Genetic disorders of hemoglobin are classified into two main categories: thalassemia and hemoglobinopathies whose most common form is sickle cell anemia.
Structure and organization of hemoglobin genes:
Chromosome 16 carries two α-globinedénommés genes respectively, from 5 ‘to 3’, a2 globin and a1-globin.These genes are composed of 3 exons and 2 introns.Each of the 4-α genes globinecode about 25% of α-globinesynthétisées chains in the erythroblast. Each chromosome 11 carries genes “non-α-globin.” Be distinguished, from 5 ‘to 3’, a duplicate gene g (Gg and Ag) of a gene, and a gene b. In normal erythroblast, there is always a perfect balance between synthesis α-globineet chains chains “no α-globin” (Fig. 1).
Molecular formulas and switching hemoglobins:
The fetal hemoglobin (HbF) is composed of two chains and two chains g (a2g2); this hemoglobin prevails during fetal life and where his birth rate is close to 85%. In the normal adult red blood cell, there are less than 1% of fetal hemoglobin with 97-98% hemoglobin A (HbA) made of two chains 2 and b chains (a2b2) and 2 to 3% hemoglobin A2 (HbA2) made of two chains and two chains (a2d2). The passage of fetal hemoglobin to hemoglobin A (switching hemoglobins) is progressive and is the end of fetal life until the age of 6 to 12 months.
A- Definition – Epidemiology – Genetics:
Thalassemias are defined by a decrease of synthesis of the globin chains. They often deficient globin chain: b-thalassemia, a thalassemia. The b-thalassemia are common in the Mediterranean South-East Asia and the thalassemia is particularly common in Southeast Asia. Thalassemic syndromes are genetically transmitted in an autosomal Mendelian fashion.
1- Pathophysiology molecular lesions:
The naturally occurring mutations resulting in defective synthesis of the β-globin chain are very numerous (over 100 currently). The classification considers the final step of protein synthesis as it persists (β + thalassemia) or not (b0-thalassemia) production of b-globin chains.
• B0-thalassemia: the deletional forms of β-thalassemia are rare, except for one that affects an ethnic group from the Indian subcontinent and which corresponds to the 0.6 kb deletion of amputating part 3 ‘b gene . 3 other common molecular defects resulting in a lack of synthesis of b-globin chains are as follows:
– The mutation of a base creating a nonsense codon causes the appearance of a stop signal at protein synthesis;
– Minor deletions or insertions of 1, 2, 3 or 4 nucleotides creating a shift in the reading frame causing the appearance of a stop codon further downstream with an abortive protein synthesis;
– Mutations of exon-intron junctions are responsible for b0-thalassemia when they touch the required consensus sequences GT 5 ‘and AG at the 3’ intron, preventing thereby a normal splicing.
• β + -thalassémies: 2 main types of molecular lesions may result in a partial defect in the synthesis of b-globin chains:
– Abnormal process messenger RNA maturation are the most common mechanisms. The most common form is a mutation in intron 1 at position 110. This mutation creates a dinucleotide AG website used for splicing and an abnormal messenger RNA quickly destroyed. Besides this non-functional mRNA, there is production of a reduced amount of a normal mRNA for the synthesis of a β-globin chain;
– Quantitative reduction in transcription is responsible for a failure to produce messenger RNA. It is due to mutations arising in the flanking sequences 5 ‘corresponding to the promoter regions of interaction between the b-globin gene and proteins of the transcriptional initiation complex with the DNA polymerase.
2- Pathophysiology of the main hematological signs:
• β-thalassémiehétérozygote: the decrease in the synthesis of the β chain of hemoglobin causes a reduction in the amount of hemoglobin in each red cell and explains microcytosis (decrease in mean corpuscular volume), reduced mean corpuscular content hemoglobin (MCH) and the reduction in the mean corpuscular hemoglobin concentration (MCHC). a pseudopolyglobulie observed with 5 to 7 million red blood cells / mm3 without anemia. Reticulocytosis is normal or slightly increased. There is a rising rate of HbA2 (> 3.5%).
