) treatment guidelines.
      both of which may lead to decreases in pulmonary blood flow, leading to stasis and microthrombosis.
      The recognition of the coagulopathy with COVID-19, and the early evidence that suggests that thrombosis in these patients is higher than that seen in similarly ill hospitalized patients with other respiratory infections, has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Current evidence in this specific population is lacking, but reports are emerging daily. The goal of this guidance statement is to review the current evidence that is available and, wherever possible, translate this into practical recommendations. Where this was not possible, the authors would like to remind readers that several well-done evidence-based guidelines regarding the management of patients with VTE and DIC in the non-COVID population exist and should direct patient care until robust trials can be completed in the COVID-19 population.
      Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • et al.
      2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      • Iba T.
      • Levy J.H.
      • Warkentin T.E.
      • et al.
      Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation.
      Given the rapidity with which new evidence is evolving, the authors consider this to be a living document with plans to update the guidance statements as appropriate.

      Methods

      The primary aim of this CHEST panel was to provide practical guidance on the most urgent questions regarding the prevention, diagnosis, and treatment of VTE in patients diagnosed with COVID-19. CHEST appointed a Chair for the panel (L. K. M.) who recruited panelists based upon their established expertise within the field of thromboembolism. The list of panelists was approved by CHEST leadership. All panel members were educated about the process and schedule. Formal conflict of interest review was not performed by the Professional Standards Committee given the timeline for the project, but all panelists were reminded that they would be required to disclose all relevant conflicts prior to voting and at the time of submission of the manuscript to the journal. The majority of panelists had no conflicts of interest to disclose. Two panelists (M. C. and G. L.) do not receive any personal honoraria and/or consulting fees but do receive funds that go directly to their institutional research fund. To reduce any perceived conflict, they abstained from voting on any statements that had overlap with their research or consulting relationships. Given the time-sensitive nature of the topic amid the ongoing COVID-19 pandemic, the schedule spanned over a period of 3 weeks and included six conference calls to discuss topic and question development, literature evaluation using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology, discussion of suggested guidance statements, modified Delphi surveys, and manuscript development.

       Question Development and Systematic search

      The panel first proposed and shared questions of clinical interest via e-mail. The questions were then worded in the Population, Intervention, Comparator, Outcome (PICO) format, and each was discussed during the first conference call. Eighteen PICO questions were originally developed, but the panel chose to focus on 13 for this version of the guidance statement (Table 1). The panel was divided into pairs who each were assigned two or three PICO questions. The pairs then conducted comprehensive searches using MEDLINE via PubMed or Ovid, Embase, and Cochrane Controlled Register of Trials. Search strategy and the details of search results depicted in a PRISMA diagram for each PICO question are available in e-Appendix 1. Search strategies and inclusion criteria were broad given the anticipated low level of evidence at the time they were conducted.
      Table 1PICO Questions
      QuestionPopulationInterventionComparatorOutcomes
      Question 1Patients with COVID-19Standard dose UFH, LMWH, fondaparinuxPlaceboVTE, bleeding, mortality
      Question 2Patients with COVID-19Intermediate dose anticoagulant thromboprophylaxisStandard doseVTE, bleeding, mortality
      Question 3Patients with COVID-19Full (treatment dose) anticoagulant thromboprophylaxisStandard or intermediate doseVTE, bleeding, mortality
      Question 4Patients with COVID-19Extended duration prophylaxis (45 days)10 days (or duration of hospitalization)VTE, bleeding, mortality
      Question 5Patients with COVID-19Antiplatelet agent prophylaxisNo antiplatelet agent prophylaxisVTE, bleeding, mortality
      Question 6Patients with COVID-19Combined mechanical and chemical prophylaxisChemical prophylaxisVTE, bleeding, mortality
      Question 7Patients with COVID-19 and objectively confirmed VTELMWH, fondaparinux, DOACUFHRecurrent VTE, bleeding, mortality
      Question 8Patients with COVID-19 and objectively confirmed VTEThrombolytic therapyAnticoagulation aloneRecurrent VTE, bleeding, mortality
      Question 9Patients with COVID-19 and objectively confirmed VTE while on standard or intermediate dose prophylaxis125%-130% dose LMWH or UFHFull dose UFH, LMWH, fondaparinux, DOACRecurrent VTE, bleeding, mortality
      Question 10Patients with COVID-19 and objectively confirmed VTE while on treatment dose anticoagulant125%-130% dose LMWH or UFHFull dose UFH, LMWH, fondaparinux, DOACRecurrent VTE, bleeding, mortality
      Question 11Patients with COVID-19Routine screening ultrasoundNo screening ultrasoundSymptomatic VTE
      Question 12Patients with COVID-19Rapidly rising D-dimerStandard elevated D-dimerSensitivity, specificity, false negative, false positive, efficiency
      Question 13Patients with COVID-19Fibrinogen, PTT, PT, INR, TT, AT, FVIII, TEG, DIC scoreD-dimerSensitivity, specificity, false negative, false positive, efficiency
      AT = antithrombin; COVID-19 = coronavirus disease 2019; DIC = disseminated intravascular coagulation; DOAC = direct oral anticoagulant; FVIII = Factor VIII; INR = international normalized ratio; LMWH = low-molecular-weight heparin; PICO = Population, Intervention, Comparator, Outcome; PT = prothrombin time; PTT = partial thromboplastin time; TEG = thromboelastography; TT = thrombin time; UFH = unfractionated heparin.

       Study Selection and Evidence Assessment

      Screening and full text selection were performed in duplicate by the pairs. No meta-analyses or randomized controlled trials were available. Most of the evidence included retrospective cohorts and case series. Thus, none of the available direct and indirect literature provided sufficient evidence for the development of evidence tables or recommendations. The panel agreed that patients with COVID-19 appear to be a unique population with evolving evidence that their risk of thrombosis is higher than other hospitalized acutely ill medical or ICU patients. When this evidence was enough (albeit very low level) to adjust existing guideline statements, the panel made modifications to existing statements from CHEST guidelines.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      When this was not possible, the panel simply applied existing guidance and adjusted the wording to this population. All of the statements in this document are thus expert opinion. When the perceived benefits outweighed perceived risks, the panel chose to “recommend” an intervention. When the balance of risk and benefit was less certain, the panel chose only to ”suggest” an intervention.

       Method for Achieving Consensus

      Search results and suggestions written by the panel pairs for each PICO question were shared with all panel members. During a conference call, suggestions were reviewed and subsequently re-written based on panel input. This was followed by another conference call with 100% participation, soliciting additional comments and input. All panel members participated in the development of suggestions to be incorporated in the initial round of the modified Delphi survey. The modified Delphi technique is a widely accepted method for the development of consensus among experts.

      Djulbegovic B, Guyatt G. Evidence vs consensus in clinical practice guidelines [published online ahead of print July 19, 2019]. JAMA. https://doi.org/10.1001/jama.2019.9751.

      To achieve consensus, an a priori decision was made to conduct up to three rounds of anonymous voting or until consensus was achieved (defined a priori as consensus agreement at ≥ 80% with a minimal response rate of 80%) for each draft recommendation, whichever came first. The survey incorporated the suggestions developed by all panelists and was developed and reviewed by the panel chair and sent to all panel members by a CHEST-designated project coordinator. The project coordinator tallied and reported the results of the survey to the group, and all votes were anonymous. The results of the survey were shared with all panel members and discussed via conference call. There was 100% survey participation from the members, and consensus was achieved on all statements. There were, however, several comments regarding clarification of wording and consistency. Following discussion and revision of statements, a second round of surveys was distributed, including 14 of the original 21 statements in which the panel clarified wording and remarks, and one new statement. There was 100% survey participation, and consensus was reached on all 22 statements in the second survey.

