Coronavirus Update – is Blood Clotting a Danger?

Doctors have observed a high level of blood clotting in COVID-19 patients. We asked Pratima Chowdary, a member of The Physiological Society’s COVID-19 Advisory Panel, for her insights

Earlier this week, the BBC reported that one third of COVID-19 patients developed dangerous blood clots. Current treatments focus mainly on anti-viral and anti-inflammatory actions, but these only address the direct effects of the virus. Pratima Chowdary, a member of The Physiological Society’s COVID-19 Advisory Panel, told us more about the potential dangers of blood clotting and the treatments doctors are investigating.

“If the virus is seen as a flood, current treatments are controlling the flood but not considering the damage caused. In addition to the drugs that treat the immune system overdrive or neutralise the virus, there is an urgent need to focus on medications that address this blood clot formation, including the use of blood thinners and clot busting agents, in the right dosage and for the right patient.

Let’s start with a few useful definitions:

  • Thrombosis: blood clotting
  • De novo thrombus formation: a clot that forms at the source rather than moving from another location in the body
  • Embolism: a clot that results from a blockage migrating through the blood vessels
  • Hypercoagulability: increased tendency of blood to clot
  • Anticoagulant: blood thinner
  • D-dimers: protein that is present when blood clot is degraded
  • CT Pulmonary angiogram: diagnostic test that gives a picture of arteries in the lungs

“So, is the reported figure of ‘one third’ of COVID-19 patients developing blood clots a realistic one? Why is it such a high proportion?

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“Case series have now been reported from multiple countries quoting a figure as high as 40 percent in patients in intensive care. Patients on the wards also have higher prevalence of blood clotting, even if not of the same magnitude as the patients on intensive care.

Excess thrombosis

“This excess thrombosis has been confirmed in autopsy reports, where more extensive thrombosis has been noted in the lungs, and thrombosis was noted in blood vessels of other organs.

“Are the blood clots different from the ones we routinely see in clinical practice?

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“A view is developing that the pulmonary artery thrombi in these patients probably represent de novo thrombus formation, unlike the typical clots which represent an embolic phenomenon – in other words, the clots are formed by new deposits in blood vessels rather than clots formed in other parts of the body that migrated. This might explain the slow onset of breathlessness. In some patients, a more typical rapid onset breathlessness secondary to rapid occlusion of the pulmonary vascular tree has been seen.

“I suspect a combination of both is common across the patient group, with the smaller peripheral thrombi representing de novo thrombus formation. The thrombi in the larger arteries probably are embolic in origin.

“So what about treatment strategies for the thrombosis? An assumption has been made that managing the excess cytokines (immune system secretions) and immune activation can address thrombosis. This is a misconception as our experience with other thrombotic conditions, including arterial and venous thrombosis shows that addressing the cause does not clear the clot. The clot is cleared through a turnover process called fibrinolysis that is intrinsic to the coagulation process. This can also be facilitated by external medications called clot busters (tissue plasminogen activator or streptokinase).

Anticoagulation treatment

“In the context of thrombosis secondary to modest inflammation or secondary hypercoagulability that is inherited or acquired, anticoagulation is the mainstay of treatment. Primarily this can address the consequences in the coagulation system, i.e. prevent progression and recurrence of thrombosis.

“There is also considerable debate if all patients should receive therapeutic anticoagulation. There are concerns about the potential risk of bleeding. A randomised trial is underway, although the trial does not require screening despite the high reported prevalence.

“A great emphasis has been put on anti-viral and anti-inflammatory strategies, but sadly studies addressing coagulation have struggled to be badged as ‘important’. While anti-viral and potentially anti-inflammatory strategies may the control the ‘flood,’ i.e. viral infection and related cytokine storm, the ‘flood damage’ i.e. fibrin in the alveoli and bloodstream needs to be addressed by alternate mechanisms.

Scientists think that the mechanism causing the increase in blood clotting in COVID-19 patients is related to the consistent finding of elevated D-dimers, typically between 4 to 10-fold increase. Also, increases as high as 100 to 150 fold have been seen in very sick patients. Elevated d-dimers have been associated with higher mortality and morbidity. The relationship with the severity of lung disease is not clear.

“Several explanations have been put forward, and the mechanisms responsible for the excess thrombosis or coagulation abnormalities in COVID-19 are not entirely clear.

Coagulation abnormalities

“Three possible mechanisms can be considered.

“Coagulation abnormalities may be secondary to the ‘cytokine storm’ (elevated secretions of the immune system). This appears to be the most prevalent belief, but it is interesting to note that patients do not have a concurrent decrease in fibrinogen or platelets.

“Typically, a cytokine storm tends to be associated with low fibrinogen, low platelets, and elevated d-dimers.

“The second possibility is that the endothelium (the layer of cells lining the blood vessels) is damaged because of adjacency to the alveolar epithelium (the thin layer in the lungs allowing gas exchange), and there is a spill-over of the severe inflammation, a bystander effect.

“This mechanism can explain the excess of pulmonary arterial thrombosis seen in this group of patients. Typically in this situation, there is an increase in fibrinolysis inhibitors in the alveoli with a spill into the circulation.

“The third possibility is that there is direct infection of the endothelial cells. There has been a case report demonstrating this possibility. .

A CT Pulmonary angiogram can demonstrate thrombi in pulmonary vasculature (the veins connecting the lungs and the heart). It has been challenging in these patients as they are breathless with resulting motion artefacts, and the presence of lung pathology makes the smaller thrombi more challenging to visualise.

“If one accepts that the pulmonary thrombi are developing de novo, screening for them will become important as patients are unlikely to present with the more traditional clinical symptoms.

Review of data

“In our institution, a review of data shows that elevated d-dimers can predict the presence of pulmonary artery thrombosis.

“At a minimum, a patient with high d-dimers, about 4 to 6 times the upper limit of normal, should have a CT Pulmonary angiogram and anticoagulation.

Other treatments possible for blood clotting include thrombolytic agents to dissolve blood clots. Thrombolysis for pulmonary embolism can be done as systemic therapy by administering the drug through a peripheral vein or catheter-directed..

“There have been a few case series where intravenous tPA (tissue plasminogen activator, an enzyme that helps to dissolve blood clots) resulted in improvement in oxygenation. Most of the studies have been conducted in patients hospitalised in intensive care for long periods, and the lack of effect in clinical outcomes may potentially be related to fibrosis (scar tissue).

“There is also a study of nebulised tPA to see if this helps improve oxygenation, through destruction of fibrin membranes in the alveoli (the air sacs in the lugs) and blood clots in small blood vessels.”

The Physiological Society brings together over 4,000 scientists from over 60 countries. The Society promotes physiology with the public and parliament alike. It supports physiologists by organising world-class conferences and offering grants for research and also publishes the latest developments in the field in its three leading scientific journals, The Journal of Physiology, Experimental Physiology and Physiological Reports.

www.physoc.org

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