– Anemia: this is in the first month, when switching hemoglobins, the synthesis deficiency b chains leads to a relative increase in chains in the erythroblast that precipitate in the form of inclusions (body of Fessas) toxic to the cell and nuclear membranes. The lesion of these membranes is responsible for the destruction of erythroblasts in the marrow.The ineffective erythropoiesis resulting anemia is the main mechanism in the β-thalassémiehomozygote. Some erythroblasts, including those that synthesize fetal hemoglobin, manage to give birth to a reticulocyte, then a red blood cell passes in the peripheral blood. The red blood circulating, depleted hemoglobin (hypochromia) distorted (poikilocytosis), has a shorter half-life and reflects the second anemia mechanism: the hyperhemolysis. Most erythroblasts being destroyed in the marrow, anemia is regenerative little less than would be the hemoglobin if the marrow was working properly;
– Morphological deformation and hypertrophy of erythroid: profound anemia of β-thalassémiehomozygote induces an increase in the secretion of erythropoietin whose role is to promote the differentiation and proliferation of hematopoietic stem cells to the erythroid compartment. The result of this hormonal stimulation significant inflation spinal erythroblastic sector. This expansion is causing the deformation of bones that make blood in children: skull, malar regions, maxillary ends of long bones mainly. The erythroid expansion is also expressed in the peripheral blood, blood erythroblastosis of up to 50 100 000 nucleated cells / mm3;
– Splenomegaly and hepatomegaly; Hypersplenism: splenomegaly and hepatomegaly appear in the first months of life and are responsible for belly fat of children with thalassemia major. The splenomegaly mechanism is complex: the hyperhemolysis and hyperplasia of the mononuclear phagocyte system (formerly reticuloendothelial system), ectopic erythropoiesis and abnormal movement of thalassemic cells clogging spleen are the main causes of hypertrophy splenic. Hypersplenism is a blood condition characterized by enlarged spleen associated with anemia and (or) and leukopenia (or) thrombocytopenia, and the disappearance of the signs of peripheral cytopenia after splenectomy. In thalassemic patients, leukopenia and thrombocytopenia are observed today than in insufficiently transfused patients.Among patients treated properly, is the steady increase in transfusion requirements measured annually in mL / kg body weight / year reflecting hypersplenism. A patient regularly transfused, the transfusion requirements exceed 200 mL / kg / year, is diagnosed with hypersplenism and should be splenectomized;
– Iron overload: it is constant in the β-thalassémiehomozygote. Two mechanisms are responsible: the digestive hyperabsorption iron and blood transfusion. Since a patient with homozygous thalassemia receives 150 to 200 mL / kg weight concentrated globular, it accumulates 0.75 to 1 g of iron / kg body weight in 10 to 12 years. This iron is distributed in the body and affects certain tissues. The primary target organ iron overload is the myocardium. The liver is still overloaded with iron. The parenchyma of endocrine glands is another target tissue of post-transfusional iron overload, martial infiltration of the thyroid, parathyroid, b cells of the islets, gonads, pituitary and hypothalamus being responsible respectively hypothyroidism, hypoparathyroidism, diabetes mellitus and gonadotropin deficiency.
3- diagnosis of β-thalassemia:
• β-thalassémiehétérozygote: the subjects are healthy. Laboratory diagnosis is based on the following signs: microcytosis without anemia or with moderate anemia between 10-12 g / dL increase in the rate of HbA2 beyond 3.5%.
• β-thalassémiehomozygote: dependent clinical forms of blood transfusion define Cooley’s anemia (or thalassemia major). The clinical signs appear in the first months of life in infants. The pallor is constant, sometimes associated with jaundice. Hepatosplenomegaly develops gradually, can acquire a considerable volume and deform the abdomen.Hyperplasia of the bones of the face gives children an unsightly: malar regions are widened, the base of the flattened nose; there hypertelorism and a protrusion of the upper jaw. The transfusion therapy now the average hemoglobin level around 12 g / dL avoids the appearance of these clinical signs. The blood count shows anemia often less than 7 g / dL, microcytic or normocytic, hypochromic (MCH <26 pg per cell and MCHC <33 g / dL) with anisocytosis and poikilocytosis. The blood erythroblastosis is usual. The marrow is rich and very erythroblastic. The hemoglobin electrophoresis allows the diagnosis of β-thalassemia is the percentage of HbF increased steadily, HbA synthesis depends on the remaining channels in the b b + thalassemia, it is zero in b0 thalassemias . The percentage of HbA2 is normal or sometimes higher. Genotypic diagnosis of molecular lesions responsible for β-thalassémieest prepared by the methods of molecular biology. If this identification is not required for clinical diagnosis, it is however necessary when a prenatal diagnosis is considered.
