Globin chain Disorders

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Globin chain Disorders by Mind Map: Globin chain Disorders

1. Hemoglobinopathies

1.1. Sickle-cell disease (Hb SS)

1.1.1. shows up at childhood

1.1.2. fatal by 30–40 years

1.1.3. exclusively in the black population

1.1.4. glutamic amino acid in position 6 replaced by valine amino acid

1.1.5. freely soluble in its fully oxygenated form.

1.1.6. deoxygenated form, formation of intracellular crystals

1.1.7. sickle shape responsible for the trapping and hemolysis of the RBCs results in intravascular hemolysis marrow becomes hyperplastic early in childhood

1.1.8. Clinical Symptoms hand-foot syndrome splenomegaly and systemic hypovolemia. Vaso-occlusive crises Aplastic crises

1.1.9. homozygous Hb SS (a) Normocytic/normochromic anemia (b) Marked polychromasia on the blood smear (c) Normoblasts found on the blood smear (d) Numerous target cells and Howell-Jolly bodies because of asplenia (e) Sickled RBCs found on the blood smear (f) Decreased osmotic fragility test (g) Neutrophilia and thrombocytosis

1.1.10. marrow aspirate shows normoblastic hyperplasia and increased iron storage.

1.1.11. Common laboratory screening tests for Hb S microscope slide with sodium metabisulfite Metabisulfite is a reducing substance that enhances deoxygenation and sickling. This test cannot differentiate homozygous Hb SS and heterozygous sickle cell trait (Hb AS). (b) Solubility (i.e., turbidity) tests Reduced Hb S is insoluble in concentrated inorganic buffers, and the polymers of Hb S produce turbidity. The amount of turbidity is proportional to the amount of Hb S in the RBCs.

1.1.12. A definitive diagnosis of Hb SS can be made with a hemoglobin electrophoresis at alkaline pH

1.1.13. Hb AS heterozygous β-chain defect no clinical signs or symptoms protects persons from the lethal effects of . Falciparum malaria rbc count and morphology normal ;few target cell All sickle cell tests are positive the Hb electrophoresis results at an alkaline pH

1.2. Hemoglobin C disease (Hb CC)

1.2.1. substitution of the glutamate at position 6 lysine amino acid

1.2.2. hematologic profile normocytic/normochromic with a mixture of microcytes and spherocytes on the blood smear. slight reticulocytosis Numerous target cells osmotic fragility test is biphasic Hexagonal or rod-shaped crystals (i.e., Hb C crystals) on PBS dehydration of older RBCs

1.3. heterozygous form (i.e., Hb AC),

1.3.1. milder form

1.3.2. moderate number of target cells

1.4. Hb D disease

1.4.1. most common in persons of Asian-Indian extraction

1.4.2. amino acid substitution in the β-chain(s) at position 121 of the glutamate glutamine amino acid

1.4.3. Hb D migrates on the electrophoretic gel with the Hb S fraction

1.4.4. sickle tests are negative

1.5. Hb E disease

1.5.1. individuals of Asian origin

1.5.2. mild anemia with moderate microcytosis and target cells on their blood smear.

1.6. Hb SC disease

1.6.1. symptoms are the same as Hb SS, but splenomegaly is more common in patients with Hb SC.

1.6.2. hematologic profile: (i) Moderate-to-mild normocytic/normochromic anemia (ii) Moderate-to-severe anisocytosis and poikilocytosis (iii) Target cells can comprise up to 85% of the RBCs (iv) Sickle cells as well as Hb CC crystals on the blood smear (v) Positive sickle cell tests

1.7. Hb SD disease

1.7.1. less severe than HbSS anemia

1.7.2. cannot be distinguished between Hb SC or sickle cell trait

1.8. Hb M

1.8.1. amino acid substitutions occur in the heme pocket where they either increase the stability of the HbM or alter the affinity of the heme ring for oxygen

1.8.2. reduction to the ferrous heme and binding of oxygen is prevented by an amino acid substitution near the heme ring.

