Hemoglobinopathies (Part Three)

Prevention and Management of Hemoglobinopathies

Prevention of homozygous homogenous or heterogeneous forms of hemoglobinopathies or any other autosomal recessive genetic disease (as dominant pathologies and in the heterozygote differ) is achieved through:

1. Genetic counseling.
2. Prenatal diagnosis.
3. Termination of pregnancy.

Hemoglobinopathies are often inherited as Autosomal Recessive Diseases. For the first time, the autosomal dominant transmission of Thalassemia was reported in an Irish family.

Practically, the greatest possibility is the marriage of a carrier for hemoglobinopathy with a healthy individual and the problematics when both parents are carriers of the same hemoglobinopathy or different hemoglobinopathies.

1. If one parent is a carrier and the other is healthy, each child of this couple has a ½ (50%) chance of being healthy and ½ (50%) of being a carrier.
2. If both parents are carriers, each child of this couple has a ¼ (25%) chance of being healthy, ½ (50%) of being a carrier, and ¼ (25%) of being sick with the severe/intermediate forms of the disease/diseases. The hematologist, geneticist fights for the last chance.
3. Up to the 16th week of pregnancy, amniocentesis can be performed on the pregnant woman, where it is possible to take the child's epithelial cells from the amniotic fluid and perform genetic analysis for hemoglobinopathy. If the severe/intermediate form of hemoglobinopathy is detected, it is up to the couple to decide on the termination or not of the pregnancy after being informed about the consequences of the disease.

Genetic counseling and testing, to prevent marriages among carriers and to prevent the birth of children with Major Thalassemia when such a marriage has taken place, is recommended for families that have carriers of Thalassemia. Such a policy exists on both sides of the island of Cyprus, in order to reduce the incidence of Major Thalassemia. This program has been in use since 1970 and includes prenatal screening and abortion. In this way, the number of children with hereditary blood diseases has been reduced to almost 0.

• According to specialist doctors, in our country there are currently about 500 people with beta thalassemia major. Meanwhile, improvements in their medical treatment have led to an extension of the average life expectancy of patients with thalassemia. Data show that before the year 2000 we did not have patients over 18 years old and today there are those over 30 years old. Patients with thalassemia need a blood transfusion every 21 days.
• According to the Ministry of Health, the average number of children born with Major Thalassemia in our country is about 20 children per year, while in recent years there has been a drastic decrease with only 2 cases last year. However, every case is excessive, as it can be avoided.

The Rule of Three

There is a relationship between the number of erythrocytes, the values of hemoglobin, and hematocrit for normochromic, normocytic erythrocytes. These three values follow the rule of three:

• The value of hemoglobin is the multiplication of the number of erythrocytes by 3.
• The value of hematocrit is the multiplication of the value of hemoglobin by 3.

Example: Erythrocytes 5,000,000 mm³ = 15 gr/dl hemoglobin (5.0 x 3) = 45% hematocrit (15 x 3).

If a patient has 5,000,000 mm³ erythrocytes and 12 gr/dl hemoglobin (and the hematocrit will be low, because not only the number of erythrocytes matters but also their volume which is reduced), it is certain that there is not a normal content of hemoglobin (it should have been 15 gr/dl), so they are hypochromic. For a doctor not dealing with hemoglobinopathies and who knows that individually the values of erythrocytes and hemoglobin are normal, there is a discrepancy between them. Ferritinemia, Hemoglobin Electrophoresis should be done.

