From each blood donor a pack with about 450 ml of total blood is collected – total because the volume carries all blood components, that is, red blood cells, white blood cells, platelets and the plasma. Since the person with thalassemia needs only the healthy hemoglobins of this fluid, the pack collected goes through a centrifugation process which separates the blood components and makes it easier for removal of everything which is not interesting. The result is a concentrate of erythrocytes (the red blood cells) of approximately 250 ml.

Did you know?
If the person with thalassemia received the total blood – and not only the concentrate of erythrocytes – during the transfusions, there would be an overload of the other components in the blood circulation capable of causing serious health problems, such as cardiac insufficiency and the accumulation of liquid in the lungs (pulmonary edema).

Special filters connected to the collection packs filter the blood already during donation. The procedure – a mandatory service offered in the blood banks by the Single Health System (SUS) – is the most efficient to remove the leucocytes (white blood cells) from the blood of the donor. Otherwise, these defense cells of the organism may release substances, the citokynes, which usually cause fever in the person with thalassemia after the transfusion. Another severe consequence of the presence of these white blood cells in the concentrate of red blood cells which will be transfused is the fact that these cells may carry microorganisms – such as the bacteria yersinia enterocolitica and the cytomegalovirus – capable of causing severe infections in the organism.

WARNING: The filtration may also occur in the blood bank lab. The problem is that in the half time – between donation and the time in which the red blood cell concentrate goes through the filter – the citokynes may have been already released, and these are the substances spread all over the fluid that will cause thrills, shivers and fever in some people with thalassemia during transfusion. There is also the possibility – already surpassed by the inefficiency presented – of filtrating the blood on the bed, that is, during transfusion to the person with thalassemia. The technique may lead to the clogging of the filters and prevent the person with thalassemia from receiving the blood appropriately. Therefore, the ideal is that the blood is filtrated at the time of the donation.

After removal of the plasma, and the platelets and white blood cells, both by centrifugation and by filtration, some substances are added to the red blood cell concentrate to preserve the healthy hemoglobins of the donor. Certain nutrients or additives increase the survival rate of the red blood cells. Blood thinners, in turn, avoid these cells to be stick and to render it difficult to transfuse.

The recommendation from the Thalassemia international federation is that, regardless of the usage of these preservatives, the blood donated is used by the person with Thalassemia up to at most seven days after donation. There are no studies attesting efficiency of the transfusion with blood stored for over one week yet.

Making the typing and fenotyping of the blood pertaining to the person with Thalassemia is the first step to define which is the best red blood cell concentrate for each person with Thalassemia to receive and thus assure an efficient and safe blood transfusion

A blood type is not defined only by the systems ABO or the RH (positive or negative). The red blood cells are listed in 26 systems of blood groups, resulting in 600 antigens in total that may be combined and be present in the surface of these cells. The red blood cells of each individual have a combination of these antigens corresponding to a kind of identity record (ID). The more similar the ID of a person with thalassemia is from the ID of the donor (that is, the more compatible), the lower the risks of the organism to create antibodies and react against the "foreign" antigens of the blood donated.

The phenotyping test, from a blood sample, is the most indicated to discover what the "ID" (the phenotype of the red blood cells) of each person with thalassemia is and should be done as soon as possible, that is, after the diagnosis of major thalassemia, for example. Otherwise, the presence of the red blood cells of the donor in the organism of the person with thalassemia may confuse the blood analysis and, to avoid that, the physician shall order a more complex exam: the genotyping.

The genotyping is an exam which also requires only one blood sample, but the technique used for analysis is more advanced and uses the molecular biology to separate the DNA (the genetic material) of each individual and, then, discover the characteristics of the donor's and receiver's blood. The most advanced method is not found in most labs and blood banks yet. (why do you mention genotyping?)

Did you know? Despite all efforts to find a blood compatible to the person with thalassemia, from 3% to 28% of the people with thalassemia, after the transfusion, end up developing antibodies which react to certain antigens of the donated blood. This reaction may cause what the physicians call hemolytic fever and prejudice the efficiency of the transfusion treatment. To avoid complications, experts recommend that at least the systems of blood groups ABO, Rhesus (RH), Kell, Kidd and Duff – which are most associated with cases of immune reactions – are checked at the time of testing compatibility between the donor's blood and the receiver's blood.

WARNING: nowadays, only by looking at the label of the blood pack, the person with thalassemia already checks whether the red blood cell concentrate he/she is to receive in the transfusion was phenotyped and filtered. It is worth mentioning that instead of the term "filtered", the patient may find "leucocytes removed", which means exactly the same thing, that is, the leucocytes (the white blood cells) were contained by a filter and removed from the blood.

Non-hemolytic fever reaction: thoracic and lumbar pain, generally caused by some blood contamination by infectious agents.

Hemolytic fever reaction: reaction by production of antibodies against antigens of the blood donated. More rare situation, because filtration of the blood removes this possibility a lot.

