This is the second part of Italian Study on Coronavirus Science.
Drugs targeting inflammation and hypercoagulability
Coagulation changes and thrombotic complications in Covid-19 patients play a significant role in terms of incidence and clinical importance, and represent one of the main variables linked to mortality. Abnormal coagulation parameters are associated with poor prognosis in patients with the new coronavirus pneumonia.
Covid-19 patient autopsies have revealed thrombi in the microvasculature, suggesting intravascular coagulation as a prominent feature of organ failure in these patients.
Therefore the most promising medications, on which great expectations are currently placed, are drugs blocking the inflammatory response which can be triggered by the novel coronavirus SARS-CoV-2. They can therefore block the following thromboembolism, responsible for clots in the arteries that carry blood to the lungs and sometimes other organs, with possible fatal consequences. Ventilation probably does not help if blood does not reach the lungs.
One of these drugs is colchicine, which showed not only anti-inflammatory activities, but also some antiviral properties: “By damaging microtubules, the drug reduced the cell entry and the intracellular trafficking of viral particles.”
Colchicine has an ability to counteract the “cytokine storm”, the over-activity of the immune system that, in response to SARS-CoV-2 virus, may destroy its own body cells, including those of the lungs.
Being well-known, inexpensive and with a long-standing use, colchicine could have an advantage over newer drugs.
Heparin, discovered in 1916, has documented efficacy for the prevention and treatment of venous thrombosis and pulmonary embolism, among other conditions.
Low-molecular-weight heparins (LMWHs) have shown a more predictable anticoagulant effect than other forms. The plasma of the blood of many patients with severe COVID-19 is hypercoagulable, increasing the possibility of clots developing in the blood vessels.
Early anticoagulation may inhibit clotting formation and reduce micro-thrombi, thereby reducing the risk of major organ damage.
The use of anticoagulants like heparins for patients with severe COVID-19 was initially recommended by an expert consensus in China. Subsequent studies evaluated the effect of LMWHs and showed lower mortality in a group of patients meeting specific criteria of sepsis-induced coagulopathy or with markedly increased D-dimer levels, indications of an altered coagulation. Elevated D-dimer is predictor of severity and mortality in COVID-19 patients.
Heparins could also display an antiviral action by inhibiting viral attachment to the body’s cells. Heparin has a structure very similar to heparan sulphate, a molecule present on the surface of the cells of our body and used by SARS-CoV-2 virus to adhere to the cell before entering it.
The anticoagulant attracts the virus which attaches itself to the drug molecule: the virus is thus “deceived” and, instead of attacking healthy cells, attacks the heparin. To confirm this, Chinese tests show in vitro its antiviral efficacy, as well as its ability to interfere with the “cytokine storm” that characterises the hyper-inflammatory phase of the disease, which is the most dangerous for the patient.
Over the past 1-2 months, many scientific papers have been published on the use of enoxaparin, one of the low-molecular-weight heparins, in Covid patients. In the Journal of Thrombosis and Haemostasis, Ning Tang et al, of Tongji Hospital, Huazhong University in Wuhan (China), 449 patients with severe Covid-19 infection were studied. Among them, 99 patients were treated with heparins for at least 7 days, of whom 94 received enoxaparin.
In patients considered as a whole no difference in 28‐day mortality was found between heparin users and non-users. But among patients with an increase in coagulation (for example those with high D-dimer levels) heparin use greatly reduced the 28‐day mortality from 52.4% to 32.8%.
Director of the Clinical Pharmacology Unit at the Polyclinic of Catania, Italy, Prof. Filippo Drago, says: “I have seen the CT scans of these patients and they are upsetting: the lung is no longer there, the patients no longer breathe except with margins of tissue, the problem however is that with assisted breathing these patients can last longer if there are no thromboembolic phenomena. Endothelial damage is catastrophic and there is even the risk of disseminated intravascular coagulation (DIC) which, when it occurs, is unstoppable: the patient dies from diffuse thrombosis.”
He adds: “The problem is different because we have the impression, supported by autopsies on different patients, that they die not so much from severe lung failure as from thromboembolic events.”
We are, however, awaiting the results of further prospective controlled studies.
Thousands of compounds are being examined and the number of those considered potentially beneficial is increasing.
An example is gabexate mesilate, another drug with a triple function: exerting potent anticoagulant action, reducing the production of inflammatory cytokines and blocking the entry of the virus into lung cells.
Today we know that the SARS-CoV-2 virus enters cells by exploiting an enzyme present inside them called Tmprss2. This substance could be a target for any therapeutic interventions capable of defeating the infection that causes Covid-19. Gabexate mesilate gabexate could block the entry of the virus into lung cells by inhibiting TMPRSS2. Nafamostat mesilate, a molecule structurally related to gabexate, has been shown to inhibit TMPRSS2 and is already under clinical testing in Covid-19.
The pathogenetic mechanisms of SARS-CoV-2 have been only partially unravelled. Of great practical importance is that it’s still not known if stable immunity against the virus develops after the first infection. Data on recovered patients are still insufficient and anecdotal.
Nevertheless, there is a great interest in the use of so-called “convalescent plasma” isolated from people who have fully recovered from a Covid-19 infection and are putatively immune, meaning that their plasma may contain antibodies produced by their immune systems in fighting the novel coronavirus and which can be transfused with that plasma to people still infected.
Many recovered patients have donated their plasma.
Over 45 trials worldwide are investigating the effects of hyperimmune plasma, including two Italian studies coordinated in Pavia and Bergamo, whose preliminary results seem encouraging.
Treatments for COVID-19: emerging drugs against the coronavirus
Journal of Thrombosis and Haemostasis
A 14 centri italiani la sperimentazione dell’enoxaparina nel COVID-19
Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19
Image by Julien Tromeur from Pixabay