      Results and Discussion

       VTE Prevalence and Incidence in Hospitalized Patients With COVID-19

      We found 11 studies that reported on VTE rates in patients diagnosed with COVID-19 (Table 2).
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      • 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.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      ,
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      All 11 were observational reports at high risk for selection bias, and eight of 11 were retrospective. These studies included a total of 1,373 patients, the majority (800 [58.0%]) of whom were treated in an ICU. One other study reported 40% (407 of 1,099) of inpatients have a high risk for VTE by Padua risk score but did not report VTE rates.
      • Wang T.
      • Chen R.
      • Liu C.
      • et al.
      Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.
      This study, however, had major limitations (eg, 8% of patients had missing values for age, and missing values for other variables were not reported). Prevalence and incidence rates of TE are reported in Tables 3 and 4. Given the heterogeneity of the studies, we chose not to pursue a pooled analysis.
      Table 2Characteristics of Studies Reporting on Prevalence or Incidence of VTE in Patients With COVID-19
      SourceStudy DesignCountryNo. of Participating CentersPeer-ReviewPatient SelectionThromboprophylaxisSample Size (ICU/Ward)Age (y)DVT ScreeningOutcome Adjudication
      Cui et al
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      Retrospective cohortChina1YesUnclearNo81/NAMean, 60YesNR
      Klok et al
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      Retrospective cohortThe Netherlands3YesConsecutive ICU admissionsNadroparin (weight-adjusted prophylactic dose)
      a During the study period, the dose of thromboprophylaxis with nadroparin was doubled in 2 of 3 participating centers; 17 of 184 (7.2%) patients were on therapeutic anticoagulation at admission.
      184/NAMean, 64NoNR
      Helms et al
      • 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.
      Prospective cohortFrance2YesConsecutive ICU admissions105/150 (70%) prophylactic heparin; 45/150 (30%) therapeutic heparin150/NAMedian, 63NoNR
      Ranucci et al
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      Prospective cohortItaly1YesUnclearIntermediate-dose nadroparin
      b Nadroparin 4,000 units twice daily, which was increased to nadroparin 6,000 units twice daily (or 8,000 units twice daily if BMI > 35 kg/m2) in all patients after performance of coagulation and viscoelastic tests.
      16/NAMedian, 61NRNR
      Spiezia et al
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      Prospective cohortItaly1YesConsecutive ICU admissionsAnticoagulant prophylaxis22/NAMean, 67NRNR
      Llitjos et al
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      Retrospective cohortFrance2YesConsecutive ICU admissions8/26 (31%) prophylactic heparin; 18/26 (69%) therapeutic heparin26/NAMedian, 68YesNR
      Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      Retrospective cohortItaly1YesConsecutive hospital admissions42/61(69%) prophylactic heparin; 17/61 (28%) weight-adjusted prophylactic heparin; 2/61 (3%) therapeutic heparin61/327Median, 66NoNR
      Poissy et al
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      Retrospective cohortFrance1YesConsecutive ICU admissionsNR
      c Of the patients with pulmonary embolism, 20 received prophylactic heparin, 1 therapeutic heparin, and 1 vitamin K antagonist with therapeutic INR at time of diagnosis.
      107/NAMedian, 57NRNR
      Thomas et al
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      Retrospective cohortUnited Kingdom1YesConsecutive ICU admissionsWeight-adjusted heparin at prophylactic dose63/NAMean, 59NoNR
      Middeldorp et al
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      Retrospective cohortThe Netherlands1YesConsecutive hospital admissionsNadroparin (weight-adjusted prophylactic dose)
      d Seven of 75 (9.3%) patients in the ICU and 12 of 123 (10%) patients on the ward continued therapeutic anticoagulation for an indication that was present at time of admission; none of those patients developed a VTE.
      ,
      e During the study period, the dose of thromboprophylaxis with nadroparin was doubled for patients admitted to the ICU.
      75/123Mean, 61Partly
      f Screening ultrasound for lower extremity DVT was performed in 38 of 75 (51%) critically ill patients and 17 of 123 (14%) patients on the ward.
      Yes
      Xu et al
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      Retrospective cohortChina1NoUnclearAnticoagulant prophylaxis in at-risk population
      g Patients with a Padua score ≥ 4 points were considered at risk for VTE; “routine thromboprophylaxis” was given to 15 of 15 (100%) ICU patients and 26 of 123 (21%) ward patients.
      15/123Mean, 52Partly
      h Screening ultrasound for lower extremity DVT was performed in all critically ill patients; no screening was performed in patients on the ward.
      NR
      NA = not applicable; NR = not reported. See Table 1 legend for expansion of other abbreviation.
      a During the study period, the dose of thromboprophylaxis with nadroparin was doubled in 2 of 3 participating centers; 17 of 184 (7.2%) patients were on therapeutic anticoagulation at admission.
      b Nadroparin 4,000 units twice daily, which was increased to nadroparin 6,000 units twice daily (or 8,000 units twice daily if BMI > 35 kg/m2) in all patients after performance of coagulation and viscoelastic tests.
      c Of the patients with pulmonary embolism, 20 received prophylactic heparin, 1 therapeutic heparin, and 1 vitamin K antagonist with therapeutic INR at time of diagnosis.
      d Seven of 75 (9.3%) patients in the ICU and 12 of 123 (10%) patients on the ward continued therapeutic anticoagulation for an indication that was present at time of admission; none of those patients developed a VTE.
      e During the study period, the dose of thromboprophylaxis with nadroparin was doubled for patients admitted to the ICU.
      f Screening ultrasound for lower extremity DVT was performed in 38 of 75 (51%) critically ill patients and 17 of 123 (14%) patients on the ward.
      g Patients with a Padua score ≥ 4 points were considered at risk for VTE; “routine thromboprophylaxis” was given to 15 of 15 (100%) ICU patients and 26 of 123 (21%) ward patients.
      h Screening ultrasound for lower extremity DVT was performed in all critically ill patients; no screening was performed in patients on the ward.
      Table 3Prevalence or Incidence of VTE in Critically Ill Patients With COVID-19
      SourceFollow-up DurationPatients Still Admitted at Study EndIsolated Leg DVTIsolated Proximal Leg DVTPE ± DVTProximal PE

      ± DVT
      Major BleedingMortality
      Cui et al
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      NRNR20/81 (25%)NRNRNRNR8/81 (10%)
      Klok et al
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      Median, 14 days65/184 (35%)1/184 (0.5%)1/184 (0.5%)65/184 (35%)46/184 (25%)NR41/184 (22%)
      Helms et al
      • 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.
      Mean, 9.6 days100/150 (67%)3/150 (2.0%)NR25/150 (17%)22/150 (15%)4/150 (2.7%)13/150 (8.7%)
      Ranucci et al
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      NR3/16 (19%)0000NR7/16 (44%)
      Spiezia et al
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      NRNR5/22 (23%)NRNRNRNRNR
      Llitjos et al
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      NR7/26 (27%)14/26 (54%)
      a Six patients on thromboprophylaxis at prophylactic doses; 7 on thromboprophylaxis at therapeutic doses, thromboprophylaxis dose for 1 patient not reported.
      NR6/26 (23%)
      b Six of 14 patients on thromboprophylaxis at therapeutic doses.
      NRNR3/26 (12%)
      Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      Median, 18 days13/61 (21%)1/61 (1.6%)Unclear
      c Inconsistent reporting of distal vs proximal DVT in published article.
      2/61 (3.3%)NRNRNR
      d In the entire study population, 92 of 388 (24%) patients died.
      Poissy et al
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      NR22/107 (21%)2/107 (1.9%)NR22/107 (21%)UnclearNR15/107 (14%)
      Thomas et al
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      Median, 8 days28/62 (45%)005/62 (8.1%)4/62 (6.5%)NR10/62 (16%)
      Middeldorp et al
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      Median, 15 daysNR
      e In the entire study population, 16 of 198 (8%) patients were still admitted at time of data analysis.
      23/75 (31%)14/75 (19%)11/75 (15%)10/75 (13%)NRNR
      f In the entire study population, 38 of 198 (19%) patients died.
      Xu et al
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      NRNR3/15 (20%)NRNRNRNRNR
      PE = pulmonary embolism. See Table 1 and 2 legends for expansion of other abbreviations.
      a Six patients on thromboprophylaxis at prophylactic doses; 7 on thromboprophylaxis at therapeutic doses, thromboprophylaxis dose for 1 patient not reported.
      b Six of 14 patients on thromboprophylaxis at therapeutic doses.
      c Inconsistent reporting of distal vs proximal DVT in published article.
      d In the entire study population, 92 of 388 (24%) patients died.
      e In the entire study population, 16 of 198 (8%) patients were still admitted at time of data analysis.
      f In the entire study population, 38 of 198 (19%) patients died.
      Table 4Prevalence or Incidence of VTE in Acutely Ill Hospitalized Patients With COVID-19
      SourceFollow-up DurationPatients Still Admitted at Study EndIsolated Leg DVTIsolated Proximal Leg DVTPE ± DVTProximal PE ± DVTMajor BleedingMortality
      Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      Median, 9 days13/327 (4%)4/327 (1.2%)3/327 (0.9%)8/327 (2.4%)NRNRNR
      a In the entire study population, 92 of 388 (24%) patients died.
      Middeldorp et al
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      Median, 4 daysNR
      b In the entire study population, 16 of 198 (8%) patients were still admitted at time of data analysis.
      2/123 (1.6%)0/1242/123 (1.6%)1/123 (0.8%)NRNR
      c In the entire study population, 38 of 198 (19%) patients died.
      Xu et al
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      NRNR1/123 (0.8%)NRNRNRNRNR
      See Table 1, 2, and 3 legends for expansion of abbreviations.
      a In the entire study population, 92 of 388 (24%) patients died.
      b In the entire study population, 16 of 198 (8%) patients were still admitted at time of data analysis.
      c In the entire study population, 38 of 198 (19%) patients died.
      A qualitative review of the 11 studies reporting VTE prevalence and incidence is presented in Table 2. Patient selection procedures varied across studies and were often unclear. A detailed description of testing procedures was also lacking in most studies. Some studies reported only DVT.
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      ,
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      Only five studies specified whether pulmonary embolism (PE) was subsegmental or more proximal,
      • 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.
      ,
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ,
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      and only three studies provided detailed information on DVT location.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      Universal screening for events also varied across studies, and in many, outcomes were reported on patients still hospitalized. Average duration of hospitalization and/or the hospital day on which CT pulmonary angiography or lower extremity compression ultrasound was performed was variably reported. Lastly, thromboprophylaxis rates in Chinese hospitals are reported to be as low as 20% in some studies,
      • Wang T.
      • Chen R.
      • Liu C.
      • et al.
      Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.
      ,
      • Tang N.
      • Bai H.
      • Chen X.
      • Gong J.
      • Li D.
      • Sun Z.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      which affects interpretation of event rates in Chinese COVID-19 populations.