Allergenic reaction: it may begin with a scratch, an urticaria by the body and evolve to an edema of glottis (swelling in the neck region, preventing the air passage). For these people with thalassemia, cleaning with physiological saline of the red blood cell concentrate is indicated.

- Encouragement policies to the regular blood donations: associations such as ABRASTA are mobilized in this regard, since, in addition to assure the stock of the blood banks, the profile of the people who really wants to donate on an annual basis is of a more conscious person, with a behavior that will not offer risks to the patients who need periodic blood transfusions.

- Check whether the services of the blood banks meet the international quality Standards: this care may be essential to assure a blood of quality and compatible to the people with thalassemia

- NAT included in the processing of the blood packs: the (Nucleic Acid Test), or NAT, is a type of test, available in Brazil only in private services, which shortens the serological window (time in which the amount of antibodies in reaction to a virus in the organism is not enough to indicate the presence of infection). With NAT, there is a reduction of over 50% in the risks of occurring transmission by virus causing diseases such as hepatitis C and Aids during the transfusion.

- Vaccination: the people with thalassemia who need periodic blood transfusions should recur to the vaccines existing to be protected, previously to receiving the first transfusion.

Washed blood: the process of washing the red blood cell concentrate with physiological saline is recommended in case of allergenic reaction to the blood donated – which does not respond to the histaminics (antiallergenic drugs) and may begin with an urticaria in the skin and evolve to a bronchospasm and even an edema of glottis (swelling in structure located in the neck causing lack of air). However, after being washed, the blood needs to be available for transportation within up to 24 hours. Other patients who benefit from the procedure are those who are born with absence of IgA*, a natural blood protein. In such case, an immune system of the person with thalassemia – if he/she was born without such protein – may cause an allergenic reaction for the presence of Iga in the donor's blood.

*IgA is the antibody performing an important role in the defense of the body when an invasion of microorganisms is verified through a mucous membrane (coated surfaces, such as the nose, eyes, lungs and the intestines). IgA is found in the blood and in some secretions such as that of the gastrointestinal tube and the nose, eyes, lungs and the motherly milk.

Thalassemia causes the iron to be accumulated in the organism. There are two ways according to which people with thalassemia absorb iron: by the diet and by transfused blood. If the excess iron is not removed, it may cause damages to important organs, such as the liver and the heart. People with thalassemia should, therefore, use special medications named chelating agents, which remove the iron from the body.

A normal healthy adult stores around 4 g of iron in the body, out of which 3 g are used to manufacture hemoglobin inside the red blood cells. As previously explained, when the red blood cells get old and die, their hemoglobin is degraded in its constituent parts: heme and globin. The iron released from the heme part is transferred through a carrier protein, named transferrin, and is recycled for production of more heme for new red blood cells. The chemical substances comprising the globin protein, known as amino acids, are reused in the production of new globins.

It means that, in a normal adult individual, the body reuses most part of the iron available, leaving too little to be excreted. Only 1 mg of iron is eliminated every day – most part from the urine, feces, skin and – in women – through menstruation. The iron thus removed from the system is replaced by the iron of the diet, absorbed by the digestive system.

In the cases of intermediate thalassemia and major thalassemia without transfusions the body tries to compensate for the severe anemia through absorption, in the digestive tract, of a significantly greater amount of iron than usual (2-5g/year as compared to 0.0015g / year in healthy individuals), to produce more red blood cells. Most part of iron absorbed depends on severity of the anemia: the more severe, more will the bone marrow expand to try to produce more and more red blood cells and, therefore, the greater the demand for iron. Other factors may also influence in the amount of iron absorbed in the intestinal tract. For example, the presence of vitamin C increases the amount of iron absorbed, while the tea and some cereals reduce it. However, the most important form of reducing the amount of iron absorbed in the intestinal tract is assuring that patients keep appropriate levels of hemoglobin. Therefore, it is important that they receive regular blood transfusions, keeping the hemoglobin levels above 9g / dl (measured previously to transfusion). Patients not appropriately transfused may absorb from 1 to 5 mg extra per day (or approximately 0.4 to 2g / year) of iron in the intestinal tract.

The major origin of iron overload in patients receiving transfusions, however, is the transfused blood. In fact, the amount of iron the patient absorbs through blood transfusions is quite greater than the amount absorbed from the diet in the intestinal tract. Therefore, it is important that patients receiving regular blood transfusions use iron chelating agents – drugs that are connected to the iron and that remove it from the system amount.

Each milliliter (ml) of red blood cells contains around 1.16mg of iron. An average blood unit contains around 250 ml of red blood cell concentrate – that is – 250 x 1.16, or around 200-290mg of iron. The degradation of these red blood cells is the main source of iron accumulated in the organism of patients receiving blood transfusions throughout life. For example, a patient receiving 30 blood units per year will have an excess of approximately 6 g of iron per year (200x30 = 6.0mg = 6g), or approximately 15-16mg/day. The body is not capable of excreting so large amount of extra iron and this iron is accumulated in the tissues and organs of the body. If this iron is not removed through medical intervention it may be extremely damaging and cause some of the most severe complications of the major thalassemia.

