Today we're exploring a COVID-complication that has caught a lot of attention on social media: hypercoagulability.

Clinical features

• Part of the syndrome of immune hyperactivity seen in severe SARS-CoV-2 infection is activation of complement pathways involved in coagulation
  • Termed COVID-associated coagulopathy (CAC) or thromboinflammation
  • Appears distinct from DIC
    • Hallmark is clotting, NOT bleeding!
  • Clinical features include
    • VTE1
      • Incidence of VTE appears very high in critically ill patients: 25% to 43%, often despite prophylactic anticoagulation2-4
      • Much lower incidence in ward patients, but data limited2
      • Outpatients: unknown
    • Arterial thrombosis
      • The incidence of arterial thrombosis in COVID is unknown
        • Two single-center studies of admitted inpatients with COVID report an incidence of 5% and 3.7% respectively4,5
      • Lay press reports describe the experience of one American physician, who notes that they have seen young patient presenting with stroke (large-vessel occlusions)6,7
      • Clinical antiphospholipid antibody syndrome (APS) has also been described in case reports, with patients presenting with limb ischemia, cerebral infarcts, and positive antiphospholipid antibodies8,9
    • Microvascular thrombosis
      • Some studies suggest that multiorgan failure secondary to microvascular damage may be an important cause of death in COVID patients

 

Lab evaluation

• Patients with severe COVID-19 infections and non-survivors (compared to those with less severe infection) have been found to have:
  • Markedly elevated D-dimer10-12
    • Patients with D-dimer > 1000 had 20x increased risk of mortality in one study!11
  • Higher PTT levels11,12
  • Platelets: typically N/high (unlike DIC); but may be low13
  • High fibrinogen and factor VIII activity (unlike DIC)14

 

Potential therapies

• Anticoagulation
  • It's been suggested that heparin may be beneficial in COVID-19, given its anticoagulant, anti-inflammatory, endothelial-protective, and antiviral properties
  • In retrospective observational studies, there is a signal for heparin for reduced mortality with heparin, particularly in critically ill patients15,16
    • Excessive bleeding was low in one study (about 1%)16
    • Note the potential for bias with these studies!
  • This group has published a nice decision algorithm that may help inform anticoagulation use in COVID patients, taking into consideration risk of VTE, D-dimer levels, and POCUS findings17
  • Bottom line: still need more evidence here!
    • While awaiting that: individualized decisions in accordance with your group/hospital/health authority policy
  • Prophylactic-dose anticoagulation is strongly recommended in all patients in the absence of very compelling contraindications18
• Antiplatelet agents
  • Some of these reports describe therapy for arterial thrombosis with ASA5
    • No high-quality data; no data on prospective use
  • One group looked at the administration of dipyridamole and its effects on in-vitro cell lines, as well as laboratory coagulation/inflammatory parameters, and on clinical outcomes19
    • The group cites effects of dipyridamole on viral replication, as well as its antiplatelet and "immune-enhancing" properties
    • Very small size and methodological issues prevent drawing any conclusions from this paper, but it's hypothesis-generating
  • Thrombolysis
    • tPA has also been trialed in select cases in patients with COVID-19 and ARDS, leading to transient improved oxygenation20
  • Management of hemorrhage/DIC
    • Bleeding does not seem as common in these patients. Opinion-only (not evidence-based) guidelines have suggestions for management of coagulation parameters in bleeding patients18
      • If bleeding: target plts > 50, fibrinogen > 2, PT ratio < 1.5 (similar to general management of pts in DIC)

 

Future directions

• Ongoing trials are looking at the safety and efficacy of anti-platelets and anti-coagulation, including aspirin, clopidogrel, rivaroxaban, tirofiban, fondaparinux and dipyridamole

 

Sources

1. Cui S, Chen S, Li X et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Apr 2020; doi:10.1111/jth.14830
2. Middeldorp S, Coppens M, van Haaps TF et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. May 2020; doi: 10.1111/jth.14888
3. 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. May 2020; doi:10.1007/s00134-020-06062-x
4. Klok F, Kruip M, van der Meer N et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Res, Apr 2020; doi:10.1016/j.thromres.2020.04.013
5. Li Y, Zhou Y, Wang M et al. Acute Cerebrovascular Disease Following COVID-19: A Single Center, Retrospective, Observational Study. SSRN, Mar 2020; doi: 10.2139/ssrn.3550025
6. Cha, A. Young and middle-aged people, barely sick with COVID-19, are dying of strokes. Washington Post online, Apr 25 2020. https://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/
7. Fox, M. Covid-19 causes sudden strokes in young adults, doctors say. CNN Health (online), Apr 23 2020. https://www.cnn.com/2020/04/22/health/strokes-coronavirus-young-adults/index.html?fbclid=IwAR2s8aUzUcA9N6Vcy02J9eNjYpkkQ2sZUqjmat-00dQpOwEtHcmgUU4eA30
8. Ma J, Xia P, Li X et al. Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19. Clin Immunol, Apr 2020; doi:10.1016/j.clim.2020.108408
9. Zhang Y, Xiao M, Zhang S et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. New Eng J Med, Apr 2020; doi:10.1056/NEJMc2007575
10. Guan W, Ni Z, Hu Y et al. Clinical characteristics of coronavirus disease 2019 in China. New Eng J Med, Feb 2020; doi:10.1056/NEJMoa2002032
11. 11. 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, Mar 2020; doi:1016/S0140-6736(20)30566-3
12. 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, Mar 2020; doi:10.1111/jth.14768
13. Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clinica Chimica Acta, Mar 2020; doi:10.1016/j.cca.2020.03.022
14. Panigada M, Bottino N, Tagliabue P et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost. Mar 2020; doi: 10.1111/jth.14850
15. Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy. J Thromb Haemost, Mar 2020; doi:10.1111/jth.14817
16. Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. Journal of the American College of Cardiology. May 2020. doi:10.1016/j.jacc.2020.05.001
17. Atallah B, Mallah SI, Al Mahmeed W. Anticoagulation in COVID-19. European Heart Journal – Cardiovascular Pharmacotherapy. April 2020. doi:10.1093/ehjcvp/pvaa036
18. Thachil J, Tang N, Gando S et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. J Thromb Haemost, Mar 2020; doi: 10.1111/jth.14810
19. Liu X, Li Z, Liu S et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharmaceutica Sinica B, Apr 2020. doi:10.1016/j.apsb.2020.04.008
20. Wang J, Hajizadeh N, Moore E et al. Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series. J Thromb Haemost, Apr 2020; doi:10.1111/jth.14828