Anticoagulation

Last updated: 19-03-2020

Incidence

  • Studies from China, Netherlands and France, on critically ill COVID-19 patients indicates about 20%-55% have evidence of coagulopathies, in the form of DVT/VTE/PE and a distinct form of disseminated intravascular coagulation (DIC) marked by hypercoagulabilit [1-4]

  • The hypercoagulable form of DIC appears to be a driver of disease severity and is a strong prognostic factor for poor outcome [1,8]

  • A case report from Italy on a 75-year-old Covid-19-positive woman hospitalized for severe bilateral pneumonia developed a pulmonary embolism; authors concluded that in absence of other major predisposing factors, suggests a casual relationship between severe infection due to COVID-19 and acute venous thromboembolism [16]

  • A research letter from a group physicians within the Mount Sinai Health System in New York City, very recently published data from 2,773 hospitalized COVID-19 patients, out of which 786 (28%) received systemic anticoagulation during hospital stay [17]

    • In-hospital mortality for anticoagulated patients was 22.5% with a median survival of 21 days, compared to 22.8% and median survival of 14 days in patients who did not receive anticoagulation 

    • Patients who received anticoagulation were more likely to require invasive mechanical ventilation (29.8% vs 8.1%, p<0.001)

    • These patients also had significantly increased baseline PTT, aPTT, lactate dehydrogenase, ferritin, C reactive protein, and D-dimer values in comparison to those who were not treated 

    • Patients who received anticoagulation were more likely to require mechanical ventilation (29.8% vs. 8.1%).

    • The difference was starker among mechanically ventilated patients (395) with an in-hospital mortality of 29.1% with a median survival of 21 days for those treated with anticoagulation as compared to 62.7% with a median survival of 9 days in patients who did not receive anticoagulation

    • Longer duration of anticoagulation treatment was associated with a reduced mortality risk (adjusted hazard ratio, 0.86 per day; 95% confidence interval 0.82 to 0.89; p<0.001). 

    • In addition, 24 patients (3%) who received anticoagulation had bleeding events, compared with 38 patients (1.9%) among those who did not receive anticoagulation.

  • In the study by Tang et al from Wuhan, 71% of non-survivors from COVID-19 infection met the criteria for DIC compared to 0.4% of survivors.

Diagnostics

  • Elevated D-dimer at admission and markedly increasing D-dimer levels (3- to 4-fold) over time are a hallmark of COVID-DIC and were associated with high mortality [1-2]

    • Likely reflecting coagulation activation from infection/sepsis, cytokine storm and impending organ failure

    • D-dimer >1,000 at admission were 20x more likely to die than those with lower values [2]

  • Monitoring platelets, D-dimer, PT, aPTT and fibrinogen levels in all COVID-19 hospitalized patients is recommended [9]

    • INR is not sufficiently sensitive for coagulopathy

Management

  • All patients hospitalized with COVID-19 should receive pharmacologic VTE prophylaxis unless a specific contraindication (e.g., active bleeding, profound thrombocytopenia) exists.

    • Studies have shown that despite DVT prophylaxis 27% [4] and 23% [8] developed thrombotic events

  • A retrospective study on a cohort from Wuhan found that giving patients with severely elevated D-dimer levels (>6-fold of the Upper limit of normal) or sepsis induced coagulopathy score of ≥4, low molecular weight heparin (mostly enoxaparin 40–60 mg/d) had lower 28-day mortality than those who did receive thromboprophylaxis [7]

  • In patients with a history of heparin-induced thrombocytopenia, use fondaparinux [11]

  • Recommendation for patients with a contraindication to pharmacologic VTE prophylaxis - consistent application of intermittent pneumatic compression devices with regular reassessment for conversion to pharmacologic prophylaxis [10]

  • In critically ill patients, it is reasonable to employ both pharmacologic and mechanical

  • VTE prophylaxis as long as no contraindication to either modality exists [10]

  • Intensity of VTE prophylaxis: 

  • The studies from Netherlands and France reported some thrombotic events, VTE and PE, respectively, in critically ill COVID-19 patients, despite standard VTE prophylaxis [4,6]

  • Recommendation for all non-critically ill hospitalized patients (i.e., not in an ICU) with confirmed or highly suspected COVID-19: standard dose VTE prophylaxis as per existing guidelines for hospitalized patients [10]

  • Recommendations for critically ill patients: Increased doses of VTE prophylaxis (e.g., enoxaparin 40 mg subcutaneous BID, enoxaparin 0.5 mg/kg subcutaneous BID, heparin 7500 units subcutaneous q8h, or low-intensity heparin infusion [10] Although most other guidelines (Thrombosis Canada) suggests continuing standard dose VTE prophylaxis as per existing guidelines for hospitalized patients.