       VTE Prevention

      The panel first aimed to address the need for VTE prophylaxis in acutely ill hospitalized (general inpatient ward) and critically ill (ICU) patients with COVID-19. Our search identified three single-center studies reporting estimates for the incidence of VTE in acutely ill hospitalized patients (Tables 2 and 4).
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ,
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      None of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs or doses. The majority of patients included in those studies received anticoagulant thromboprophylaxis at prophylactic or higher dose. Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      reported a cumulative incidence of venous and arterial thromboembolic events of 6.6% during hospital admission. A total of 2.4% of the patients developed a PE, and 0.9% of the patients were diagnosed with a symptomatic isolated proximal DVT of the lower extremities. As reported by Middeldorp et al,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      the cumulative incidence of symptomatic VTE was 9.2% at 14 days, comprising one patient with proximal PE, one patient with subsegmental PE, and two patients with distal DVT. Xu et al
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      reported confirmation of DVT in one of 123 (0.8%) patients on the ward.
      Noteworthy, most COVID-19 patients would have been eligible for at least one of the three landmark randomized controlled trials of anticoagulant thromboprophylaxis in acutely ill medical inpatients.
      • Cohen A.T.
      • Davidson B.L.
      • Gallus A.S.
      • et al.
      Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.
      • Leizorovicz A.
      • Cohen A.T.
      • Turpie A.G.
      • et al.
      Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.
      • Samama M.M.
      • Cohen A.T.
      • Darmon J.Y.
      • et al.
      A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.
      In these studies, the proportion of patients who developed symptomatic VTE or any VTE at 14 to 21 days was 0.3% to 1.0% and 2.8% to 5.6%, respectively.
      • Cohen A.T.
      • Davidson B.L.
      • Gallus A.S.
      • et al.
      Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.
      • Leizorovicz A.
      • Cohen A.T.
      • Turpie A.G.
      • et al.
      Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.
      • Samama M.M.
      • Cohen A.T.
      • Darmon J.Y.
      • et al.
      A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.
      Because the incidence of VTE in acutely ill medical inpatients is too low (below 1% without thromboprophylaxis) to justify anticoagulant thromboprophylaxis—and incurred risk of bleeding—in every patient,
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      several risk stratification scores have been developed to identify medical inpatients at higher risk of VTE. The Padua and IMPROVE risk scores are the most extensively validated scores
      • Barbar S.
      • Noventa F.
      • Rossetto V.
      • et al.
      A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.
      ,
      • Spyropoulos A.C.
      • Anderson Jr., F.A.
      • FitzGerald G.
      • et al.
      Predictive and associative models to identify hospitalized medical patients at risk for VTE.
      but both showed heterogeneous discriminatory performance in external validation studies
      • Spyropoulos A.C.
      • Anderson Jr., F.A.
      • FitzGerald G.
      • et al.
      Predictive and associative models to identify hospitalized medical patients at risk for VTE.
      • Cobben M.R.R.N.B.
      • Lijfering W.M.
      • Cannegieter S.C.
      Validation of risk assessment models for venous thrombosis in hospitalized medical patients.
      • Cohen A.T.
      • Spiro T.E.
      • Spyropoulos A.C.
      • et al.
      D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.
      • Gibson C.M.
      • Spyropoulos A.C.
      • Cohen A.T.
      • et al.
      The IMPROVEDD VTE Risk Score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification.
      • Greene M.T.
      • Spyropoulos A.C.
      • Chopra V.
      • et al.
      Validation of risk assessment models of venous thromboembolism in hospitalized medical patients.
      • Mahan C.E.
      • Liu Y.
      • Turpie A.G.
      • et al.
      External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR).
      • Moumneh T.
      • Riou J.
      • Douillet D.
      • et al.
      Validation of risk assessment models predicting venous thromboembolism in acutely ill medical inpatients: a cohort study.
      • Nendaz M.
      • Spirk D.
      • Kucher N.
      • et al.
      Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).
      • Rosenberg D.
      • Eichorn A.
      • Alarcon M.
      • McCullagh L.
      • McGinn T.
      • Spyropoulos A.C.
      External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system.
      • Vardi M.
      • Ghanem-Zoubi N.O.
      • Zidan R.
      • Yurin V.
      • Bitterman H.
      Venous thromboembolism and the utility of the Padua Prediction Score in patients with sepsis admitted to internal medicine departments.
      and they lack validation in an impact study. Considering that hospitalized patients with COVID-19 are confined to their room, immobilization, a major risk factor for VTE in medical inpatients,
      • Darzi A.J.
      • Karam S.G.
      • Charide R.
      • et al.
      Prognostic factors for VTE and bleeding in hospitalized medical patients: a systematic review and meta-analysis.
      affects many inpatients with COVID-19. Infectious disease is an additional risk factor for VTE,
      • Darzi A.J.
      • Karam S.G.
      • Charide R.
      • et al.
      Prognostic factors for VTE and bleeding in hospitalized medical patients: a systematic review and meta-analysis.
      which is present in all patients with COVID-19. Taking into account those risk factors and that the current estimates of the incidence of VTE in non-critically ill patients with COVID-19 is well above 1% even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with COVID-19 at increased risk of VTE. We therefore suggest against individualized VTE risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patients with COVID-19 in the absence of contraindications.
      1. In the absence of contraindications, in acutely ill hospitalized patients with COVID-19, we suggest anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis.
      Our search identified 11 studies providing estimates for the incidence or prevalence of VTE in critically ill patients with COVID-19 (Table 2 and 3).
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      • 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.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      ,
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      None of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs. The proportion of critically ill patients with COVID-19 diagnosed with VTE on at least standard dose anticoagulant thromboprophylaxis ranged from 0% to 54%
      • 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.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      ,
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      ; the reported cumulative incidence of VTE during hospital stay ranged from 20% to 59%.
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      ,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ,
      • Poissy J.
      • Goutay J.
      • Caplan M.
      • et al.
      Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
      ,
      • Thomas W.
      • Varley J.
      • Johnston A.
      • et al.
      Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
      One single-center retrospective cohort study of 449 patients hospitalized in the Tongji Hospital in Wuhan suggests that heparin at prophylactic dose is associated with an absolute mortality reduction of 24% in patients with sepsis-induced coagulopathy (SIC) compared with no anticoagulant thromboprophylaxis.
      • Tang N.
      • Bai H.
      • Chen X.
      • Gong J.
      • Li D.
      • Sun Z.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      No mortality difference was shown in patients who were less sick. Considering that low-molecular-weight heparin (LMWH) at prophylactic doses did not reduce mortality in a randomized placebo-controlled trial in critically ill patients with COPD,
      • Fraisse F.
      • Holzapfel L.
      • Couland J.M.
      • et al.
      Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France.
      the mortality difference in sick patients with COVID-19 appears striking. However, the study has several major limitations. A total of only 22% of the patients received thromboprophylaxis; thromboprophylaxis was defined as the use of heparin ≥ 7 days, which may have introduced immortal time bias; and the analysis was not adjusted for other potential confounders.
      In critically ill medical patients without COVID-19, the failure rate of anticoagulant thromboprophylaxis in randomized controlled trials ranged from 6% to 16%.
      • Fraisse F.
      • Holzapfel L.
      • Couland J.M.
      • et al.
      Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France.
      PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, et al. Dalteparin versus unfractionated heparin in critically ill patients.
      • Shorr A.F.
      • Williams M.D.
      Venous thromboembolism in critically ill patients. Observations from a randomized trial in sepsis.
      The incidence of VTE in cohort studies of critically ill medical patients varies depending on patient population.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Pooled risk estimates for benefits and harms of anticoagulant thromboprophylaxis in critically ill medical patients without COVID-19 differ across meta-analyses,
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ,
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      ,
      • Alhazzani W.
      • Lim W.
      • Jaeschke R.Z.
      • Murad M.H.
      • Cade J.
      • Cook D.J.
      Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials.
      but practice guidelines consistently recommend anticoagulant thromboprophylaxis with LMWH (or unfractionated heparin [UFH]) over no such therapy.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ,
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      We recommend anticoagulant thromboprophylaxis in all critically ill patients with COVID-19, because current evidence suggests that the failure rate of thromboprophylaxis in critically ill patients with COVID-19 seems higher than in randomized controlled trials assessing anticoagulant thromboprophylaxis in critically ill medical patients without COVID-19 and at least as high as the failure rate in prospective cohort studies of critically ill patients with severe sepsis or septic shock.
      • Kaplan D.
      • Casper T.C.
      • Elliott C.G.
      • et al.
      VTE incidence and risk factors in patients with severe sepsis and septic shock.
      2. In the absence of a contraindication, in critically ill patients with COVID-19, we recommend anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis.

       Choice of Agent

      We did not identify any studies allowing for comparisons between different anticoagulants for thromboprophylaxis in acutely ill hospitalized patients with COVID-19. LMWH, UFH, fondaparinux, and direct oral anticoagulants (DOACs) have each been assessed in randomized trials of thromboprophylaxis in acutely ill hospitalized patients without COVID-19.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      Compared with placebo, parenteral anticoagulant thromboprophylaxis with LMWH or fondaparinux reduces the risk of symptomatic PE and any DVT.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      Pooled results indicate no statistically significant difference in symptomatic DVT, major bleeding, or mortality.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      No difference in critical outcomes have been shown in randomized trials comparing LMWH and UFH; no randomized study compared fondaparinux with LMWH/UFH.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      Compared with LMWH, DOACs do not reduce the risk of PE or symptomatic DVT but are associated with an increased risk of major bleeding (relative risk [RR], 1.70; 95% CI, 1.02-2.82).
      • Neumann I.
      • Izcovich A.
      • Zhang Y.
      • et al.
      DOACs vs LMWHs in hospitalized medical patients: a systematic review and meta-analysis that informed 2018 ASH guidelines.
      Therefore, the panel recommends using LMWH, fondaparinux, or UFH over the use of DOACs in acutely ill hospitalized patients with COVID-19. Considering the reduced nursing staff exposure with LMWH or fondaparinux due to the once-daily administration and the possibly lower risk of heparin-induced thrombocytopenia with LMWH or fondaparinux compared with UFH, we suggest LMWH or fondaparinux over UFH in acutely ill hospitalized patients with COVID-19.
      3. In acutely ill hospitalized patients with COVID-19, we suggest anticoagulant thromboprophylaxis with LMWH or fondaparinux over anticoagulant thromboprophylaxis with UFH; and we recommend anticoagulant thromboprophylaxis with LMWH, fondaparinux or UFH over anticoagulant thromboprophylaxis with a DOAC.
      Remarks: The panel favors LMWH and fondaparinux over UFH to limit staff exposure. The panel cautions against the use of DOACs in these patients secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be receiving concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and thus bleeding risk associated with the DOACs.
      We did not identify any studies allowing for comparisons between different anticoagulants for thromboprophylaxis in critically ill patients with COVID-19. LMWH and UFH are the only anticoagulants which have been assessed in randomized trials of thromboprophylaxis in critically ill patients without COVID-19. The panel therefore recommends using LMWH or UFH over other options such as fondaparinux or DOAC. Pooled results of three randomized controlled trials indicate no difference between LMWH and UFH in symptomatic DVT, major bleeding, or mortality.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • et al.
      Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ,
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      The Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) of 3,746 critically ill patients showed a lower risk of symptomatic PE with dalteparin 5,000 units daily compared with UFH 5,000 units BID (hazard ratio, 0.51; 95% CI, 0.30-0.88).
      PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, et al. Dalteparin versus unfractionated heparin in critically ill patients.
      Even though this difference was only driven by 19 events, the panel suggests LMWH over UFH for critically ill patients with COVID-19, because LMWH has the additional advantages over UFH that it has a potential lower risk of heparin-induced thrombocytopenia and that it requires fewer nursing staff contact given its once-daily administration regimen.
      4. In critically ill patients with COVID-19, we suggest anticoagulant thromboprophylaxis with LMWH over anticoagulant thromboprophylaxis with UFH; and we recommend anticoagulant thromboprophylaxis with LMWH or UFH over anticoagulant thromboprophylaxis with fondaparinux or a DOAC.
      Remarks: The panel favors LMWH over UFH to limit staff exposure. The panel strongly cautions against the use of DOACs in critically ill patients secondary to their hemodynamic instability, the high likelihood of drug-drug interactions, and the high incidence of acute kidney injury in these patients. In addition, there is a lack of evidence for anticoagulant thromboprophylaxis even in non-COVID critically ill patients.
      Our literature search did not identify any randomized trials assessing the efficacy and safety of aspirin (or any other antiplatelet agent) for VTE prophylaxis in COVID-19 patients requiring hospitalization. Due to the absence of direct evidence, the guideline panel decided to consider indirect evidence available from systematic reviews of randomized controlled trials conducted in non-COVID-19 patients. The Antiplatelet Trialists’ Collaboration produced a detailed overview of randomized trials to determine the efficacy of antiplatelet therapy for VTE prophylaxis. They reported a modest reduction in the odds of having detectable DVT in high-risk medical patients.
      Collaborative overview of randomised trials of antiplatelet therapy—III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration.
      In contrast, systematic reviews have shown that heparins reduce the risk for developing PE (RR, 0.59; 95% CI, 0.45-0.78), symptomatic proximal DVT (RR, 0.28; 95% CI, 0.06-1.37), and symptomatic distal DVT (RR, 0.75; 95% CI, 0.17-3.34).
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      Based on indirect comparisons, we expect the net benefit of anticoagulant thromboprophylaxis in COVID-19 patients requiring hospitalization to be substantially greater than the benefits of aspirin thromboprophylaxis. Consequently, we do not consider antiplatelet agents a reasonable alternative to anticoagulant prophylaxis in these patients for VTE events.
      5. In critically ill or acutely ill hospitalized patients with COVID-19, we recommend against the use of antiplatelet agents for VTE prevention.

