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General information

Recessive hereditary defects of the hemoglobin genes may induce hemoglobinopathies (HbP's). HbP's may originate in rare cases from a de novo mutation or come to expression in semi-dominant form in the heterozygous but in general HbP's are hereditary diseases expressed in a recessive manner.
HbP's can be subdivided in two major categories: the expression defects or thalassemias and the structure defects or abnormal hemoglobins. Expression defects of the a-genes may generate severe pathologies in the fetus (Hb Bart's hydrops foetalis) and/ or intermediate phenotypes in postnatal life (HbH disease).
The severe HbP's, representing a major problem for public health are induced by a number of frequent occurring mutations of the b-globin genes such as HbS, HbE, C, D-Punjab and b-thalassemia.

Carriers of b-thalassemia or HbS are usually healthy and characterized by their microcytic hypochromic parameters with or without a mild anemia and or by their anomalous Hb pattern. The severe homozygous or compound heterozygous cases of b-thalassemia are born healthy but at the age of 6 months become severely anemic and progressively develop a severe transfusion dependent hemolytic. Similarly, a healthy born baby homozygous for the HbS mutation or compound heterozygous HbS/b-thal, HbS/C, S/E, S/D, S/O or others, may develop acute infections, harsh infarctial pain and hemolytic crises in the second semester of life, characteristic of the severe sickle cell disease (SCD). For most patients affected with the severe forms, rigorous preventive and supporting therapy is the only alternative. In cases when a suitable donor is present, BMT may cure thalassemia major or severe SCD. However the risk of rejection or graft versus host disease cannot be underestimated.

The Dutch population at risk: In The Netherlands 15% of the population consists of recent immigrant and their progeny. Depending from the population and the type of HbP, individuals from this quite heterogeneous population have 2-10% chance of being a healthy HbP carrier. Moreover, in the large Dutch cities 40 to 60% of the population younger than 18 is of recent allochthonous origin. This young population chooses a partner mostly inside the own ethnic group and frequently inside the own family and produces 40.000 newborns a year. Prudently estimating the incidence of HbP major 1:1000 we may expect at the least 40, probably 60 newborn affected with SCD, b-thal major or other severe forms each year. Adding these newborns to the patients already in the country (>550) soon a constant group of more than 1000 patients will be present in the Netherlands. This figure is comparable with the number of patients affected with cystic fibrosis.
Primary prevention: The globin genes and their expression mechanisms have been known for many years. However, in spite of the many efforts of dedicated scientist, a cure for these diseases, excluding BMT, is not yet available. Conversely, primary prevention strategies have been successfully applied in many countries where the occurrence of HbP major has virtually disappeared. A combined multidisciplinary effort is needed from the Dutch health care structures. GP, Gynecologists, Obstetricians, Hematologists, Neonatologists, Labs and Genetic Centers should join forces to implement a primary prevention program for the population at risk in the country.
The prevention strategy: The most efficient strategies applicable to the socio-cultural situation in the Netherlands have been extensively tested for applicability and efficiency in several countries and consist of three elements: information, carrier diagnostics and genetic counseling. These elements can be provided by the existing public health structures present in the country at three levels.
  1. During the pre-marital or pre-conception phase by the GP or specialist followed by carrier diagnostics, identification of couples at risk and genetic counseling.
  2. At early pregnancy followed by identification of couples at risk and counseling.
  3. At the neonatal level referring the couples of affected neonates for genetic counseling.
The diagnostics: Basic carrier diagnostics is available in most central laboratories in the country and referral to specialized laboratories or to the reference lab in Leiden is possible at all times. Click for a diagnostic protocol or for an analysis request form.

The sickle cell disease (SCD)

HbS is with HbE probably the most frequent abnormal Hb in the world population. HbS occur as a recessive trait in persons from African, Mediterranean, west and Middle East and Asian origin.
Due to the substitution of glutamic acid by a valine at position 6 the normal b globin chain is modified into bS. When HbS reach a concentration in the red cell higher than 50% interaction between the HbS molecules may take place during the de-oxygenated state, forming long polymers which change the shape of the flexible red cells into the rigid sickle cells.