    • Guidelines recommend against using biomarker thresholds, such as D-Dimer, as a sole reason to trigger escalation of anticoagulant dosing [10]

  • Therapeutic-intensity anticoagulation empirically (in the absence of confirmed or suspected VTE)

    • Therapeutic anticoagulation with heparin has been suggested for patients with D-dimer over 2,000 ng/ml, but this remains unproven [7,12]

    • Systemic administration of thrombolytics for PE has been associated with major bleeding and intracranial hemorrhage rates of almost 10% and 1-2%, respectively [13]

    • There is currently no high-quality evidence for administering alteplase or any other thrombolytic for the treatment of COVID-19 pulmonary microthrombi. 

      • Very late-stage, profound disease may be marked by low fibrinogen levels, which could theoretically produce a hemorrhagic phenotype.  

      • Anticoagulation could theoretically be harmful in that situation

  • Post-discharge management:

    • Patients hospitalized for acute medical illness are at increased risk for VTE for up to 90 days after discharge. 

    • This finding should apply to COVID-19 patients, though data on incidence are not yet available.

      • Thorough evaluations for any clinically relevant drug-drug interactions in patients with COVID-19 who require concomitant anticoagulation should be done at the time of discharge

    • A full 3 month course of anticoagulation is recommended for anyone initiated on therapeutic anticoagulation for a presumed thrombus and cannot be monitored via rapid imaging 

      • A regulatory-approved thromboprophylaxis regimen after discharge can be initiated (e.g., betrixaban 160 mg on day 1, followed by 80 mg once daily for 35-42 days; or rivaroxaban 10 mg daily for 31-39 days) [14, 15]

    • Anticoagulation stewardship in transition of care should be applied to patients with COVID-19 prior to hospital discharge on an anticoagulant. 

 

 

References

  1. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18: 844-7. 

  2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.

  3. Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020 Apr. 9 [Epub ahead of print]. doi: 10.1111/jth.14830.

  4. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020 Apr 10 [Epub ahead of print]. pii: S0049-3848(20)30120-1. doi: https://doi.org/10.1016/j.thromres.2020.04.013

  5. Middeldorp, S., Coppens, M., van Haaps, T.F., Foppen, M., Vlaar, A.P., Müller, M.C., Bouman, C.C., Beenen, L.F., Kootte, R.S., Heijmans, J., Smits, L.P., Bonta, P.I. and van Es, N. (2020), Incidence of venous thromboembolism in hospitalized patients with COVID‐19. J Thromb Haemost. Accepted Author Manuscript. doi:10.1111/jth.14888

  6. Helms, J., Tacquard, C., Severac, F. et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06062-x

  7. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020 Mar. 27 [Epub ahead of print]. doi: 10.1111/jth.14817.

  8. Spiezia, L, Boscolo, A, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Coagulation and Fibrinolysis. 2020; DOI: 10.1055/s-0040-1710018

  9. Barnes, G.D., Cuker, A., et al. Thrombosis and COVID-19: FAQs For Current Practice. American College of Cardiology. 2020. https://www.acc.org/latest-in-cardiology/articles/2020/04/17/14/42/thrombosis-and-coronavirus-disease-2019-covid-19-faqs-for-current-practice

  10. Barnes, G., Burnett, A., Thromboembolism and Anticoagulant Therapy During the COVID-19 Pandemic: Interim Clinical Guidance from the Anticoagulation Forum. The Journal of Thrombosis and Thrombolysis. 2020 https://acforum-excellence.org/Resource-Center/resource_files/1549-2020-05-07-133522.pdf

  11. Kreuziger, L.B., Lee, Agnes, COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. American Society of Hematology. 2020. https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation

  12. Ling Lin, Lianfeng Lu, Wei Cao & Taisheng Li (2020) Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia, Emerging Microbes & Infections, 9:1, 727-732, DOI: 10.1080/22221751.2020.1746199

  13. Wang J, Hajizadeh N, Moore EE, McIntyre RC, Moore PK, Veress LA, et al. Tissue Plasminogen Activator (tPA) Treatment for COVID‐19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series. J Thromb Haemost 2020. https://doi.org/10.1111/jth.14828 Pediatric 

  14. Cohen et al, Extended thromboprophylaxis with betrixaban in acutely ill medical patients. NEJM, 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa1601747

  15. Weitz et al, Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials, Thrombosis and Haemostasis, 2020, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0039-1701009

  16. Gian Battista Danzi, Marco Loffi, Gianluca Galeazzi, Elisa Gherbesi, Acute pulmonary embolism and COVID-19 pneumonia: a random association?, European Heart Journal, , ehaa254, https://doi.org/10.1093/eurheartj/ehaa254

  17. Ishan Paranjpe, Valentin Fuster, Anuradha Lala, Adam Russak, Benjamin S. Glicksberg, Matthew A. Levin, Alexander W. Charney, Jagat Narula, Zahi A. Fayad, Emilia Bagiella, Shan Zhao, Girish N. Nadkarni, Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19, Journal of the American College of Cardiology, 2020, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2020.05.001.

© 2020 by MMAC. Proudly created with Wix.com

Icon made by Freepik from www.flaticon.com

Icon credits to Adrien Coquet from The Noun Project