Practical Importance in Evaluating Carriers of Hemoglobinopathies

1. They are mild born diseases, they are not treated. Only diagnosed. The laboratory changes described above are permanent throughout life. If there are changes, other anemias are superimposed, which if evaluated and treated properly are correctable.
2. They can be discovered during life, may never be discovered. Changes in the ratio between the number of erythrocytes and hemoglobin are distinguished only by the hematologist. There are many errors in evaluating this ratio (some doctors evaluate as an indicator of anemia, the number of erythrocytes, some the value of hemoglobin and it is possible that they individually are normal, but do not match each other).
3. They have no impact on the life expectancy and morbidity of the carrier.
4. Carriers of Thalassemia Minor, have no restrictions for any kind of work, or physical activity. Pete Sampras and Zinedine Zidane (the first of Greek origin, the second Algerian) reached the highest levels of sport. Their main concern was only increased sweating. http://powerofthegene.com/joomla/index.php/genetically-inherited-diseases/blood-disorders/thalassemia.
5. Care should be taken for sickle cell disease carriers, who in conditions of heavy physical activity (military, athletes), or at high altitudes may suffer from the disease's vaso-occlusive crises with some cases resulting in death. Military personnel and athletes of heavy sports must undergo Hemoglobin Electrophoresis as a requirement. http://www.ncbi.nlm.nih.gov/pubmed/22442191. http://www.ncbi.nlm.nih.gov/pubmed/22809753. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569637/.
6. If a carrier of Thalassemia has other diseases or needs surgical intervention, they will be treated as a normal individual. Care for sickle cell disease carriers during pregnancy and surgery.
7. Due to the increased destruction of erythrocytes (hemolysis), more bilirubin will be produced, resulting in a more frequent formation of stones in the gallbladder (cholelithiasis). Care with a history of cholelithiasis, anemia, especially when there is a family character, should also suspect Thalassemia Minor.
8. Due to the increased destruction of erythrocytes (hemolysis) and the tendency to increase iron absorption (in normal people iron absorption is adjusted according to the body's needs), the amount of iron (Ferritinemia) is normal or increased. In such cases, it makes no sense to use iron. Only if ferritinemia is found to be low (mainly due to small recurrent blood losses) will iron be used. If there is only low ferritinemia (Iron Deficiency), treatment with the Therapeutic Dose of iron will be done until this deficiency is corrected, if there is also Anemia from Iron Deficiency, a part of the anemia related to the lack of iron (but not the congenital anemia) will be corrected and the treatment will be discontinued with the correction of the Iron Deficiency. The cause of the iron loss should be evaluated (benign, malignant).
9. Due to the increased destruction of erythrocytes (hemolysis) and compensatory increase in erythropoiesis in the Red Bone Marrow, the raw materials for the production of erythrocytes will be consumed, where the most at risk is Folic Acid (reserves only for 2 months). If its deficiency occurs, Anemia from Folic Acid Deficiency may be installed, which is anyway correctable in the treatment with the Therapeutic Dose of Folic Acid (a part of the anemia related to the lack of Folic Acid will be corrected, but not the congenital part of anemia). To prevent Folic Acid deficiency and the corresponding anemia, regular prophylaxis with Folic Acid is used.
10. But iron, Folic Acid are not treatments for Thalassemia Minor. They are used to correct or prevent the corresponding superimposed anemias. People mistakenly take them as treatment for Thalassemia Minor and expect its correction. No correction should be expected, Thalassemia Minor is incurable, permanent throughout life.
11. The only concern of the doctor for hemoglobinopathies is: to prevent major/intermediate forms of the Thalassemic Syndrome and Sickle Cell Anemia, which occur when both members of the couple are carriers/sick with hemoglobinopathy. If Hemoglobin Electrophoresis is not done, everything is left to chance, as has happened until a few years ago and still happens.
12. The birth of Sickle Cell Anemia can be forgiven, because there is no clinic and laboratory changes, but the birth of severe forms of the Thalassemic Syndrome, the carriers of which have mild laboratory and clinical changes, cannot be forgiven.
13. Hemoglobin Electrophoresis should not be done if the patient has just been transfused (to be done 2 months after the last transfusion), when the child is < 1 year old, and when the blood contains clots.
14. Hemoglobinopathies are often accompanied by hemolytic anemia from enzymatic deficiencies, especially with G6PDH deficiency (to be suspected when hemoglobin decreases).
15. From the marriage of a carrier or a sick person with Thalassemia with a carrier or a sick person with Sickle Cell Disease, children with both pathologies at the same time (Thalasso-Sickle Cell Disease) are born or can be born.
16. Treatment of major/intermediate forms compatible with life:
    • Treatment with blood transfusion + iron chelators.
    • Cure (healing) – Allogeneic Red Bone Marrow Transplant with its difficulties, cost, and efficiency.