       Dosing Regimen for Anticoagulant Thromboprophylaxis

      We found no studies that reported a comparison of one specific anticoagulant thromboprophylaxis regimen to another. One retrospective study reported a reduction in mortality with heparin at prophylactic doses (most were on 40-60 mg enoxaparin per day) compared with no prophylaxis in a highly select group of ICU patients.
      • Tang N.
      • Bai H.
      • Chen X.
      • Gong J.
      • Li D.
      • Sun Z.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      This study suffers from confounding by indication for prophylaxis and lack of adjustment for co-factors in the specific analysis that found a mortality difference with heparin. For all comers in this study, there was no mortality difference related to heparin prophylaxis. In a single-center retrospective study of 2,773 patients, of whom 786 (28%) received therapeutic anticoagulation, in-hospital mortality was similar between anticoagulated and non-anticoagulated patients (22.5% vs 22.8%).
      • Paranjpe I.
      • Fuster V.
      • Lala A.
      • et al.
      Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19.
      Among patients who were mechanically ventilated, in-hospital mortality was lower in patients who received anticoagulation (29%, median survival of 21 days) than in those who did not receive anticoagulation (63%, median survival of 9 days). In a multivariable Cox proportional hazards model, longer duration of therapeutic anticoagulation was associated with a reduced risk of mortality. The risk of major bleeding was 3% and 1.9% in anticoagulated and non-anticoagulated patients, respectively. Of note, pulmonary hemorrhage was not part of the definition of major bleeding, and the incidence of VTE was not reported. While this study is hypothesis-generating and supports the rationale for randomized controlled trials evaluating thromboprophylaxis at therapeutic doses, it should not inform patient management due to its limitations. First, the authors did not specify anticoagulant agents, the indication for anticoagulation, and whether non-anticoagulated patients did receive anticoagulant thromboprophylaxis. Second, the results may be flawed by immortal time bias, confounding by indication, and other residual confounding. Finally, the median duration of anticoagulation was 3 days, which challenges the biological plausibility of the large mortality reduction observed among patients who were mechanically ventilated.
      Several studies provide data that are indirectly relevant. A retrospective, observational report on 16 ICU patients (all mechanically ventilated and diagnosed with ARDS) reported no VTE events in patients who had VTE anticoagulant thromboprophylaxis titrated to serum coagulation studies and adjusted for BMI.
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      They used LMWH, anti-thrombin concentrate, and clopidogrel, and there is no report on bleeding rates. Several other studies report high VTE rates despite standard prophylaxis in critically ill COVID-19 patients.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • et al.
      COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      ,
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      Because all identified studies of VTE rates and anticoagulant thromboprophylaxis regimens for hospitalized COVID-19 patients are observational with select populations, definitive interpretation is difficult. It seems that critically ill, intubated patients with COVID-19 can develop a profound coagulopathy and form clot at a high rate despite prophylaxis. While adjusting prophylaxis by coagulation studies seems reasonable, specific protocols have not been systematically studied nor bleeding rates reported. Of note, several studies have reported critically ill COVID-19 patients are at high risk for bleeding based on the IMPROVE bleeding risk score.
      • Xu J.F.
      • Wang L.
      • Zhao L.
      • et al.
      Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
      ,
      • Wang T.
      • Chen R.
      • Liu C.
      • et al.
      Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.
      Until we have more data, an accurate risk-benefit assessment of VTE vs bleeding, particularly with increasing anticoagulant thromboprophylaxis above standard dosing, is not possible.
      A recent guideline reviewed the data on SIC and DIC in non COVID-19 patients.
      • Iba T.
      • Levy J.H.
      • Warkentin T.E.
      • et al.
      Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation.
      The authors noted that SIC/DIC can lead to a pro-thrombotic coagulopathy. They concluded that adjustment to standard anticoagulant thromboprophylaxis in the presence of SIC/DIC remains controversial but could be considered. Whether COVID-19 induces a different or more profound type of SIC/DIC remains unknown, but even if one assumes it is similar to non-COVID-19 SIC/DIC, the optimal approach to anticoagulant thromboprophylaxis is uncertain.
      6. In acutely ill hospitalized patients with COVID-19, we recommend current standard dose anticoagulant thromboprophylaxis over intermediate (LMWH BID or increased weight-based dosing) or full treatment dosing, per existing guidelines.
      Remarks: Although there has been some concern for increased risk of VTE in hospitalized COVID-19 patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials.
      7. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis over intermediate (LMWH BID or increased weight-based dosing) or full treatment dosing, per existing guidelines.
      Remarks: Although there is anecdotal and observational data that suggest an increased VTE risk in critically ill patients with COVID-19, it is not clear if the most severely ill COVID-19 patients occupy a different level of risk for VTE than other severely ill nonsurgical, medical ICU patients. There are also insufficient data regarding bleeding risk in this population, and given severity of illness, it may be just as likely that critically ill COVID-19 patients are at high risk of adverse bleeding complications. Finally, it is not clear that this population has a higher risk of VTE when treated with standard doses of anticoagulant thromboprophylaxis per existing guidelines.

       Duration of Thromboprophylaxis

      Our search identified no study reporting incidence of VTE or major bleeding after hospital discharge in patients with COVID-19. In non-COVID patients, a significant proportion of VTE events associated with hospitalization occur after discharge.
      • Cohen A.T.
      • Davidson B.L.
      • Gallus A.S.
      • et al.
      Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.
      • Leizorovicz A.
      • Cohen A.T.
      • Turpie A.G.
      • et al.
      Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.
      • Samama M.M.
      • Cohen A.T.
      • Darmon J.Y.
      • et al.
      A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.
      ,
      • Amin A.N.
      • Varker H.
      • Princic N.
      • Lin J.
      • Thompson S.
      • Johnston S.
      Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients.
      Anticoagulant thromboprophylaxis up to 45 days after discharge reduces the risk of VTE following hospital admission (RR, 0.61; 95% CI, 0.44-0.83) but increases the risk of major bleeding (RR, 2.04; 95% CI, 1.42-2.91).
      • Bajaj N.S.
      • Vaduganathan M.
      • Qamar A.
      • et al.
      Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis.
      A post hoc analysis of the MAGELLAN trial suggests that extended thromboprophylaxis is associated with a net benefit in patients at high risk of VTE as per modified IMPROVE score and low risk of bleeding (ie, absence of active cancer, dual antiplatelet therapy, history of bronchiectasis or pulmonary cavitation, active gastroduodenal ulcer, or any bleeding in the previous 3 months).
      • Spyropoulos A.C.
      • Lipardi C.
      • Xu J.
      • et al.
      Modified IMPROVE VTE Risk Score and Elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for Extended Thromboprophylaxis.
      However, in the MARINER trial of 12,069 patients at risk of VTE as per modified IMPROVE score, rivaroxaban 10 mg daily for 45 days after hospital discharge did not reduce symptomatic VTE.
      • Spyropoulos A.C.
      • Ageno W.
      • Albers G.W.
      • et al.
      Rivaroxaban for thromboprophylaxis after hospitalization for medical illness.
      The 2018 American Society of Hematology practice guideline recommends against the use of extended thromboprophylaxis, because they determined a net harm associated with extended thromboprophylaxis.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      Many hospitalized patients with COVID-19 would likely have been eligible for randomized controlled trials assessing extended thromboprophylaxis, and it appears therefore justified to extrapolate relative treatment effects from those studies to hospitalized patients with COVID-19. Assuming that patients with COVID-19 incur the same risk of bleeding as patients without COVID-19 at high risk of VTE (ie, 0.7% at 35 days after discharge without extended thromboprophylaxis in patients at low risk of bleeding)
      • Spyropoulos A.C.
      • Lipardi C.
      • Xu J.
      • et al.
      Modified IMPROVE VTE Risk Score and Elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for Extended Thromboprophylaxis.
      and that symptomatic VTE is associated with a similar burden to patients as major bleeding,
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      the panel suggests that extended thromboprophylaxis would result in a net benefit in patients with COVID-19 at low bleeding risk, if the risk of symptomatic VTE would be above 1.8% at 35 to 42 days after hospital discharge. Despite evidence suggesting a higher risk of VTE during hospitalization in patients with COVID-19 than in patients without COVID-19, the panel recommends only inpatient anticoagulant thromboprophylaxis, because post-discharge VTE and major bleeding rates in COVID-19 patients are currently unknown.
      8. In patients with COVID-19, we recommend inpatient thromboprophylaxis only over inpatient plus extended thromboprophylaxis after hospital discharge.
      Remarks: Extended thromboprophylaxis in patients with COVID-19 at low risk of bleeding should be considered, if emerging data on the post-discharge risk of VTE and bleeding indicate a net benefit of such prophylaxis. See text for assumptions indicating net benefit.