1- Pathophysiology molecular lesions:
In the majority of cases, the molecular lesion responsible of a-thalassemia is a deletion. Since there are 4 genes-globin, there has 4 types of thalassemia. Table I presents the current nomenclature of the main a-thalassemia.
• a + -thalassémies: they are the result of uneven crossingover between homologous regions and duplicated genes has globin. The a + -thalassémies are rarely caused by point mutations.
• a0-thalassemia: the lack of expression of two genes on the same chromosome contiguous corresponds to a 0-thalassemia heterozygous. These thalassemias are due to deletions which carry all of the genes in cis and which extend on either side of the locus on a variable length ranging from 5.2 to 62 kb. The most common is the Asian deletion (- -SEA).
2 Pathophysiology of the main hematological signs:
• deletion of an α-globin gene: no clinical, hématimétrique electrophoretic or translation of the deletion of a gene-globin.
• deletion of two α-globin genes: the hemoglobin synthesis defect resulting from deletion of two genes explained microcytosis (MCV decreased), hypochromia, decreasing the MCH and MCHC reduction.
• Deletion of 3 α-globin gene (Hb H):
– Anemia is present at birth, microcytic and hypochromic. The hemoglobin level is around 7 to 8 g / dL. During fetal life, birth and the first weeks of life, the g chains excess relative to tétramérisent to give a hemoglobin molecule called hemoglobin Bart’s. Later, when the switching of the haemoglobins is completed, the relative excess of chains is b tétramérise to give hemoglobin H. hemoglobin Bart’s at birth is around 20 to 30%; in older patients, the hemoglobin H varies from 3 to 30% depending on case. In the marrow, there is an enlarged erythroid with a certain degree of ineffective erythropoiesis. Circulating red blood cells are abnormal and a shortened half-life. Thus, anemia has a dual mechanism, but hyperhemolysis dominates the ineffective erythropoiesis;
– The mechanism for skeletal deformities is similar to that of β-thalassemia;
– The mechanisms responsible hepatomegaly, splenomegaly and hypersplenism are identical to those which have been described in the β-thalassemia;
– The two mechanisms responsible for iron overload in thalassemia is a digestive hyperabsorption iron and blood transfusion, as in b-thalassemia.
• Deletion of four α-globin genes (hydrops fetalis) anemia occurs during the fetal period. It is intense and is complicated by hydrops fetalis. The disease is incompatible with life and death occurs in utero or shortly after birth. If the child’s blood can be taken before he died, electrophoresis note the presence of hemoglobin Bart’s (at least 80%) and hemoglobin H (about 10%) without HbA or HbF. For the mother, the move towards toxemia with his mortal risk is common. The risk of hydrops fetalis justifies prenatal diagnosis in a-thalassemia.
3- Diagnosing a-thalassemia:
• deletion of 1 or 2 α-globin genes: no clinical symptomatology of the deletion of 1 or 2 of? -globin Genes. In case of deletion of one gene-globin, blood count is normal; the HbA2, can be lowered. Molecular biology has shown a + thalassemia heterozygous. In case of deletion of two genes-globin, there microcytosis about 70 fl without anemia or with a moderate anemia between 10 and 13 g / dL hemoglobin. The HbA2 is decreased. The presence of hemoglobin Bart’s at birth is transient. Molecular biology is the diagnosis between a + thalassemia homozygous and heterozygous a0 thalassemia.
