Melatonin, Endothelium and Covid-19

The use of melatonin in patients with Covid-19 infection has been proposed by several parties and, recently, researchers from Columbia University in New York reported that melatonin is significantly associated with survival of intubated COVID-19 patients.[1]

I also understand that there are several resuscitation divisions that, to date, employ this substance in their treatment protocols.

To justify the use of melatonin in Covid-19 infections the anti-inflammatory action of this substance, the antioxidant, anti-free radical, immunomodulatory, and also the inhibitory actions on vascular permeability have been called into question, when the same is pathologically altered.

This last action, timidly appeared in the most recent works, could become a priority in the general scientific consideration if the relationship between melatonin, platelets and endothelium were known. Vascular permeability, in fact, depends on the state of health of the endothelium – the cellular layer that covers the intimate of blood vessels for about 7000 m2 and regulates important functions such as, for example, blood fluidity, vessel tone, nutrients exchange, the passage of immune cells from the circulatory system to tissues – and the integrity of the endothelium depends, in turn, also on melatonin, which acts at this level both directly and indirectly, through platelets.

Professor Luigi Di Bella, the first physician in the world to use this substance in clinical practice, spoke about the relationship between melatonin, platelets and endothelium (in 1972 Di Bella began his therapeutic experience with melatonin by administering it to a thrombocytopenic patient).[2]

We owe to his research almost all the experimental works on the subject.[3]

I wrote that the action of melatonin on vascular permeability could be considered the most decisive, for the purpose of understanding the mechanisms of action of this substance in Covid-19, for a very simple reason: the infections by new Coronavirus, especially the most severe, can be considered diseases of the endothelium.

In fact, there is agreement that endothelial dysfunction is responsible for the microvascular thrombotic complications typical of severe cases of Covid-19, just as there is agreement that endothelial dysfunction present in comorbidities such as diabetes, hypertension and obesity contributes to the increased frequency of deleterious pulmonary and extrapulmonary complications of the disease in these patients.

Since endothelial functions are impaired in Covid-19 infections, restoring these functions to normal is a therapeutic goal. In the final part of the article “Covid-19 is, in the end, an endothelial disease”, Peter Libby and Thomas Lüscher, write among other things that“To combat the adverse balance between thrombotic and fibrinolytic properties of the endothelium, numerous anticoagulant and antiplatelet therapies are under evaluation in ongoing and planned clinical trials in COVID-19. Key questions that require an answer in this domain are which agents to give to whom and in what doses, given the narrow therapeutic window of such agents, and the common concomitant conditions that elevate bleeding risk in many COVID-19 patients.”[4]

With drugs that decrease thrombotic risk, as is also reiterated in the preceding work, the problem is the increased hemorrhagic risk.

Now, to the best of my knowledge, melatonin is the only substance with antiplatelet activity that not only does not increase hemorrhagic risk but actually counteracts it. In 2002 I witnessed the cessation of a severe bleeding after only 5 days of melatonin intake at a dosage of 40 mg/day (the patient, thrombocytopenic, had been transfused 28 bags of red blood cells in one week),[5] and in thrombocytopenic patients taking melatonin it is common to find the disappearance of signs of bleeding (petechiae, bruises, ecchymoses, etc.) even in the absence of numerical rise of platelets.[6]

In 2005, having observed favorable results with melatonin even in systemic sclerosis (scleroderma), a disease whose “primummovens” is believed to be endothelial damage, and having already, at the time, a work on this subject accepted for publication by the American Journal of Therapeutics (published in 2006),[7] I thought it might be useful to try to integrate the knowledge we had of melatonin in relation to platelets and endothelium. When the work was ready, with the title Melatonin: a key in platelet physiology and platelet-endothelium interrelations, I submitted it to a well-known international journal of physiology.

In the intentions that publication should have made a wide audience of doctors acquainted with concepts that were not known yet, and proposed a comprehensive physiological vision of the interrelationships melatonin-platelet-endothelium, and highlight the new therapeutic perspectives that could result.

In December 2005 I received the answer from the editor of the journal: the work would not have been published. I propose it in this context (see MELATONIN: A KEY IN PLATELET PHYSIOLOGY AND PLATELET-ENDOTHELIUM INTERRELATIONS).

[1]RamlallV, ZuckerJ, TatonettiN, Melatonin is significantly associated with survival of intubated COVID-19 patients, medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20213546.

[2] Todisco M, Non morirai di questo male, Ed. Sestante, 1995, pp. 31-32.

[3] Prof. Di Bella’s scientific publications are available at http://www.metododibella.org.

[4]LibbyP and Lüscher  T, Covid-19 is, in the end, an endothelial disease, European Heart Journal (2020) 41, 3038-3044.

1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Heart Division, Royal Brompton&Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK.

[5]Todisco M et al., Severe bleeding symptoms in refractory idiopathic thrombocytopenic purpura: a case successfully treated with melatonin. Am J Ther 2003; 10:135-136.

[6]Todisco M, Storie di piastrinopenia. Vimarangiu, 2016.

[7]Todisco M,Effectiveness of a treatment based on melatonin in five patients with systemic sclerosis. Am J Ther. 2006 Jan-Feb;13(1):84-7. doi: 10.1097/01.mjt.0000162012.58990.4f.