       Role of Mechanical Prophylaxis

      We were unable to identify any studies that reported on mechanical methods for prophylaxis in COVID-19 patients. While it may seem reasonable to add mechanical to pharmacological prophylaxis in patients thought to be at high baseline risk for VTE, a recent randomized controlled trial found no benefit to this approach.
      • Arabi Y.M.
      • Al-Hameed F.
      • Burns K.E.A.
      • et al.
      Adjunctive intermittent pneumatic compression for venous thromboprophylaxis.
      Therefore, it seems unlikely that mechanical, in addition to pharmacological, prophylaxis will affect VTE rates in critically ill patients with COVID-19.
      9. In critically ill patients with COVID-19, we suggest against the addition of mechanical thromboprophylaxis to pharmacological thromboprophylaxis.
      Remarks: Although there is no evidence supporting the combination of mechanical and chemical thromboprophylaxis for patients with COVID-19 who are critically ill, it is not likely that adding mechanical prophylaxis in this population would cause major harm. We recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis.
      10. In critically ill patients with COVID-19 who have a contraindication to pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis.

       Diagnosis of VTE

       Role of Screening Ultrasound

      Screening ultrasound for asymptomatic DVT is not routinely performed in critically ill patients. Lower extremity ultrasound is reserved for critically ill patients with a clinical suspicion for VTE. General screening ultrasound carries an increased risk of personnel exposure and resource utilization during the COVID-19 pandemic. As we have noted, there is growing evidence to suggest that patients with COVID-19 are at an increased risk of VTE events.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Marone E.M.
      • Rinaldi L F.
      Upsurge of deep venous thrombosis in patients affected by COVID-19: preliminary data and possible explanations.
      This risk is exacerbated in critically ill ICU patients compared with those on a general medical ward.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      Middeldorp et al
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      reported an increased incidence of venous thrombosis in ICU (32%) vs non-ICU patients (1.6%). Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      reported similar venous thrombosis rates in ICU (4.16%) vs non-ICU patients (1.27%). Cui et al
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      suggested a 25% (20 of 81 ICU patients) rate of DVTs in their critically ill cohort, but none of the patients in the study were on pharmacological thromboprophylaxis. We found inconsistent methods of ultrasound screening in COVID-19 patients. In the study by Middeldorp et al,
      • Middeldorp S.
      • Coppens M.
      • van Haaps T.F.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ultrasound was performed every 5 days in ICU patients, and 10 days prior to data analysis in cross-sectional fashion for general ward patients. In a second study by Llitjos et al,
      • Llitjos J.F.
      • Leclerc M.
      • Chochois C.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      screening ultrasound was performed at the time of ICU admission (between day 1 and 3) and then at day 7. We therefore suggest against routine screening, but suggest a low threshold for performing lower extremity ultrasound or full body ultrasound in COVID-19 patients who experience abrupt hypoxemia or clinical deterioration. Tables 3 and 4 summarize the reported DVT incidence in the published literature.
      11. In critically ill COVID-19 patients, we suggest against routine ultrasound screening for the detection of asymptomatic DVT.
      Remarks: Although we suggest against a routine screening ultrasound for critically ill COVID-19 patients, we note that clinicians should have a low threshold for performing ultrasound in patients with a reasonable degree of clinical suspicion for VTE. Lower extremity ultrasound should also be part of point of care ultrasound, particularly in situations like unexplained right ventricular dysfunction, unexplained/refractory hypoxemia or in patients with suspected PE who are unable to undergo a diagnostic study (ie, unstable for transport or advanced renal failure). It should be noted that even if clot is not visualized on lower extremity ultrasound, PE is not fully excluded.

       Role of D-Dimer and Other Biomarkers in the Diagnosis of VTE

      Currently, there are few studies that have evaluated either D-dimer levels, at a single cut point value or using dynamic change, or other laboratory values, to predict a diagnosis of VTE in patients with COVID-19. The lack of systematic surveillance for DVT and PE has severely limited the ability to establish a meaningful context for biomarkers.
      Two studies described biomarkers, including D-dimer, in relationship to VTE diagnosis but did not describe systematic evaluation for suspected VTE which must be employed to understand sensitivity and specificity.
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      Cui et al
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      reported only DVT rather than DVT and PE, which further brings to question which diagnostic procedure was employed as venous ultrasound cannot be employed in isolation to diagnose PE. Furthermore, it was not clear what diagnostic imaging was employed and if imaging was triggered by clinical parameters or as screening as only DVTs were found. The study suggested a 94% negative predictive value for D-dimer cutoff of 1.0 μg/mL but did not compare vs other biomarkers which correlated with VTE.
      • Cui S.
      • Chen S.
      • Li X.
      • Liu S.
      • Wang F.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      They also reported that other laboratory markers correlated with increased risk of VTE, including the activated partial thromboplastin time (aPTT) and lymphocyte count, but did not evaluate single cut points or trending values. Klok et al
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      did not report on D-dimer levels but noted that prolongation of the prothrombin time > 3 seconds or the aPTT > 5 seconds were independently predictors of VTE. Again, the VTE surveillance was not well described.
      Tang et al
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      did not report on VTE incidence but noted derangement in coagulation and clotting markers (prothrombin time, aPTT, D-dimer, and fibrin degradation products) were higher in non-survivors. Dramatic increase of D-dimer also correlated with increase in all-cause mortality. It may follow that thrombosis is a major contributor to increase in all-cause mortality, as survival improved when patients received parenteral anticoagulation.
      • Tang N.
      • Bai H.
      • Chen X.
      • Gong J.
      • Li D.
      • Sun Z.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      In conclusion, there is insufficient data to guide clinical practice for VTE diagnosis based on laboratory values. We suggest as in other inpatient populations biomarkers not be employed in the diagnostic evaluation for suspected DVT or PE.

       VTE Treatment

      Our literature search did not identify any randomized trials assessing the efficacy and safety of anticoagulants for the treatment of acute VTE in hospitalized or critically ill COVID-19 patients.
      Although clinical practice guidelines recommend the use of DOACs for the vast majority of patients with acute symptomatic VTE,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • et al.
      2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      there are reasons to make different suggestions for the preferred anticoagulant in patients with COVID-19, particularly for the critically ill: 1) many of these patients require administration of inhibitors or inducers of P-glycoprotein or strong inhibitors or inducers of cytochrome P450 enzymes. Treatment with potent P-glycoprotein inhibitors (eg, antiretrovirals, azithromycin, others) was an exclusion criterion in most landmark randomized trials that assessed the efficacy and safety of DOACs in patients with acute VTE.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Hokusai V.T.E.I.
      • Buller H.R.
      • Decousus H.
      • et al.
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Büller H.R.
      • Prins M.H.
      • et al.
      EINSTEIN–PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      A recent study enrolled 12 consecutive patients on DOACs who were hospitalized with severe COVID-19.
      • Testa S.
      • Prandoni P.
      • Paoletti O.
      • et al.
      Direct oral anticoagulant plasma levels striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents. The Cremona experience.
      For each patient, C-trough DOAC level was compared with the one measured before hospitalization. On average, C-trough levels were six times higher during hospitalization than in the pre-hospitalization period; 2) GI dysfunction is a common problem in the critically ill patient, and can significantly affect the pharmacokinetics of oral drugs; and 3) acute renal failure is also common in the setting of critical illness, and DOACs are contraindicated in patients with severe (eg, creatinine clearance < 30 mL/min) renal failure. For these reasons, the panel endorsed that in critically ill COVID-19 patients with proximal DVT or PE, parenteral anticoagulation might be preferred to oral anticoagulant therapy.
      Unfractionated heparin has an unpredictable dose response and a narrow therapeutic window; therefore, monitoring is essential to ensure optimal efficacy and safety. Alternatively, LMWHs and fondaparinux have more predictable pharmacokinetics and a greater bioavailability than UFH. Due to these pharmacologic features, body weight-adjusted doses of LMWH or fondaparinux can be administered subcutaneously without laboratory monitoring in the majority of these patients. UFH, not LMWH, can be affected by the phenomenon of heparin resistance which can “pseudo,” in which the aPTT does not reflect the anti-Xa effect (best managed by avoiding the aPTT and monitoring by anti-Xa levels), and true resistance in which case acute phase reactants common in inflammatory states increase UFH clearance and can greatly increase the doses required. The former situation is common with elevated Factor VIII levels, common in COVID-19 patients. The latter situation may delay attainment of therapeutic levels of anticoagulation, which is highly undesirable in an acute VTE situation.
      • Smythe M.A.
      • Priziola J.
      • Dobesh P.P.
      • Wirth D.
      • Cuker A.
      • Wittkowsky A.K.
      Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.
      ,
      • Hirsh J.
      • Raschke R.
      Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      Based on this, and to avoid risk of exposure for staff, we suggest that LMWH or fondaparinux be used over UFH in critically ill COVID-19 patients with proximal DVT or PE. UFH might be preferred over LMWH or fondaparinux in patients at high bleeding risk (including those with severe renal failure [creatinine clearance < 30 mL/min]), or in those with overt or imminent hemodynamic decompensation due to PE, in whom primary reperfusion treatment may be necessary). Outpatients with COVID-19 and acute PE have not been described, but the approach to these patients can follow existing guidelines. Patients with VTE in the setting of COVID-19 are considered to have a provoking factor, and thus initial treatment should be for at least 3 months.
      12. For acutely ill hospitalized COVID-19 patients with proximal DVT or PE, we suggest initial parenteral anticoagulation with therapeutic weight adjusted LMWH or IV UFH. The use of LWMH will limit staff exposure and avoid the potential for heparin pseudo-resistance. In patients without any drug-to-drug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. Dabigatran and edoxaban can be used after initial parenteral anticoagulation. Vitamin K antagonist therapy can be used after overlap with initial parenteral anticoagulation.
      Remarks: The panel has downgraded the most recent CHEST recommendation regarding the use of oral anticoagulants in patients hospitalized with COVID-19 secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the DOACs. Thus, LMWH or UFH are favored over oral anticoagulants.
      13. For outpatient COVID 19 patients with proximal DVT or PE and no drug-to-drug interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. Initial parenteral anticoagulation is needed before dabigatran and edoxaban. For patients who are not treated with a DOAC, we suggest vitamin K antagonists over LWMH (for patient convenience and comfort). Parenteral anticoagulation needs to be overlapped with vitamin K antagonists.
      14. In critically ill COVID-19 patients with proximal DVT or PE, we suggest parenteral over oral anticoagulant therapy. In critically ill COVID-19 patients with proximal DVT or PE who are treated with parenteral anticoagulation, we suggest LMWH or fondaparinux over UFH.
      Remarks: UFH might be preferred over LMWH or fondaparinux in patients at high bleeding risk (including those with severe renal failure), or in those with overt or imminent hemodynamic decompensation due to PE, in whom primary reperfusion treatment may be necessary. The decision to use UFH should be balanced with the risks associated with extra staff exposure and issues with heparin resistance as above.
      15. For COVID 19 patients with proximal DVT or PE, we recommend anticoagulation therapy for a minimum duration of three months.