• Deletion of 3 α-globin gene (Hb H): the Hb H disease is characterized by chronic hemolytic anemia by morphological deformities thalassemia type, but reduced. The clinical course is that of a moderate thalassemia, and children reach adulthood in general. The most common complication is splenomegaly with hypersplenism risks; the others are the worsening of anemia due to superimposed infection or drug intake, leg ulcers, the usual complications of hemolysis as cholelithiasis and folic acid deficiency. The Hb H disease is characterized by hemolytic anemia moderate (7-9 g / dL).Anaemia is microcytic, hypochromic punctuated with red blood cells. The precipitation of hemoglobin in red blood cells H appears in the form of Heinz bodies, but only in splenectomized patients. The hemoglobin electrophoresis demonstrates the hemoglobin H. Molecular biology establishes the genotypic diagnosis.
• Deletion of four α-globin genes (hydrops fetalis): the complete abolition of the expression of α-4 genes globinen’est not compatible with life. Death occurs in utero or shortly after birth in an array of hydrops fetalis. Anemia is intense to less than 6 g / dL of hemoglobin with a mean cell volume of 110-120 fl. In electrophoresis, there is presence of hemoglobin Bart’s, H embryonic hemoglobin and hemoglobin type Portland without hemoglobin A and F.
Sickle cell disease:
A- Definition – Epidemiology:
Sickle cell disease is a genetic disorder of hemoglobin due to the mutation of the sixth codon of the β globin chain (β6 Glu Val). This condition is common in Africa, North and South America, the Caribbean, the countries of North Africa, Sicily, Greece, throughout the Middle East, and it is found in India. In recent decades, the drépanoctyose is also present in Western Europe.
Sickle cell anemia is a disease transmitted in an autosomal recessive Mendelian fashion. Heterozygotes are called AS and called homozygous SS. There are other hemoglobin abnormalities may be associated with sickle cell anemia: hemoglobin C and b-thalassemia, genetic defects of hemoglobin which are also transmitted in an autosomal recessive mode. When these anomalies are associated, they give birth to or compound heterozygous SC Sb thalassemia. The sickle cell disease and compound heterozygotes SC and Sb thalassemia are grouped under major sickle cell syndromes.
C- molecular pathophysiology, cellular and vascular sickle cell disease:
1- polymerization of sickle hemoglobin molecules:
In sickle cell hemoglobin S, the replacement of a glutamic acid by a valine at position β6 on the surface of the molecule causes a series of structural modifications which account for the decrease in its solubility, and polymerization of the deoxygenated form . The polymerization is observed in vitro in hemoglobin concentrated solutions, as well as in vivo in the red blood cell. This polymerization results in the formation of a gel. It has been shown in vitro that the gel formation by deoxyhemoglobin S molecules was not an instant phenomenon, but it was preceded by a latency period of variable duration, ranging from milliseconds to minutes . Physicochemical factors promote polymerization and gel formation: increasing the temperature, lowering the pH and increasing ionic concentration. The hemoglobin concentration is a key factor influencing deoxyhaemoglobin polymerization of the molecules of S. It is for this reason that the a-thalassemia, sickle cell disease often associated, have an adverse effect on polymerization since 1a decrease in hemoglobin concentration intraerythrocytic. Hemoglobin F is another important biological factor to be considered since this molecule does not copolymerized with hemoglobin S. The inhibitory effect of hemoglobin F in the polymerization occurs from the initial stage of the formation of the polymer; thus, by way of example, an increase in fetal hemoglobin percentage from 10 to 25% of total hemoglobin per 100 multiplies the lag time in vitro.
2- The polymerization distorts the cell:
In the normal red blood cell, the hemoglobin is at a concentration of 33 g / dL, which is the value of MCHC. The polymerization of hemoglobin S molecules in their deoxygenated configuration causes the intracellular formation of long elongated fibers. The formation of these intracellular fibers causes a change in shape of the red blood cell that acquires a false appearance: the sickle cell. Falciformées the cells are heterogeneous, both as regards their morphological appearance as their density. The percentage of dense cells (d> 1.120) is low or even zero in normal subjects; it is higher or lower in subjects with sickle cell disease. The densest cells contain sickle cells, which, after several cycles of sickling, are deformed permanently. In fact, the phenomenon of sickling-défalciformation is reversible for several cycles until the final fixing of the cell in the form of a sickle cell irreversible. Irreversible sickle cell are cells in which there is hemoglobin concentrations above 40 g / dL.
