Foreword: from Storie di Piastrinopenia:[1] (English translation) A work on melatonin and platelets (and endothelium) that has not found publishers.

In 2005, having observed favorable results with melatonin also in systemic sclerosis (scleroderma), a disease whose “primummovens” is believed to be endothelial damage, and having already, at that time, a work on this subject accepted for publication by the American Journal of Therapeutics[2] (published in 2006), I thought it 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.

Clearly, my arguments were, so to speak, of logical-deductive order, since I had only clinical experience; there were not, nor could there have been, any results of basic or laboratory research that I had conducted. The synthesis I proposed, therefore, integrated the results of experimental work of others with what had been observed by me in clinical practice.

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.

Dec 21, 2005

Reference no.: H-01350-2005

Title: Melatonin: a key in platelet physiology and platelet-endothelium interrelations.

Authors: Mr. Mauro Todisco, 1) Mauro Todisco

Dear Mr Mauro Todisco:

Thank you for submitting your paper for publication in the […]

I have read the above referenced manuscript and find it is a brief review of the involvement of melatonin in the regulation of platelet-endothelium functions, rather than a report of previously unpublished data on the subject. As such, the manuscript is not suitable for publication as an original paper in […]

I hope this decision will not detract you from submitting your original work for publication in the journal.

Yours sincerely

While accepting and respecting the decision communicated to me, in line with the purpose that had guided the writing of that work, I wrote to the journal editor the following answer:

Dear A. N.,

your review about the work I submitted assume that the subject matter is very well known in physiology and, more generally, in medicine. To me it is exactly the opposite. It is not known to me, in fact, any text of physiology where is written, for example, that platelets contain melatonin, or that melatonin is essential in the function of platelets and endothelium, or that, in medicine, melatonin is of recognized usefulness in the treatment of thrombocytopenias. To confirm the above, the result of the search conducted on Medline for “melatonin in the regulation of platelet-endothelium functions” (I used a sentence of your answer for the search) does not find any published scientific work (I transmit in attachment the result of the search).

It is, therefore, a topic that has the characteristic of novelty for almost all doctors, a topic from whose knowledge, however, many patients could benefit: the thrombocytopenics, first of all (the last two patients with thrombocytopenia refractory to corticosteroids that I treated were able to avoid splenectomy thanks to melatonin), but also patients with systemic sclerosis, whose improvement with a treatment based on melatonin confirmed me the endothelial-trophic role already hypothesized for this substance by prof. Luigi Di Bella. […]


Below is the text of that work.






While melatonin is well known for its interrelationships with circadian rhythms, the same cannot be said for its close connections with platelets. Melatonin is derived from serotonin through a process of acetylation mediated by the enzyme serotonin-N-acetyltransferase (NAT), and a subsequent methylation promoted by the enzyme hydroxyindol-O-methyltransferase (HIOMT).

Platelets incorporate serotonin internally against a concentration gradient, and serotonin is the major constituent of platelet dense granules.

In vitro, melatonin promotes platelet outflow from rat marrow megakaryocytes;[3] melatonin has also been described to exert a therapeutic effect in thrombocytopenic subjects.[4],[5]

Platelets contain substantial amounts of melatonin; in humans, melatonin is concentrated about 400 times more than in plasma,[6] which is also the case for serotonin.[7]

Platelets synthesize melatonin from serotonin,[8] but not only that; they incorporate melatonin at the level of their membrane through an active, saturable, temperature-dependent transport mechanism.[9] Platelets are essential for the anatomical and functional integrity of the endothelium: in thrombocytopenia there is an increase in vascular fragility associated with ultrastructural changes of the endothelium that disappear with the return to a normal platelet count.[10]

On the other hand, melatonin can stop bleeding in thrombocytopenic patients even if platelet counts do not increase,[11],[12] as if melatonin exerts a direct, stabilizing action on the endothelium and replaces platelets in their function.

An action of melatonin on the endothelium is also confirmed by the favorable results we have observed with a melatonin-based regimen in patients with Systemic Sclerosis (Scleroderma), a disease whose “primummovens” is precisely endothelial damage.[13],[14]

Considering that platelets metabolize melatonin and are essential for the integrity of the endothelium, our clinical findings with the use of melatonin in scleroderma show that melatonin has a key role in the endothelium-trophic function of platelets.

In this activity, melatonin may play not only a direct role – when it is released and interacts with endothelial cells – but also an indirect role through its influences on platelet lifespan.

Melatonin, in fact, interacts with purine and pyrimidine receptors[15] and reverses the aggregating activity of ADP;[16]when aggregation is irreversible, the latter activity determines the disappearance of the circulation of the platelets involved and the complete release of the substances contained within them. By reversing the aggregation promoted by ADP, melatonin allows the platelets to disaggregate and resume their journey in the circulatory stream.

