THROMBOSIS IN COVID-19 

The list of complications from Covid-19 continues to rise. The pathophysiology of the illness is still somewhat elusive in a lot of respects, not the least of which involves the formation of thrombosis in both arterial and venous beds1. This is all the more alarming in the presence of widespread pharmacologic DVT prophylaxis in hospitalized patients. Thrombosis among ICU patients receiving enoxaparin occur in 31% of cases in a study done in Holland with PE being the most common type; venous thrombosis made up 27% while arterial thrombosis occurred at a rate of 3.7%.2 Thrombus formation is associated with poorer prognosis. Microthrombi at autopsy are found frequently disseminated in the lungs and other organs. This points toward the serious importance of thrombus prevention in the setting of the disease. However other complications include CVA (infarct> hemorrhage)3.

There are any number of mechanisms stipulated to explain the enhanced procoagulating effect noted (Figs 1-3). However, it’s different than classic DIC because it is not a consumption coagulopathy and it’s not associated with thrombocytopenia or low fibrinogen level. Of interest is the mention of endothelial dysfunction, the hallmark of metabolic syndrome, far more common in our kinfolk. The interaction of cytokines and endothelial dysfunction is a well described cascade of pathologic reactions and is illustrated in Fig 44.

Fig 1 (from Iba et al)

  

Fig 2 (Iba et al)

Fig. 3 (Bonny et al)

 

Mécanismes proposés de la coagulopathie de la COVID-19. L’infection par le SARS-CoV-2 engendre une atteinte pulmonaire, principalement décrite comme du dommage alvéolaire diffus. Une hypoxémie survient en cas d’atteinte sévère. En réponse à l’hypoxémie, il existe une induction de la voie de signalisation des « hypoxia inducible transcription factors » qui concoure à activer la coagulation, à supprimer la fibrinolyse et à inhiber les anticoagulants circulants naturels. Dans le même temps, l’infection engendre un recrutement de cellules mononuclées au niveau de la barrière alvéolo-capillaire. Celles-ci, à la suite de l’induction de la voie NF-κB, vont sécréter des cytokines pro-inflammatoires (TNF-α, IL-1 et IL-6) qui vont favoriser la libération de l’inhibiteur de l’activateur du plasminogène (PAI-1) et l’inhibition des anticoagulants naturels. Aussi, elles favorisent l’activation de la coagulation par la génération de facteur tissulaire. Cette activation est soutenue par l’activation plaquettaire. L’activation de l’endothélium, secondaire à une atteinte virale spécifique et/ou une activation du complément, favorise la coagulation et l’interaction avec les plaquettes circulantes. Finalement, la fibrine, les globules rouges et les plaquettes s’agrègent, réalisant un thrombus fibrino-cruorique.

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Fig 4 (Shao et al)

  

A sensible approach to treating patients with Covid-19 who have hypoxemia is to follow the Marik protocol, named after the chief of Respiratory diseases at Eastern Virginia Med School. It’s one that takes into consideration the latest data on the use of vitamin D, C, thiamine, the aggressive use of corticosteroids, especially in the case of the dreadful Macrophage Activation Syndrome, originally described as a rare complication of Kawasaki Syndrome. One needs to bear in mind this protocol has a low threshold for using full anticoagulant dose. Patients that require >4L/min of oxygen receive it (1mg/kg Q12hrs.)

The next issue to be tackled is the outpatient treatment for DVT prevention upon discharge. Again, this is not yet well defined. Some recommend anticoagulant treatment up to 2 months. The problem with anticoagulation therapy is the forever risk of bleeding, regardless of dose used. It comes down to a balance between risk and benefit. As more data become available, the recommendation for widespread use of anticoagulant upon discharge will be better established. Some people recommend a middle of the road approach of either full dose aspirin or dipyridamole. However, this is not yet standard or widespread treatment.

So far, it has become clear that not one single therapeutic intervention suffices against this very clever virus. One needs to use the full armamentarium of available therapeutic interventions. We are still learning as we along.

 

Fig 5-Marik protocol

References:

  1. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019 [published online ahead of print, 2020 May 27]. Crit Care Med. 2020;10.1097.
  2. Klok, FA, et al. Incidence of thrombotic complications in critically ill ICU patients with Covid-19. Thrombosis Research, 191 (2020) 145-147.
  3. Divani AA, Andalib S, Di Napoli M, et al. Coronavirus Disease 2019 and Stroke: Clinical Manifestations and Pathophysiological Insights. J Stroke Cerebrovasc Dis. 2020;29(8):104941.
  4. Shao Y, Cheng Z, Li X, Chernaya V, Wang H, Yang XF. Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction–a novel mechanism for maintaining vascular function. J Hematol Oncol. 2014;7:80. Published 2014 Oct 31. doi:10.1186/s13045-014-0080-6
  5. Bonny V, Maillard A, Mousseaux C, Plaçais L, Richier Q. COVID-19 : physiopathologie d’une maladie à plusieurs visages [COVID-19: Pathogenesis of a multi-faceted disease] [published online ahead of print, 2020 May 27]. Rev Med Interne. 2020;doi:10.1016/j.revmed.2020.05.003.

 

REYNALD ALTEMA, MD

 

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