Melatonin and Autohemotherapy: regression of diabetic lesions of the lower limbs. Regarding the case of A.G.

Why I believe it is important

  • Because, in almost forty years of professional activity, I have never observed an improvement such as that observed in some of A.G.’s lesions.

In similar cases I have always witnessed the progression to gangrene and sepsis, when no amputations have been performed.

  • Because the same treatment followed by A.G. can be useful for other patients with vascular problems, e.g. those with diabetic foot, first of all, but also those with other arteriopathies (such as coronary, carotid, etc.).

Why I proposed the treatment to A.G.

A.G. was the first patient with vascular problems I associated autohaemotherapy, practised on a weekly basis, with melatonin and other substances such as vitamins C and E.

Autohaemotherapy, which I started using in the early 2000s for the treatment of herpes simplex, consists of administering to the patient, intramuscularly, blood freshly taken from one of his veins (the amount of blood to be used varies between 5 and 20 ml, depending on the case).

In the case of A.G., what happened at the end of April this year to another patient of mine suffering from lower limb arteriopathy obliterans oriented me towards this treatment modality.

In February 2022, after a vascular surgery visit, this patient had been put on the list for revascularisation surgery. In the meantime, I suggested her to have a few sessions of autohaemotherapy because, from listening to an interview with Dr Luiz Moura, I had learned that an elderly Brazilian colleague had solved a similar problem using this method.

By the time, the patient had been called to proceed with the unblocking I had already practiced six sessions of autohaemotherapy. To her surprise and then mine, listening to her as she reported it to me, the planned surgery had not been performed because it was not urgent, the doctor had told her this time after having examined her. 

So, when I went to A.G. for the usual injection of red blood cell growth factors (A.G. has an anaemia resulting from renal insufficiency in turn caused by diabetes) I told her about what had happened and suggested we also try the weekly autohaemotherapy.

What happened afterwards was documented by photos taken by the nurse who follows A.G. at home for medication.

How the treatment may have acted

There is no doubt that where A.G.’s lesions have improved, there must have been an increase in blood flow in the areas of the alterations.

The significant improvement in the necrotic lesion affecting the first toe of the right foot is of particular interest. Here it is legitimate to believe that diabetic microangiopathy, i.e. the anatomical and functional impairment of the microcirculation, is co-implicated in the onset of the lesion, so that the result obtained by A.G. could indicate a usefulness of the treatment at this level too.

What mechanisms may have come into play in determining the result?

Without any claim to being exhaustive I propose the following causal hypothesis considering:

(a) certain functions exercised in the body by mononuclear phagocytes, i.e. monocytes, produced by the bone marrow, and macrophages, i.e. the cells in which circulating monocytes mature and transform once they have settled in the tissues.

(b) certain functions performed by platelets.

(c) the influences exerted over the functions referred to in letters (a) and (b) respectively by autohemotherapy and melatonin.

Concerning point a)

The mononuclear phagocyte system, the term by which the Aschoff-Landau reticuloendothelial system is nowadays referred to, plays a fundamental role in the body defence against pathogens (bacteria, viruses, fungi, parasites), but it also performs functions that go beyond the strictly immune ones. Being made up of cells with the ability to phagocytose substances of various kinds (fibrin micro-aggregates, toxins, inert foreign substances, etc.), it can be considered as the cleansing enterprise of the body, so much so that its cells are often referred to as the body’s ‘scavengers’.

Now, monocytes and macrophages perform, among others, the task of keeping arterial vessels clean by removing fats that, as a result of an injury to the endothelium, i.e. the carpet of cells that covers the blood vessel wall, penetrate the layer of the arterial wall immediately beneath it: the intima.

Already in 1981, Ross G. Gerrity, of the Research Division of the Cleveland Clinic Foundation, Ohio, in a paper published in the American Journal of Pathology demonstrated the existence of a ‘monocyte scavenging system’ in which a large number of circulating monocytes invade the intima of the areas at risk of injury, become phagocytosing, accumulate lipids and migrate back into the blood stream through the arterial endothelium, and then ‘dispose’ of the phagocytosed fats, probably in the reticuloendothelial system.

With this in mind, it seems sensible to assume that the progression of the atherosclerotic lesion may, at least in part, be the result of the inability of the mononuclear phagocyte system to remove sufficient lipids; Adams, Bayliss and Turner, pathologists at Guy’s Hospital Medical School in London, thought this as early as 1975, when they wrote that “However, irrespective of what causes lipid deposition in atherosclerosis, its accumulation must reflect a failure to remove lipids from part of phagocytosis.”

On closer inspection, this hypothesis would not even conflict with the current model of the genesis of atherosclerosis called the ‘damage reaction hypothesis’, according to which the initial event would be a lesion to the endothelium and the mononuclear phagocytes – monocytes and macrophages – would be involved in the progression of the disease.