The clinical symptoms of the iron overload usually appear around the 10 years of age, although evidences of the toxic effects of iron have been found in the liver of children much younger. The injury to the liver – known as fibrosis – is initiated within two years after beginning of the transfusions. A severe injury in the liver (cirrhosis) may develop before the 10 years of age if no treatment is implemented to remove the excess iron, mainly if the patient has hepatitis B and/ or C. Cardiac diseases – one of the most frequent death causes in the major thalassemia – are also reported within a period of 10 years after beginning of the transfusion program, although cardiac insufficiency usually does not occur before the 15 years or more of transfusions.

The iron overload is also the most important cause of the sexual maturation retardation in patients with thalassemia, affecting approximately half of the patients, both from the female and male genders. Furthermore, the iron overload may bring difficulty for women who want to have a child (around 25% of the cases), and is, usually, a cause for development of diabetes mellitus.

In the long term, the excess iron causes bone complications and damages to other important organs, such as the thyroid and the parathyroid. Therefore, the patients should be treated for its removal; otherwise, the iron will be accumulated in the organism, with serious consequences in terms of quality and extension of the patient's life.

As iron is accumulated in the body – whether as a result of thalassemia per se, the blood transfusion therapy, or of both – its major carrier protein in the blood, the transferrin, gets saturated. With no transferrin in the free form (not connected to the iron), the free iron – too damaging to the organism – begins to circulate in the blood. The iron is also accumulated in the tissues, connected to storage proteins named ferritin (4c) and hemosiderin. The iron stored in these proteins is less damaging than the free iron. However, the body continuously degrades ferritin and hemosiderin, which release certain amounts of iron in the free form. The iron may also be released from such storage proteins when the patient is sick.

The iron not connected to the transferrin – that which remains in the system when there is no tranferrin for connections – is unstable. It means that it may easily gain or lose a negative load, called electron. When the iron gains an electron, it ceases to have three positive loads (type of iron known as 3+ or ferric iron) and starts to have two positive loads (2+ or ferrous iron). When the iron changes to the states 2+ and 3+, it produces dangerous substances named free radicals, that may cause extensive damage to the tissues of the organism.

The most known process for production of free radicals is named Fenton's reaction – a chemical reaction simplified as follows:

Generation of a radical hydroxyl (OH)

What are they: drugs with active substances capable of connecting to the iron, then comprising a compound that may be excreted from the organism by means of the urine and feces. Without such help, the body is not capable of eliminating the excess mineral in the blood.

Candidate to the chelation therapy: the person with thalassemia under treatment with periodical blood transfusions.

When to Begin the iron chelation: after the 10th transfusion or when the level of ferritin – the iron storage protein, found in all cells – is above 1000 ng/dl (nanograms per deciliter of blood).

What are the types of chelating agents: There are three types currently available for the people with thalassemia, and each one of them represents a landmark in the evolution of the thalassemia treatment.

Deferoxamine (Desferal): was the first chelating agent to arise in the market, in the 70's, but despite efficiency in eliminating the iron from the organism, it found resistance from many people with thalassemia, due to its administration form: by subcutaneous route, with the aid of an infusion pump, during 12 to 14 continuous hours (usually at night in bed) and from five to six times a week.

Deferiprone (Ferriprox): the second chelating agent to be released came one decade after the deferoxamine and with many advantages in relation to the pioneer. It could be taken orally – although in a greater frequency, three times a day – and, in accordance with studies, it has the capacity of eliminating faster the excess iron in the organism. In some cases, association of deferoxamine and deferiprone is recommended to intensify excretion of the iron.

Deferasirox (Exjade): the most recent drug, released in 2006 in Brazil, is also a pill, but to make it more easier adhesion to the treatment, it should that must be dissolved into water and ingested only once a day . (It is not a choice!). It is too (?) efficient to eliminate the iron overload in the liver, but there are few studies to assess its power in relation to the removal of the mineral from the heart. (there are data proving the removal of iron from heart; the problem is the no effect on the ejection fraction)

How can the therapy be applied: there is a combined therapy (which associates usage of Desferal with Ferriprox) and the monotherapy. There are no studies yet attesting efficiency of Exjade in association with other chelating agents.

According to experts, there is no chelating agent better than the other, and the choice of the ideal drug for each person with thalassemia should consider factors such as side effects, amount of iron accumulated in the liver and the heart, clinical status of the person with thalassemia... Only the physician will be able to say what is the best treatment to follow and, to help him, the Scientific Committee of ABRASTA developed an iron chelation protocol (experts may access it at the website area SUPPORT TO PHYSICIANS, in the link TREATMENT PROTOCOL).

WARNING FROM THE EXPERT: The chelating therapy should be indicated and monitored by an experienced hematologist from a specialized center, so that the results are periodically monitored and, as required, the medication can be changed.