1.9. Hemoglobin Chesapeake

1.9.1. is an α-chain abnormality that results in a mild polycythemia.

1.10. hemoglobin Kansas

1.10.1. associated with decreased oxygen affinity and cyanosis

1.11. Unstable hemoglobins

1.11.1. amino acid substitution at a place in the α or β chain that affects the formation of the bonds between chains

1.11.2. Hb precipitates Heinz bodies majority removed by the spleen

1.11.3. Jaundice and splenomegaly are common

1.11.4. darkly pigmented urine

1.11.5. Following splenectomy, Heinz bodies are numerous in the circulating RBCs.

1.11.6. detected by heat instability test and the isopropanol precipitation test

2. Thalassemias

2.1. Homozygous β-Thalassemia (thalassemia major

2.1.1. decrease or an absence in β-chain production by both gene alleles.

2.1.2. γ -chain production is high, which results in increased Hb F excess of α-chains due to a lack of matching β-chains.

2.1.3. Clinical symptoms of β-Thalassemia major include (a) Jaundice and splenomegaly early in childhood (b) Prominent frontal bones (i.e., cheek, jaws) (c) Chronic marrow hyperplasia resulting in a thinned cortex of the long bones (d) Stunted growth and delayed puberty (e) Hemochromatosis from regular transfusions (f) Cardiac failure (i.e., major cause of death) due to myocardial siderosis by 30 years of age

2.1.4. hematologic profile microcytic/hypochromic anemia poikilocytosis and anisocytosis in RBCs reticulocyte count is less elevated The osmotic fragility test is decreased Serum iron is increased The indirect bilirubin level is increased. The MCV is decreased with an increased RDW.

2.1.5. Marrowaspirate reveals normoblastic hyperplasia, increased storage iron, and sideroblasts.

2.1.6. three genetic forms β+-Thalassemia partial decrease in β-chain production Mediterranean descent

2.2. Heterozygous β-Thalassemia (i.e., thalassemia minor)

2.2.1. absence or decrease in β-chain production at one gene allele

2.2.2. clinical symptoms microcytic/hypochromic slight hemolytic jaundice and splenomegaly.

2.2.3. hematologic profile RBC count is increased Hb and Hct are reduced RDW is increased poikilocytosis, target cells, and basophilic stippling Osmotic fragility is decreased. Serum iron levels are normal to high

2.2.4. δ-β-Thalassemias clinical symptoms similar to β-Thalassemias electrophoretic pattern shows an absence of Hb A and Hb A2

2.2.5. Hb Lepore syndromes abnormal Hb that has a normal α-chain combined with a fused δβ-chain microcytic/ hypochromic anemia

2.3. Sickle cell thalassemia (i.e., Hb S β-Thalassemia)

2.3.1. MCV and MCH are lower

2.3.2. Hb A2 is increased to greater levels than that seen in Hb SS.

2.3.3. Hb S β◦ -Thalassemia (i) Hb A: none (ii) Hb S: 75% to 90% (iii) Hb F: 5% to 20% (iv) Hb A2: >4.5%

2.3.4. Hb S β+-Thalassemia (i) Hb A: 15% to 30% (ii) Hb S: >50% (iii) Hb F: 1% to 20% (iv) Hb A2: increased >4.5%

2.3.5. hematologic characteristics (i) Marked microcytosis (ii) Variable hypochromia (iii) Many target cells (iv) Rare sickle cells (v) Low MCV and MCH (vi) Positive sickle cell tests

2.4. Hb C β-Thalassemia

2.4.1. Hb C β◦ -Thalassemia (i) Hb C: 90% to 95% (ii) Hb F: 5% to 10% (iii) Hb A: none

2.4.2. HbCβ+ -Thalassemia (i) Hb A: 20% to 30% (ii) Hb C: 70% to 80% (iii) Hb F: normal (iv) Hb A2: masked on electrophoresis by Hb C

2.4.3. Hb E β-Thalassemia Southeast Asian disease resembling thalassemia major (a) Hb E: 15% to 95% (b) Hb F: 5% to 85% (c) Hb A: none

