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COVID-19 and Blood Clots

“Dr. Andrea Obi, the 2019 Wylie Scholar, shares her perspective on the current understanding of COVID-19’s impact on venous thromboembolism (VTE) and how her research may answer ongoing questions and lead to treatments for the disease.”

Preface

Nipun Bhandari, MD, MPH

We at Vascular Cures work closely with physicians and surgeons who are not only on the frontlines caring for patients during the COVID-19 pandemic, but also leading groundbreaking research into potential treatments. Among them is Dr. Andrea Obi, the 2019 recipient of the Wylie Scholar Award for her work on the “Impact of bone marrow progenitor cells’ epigenetic memory on venous thrombus formation and resolution,” studying how blood clots form and resolve. Dr. Obi graduated from the University of Michigan Honors College, completed medical school at Loyola University, and her general surgery residency and vascular surgery fellowship at the University of Michigan where she was the recipient of multiple research and education awards. She is now a faculty vascular surgeon at the University of Michigan with a comprehensive surgical practice and basic science lab. We are fortunate to have Dr. Obi share her perspective on the current understanding of COVID-19’s impact on venous thromboembolism (VTE) and how her research may answer ongoing questions and lead to treatments for the disease.

Viral Pneumonia, Venous Thrombosis and Monocytes

Andrea Obi, MD

The link between pulmonary infection and venous thromboembolism (VTE) has been established by large population studies.1,2 A mild elevation in risk of VTE extends beyond the time of infection for weeks, months and even a year after recovery.  During the 2009 H1N1 viral pneumonia pandemic, a very exaggerated risk of fatal VTE amongst severely ill patients in our intensive care unit was observed.  Treatment of these patients with anticoagulation (heparin) reduced the risk of thrombosis.3

Fast-forwarding 10 years – we see remarkable similarities with COVID infection and the risk of VTE.  The overall risk of VTE is ~5-6% amongst patients in medical and surgical ICU settings.  However, amongst patients with SARS-CoV2 infection, this risk is elevated between 24-40%, similar to the 37% observed amongst critically ill patients with viral H1N1 pneumonia.4,5  Again, blood thinners seem to play a crucial role: in an article released from the Journal of the American College of Cardiology, treatment with therapeutic doses of heparin anticoagulants were associated with a lower risk of death.6 Whether this is due to a direct effect of heparin on blood clotting or via an indirect effect by inhibiting plasmin-mediated activation of the spike proteins or viral entry into the cells is unknown.

However, treating patients with blood thinners isn’t without risk. Patients in the ICU are already at increased risk of bleeding from compromise of essential organs such as the kidney and liver; they can develop ulcers that bleed in response to physiological stress, and they may develop disordered coagulation due to infection. Treatment with blood thinners is a blunt tool.  It is widely available and effective, but it may result in significant bleeding in 2-19% of patients treated. Patients with bleeding may require a transfusion or in the worst case scenario may die from bleeding into a critical organ space such as the brain.

In our lab, we evaluate the immune cells involved in the blood clotting process.  One of these cells, the monocyte/macrophage, is the predominant cell type found in the lungs and other organs of patients infected by COVID 19.7  In the setting of infection, monocytes are released from the bone marrow and traffic to the area of infection, helping to fight off bacteria and viruses, and also facilitating the process of repair.  However, when dysregulated, they may contribute to the pathogenesis of clotting, and potentially harmful VTE such as is seen in COVID19+ patients.  Although no direct evidence exists given the novelty of the virus, there are a few different mechanisms by which monocytes may contribute to this increased risk of thrombosis.  Monocytes are both a source of tissue factor, a key enzyme in the clotting cascade and manufacture enzymes such as tissue factor pathway inhibitor, which serves to counteract blood clotting.  Monocytes also participate in cross-talk with the vascular endothelium.  For instance, activated endothelial cells may recruit tissue factor expressing monocytes to an area of inflammation by releasing chemokines and upregulating binding proteins.8

Knowing more about the exact process by which monocytes contribute to infection and thrombosis is essential moving forward.  If we can understand and target the mechanism we may be able to develop therapy with improved side effect profiles compared to anticoagulants. Currently, there are active trials ongoing that are studying inflammatory cytokines associated with monocyte activation (TNF-α/IFN-γ) and proliferation (GM-CSF). With greater understanding of the processes involved, we may be able to further refine our treatment targets and strategies.

 

  1. Schmidt M, Horvath-Puho E, Thomsen RW, Smeeth L, Sorensen HT. Acute infections and venous thromboembolism. J Intern Med. 2012;271(6):608-618.
  2. Gangireddy C, Rectenwald JR, Upchurch GR, et al. Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg. 2007;45(2):335-341; discussion 341-332.
  3. Obi AT, Tignanelli CJ, Jacobs BN, et al. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord. 2019;7(3):317-324.
  4. 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.
  5. Klok FA, Kruip, M., van der Meer, N. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020.
  6. 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.
  7. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-422.
  8. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020.

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