       Thrombolytic Therapy

      Our literature search did not identify any randomized trials or prospective cohort studies assessing the efficacy or safety of any thrombolytic therapies for the management of critically ill patients with COVID-19 without objective evidence of VTE and VTE-associated hypotension. This includes either systemic delivery or catheter-directed thrombolysis.
      Due to the absence of direct evidence, the guideline panel decided to consider indirect evidence from another population of patients receiving thrombolysis. In a randomized trial of normotensive patients without COVID-19 but with objectively confirmed PE and right heart strain, systemic thrombolysis was associated with major bleeding in 11.5% of patients.
      • Meyer G.
      • Vicaut E.
      • Konstantinides S.V.
      Fibrinolysis for intermediate-risk pulmonary embolism.
      The risk of major bleeding has not been systematically assessed during COVID-19. Diffuse alveolar damage

      Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study [published online ahead of print May 6, 2020]. Ann Intern Med. https://doi.org/10.7326/M20-2003.

      and frank alveolar hemorrhage have been identified in autopsy specimens from COVID-19 patients,
      • Tian S.
      • Xiong Y.
      • Liu H.
      • et al.
      Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
      suggesting that bleeding risk could be high. Therefore, we recommend against thrombolytic therapy in COVID-19 patients without objectively confirmed PE and PE-induced hypotension (systolic BP < 90 mm Hg or BP drop ≥ 40 mm Hg lasting for longer than 15 minutes).
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • et al.
      2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      Patients with objectively confirmed PE who are normotensive represent a wide spectrum of disease. Some are very low risk of adverse outcome. Others are at the more severe end of the spectrum and may present with signs, imaging, or laboratory markers that suggest the presence of right ventricular dysfunction. As we have stated in earlier CHEST Guidelines,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      these patients should be monitored closely for signs of deterioration. Clearly patients who develop hypotension meet criteria for thrombolytic therapy. Deterioration that has not resulted in frank hypotension may also prompt the use of thrombolytic therapy (progressive increase in heart rate, progressive decrease in systolic BP, an increase in jugular venous pressure, worsening gas exchange, signs of shock, progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers). This recommendation was based on the trial by Meyer et al,
      • Meyer G.
      • Vicaut E.
      • Konstantinides S.V.
      Fibrinolysis for intermediate-risk pulmonary embolism.
      in which almost 90% of patients with intermediate risk PE who received rescue thrombolysis survived.
      None of the existing scores for assessing bleeding risk in patients with VTE have been studied or validated in patients with COVID-19. Until recently, we lacked any scores that were derived specifically from patients being treated with anticoagulants for VTE. Thus, we cannot recommend a specific risk score in patients with COVID-19. Several risk scores have been suggested, and many of the variables overlap between scores. We suggest that providers rely on institutional methods for assessing bleeding risk and would refer the reader to items noted to be associated with increased risk of bleeding as outlined in the most recent CHEST Guidelines
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      (age, previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, previous stroke, diabetes, anemia, antiplatelet therapy, poor anticoagulant control, comorbidities, recent surgery, frequent falls, alcohol abuse, non-steroidal antiinflammatory use).
      16. In most patients with COVID-19 and acute, objectively confirmed PE not associated with hypotension (systolic BP < 90 mm Hg or BP drop of ≥ 40 mm Hg lasting longer than 15 minutes), we recommend against systemic thrombolytic therapy.
      Remarks: Please see statement 18 for the select patients that may require systemic thrombolysis.
      17. In patients with COVID-19 and both acute, objectively confirmed PE and hypotension (systolic BP < 90 mm Hg) or signs of obstructive shock due to PE, and who are not at high risk of bleeding, we suggest systemically administered thrombolytics over no such therapy.
      18. In patients with COVID-19 and acute PE with cardiopulmonary deterioration due to PE (progressive increase in heart rate, a decrease in systolic BP which remains > 90 mm Hg, an increase in jugular venous pressure, worsening gas exchange, signs of shock [eg, cold sweaty skin, reduced urine output, confusion], progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers) after initiation of anticoagulant therapy who have not yet developed hypotension and who have a low risk of bleeding, we suggest systemic thrombolytic therapy over no such therapy.
      19. We recommend against the use of any advanced therapies (systemic thrombolysis, catheter-directed thrombolysis or thrombectomy) for most patients without objectively confirmed VTE.
      Remarks: Thrombolysis may be considered in select patients when cardiac arrest is suspected to be caused by PE and imaging is not obtainable. We would suggest that providers consider the differential of right ventricular strain (preexisting pulmonary hypertension, high positive end-expiratory pressure, severe ARDS) before entertaining the use of empiric thrombolysis.
      20. In those patients with COVID-19 receiving thrombolytic therapy, we suggest systemic thrombolysis using a peripheral vein over catheter directed thrombolysis.

       Recurrent VTE

      Our literature search did not identify any randomized trials assessing the efficacy and safety of different anticoagulation regimens for the management of recurrent VTE despite anticoagulation in patients with COVID-19. There are no randomized trials or prospective cohort studies that have evaluated management of patients with recurrent VTE despite anticoagulation. Important factors to consider include compliance, adequate absorption of DOACs, and absence of potential drug-to-drug interactions.
      Due to the absence of direct evidence, the guideline panel decided to consider indirect evidence (low-quality) available from other another population at high risk of recurrent VTE, patients with cancer-associated thrombosis. There are no studies assessing the treatment of recurrent VTE despite anticoagulation with DOACs. One retrospective study reported reasonable outcomes (recurrent VTE of 9% [95% CI, 2 to 25]) when using therapeutic weight-adjusted LMWH in patients with recurrent VTE despite oral anticoagulation with vitamin K antagonists.
      • Luk C.
      • Wells P.S.
      • Anderson D.
      • Kovacs M.J.
      Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.
      Two small retrospective cohort studies have also reported reasonable outcome by increasing the dose of LMWH to 125% and 130% in patients with recurrent events despite therapeutic weight-adjusted LMWH.
      • Carrier M.
      • Le Gal G.
      • Cho R.
      • Tierney S.
      • Rodger M.
      • Lee A.Y.
      Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.
      ,
      • Ihaddadene R.
      • Le Gal G.
      • Delluc A.
      • Carrier M.
      Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis.
      The rate of recurrent VTE and major bleeding was 8.6% (6 of 70; 95% CI, 4.0-17.5) and 4.3% (3 of 70; 95% CI, 1.5-11.9), respectively, among patients receiving increased dose (125% to 130%) of LMWH.
      • Carrier M.
      • Le Gal G.
      • Cho R.
      • Tierney S.
      • Rodger M.
      • Lee A.Y.
      Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.
      Finally, an International Society on Thrombosis and Haemostasis registry showed comparable findings to the aforementioned studies.
      • Schulman S.
      • Zondag M.
      • Linkins L.
      • et al.
      Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.
      Based on indirect comparisons, we expect the net benefit of increasing the dose of LMWH by 25% to 30% in patients with COVID-19 and recurrent VTE despite therapeutic anticoagulation with LMWH and switching to LMWH in patients failing oral anticoagulation with a DOAC or vitamin K antagonist.
      21. In patients with COVID-19 and recurrent VTE despite anticoagulation with therapeutic weight adjusted LMWH (and documented compliance), we suggest increasing the dose of LMWH by 25% to 30%.
      22. In patients with COVID-19 and VTE despite anticoagulation with apixaban, dabigatran, rivaroxaban or edoxaban (and documented compliance), or vitamin K antagonist therapy (in the therapeutic range) we suggest switching treatment to therapeutic weight-adjusted LMWH.

      Summary/Conclusions

      The guidance statements in this document were specifically created to address what were felt to be common, urgent clinical questions that frontline providers are likely to face regarding VTE and hypercoagulability in patients with COVID-19.
      There are important limitations with this guidance. First is the lack of direct evidence to inform the guidance. Clearly more is being shared on a daily basis, but this emphasizes the importance of enrolling patients in clinical trials wherever possible and the need for international collaboration in collecting and rapidly disseminating relevant clinical experience, gaps in knowledge, and the research agenda. Second, due to the urgency of the situation, the panel was unable to address all of the likely questions that have arisen. As we consider this a living document that will be updated, we will incorporate additional questions to these updates as needed. Finally, and perhaps most importantly, the current body of evidence does not allow us to delineate between macro (DVT/PE) and microthrombosis, and the approach to these may differ. It is possible that studies looking for the prevalence of DVT and PE fail to represent the microthrombosis which could drive at least a portion of mortality in these patients.
      The strengths of this document are the multidisciplinary panel that was composed of experienced clinicians and researchers in the field, many with extensive experience in the development of evidence-based guidelines. In addition, despite the lack of a robust evidence base, the panel followed a robust methodologic approach to formulate specific questions, evaluate the literature, and seek consensus.
      We must acknowledge that there are > 10 other international guidelines, guidance statements, or online references that address this topic (although most focus on prevention, not diagnosis or treatment).
      Clinical management of severe acute respiratory infection when COVID-19 is suspected.
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.
      • Bikdeli B.
      • Madhavan M.V.
      • Jimenez D.
      • et al.
      COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.
      • Casini A.
      • Alberio L.
      • Angelillo-Scherrer A.
      • et al.
      Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19—a Swiss consensus statement by the Working Party Hemostasis.
      • Hunt B.R.A.
      • McClintock C.
      Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19.
      • Marietta M.
      • Ageno W.
      • Artoni A.
      • et al.
      COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).

      Oudkerk M, Büller HR, Kuijpers D, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: report of the National Institute for Public Health of the Netherlands [published online ahead of print April 23, 2020]. Radiology. https://doi.org/10.1148/radiol.2020201629.