3- Theological Implications of sickling:
The main rheological anomalies in sickle cell disease is a steady increase in viscosity and a decrease in cell deformability. These two phenomena are very dependent on hematocrit and especially net that is high. The low hematocrit (20-25%) observed in sickle cell anemia reduces the effect of these abnormalities.
4- Disorders of microcirculation in SCD: adhesion of sickle erythrocytes to vascular endothelium:
The adhesion of sickle cells to vascular endothelium was initially demonstrated in vitro in a culture system endothelial cells from umbilical veins and bovine aortic. This initial observation was subsequently confirmed in other experimental systems and in particular mésocæcum perfusion experiments with rats and endothelialized rooms. The phenomenon of adhesion of sickle cells to the endothelium is dependent on the characteristics of blood flow. In conditions of laminar flow, cell adhesion is very limited or non-existent, unlike what happens in turbulent flow areas of certain areas of the capillary circulation. The most important adherence is observed in vessels of 7 to 10 microns in diameter. The adhesion of sickle red blood cells to the endothelium causes circulatory slowdown and induced sickling and vaso-occlusion. Protein molecules involved in the adhesion phenomena have been identified, at least for some of them.They relate mainly to young cells, reticulocyte, and involve proadhésives molecules such as integrin VLA-4 and CD36 glycoprotein. Partners to the surface of the endothelium are also CD36 and, after activation of these cells, VCAM-1 protein. The VCAM-1 VLA-4 interaction is direct, while that relating to the two CD36 molecules on the red cell and the endothelium involves a bypass plasma thrombospondin. Other interaction mechanisms are not excluded, but are not yet identified.
5- arterial vascular abnormalities in sickle cell disease:
Some neurological complications of sickle cell disease are attributed to a more or less complete blockage of arteries supplying the brain: carotid, anterior cerebral and spinal. This is partial or total occlusion of the vessel lumen with aspects of “moyamoya” (substitution networks) in some patients. Histological studies have shown that the narrowing or occlusion of these vessels were due to intimal hyperplasia comprising a proliferation of smooth muscle cells and fibroblasts, associated with a partial destruction of the internal elastic lamina and outbreaks of fibrosis of the media.Arterial abnormalities due to intimal hyperplasia have also been described in the splenic vessels, pulmonary arteries, renal arteries, arterioles from tissues surrounding leg ulcers, particularly arterioles of the retina including the occlusion is considered to be responsible for sickle cell retinopathy.
D- Pathophysiology of main clinical signs of SCD:
The main clinical signs of sickle cell disease is anemia and acute or chronic complications of vaso-occlusion.
1- Pathophysiology of anemia:
The direct consequences of the polymerization of the molecules of hemoglobin S in sickle cell disease are deformation and embrittlement of the red cell, the latter explaining hemolytic anemia. The mean hemoglobin in sickle cell patients homozygous is between 6 and 10 g / dL, with a reticulocyte percentage of 5 to 15%. This hemoglobin allows tissue oxygen supply near normal, due to the increased circulatory dynamics and a decreased affinity of the sickle cell hemoglobin for oxygen. The increase in medullary production requires supplementation of folate intake to prevent the development of megaloblastic anemia. The hyperhemolysis translates clinically by a free bilirubin jaundice that occurs with a prevalence of higher when the subjects are older. The flow of bilirubin in the bile duct contributes to the formation of a pigment gallstones which is seen in 30% of patients before twenty. Several mechanisms may aggravate anemia: any inflammatory condition slows bone marrow red cell production as evidenced by the reduction of the reticulocytosis; folate deficiency secondary to hemolytic anemia; iron deficits; the PRCA crises, mostly attributable to parvovirus B19, often occurring in childhood; the sequestration syndrome spleen, due to rapid sequestration of a large portion of red cell mass in the spleen common symptom leading to acute anemia in young children.