Carriers: The HbS concentration in the red cells of the carrier (heterozygous) rarely exceeds 45% and is often as low as 20% due to the frequent coexistence of a-thalassemia. Due to the presence of sufficient HbA in all red cells, symptoms are usually absents in the carrier. However, in exceptional circumstances (heavy physical stress, high altitude, hypoxia, narcosis) the symptoms of SCD may manifest in the carrier as well. Cases of HbS heterozygosity with 50% HbS expression and a mild SCD phenotype have been observed in our laboratory without any molecular evidence of b-thalassemia.

The patient: SCD can be induced by homozygosity for the bS mutation (HbS/S) or by combinations of bS with b-thalassemie or with other structural mutants (HbC, D-Punjab, O-Arab, HbE and others.). The symptoms can differ from mild to very severe and the amount of fetal hemoglobin (HbF) expressed in post-natal life is the main modulating factor. The presence of 5-6% or more HbF may greatly reduce the polymerization of the HbS molecules and the pathology of the disease. However, severe cases may manifest the first symptoms at 6-7 months already. The severity of symptoms such as acute hemolysis (RBC= 2,5-4 x1012/l) and vaso occlusive episodes in longs, liver, spleen, kidney, gut, brain penis, bones and eyes increases with the disappearance of fetal hemoglobin and progress with age. Acute chest syndrome may result fatal in non-diagnosed babies and pain as a consequence of spleen infarctions and osteonecrosis can be excruciating.

Treatment: Depending from age and severity the following options can be considered.
  • Pneumococcus vaccine en preventive treatment with antibiotic up to the age of 6 to 12 years, to reduce the risk of acute infections in long and brain.
  • Folic acid suppletion.
  • Prevention of precipitating factors that may trigger crises such as dehydratation, hypoxia, stasis, acidosis. Low temperatures and heavy physical stress.
  • Hydratation and pain treatment during crises.
  • Blood transfusion during acute cellular sequestration en a-plastic crises.
  • Regular exchange transfusion to reduce severe and frequent crises keeping a low PCV.
  • Bone marrow transplant with HLA identical donors and only in severe cases.
  • Hydroxyurea treatment to increase fetal hemoglobin and reduce cell adherence.

b-Thalassemia major

Many different molecular defects may block the expression of the globin genes. Homozygosity or compound heterozygosity for these mutations can induce the severe b-thalassemia major phenotype. High expression of fetal hemoglobin at birth protects the affected baby from having symptoms for about 6 months. After that, due to the total absence of b globin, postnatal hemoglobin (HbA) cannot be formed resulting is severe anemia. The erythropoietic stimulus induces hyperplasia of the bone marrow and the excess of free a chains ineffective erythropoiesis and hemolysis. Without intensive transfusion therapy hypoxia will stimulate erythropoiesis, which will remain ineffective and expand to virtually all bones inducing skeletal malformations. Extramedullary erythropoiesis will damage lever and spleen and hepatosplenomegaly develops rapidly. The presence of a high HbF expression and a-thalassemia are modulating factors in b-thal major.

Treatment: Depending from age and status the following options are available.
  • Bone marrow transplant with a HLA identical sibling in patients with moderate iron accumulation and/or portal fibrosis offers a good chance for a permanent cure. However, conditioning with cytotoxic agents, graft rejection and relapse, acute severe or chronical graft versus host disease (GVHD) and psychological burden, are the adverse aspects that must be carefully considered against the today alternative of 40 years (or longer) acceptable life with good transfusion chelation therapy.
  • If BMT is not an option, life long transfusion chelation therapy is the only alternative.
  • A constant Hb level, maintained above 11 grams with frequent transfusions, have been proved to be effective in keeping the patients in good shape and in reducing complications. However, transfusion itself produce the main complication: iron overload.
  • Chelation is essential. Desferal by subcutaneous infusions or Ferriprox tablets are used (see 1,2). Both products have acceptable side effects which must be monitored. Deasferal has the advantage of eliminating iron through urine and feces and the disadvantage of the subcutaneous infusion. Ferriprox has the advantage of oral intake and have been proved to be particularly effective reducing life threatening iron accumulation in vital organs (see 3).
  • Splenectomy and prophylactic treatment against infections.
  • Multi disciplinary care for the many complications.