      • Thachil J.
      • Tang N.
      • Gando S.
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID-19.

      Vivas D, Roldán V, Esteve-Pastor MA, et al. Recommendations on antithrombotic treatment during the COVID-19 pandemic. Position statement of the Working Group on Cardiovascular Thrombosis of the Spanish Society of Cardiology [article in Spanish] [published online ahead of print April 22, 2020]. Rev Esp Cardiol. https://doi.org/10.1016/j.recesp.2020.04.006.

      • Zhai Z.
      • Li C.
      • Chen Y.
      • et al.
      Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines.
      • Barnes G.D.
      • Burnett A.
      • Allen A.
      • et al.
      Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum.
      While this can seem overwhelming, the authors would like to emphasize the relative consistency in these statements. Most of these guidelines recommend VTE prevention in all hospitalized patients with COVID-19,
      Clinical management of severe acute respiratory infection when COVID-19 is suspected.
      ,
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.
      ,
      • Casini A.
      • Alberio L.
      • Angelillo-Scherrer A.
      • et al.
      Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19—a Swiss consensus statement by the Working Party Hemostasis.
      ,
      • Marietta M.
      • Ageno W.
      • Artoni A.
      • et al.
      COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).

      Oudkerk M, Büller HR, Kuijpers D, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: report of the National Institute for Public Health of the Netherlands [published online ahead of print April 23, 2020]. Radiology. https://doi.org/10.1148/radiol.2020201629.

      • Thachil J.
      • Tang N.
      • Gando S.
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID-19.
      while some do recommend risk assessment to guide the decision.
      • Bikdeli B.
      • Madhavan M.V.
      • Jimenez D.
      • et al.
      COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.
      ,
      • Hunt B.R.A.
      • McClintock C.
      Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19.
      ,
      • Zhai Z.
      • Li C.
      • Chen Y.
      • et al.
      Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines.
      As we discussed earlier, given the underlying risk factors present in these patients and that the current estimates of the incidence of VTE in non-critically ill patients with COVID-19 is well above 1% even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with COVID-19 at increased risk of VTE. We therefore suggest against individualized VTE risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patients with COVID-19 in the absence of contraindications. Almost all of these documents recommend standard dosing for anticoagulant thromboprophylaxis. One mentions escalating the dose, stating that it can be considered in patients with a large increase in the D-dimer level or severe respiratory failure.
      • Casini A.
      • Alberio L.
      • Angelillo-Scherrer A.
      • et al.
      Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19—a Swiss consensus statement by the Working Party Hemostasis.
      Another suggests increased dosing in the critically ill patient with COVID-19, but recognizes that this was based largely on expert opinion.
      • Barnes G.D.
      • Burnett A.
      • Allen A.
      • et al.
      Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum.
      The statements are consistent in the recommendation for the use of LMWH or UFH in COVID-19 patients. Those that address the use of mechanical prophylaxis note that it should be used in patients with a contraindication,
      Clinical management of severe acute respiratory infection when COVID-19 is suspected.
      ,
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.
      ,
      • Marietta M.
      • Ageno W.
      • Artoni A.
      • et al.
      COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).
      ,
      • Zhai Z.
      • Li C.
      • Chen Y.
      • et al.
      Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines.
      ,
      • Barnes G.D.
      • Burnett A.
      • Allen A.
      • et al.
      Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum.
      or can be added to anticoagulant thromboprophylaxis in patients who are completely immobilized.
      • Hunt B.R.A.
      • McClintock C.
      Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19.
      ,
      • Barnes G.D.
      • Burnett A.
      • Allen A.
      • et al.
      Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum.
      Finally, only a few of these statements address the issue of extended duration prophylaxis. Bikdeli et al
      • Bikdeli B.
      • Madhavan M.V.
      • Jimenez D.
      • et al.
      COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.
      note that there are no data in this population, although they state that it would be reasonable to take an individualized approach in each patient after risk stratifying for both thrombosis and bleeding risk. The Italian Society on Thrombosis and Haemostasis recommends prophylaxis throughout the hospitalization and for an additional 7 to 10 days’ post-discharge.
      • Marietta M.
      • Ageno W.
      • Artoni A.
      • et al.
      COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).
      The American Society of Hematology recommends following current guidelines, which recommend against extended duration prophylaxis in hospitalized medical patients.
      • Schunemann H.J.
      • Cushman M.
      • Burnett A.E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
      ,
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.
      As we noted earlier, we endorse this approach because the post-discharge VTE and major bleeding rates in COVID-19 patients are currently unknown.
      It is our hope that clinicians caring for patients with COVID-19 will find this document helpful. Clearly, we still need well-designed randomized trials to answer many of our pressing questions. These include optimal dosing of prophylactic anticoagulant therapy, patients who might benefit from full-dose anticoagulant treatment, and the unique role of macro- and microthrombosis in COVID-19. We hope that this version of guidance will serve as a call to enroll patients in clinical trials wherever possible. We would also like to use this document as a call to reason. We are in a time of unprecedented economic, social, and medical uncertainty. We have been trained to accept uncertainty, and to be wary of undesirable consequences of acting too quickly on new observations that may not affect our usual care. As physicians, we are trained to practice evidence-based medicine. We need to always remember that any intervention can cause harm. In a time when our decisions may be driven by emotion, we risk the tendency to rely on anecdotes and early, small case series or cohorts. As recently stated by Zagury-Orly and Schwartzstein, “We must reason critically and reflect on the biases that may influence our thinking processes, critically appraise evidence in deciding how to treat patients, and use anecdotal observations only to generate hypotheses for trials that can be conducted with clinical equipoise. We must act swiftly but carefully, with caution and reason.”
      • Zagury-Orly I.
      • Schwartzstein R M.
      Covid-19—a reminder to reason.
      We look forward to updating this guidance when well-designed trials have been completed.

      Acknowledgments

      Author contributions: L. K. M. had full responsibility over the manuscript. S. B., M. C., J. F. C., K. D., A. B. H., D. J., G. L., L. K. M., P. R., T. T., and P. W. played an equal role in development of the PICO questions and drafting of the recommendations. L. K. M. drafted the initial manuscript. T. T. prepared the tables and e-Appendix 1. S. B., M. C., J. F. C., K. D., A. B. H., D. J., G. L., P. R., T. T., and P. W. contributed equally to drafting sections of the manuscript and overview/editing of the manuscript.
      Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. C. and G. L. receive research funding to their institution. None declared (L. K. M., T. T., S. B., J. F. C., K. D., A. B. H., D. J., P. R., P. W.).
      Role of sponsors: CHEST was the sole supporter of these guidelines, this article, and the innovations addressed within.
      Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.

      Supplementary Data

      References

      1. Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19 [published online ahead of print April 18, 2020]. Am J Emerg Med. https://doi.org/10.1016/j.ajem.2020.04.048.

        • Lillicrap D.
        Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia.
        J Thromb Haemost. 2020; 18: 786-787
        • 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: 844-847
        • Cui S.
        • Chen S.
        • Li X.
        • Liu S.
        • Wang F.
        Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
        J Thromb Haemost. 2020; 18: 1421-1424
        • 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 Med. 2020; 46: 1089-1098
        • Klok F.A.
        • Kruip M.
        • van der Meer N.J.M.
        • et al.
        Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
        Thromb Res. 2020; 191: 145-147
        • Klok F.A.
        • Kruip M.J.H.A.
        • van der Meer N.J.M.
        • et al.
        Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
        Thromb Res. 2020; 191: 148-150
        • Llitjos J.F.
        • Leclerc M.
        • Chochois C.
        • et al.
        High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
        J Thromb Haemost. 2020; 18: 1743-1746
        • Lodigiani C.
        • Iapichino G.
        • Carenzo L.
        • et al.
        Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
        Thromb Res. 2020; 191: 9-14
        • Middeldorp S.
        • Coppens M.
        • van Haaps T.F.
        • et al.
        Incidence of venous thromboembolism in hospitalized patients with COVID-19.
        J Thromb Haemost. 2020; 18: 1995-2002
        • Poissy J.
        • Goutay J.
        • Caplan M.
        • et al.
        Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence.
        Circulation. 2020; 142: 184-186
        • Spiezia L.
        • Boscolo A.
        • Poletto F.
        • et al.
        COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
        Thromb Haemost. 2020; 120: 998-1000
        • Thomas W.
        • Varley J.
        • Johnston A.
        • et al.
        Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.
        Thromb Res. 2020; 191: 76-77
        • Xu J.F.
        • Wang L.
        • Zhao L.
        • et al.
        Risk assessment of venous thromboembolism and bleeding in COVID-19 patients [published online ahead of print March 24, 2020].
        Preprints. 2020;
      2. Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study [published online ahead of print May 6, 2020]. Ann Intern Med. https://doi.org/10.7326/M20-2003.

        • Escher R.
        • Breakey N.
        • Lämmle B.
        Severe COVID-19 infection associated with endothelial activation.
        Thromb Res. 2020; 190: 62
      3. Coronavirus Disease 2019 (COVID-19) treatment guidelines.
      4. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.
        www.nice.org/uk/guidance/ng89
        Date accessed: May 3, 2020
        • Kahn S.R.
        • Lim W.
        • Dunn A.S.
        • et al.
        Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: e195S-e226S
        • Kearon C.
        • Akl E.A.
        • Ornelas J.
        • et al.
        Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
        Chest. 2016; 149: 315-352
        • Konstantinides S.V.
        • Meyer G.
        • Becattini C.
        • et al.
        2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
        Eur Respir J. 2019; 54
        • Schunemann H.J.
        • Cushman M.
        • Burnett A.E.
        • et al.
        American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.
        Blood Adv. 2018; 2: 3198-3225
        • Iba T.
        • Levy J.H.
        • Warkentin T.E.
        • et al.
        Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation.
        J Thromb Haemost. 2019; 17: 1989-1994
      5. Djulbegovic B, Guyatt G. Evidence vs consensus in clinical practice guidelines [published online ahead of print July 19, 2019]. JAMA. https://doi.org/10.1001/jama.2019.9751.