2- Pathophysiology of vaso-occlusion:
under the term vaso-occlusion is meant the consequences of perfusion defect of body tissues resulting from all of molecular phenomena, cellular and vascular described above. The rapid or progressive character of the anomaly traffic is the cause of acute and chronic complications. Complications are different in different vascular territories interested microcirculation, artery or vein.
• Pathophysiology of painful bone crisis: slowing or stopping bone vascularization is the origin of a bone infarction causing pain. The phenomenon may be due to the sequence of events, membership sickle cell red blood cells to the endothelium, engorgement of the vascular lumen, circulatory slowdown. It also admits that it can be initiated by a reflex neurovascular caused by cold, stress, stress, etc., which would explain the multifocal nature of some painful crises.
• Pathogenesis of infections susceptibility to infection does not respond to the same mechanisms for different types of infections and germs in question: – septicemia and meningitis: the sickle cells cause traffic congestion and splenic infarction iterative affecting the function of defense against infection of the spleen. Thus, as with all splenectomized patient, sickle cell patients are at risk of post-splenectomy severe infections, including sepsis and meningitis caused by encapsulated bacteria, Streptococcus pneumoniae and Haemophilus influenzae;
– Osteomyelitis: in sickle cell patients, multifocal osteomyelitis is readily and rapidly extensive. In over half of cases they are due to so-called minor salmonella: Typhi murium, Typhi Panama, etc., and staphylococci, E. coli, etc. The accepted mechanism of these infections is: occasionally bacteremia, germ occurring in a non or poorly vascularized bone area due to a phenomenon of vaso-occlusion will develop and cause of osteomyelitis.
• Pathophysiology of organ damage:
– Acute complications: acute sickle erythrocytes sequestration in the spleen, liver or cavernosa is causing acute splenic sequestration syndromes or liver and priapism. Acute occlusion of the central retinal artery causes amaurosis.Renal papillary necrosis are due to perfusion defects arteries renal pyramids (vasa recta). Ischemic strokes are due to blockage of cerebral arteries. Acute chest syndrome corresponds to several causes (vascular, infectious, thromboembolic …) vascular origin being due to the obliteration of the pulmonary microcirculation by sickle.
– Chronic complications: chronic perfusion defect of some tissues and organs is causing their degeneration or their necrosis. Thus the leg ulcers explains, retinopathy, avascular bone necrosis especially of the hip, the alterations of the kidney, lung, heart, causing chronic shortcomings interesting these bodies.
The clinical description of sickle cell disease involves the basic state of the patients, acute complications and chronic complications.
• The basic condition is characterized by chronic hemolytic anemia. Splenomegaly observed in the first months of life is still a few years to disappear spontaneously “autosplénectomie”. Weight and height growth is normal but sickle cell subjects willingly lean. Puberty is satisfactorily with, however, a delay relative to non sickle cell population of the same age. Fertility is normal in adults.
• Acute complications are dominated by painful crises that associate fever and pain. The pain is localized or multifocal.They are of varying intensity, sometimes requiring the use of major analgesics (morphine) for processing. Infections, responsible for a significant share of mortality and morbidity, are characterized in young children by the frequency of meningitis and septicemia Streptococcus pneumoniae and Haemophilus influenzae. Osteomyelitis, and extensive multifocal willingly, due to minor salmonella or staphylococcus. One must know the severity of lung infections Mycoplasma pneumoniae. Chronic anemia of sickle cell anemia is a moderate hemolytic anemia. Some indicated ABOVE situations may make it worse. Serious vasoocclusive accidents are a series of complications characterized by an organic deficit strokes responsible for neurological or sensory deficits, acute chest syndrome defined by the association of lung function and physical signs to an abnormal chest X-ray image, priapism, amaurosis, hematuria, papillary necrosis.
• Chronic complications are more readily observed in adolescents and adults than in children. This leg ulcers, bone necrosis of the hips and shoulders, sickle cell retinopathy, kidney damage ranging from hyposténurie and microalbuminuria to end stage renal failure, chronic lung or heart failure. Cholelithiasis is related to chronic complications.