The presence of these cells inside the atherosclerotic plaques, in fact, as well as their consequent participation in the atherosclerotic inflammatory processes, could be due, for some reason, to the fact that those same cells, once they have entered the deposit they are supposed to empty, are then unable to get out.

Concerning point b)

We are well aware of the influence of platelets on coagulation, but one of their most important functions is that of contributing decisively to the anatomical and functional integrity of the vascular endothelium, the cellular layer that for about 7000 m2 covers the intima of the blood vessels and regulates very important functions such as, for example, blood fluidity, vascular tone, nutrient exchanges, and the passage of immune cells from the circulatory system to the tissues.

The endothelium requires continuous metabolic processes of synthesis and repair that the platelets carry out through chemical signals, by means of momentary interactions (give-and-go mechanism), or through cell-cell adhesions mediated by receptors, and the endothelium-trophic function of the platelets can be considered as the result, the synthesis, of all interactions, even of an opposite nature, that occur between the endothelium and the platelets during their travels in the circulatory system. As we have seen in point a) above, today it is believed that the atherosclerotic process begins with endothelial damage and with the subsequent passage of lipids within the intima. This fact alone, given the impact that atherosclerotic vascular problems have as a cause of death and disability, would account for the absolute importance of the endothelium-trophic function exercised by platelets, a function to the full performance of which, as we shall see, melatonin contributes decisively.

With regard to point c) concerning the influence of autohaemotherapy on the mononuclear phagocyte system

We have already seen that the mononuclear phagocyte system plays a significant role in keeping the arteries clean. It follows that having tools capable of acting on the efficiency of that system, tools, let us say, capable of activating the body’s cleansing enterprise, could be particularly useful in anti-atherosclerotic terms. In fact, research is also moving in this direction; recently, for example, the news highlighted a study conducted by US universities on nanoparticles which were able to activate macrophage phagocytosis in mice.

Well, eighty-two years ago, in 1940, a Brazilian surgeon, Jessé Teixeira, published a paper* in which he reported that he had effectively practised autohaemotherapy to prevent pulmonary complications on 150 patients who had undergone surgery and, among the mechanisms responsible for that favourable result, he named stimulation of the mononuclear phagocyte system.

‘Aschoff-Landau’s reticuloendothelial system is powerfully stimulated by autohaemotransfusion,’ he wrote, and in support of this statement he listed the results of a number of experiments including one in which, with autohaemotherapy the percentage of monocytes present in the fluid of a vesicle formed on the skin following the application of a substance with vesicidal action had risen from 5% to 22% in eight hours, was still at 20% after 72 hours and had gradually returned to 5% over 7 days (a clarification: by the term autohaemotransfusion Teixeira means autohaemotherapy; he writes, in fact, that “… while the patient is still on the operating table, 20 cc of blood is taken from a vein in the fold of the elbow, which is immediately injected into the buttock. …”).

Texeira had conducted his study at the urging of Dr Sylvio D’Avila, the brilliant young director of the department where he was an intern, who had read in the American Journal of Surgery the article Autohemotransfusion in Preventing Postoperative Lung Complications by Dr Michael W. Mettenletter.**

Mettenletter, a New York Hospital surgeon and post-graduate professor of Surgery, reported there that he had used autohemotherapy as a preventive medicine tool in three hundred patients and had experienced post-operative lung complications in only one case.

Texeira also wrote that he had failed to publish in his article a large number of cases, also favourable to the usefulness of the method, which had been observed by colleagues whose names and institutes he mentioned.

I wanted to contextualise Teixeira’s work not only because a surprising interest in autohaemotherapy emerges in several surgeons of the time, but also because the global number of cases in favour of the preventive utility of this method appears more than remarkable.

The action of autohaemotherapy on the monocyte-macrophage system described by Teixeira was confirmed in a 2007 study in which the author, Dr. Moara Rosin, conducting research on ten healthy volunteers, documented an average increase in the percentage of monocytes in peripheral blood of 37.5% and 54.1% respectively two and five days after autohaemotherapy.

*Jessé Teixeira, Autohemotransfusäo complicaçöes pulmonares pós-operatório; Brasil-Cirúrgico, vol. II, March 1940, no. 3, pp. 213-230.

**Michael W. Mettenletter, Autohemotransfusion in Preventing Postoperative Lung Complications; The American Journal of Surgery, vol. 32, Issue 2, May 1936, pp. 321-323.

With regard to point c) concerning the influence of melatonin on the endothelial-trophic function of platelets

While the role of platelets in maintaining the anatomical-functional integrity of the endothelium is accepted, the same cannot be said for the role melatonin plays in this regard.

The late Prof. Luigi Di Bella, former professor of Physiology at the University of Modena, investigated these relationships; to him we owe the studies on the intimate connections that exist between platelets and this substance.