        • Ranucci M.
        • Ballotta A.
        • Di Dedda U.
        • et al.
        The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
        J Thromb Haemost. 2020; 18: 1747-1751
        • Wang T.
        • Chen R.
        • Liu C.
        • et al.
        Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.
        Lancet Haematol. 2020; 7: e362-e363
        • Tang N.
        • Bai H.
        • Chen X.
        • Gong J.
        • Li D.
        • Sun Z.
        Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
        J Thromb Haemost. 2020; 18: 1094-1099
        • Cohen A.T.
        • Davidson B.L.
        • Gallus A.S.
        • et al.
        Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.
        BMJ. 2006; 332: 325-329
        • Leizorovicz A.
        • Cohen A.T.
        • Turpie A.G.
        • et al.
        Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.
        Circulation. 2004; 110: 874-879
        • Samama M.M.
        • Cohen A.T.
        • Darmon J.Y.
        • et al.
        A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.
        N Engl J Med. 1999; 341: 793-800
        • Barbar S.
        • Noventa F.
        • Rossetto V.
        • et al.
        A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.
        J Thromb Haemost. 2010; 8: 2450-2457
        • Spyropoulos A.C.
        • Anderson Jr., F.A.
        • FitzGerald G.
        • et al.
        Predictive and associative models to identify hospitalized medical patients at risk for VTE.
        Chest. 2011; 140: 706-714
        • Cobben M.R.R.N.B.
        • Lijfering W.M.
        • Cannegieter S.C.
        Validation of risk assessment models for venous thrombosis in hospitalized medical patients.
        Res Pract Thromb Haemost. 2019; 3: 217-225
        • Cohen A.T.
        • Spiro T.E.
        • Spyropoulos A.C.
        • et al.
        D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.
        J Thromb Haemost. 2014; 12: 479-487
        • Gibson C.M.
        • Spyropoulos A.C.
        • Cohen A.T.
        • et al.
        The IMPROVEDD VTE Risk Score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification.
        TH Open. 2017; 1: e56-e65
        • Greene M.T.
        • Spyropoulos A.C.
        • Chopra V.
        • et al.
        Validation of risk assessment models of venous thromboembolism in hospitalized medical patients.
        Am J Med. 2016; 129 (1001.e1009-1001.e1018.)
        • Mahan C.E.
        • Liu Y.
        • Turpie A.G.
        • et al.
        External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR).
        Thromb Haemost. 2014; 112: 692-699
        • Moumneh T.
        • Riou J.
        • Douillet D.
        • et al.
        Validation of risk assessment models predicting venous thromboembolism in acutely ill medical inpatients: a cohort study.
        J Thromb Haemost. 2020; 18: 1398-1407
        • Nendaz M.
        • Spirk D.
        • Kucher N.
        • et al.
        Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).
        Thromb Haemost. 2014; 111: 531-538
        • Rosenberg D.
        • Eichorn A.
        • Alarcon M.
        • McCullagh L.
        • McGinn T.
        • Spyropoulos A.C.
        External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system.
        J Am Heart Assoc. 2014; 3e001152
        • Vardi M.
        • Ghanem-Zoubi N.O.
        • Zidan R.
        • Yurin V.
        • Bitterman H.
        Venous thromboembolism and the utility of the Padua Prediction Score in patients with sepsis admitted to internal medicine departments.
        J Thromb Haemost. 2013; 11: 467-473
        • Darzi A.J.
        • Karam S.G.
        • Charide R.
        • et al.
        Prognostic factors for VTE and bleeding in hospitalized medical patients: a systematic review and meta-analysis.
        Blood. 2020; 135: 1788-1810
        • Fraisse F.
        • Holzapfel L.
        • Couland J.M.
        • et al.
        Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France.
        Am J Respir Crit Care Med. 2000; 161: 1109-1114
      6. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, et al. Dalteparin versus unfractionated heparin in critically ill patients.
        N Engl J Med. 2011; 364: 1305-1314
        • Shorr A.F.
        • Williams M.D.
        Venous thromboembolism in critically ill patients. Observations from a randomized trial in sepsis.
        Thromb Haemost. 2009; 101: 139-144
        • Alhazzani W.
        • Lim W.
        • Jaeschke R.Z.
        • Murad M.H.
        • Cade J.
        • Cook D.J.
        Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials.
        Crit Care Med. 2013; 41: 2088-2098
        • Kaplan D.
        • Casper T.C.
        • Elliott C.G.
        • et al.
        VTE incidence and risk factors in patients with severe sepsis and septic shock.
        Chest. 2015; 148: 1224-1230
        • Neumann I.
        • Izcovich A.
        • Zhang Y.
        • et al.
        DOACs vs LMWHs in hospitalized medical patients: a systematic review and meta-analysis that informed 2018 ASH guidelines.
        Blood Adv. 2020; 4: 1512-1517
      7. Collaborative overview of randomised trials of antiplatelet therapy—III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration.
        BMJ. 1994; 308: 235-246
        • Paranjpe I.
        • Fuster V.
        • Lala A.
        • et al.
        Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19.
        J Am Coll Cardiol. 2020; 76: 122-124
        • Amin A.N.
        • Varker H.
        • Princic N.
        • Lin J.
        • Thompson S.
        • Johnston S.
        Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients.
        J Hosp Med. 2012; 7: 231-238
        • Bajaj N.S.
        • Vaduganathan M.
        • Qamar A.
        • et al.
        Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis.
        PLoS Med. 2019; 16e1002797
        • Spyropoulos A.C.
        • Lipardi C.
        • Xu J.
        • et al.
        Modified IMPROVE VTE Risk Score and Elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for Extended Thromboprophylaxis.
        TH Open. 2020; 4: e59-e65
        • Spyropoulos A.C.
        • Ageno W.
        • Albers G.W.
        • et al.
        Rivaroxaban for thromboprophylaxis after hospitalization for medical illness.
        N Engl J Med. 2018; 379: 1118-1127
        • Arabi Y.M.
        • Al-Hameed F.
        • Burns K.E.A.
        • et al.
        Adjunctive intermittent pneumatic compression for venous thromboprophylaxis.
        N Engl J Med. 2019; 380: 1305-1315
        • Marone E.M.
        • Rinaldi L F.
        Upsurge of deep venous thrombosis in patients affected by COVID-19: preliminary data and possible explanations.
        J Vasc Surg Venous Lymphat Disord. 2020; 8: 694-695
        • Agnelli G.
        • Buller H.R.
        • Cohen A.
        • et al.
        Oral apixaban for the treatment of acute venous thromboembolism.
        N Engl J Med. 2013; 369: 799-808
        • Hokusai V.T.E.I.
        • Buller H.R.
        • Decousus H.
        • et al.
        Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
        N Engl J Med. 2013; 369: 1406-1415
        • Büller H.R.
        • Prins M.H.
        • et al.
        • EINSTEIN–PE Investigators
        Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
        N Engl J Med. 2012; 366: 1287-1297
        • Bauersachs R.
        • Berkowitz S.D.
        • et al.
        • EINSTEIN Investigators
        Oral rivaroxaban for symptomatic venous thromboembolism.
        N Engl J Med. 2010; 363: 2499-2510
        • Testa S.
        • Prandoni P.
        • Paoletti O.
        • et al.
        Direct oral anticoagulant plasma levels striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents. The Cremona experience.
        J Thromb Haemost. 2020; 18: 1320-1323
        • Smythe M.A.
        • Priziola J.
        • Dobesh P.P.
        • Wirth D.
        • Cuker A.
        • Wittkowsky A.K.
        Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.
        J Thromb Thrombolysis. 2016; 41: 165-186
        • Hirsh J.
        • Raschke R.
        Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
        Chest. 2004; 126: 188S-203S
        • Meyer G.
        • Vicaut E.
        • Konstantinides S.V.
        Fibrinolysis for intermediate-risk pulmonary embolism.
        N Engl J Med. 2014; 371: 581-582
        • Tian S.
        • Xiong Y.
        • Liu H.
        • et al.
        Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
        Mod Pathol. 2020; 33: 1007-1014
        • Luk C.
        • Wells P.S.
        • Anderson D.
        • Kovacs M.J.
        Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.
        Am J Med. 2001; 111: 270-273
        • Carrier M.
        • Le Gal G.
        • Cho R.
        • Tierney S.
        • Rodger M.
        • Lee A.Y.
        Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.
        J Thromb Haemost. 2009; 7: 760-765
        • Ihaddadene R.
        • Le Gal G.
        • Delluc A.
        • Carrier M.
        Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis.
        Thromb Res. 2014; 134: 93-95
        • Schulman S.
        • Zondag M.
        • Linkins L.
        • et al.
        Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.
        J Thromb Haemost. 2015; 13: 1010-1018
      8. Clinical management of severe acute respiratory infection when COVID-19 is suspected.
      9. COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.
        • Bikdeli B.
        • Madhavan M.V.
        • Jimenez D.
        • et al.
        COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.
        J Am Coll Cardiol. 2020; 75: 2950-2973
        • Casini A.
        • Alberio L.
        • Angelillo-Scherrer A.
        • et al.
        Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19—a Swiss consensus statement by the Working Party Hemostasis.
        Swiss Med Wkly. 2020; 150: w20247
        • Hunt B.R.A.
        • McClintock C.
        Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19.
        • Marietta M.
        • Ageno W.
        • Artoni A.
        • et al.
        COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).
        Blood Transfus. 2020; 18: 167-169
      10. Oudkerk M, Büller HR, Kuijpers D, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: report of the National Institute for Public Health of the Netherlands [published online ahead of print April 23, 2020]. Radiology. https://doi.org/10.1148/radiol.2020201629.

        • Thachil J.
        • Tang N.
        • Gando S.
        • et al.
        ISTH interim guidance on recognition and management of coagulopathy in COVID-19.
        J Thromb Haemost. 2020; 18: 1023-1026
      11. Vivas D, Roldán V, Esteve-Pastor MA, et al. Recommendations on antithrombotic treatment during the COVID-19 pandemic. Position statement of the Working Group on Cardiovascular Thrombosis of the Spanish Society of Cardiology [article in Spanish] [published online ahead of print April 22, 2020]. Rev Esp Cardiol. https://doi.org/10.1016/j.recesp.2020.04.006.

        • Zhai Z.
        • Li C.
        • Chen Y.
        • et al.
        Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines.
        Thromb Haemost. 2020; 120: 937-948
        • Barnes G.D.
        • Burnett A.
        • Allen A.
        • et al.
        Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum.
        J Thromb Thrombolysis. 2020; 50: 72-81
        • Zagury-Orly I.
        • Schwartzstein R M.
        Covid-19—a reminder to reason.
        J Med. 2020; 383: e12