• phenotypic Diagnosis: hematological characteristics of the main major sickle cell syndromes are shown in Table II.We note the following: the average rate of circulating hemoglobin in sickle cell anemia patients is close to 8 g / dL;there are significant variations among patients 6 to 10 g / dL; the HbF is important to determine because of its prognostic significance. The mortality and morbidity of the disease are much less severe than the HbF is high. The compound heterozygous patients are not anemic SC, their reticulocytosis is between 140 and 200,000 / mm 3, indicating an offset hyperhemolysis; leukocytosis is often high 10 000- 20 000 cells / mm3, particularly in sickle cell anemia patients, due to leukocytosis neutrophils; this feature is observed even without any infectious or inflammatory complication; the platelet count is normal or slightly increased due to the autosplénectomie that occurs in the disease.
• Genotypic diagnosis comprises the following three tests:
– Identification of the sickle cell mutation: the identification of the mutation of the sixth codon of the gene b-globin is made by polymerase chain reaction followed by enzymatic digestion (by MstII, for example); fragments generated by the enzyme are different depending on whether the gene is normal or mutated b. This identification is made in transfused patients when the phenotypic diagnosis is not possible to establish the diagnosis of certain complex genetic forms (eg, the combination of sickle cell trait in hereditary persistent HbF), and in prenatal diagnosis;
– Search for a thalassemia associated with sickle cell disease: it is part of the laboratory diagnosis of sickle cell anemia. Indeed, the deletion of 1 or 2-α genes globineprovoque phenotypic changes (increase of circulating hemoglobin, decrease in mean corpuscular volume reduction reticulocytosis). The association of SCD in a- thalassemia is common. Identification of a-thalassemia also has a relative prognostic value; Indeed, it was shown that sickle cell patients homozygous carriers of a thalassemia were statistically more likely than others to make painful crises and bone necrosis, and in contrast, they were less at risk of to stroke;
– Determination of the restriction haplotype associated with the sickle cell mutation: the restriction haplotype linked to the bS mutation corresponds to positive or negative enzymatic restriction sites, ordered identically in a given gene context. This defines the haplotypes Benin, Senegal, Bantu and Indians. It showed a connection between the haplotype and the level of expression of HbF; the HbF is strong among Senegalese and Indian lower in the Bantu, and intermediate in Benin. In 1999, the haplotypes are not to be considered in a given patient as an individual predictive marker of clinical severity, but as an important biological made known in the analysis of multigenic factors of the clinical variability of the disease.
Highlights to include:
Thalassemia • Severe forms of β-thalassémiehomozygote (thalassemia major or Cooley’s anemia) are characterized by anemia whose mechanism is double, ineffective erythropoiesis and hyperhemolysis. The erythroid expansion is causing morphological and skeletal deformities. Blood transfusion corrects anemia and reduces the erythroid expansion, but is the main cause of iron overload that reports of mortality and morbidity of the disease being treated.Some forms of a-thalassemia are at the origin of chronic hemolytic anemia or a hydrops fetalis syndrome incompatible with life. Phenotypic diagnosis of thalassemia is done by the study of hemoglobin; genotypic diagnosis uses the molecular analysis of globin genes (deletions, mutations).
• Sickle The sickle cell disease is the most severe form of sickle cell syndromes major. The polymerization of hemoglobin S molecules is the origin of the phenomenon of sickling of sickle cell red cell. There are 2 sides to the clinical disease: hyperhemolysis and vasoocclusive phenomena. These are different from one patient to another, explaining the great clinical heterogeneity of the disease. Hemoglobin Sickle cell is identified by the phenotypic study of hemoglobin. Genotypic diagnosis has its main indication in prenatal diagnosis.
Strong Points to remember:
• Thalassemia and sickle cell anemia are two different genetic diseases of hemoglobin in their pathophysiology and clinical expression.
• Thalassemia is characterized by severe chronic anemia.
• The sickle cell disease is characterized by mild chronic hemolytic anemia and vaso-occlusive complications including acute expression of pain, infection, organic impairments (stroke, acute chest syndrome) and chronic expression, ulcers skin, retinopathy, bone necrosis.