Considering that the anatomical and functional integrity of the vascular endothelium requires continuous metabolic processes of synthesis and repair, processes that platelets carry out through paracrine signals, through momentary interactions (give-and-go mechanism), or through cell-cell adhesions mediated by receptors,[17] and considering that the endothelial-trophic function can be considered as the result, the synthesis, of all the interactions, even of opposite nature, that occur between the endothelium and platelets during their travels in the circulatory system, melatonin, by physiologically prolonging the mean life of platelets, facilitates the complete performance of the multiple platelet activities and allows, in this way, that the same activities result adequate, in time and space, to the needs of the underlying endothelium.

Thus, comparing the network of blood vessels to that of roads, and platelets to vehicles equipped for the maintenance and repair of the latter, melatonin can be seen not only as a producer of maintenance units (we have seen that melatonin stimulates the release of platelets from bone marrow megakaryocytes), but also as a manager who, in addition to direct intervention, plays a role in regulating the repair material to be used, preventing an inappropriate or excessive release of the same material from hindering the circulation rather than facilitating it.

Since the endothelium regulates essential functions for life and health such as vascular tone, blood fluidity and cellular exchanges of nutrients, the action of melatonin on the endothelium can first of all explain the reason for the multidisciplinarity of this substance; secondly, it can contribute to a critical reconsideration of the idea, prevalent today, according to which platelets are an enemy to be fought when there are abnormalities of the endothelium.

This is the case, for example, in Systemic Sclerosis, in which anti-platelet drugs are commonly used even though double-blind studies have revealed their ineffectiveness.[18]

Indeed, if the conception of platelets as a source of vascular disturbances is unquestionable in an acute intervention context, it may instead be objectionable in a chronic intervention context. If platelets are essential to the anatomical and functional integrity of the endothelium, an intervention aimed at antagonizing their activity could cause endothelial abnormalities responsible in turn for vascular disorders. On the other hand, it has been demonstrated, in vivo, that the antithrombotic efficacy of antiplatelet drugs does not increase with increasing dosage, and that higher-dose antiplatelets fail to decrease thrombus formation in case of experimentally induced endothelial damage.[19]

As in thrombocytopenia, also in the approach to chronic endothelial damage, melatonin, through its key role in the regulation of platelet physiology, may pave the way for a new intervention strategy: one aimed at supporting platelets in their basic, essential, endothelial-trophic activity.”

Dr. Mauro Todisco

[1] Todisco M, Storie di Piastrinopenia, Vimarangiu, 2016, pp. 94-97.

[2]Todisco M, Effectiveness of a treatment based on melatonin in five patients with systemic sclerosis, American Journal of Therapeutics. 2006; 13:84-87.

[3] Di Bella L et al.,Boll Soc It Biol Sper 1979; 55:318-330.

[4]Di Bella L, Rossi MT, Scalera G, Perspectives in pineal function. In: AriensKappers J., Pévet P., eds. The pineal gland in vertebrates including man (Progress in Brain research, Vol. 52). Amsterdam: Elsevier North Holland Biomedical Press 1979:475-478.

[5] Todisco M RossiN,Melatoninforrefractoryidiopathicthrombocytopenic purpura: a Report of 3 Cases. Am J Ther2002; 9:524-526.

[6] Lemaitre BJ et al., Melatonin content, uptake and synthesis by blood platelets. EPSG 2nd Colloquium, Giessen, 1981. EPSG newsletter, edited by Pévet P, Tapp E, Suppl 3:42, 1981.

[7]Maurer-Spurej E et al., A novel immunocytochemical assayfor the detection of serotonin in platelets. Br J of Hem 2002;116:604-611

[8] See note 11.

[9] See note 11.

[10] Kitchens CS, Weiss L, Ultrastructural changes of endothelium associated with thrombocytopenia. Blood 1975; 46:567-578.

[11] Di Bella L et al., Platelet turnover as influenced by Melatonin. In: Birau N, Schloot W, eds. International Symposium on Melatonin. September 28-30, 1980. Bremen, 1980:117.

[12] 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.

[13] LeRoy EC, Pathogenesis of systemic sclerosis (scleroderma). In: Koopman WJ, ed. Arthritis and Allied Conditions, 13th ed. Baltimore: Williams & Wilkins; 1997:1481.

[14] Gilliland BC, Systemic sclerosis (scleroderma). In: Braunwald E, Fauci A, Kasper D, et al, eds. Harrison’s Internal Medicine, 15th ed. New York: McGraw-Hill;2001:1937-1947.

[15] Di Bella L et al.,Formazione di complessi fra melatonina e basi puriniche e pirimidiniche. Boll Soc It Biol Sper 1976;52:157.

[16] Di Bella L et al., Molecular mechanism of bone marrow thrombocytogenesis by melatonin. EPSG Newslett 1981; Suppl 3:126.

[17]Warkentin TE et al., Platelet-endothelial interactions: Sepsis, HIT, and antiphospholipis syndrome. Hematology, Jan 2003:497-519.

[18] Beckett VL et al., Trial of platelet-inhibiting drug in scleroderma. Double-blind study with dipyridamole and aspirin. Arthritis Rheum 1984;27(10):1137-1143.

[19] Nishimura H et al., In vivo evaluation of antiplatelet agents in gerbil model of carotid artery thrombosis. Stroke, 1996;27:1099-1104.