One day, in the mid-1990s, during one of my visits to his study, the Professor told me that he had begun to understand something about melatonin during a car journey from Modena to Trento. In the car, together with him and the driver, was a leukaemia patient with an extremely low platelet count. Di Bella expected a haemorrhagic event at any moment, but nothing happened.

“Yes, he had no platelets,” he said, “but he had melatonin.”

The Professor meant that the melatonin taken by the patient had, as it were, replaced the platelets in their function, preventing bleeding.

Years later, thanks to melatonin, I witnessed the cessation of life-threatening bleeding in a severely thrombocytopenic female patient who had already had to transfuse twenty-eight bags of red blood cells in one week.

On that occasion I had prescribed melatonin at twice the dosage I was using at the time in thrombocytopenics, and the bleeding had stopped after five days of taking the substance without the platelet count rising again, as if, again, melatonin had replaced the platelets in their anti-haemorrhagic function.

I proposed the case for publication to the American Journal of Therapeutics, which had already accepted other works of mine; it was published in 2003 in No. 10 of the journal (pp. 135-136) with the title ‘Severe bleeding symptoms in refractory idiopathic thrombocytopenic purpura: a case successfully treated with melatonin’.

What do the case of the leukaemic passenger and of the thrombocytopenic patient mean? Melatonin is essential for the stabilizing and anti-haemorrhagic function performed by platelets on the endothelium.

On the other hand, platelets are capable of synthesising melatonin and contain it within them in concentrations four hundred times higher than in plasma.

Melatonin, for its part, is able to disaggregate platelets when they are aggregated.

Now, since platelet aggregation, if it becomes irreversible, results in the disappearance of platelets from the circulation and the concomitant release of all the material contained within them, melatonin, by disaggregating platelets, physiologically prolongs their life span. This effect, in turn, facilitates the complete unfolding of the multiple platelet activities and helps to allow these activities to be adequate, in time and space, to the needs of the underlying endothelium.

To simplify, we could compare the network of blood vessels to that of roads: the platelets can then be assimilated to vehicles that circulate equipped with the materials needed for road maintenance, while melatonin can be considered as an operator who, in addition to taking part in the maintenance activity itself, intervenes in the management of the repair material inside the vehicles (the platelets).

In 2005, having observed favourable results with melatonin also in systemic sclerosis (scleroderma), a disease whose ‘primum movens’ is thought to be endothelial damage, and having already, at the time, a paper on this subject accepted for publication by the American Journal of Therapeutics (it was published in 2006 in No. 13 of the journal, pp. 84-87), I thought it might be useful to try to integrate the knowledge we had of melatonin in relation to platelets and endothelium. When the paper 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.

The intention was for that publication to make known to a wide audience of physicians things that were not known, to propose an overall physiological vision of the melatonin-platelet-endothelium interrelationships, and to highlight the new therapeutic perspectives that could derive from it. In December 2005, I received a negative response from the editor of the journal: the work would not have been published.

On this site I have reproposed that work, in its Italian version, in “Melatonin, endothelium and Covid-19“, and in the English version in “MELATONIN: A KEY IN PLATELET PHYSIOLOGY AND PLATELET-ENDOTHELIUM INTERRELATIONS”.

Final considerations

On 29 May 2022, I published on this site the article A.G.: a case to follow, where I described what had happened up to that time following a treatment based on melatonin and autohaemotherapy practised weekly to an eighty-eight-year-old diabetic patient of mine with severe renal insufficiency and trophic and necrotic lesions in her lower limbs.

The article closed with a commitment to provide information on the patient’s clinical status over the next two months.

We have now reached 12 August and, I think, some conclusions can be drawn. As can be seen from the observation of the photos, some of the lesions have evolved very favourably: the lesion on the right calf has improved most rapidly, and is now resolved; there has been a marked improvement in the left heel and, what I think most surprising, also in the first toe on the right foot. In fact, I do not believe that anyone, looking at the photos of that toe taken on May 3, 10 and 13, would have proposed anything other than amputation.

Now, considering that I have never before seen results such as those observed on A.G. and that the only difference, compared to my previous therapeutic proposals, was in this case the autohaemotherapy practised every week, I am led to think that this method and the timing of its execution were fundamental to the result.

In the preceding pages I have proposed an interpretation of the mechanisms which may be implicated in the vascular action of both autohaemotherapy and melatonin, but, going back to comparing blood vessels to roads, I think, as I said a few lines ago in other words, that the repeated activation of an army of sweepers (the one promoted by autohaemotherapy), even before the ordinary maintenance of the road surface (the one operated by platelets), was decisive in A.G.’s result.

In any case, the future will clarify the possibilities of this approach in the treatment of vascular problems. At the moment, the only other patient on whom I have used it is a diabetic and hypertensive patient of mine who, like A.G., is eighty-eight years old, with a painful arterial vascular ulcer on her right leg.

The lesion healed in two weeks.

Dott. Mauro Todisco