2.4.4. α-Thalassemias partial or total decrease in the production of α-chains α-Thalassemia(i.e.,α+-Thalassemia) is a deletion of only one gene and is represented as -α/αα. Mild α-Thalassemia(i.e.,α◦-Thalassemia) is a deletion of two α-globin genes, and is represented as –/αα. Severe Hydrops fetalis w/ Hb Bart most severe form of α-Thalassemia diploid genotype of –/–, which represents the absence of all α-chains. incompatible with life electrophoretic pattern: Hb H disease(i.e.,α-Thalassemia major) is a thalassemia in which three of the four α-globin genes are absent (i.e., –/–α). chronic hemolytic anemia hematologic characteristics: α-Thalassemia minor patients are lacking two of the four α-globin genes mild anemia, microcytosis, and normal serum iron Diagnosis Silent carrier of α-Thalassemia (i.e., heterozygous α+-Thalassemia) only one defective α-globin gene Hemoglobin constant spring (Hb CS) α-chain variant with 31 extra amino acids. α-Chains are functionally normal but synthesized more slowly electrophoretic pattern:

3. Deoxyribonucleic acid (DNA) disorders

3.1. Megaloblastic anemia

3.1.1. Macrocytic/normochromic

3.2. Macrocytic anemia with a megaloblastic marrow

3.2.1. ineffective hematopoiesis

3.3. Vitamin B12 (i.e.,cyanocobalamin)

3.3.1. Metabolism occurs in the small intestine

3.3.2. Dietary B12 is released from digestion of animal proteins in meats and is bound by Gastric intrinsic factor(IF)

3.3.3. Normal serum vitamin B12 values range 200 to 900 ng/L

3.3.4. Vitamin B12 cofactor in the conversion of methyl tetrahydrofolate (i.e., folic acid) to tetrahydrofolate

3.3.5. Common cause of vitamin B12 deficiency defective production of IF

3.3.6. Pernicious anemia(PA) “conditioned” nutritional deficiency of B12, caused by failure of the gastric mucosa to secrete IF. Imherited disorder, persons older than 40 years Other causes of PA include the following Gastrectomy Defective absorption of vitamin B Lack of availability of vitamin B12 in the small intestine

3.4. Folic acid

3.4.1. primarily acquired from the diet

3.4.2. 50mg Minimum daily requirement

3.4.3. Storage Liver

3.4.4. 5 to 21 mcg/L, and 150 to 600 mcg/L Normal serum reference values and RBC folate

3.4.5. megaloblastic anemia caused by folate deficiency is most commonly due to insufficient dietary intake

3.4.6. Causes of deficiency Liver disease associated with alcoholism nontropical sprue, intestinal blind-loop syndrome, and adult celiac disease. Defective absorption of folate chemotherapydrugs(e.g.,methotrexate),

4. Hemolytic anemias

4.1. Intrinsic hemolytic anemias

4.1.1. hereditary and occur from defects in the RBC membrane, metabolism, or the Hb molecule.

4.2. Extrinsic hemolytic anemias

4.2.1. RBC survival disorders that are acquired and occur secondary to a primary condition or stimulus.

4.3. Hemolysis caused by RBC membrane disorders

4.3.1. Hereditary spherocytosis (HS) a moderate-to-severe anemia. Cause Splenomegaly defect in spectrin Laboratory tests useful in the diagnosis of HS include (a) Blood smear with spherocytes (b) Osmotic fragility test (c) Autohemolysis test Autosomal dominant

4.3.2. Hereditary eliptocytosis (HE) a defect of spectrin Elliptocytes are abundant 90% are nonanemic. The other 10% of patients have a mild-to-moderate hemolytic anemia. Autosomal dominant

4.3.3. Hereditary pyropoikilocytosis(HPP) autosomal recessive Rarely in blacks defective spectrin function.

4.3.4. Hereditary stomatocytosis Stomatocytes slit-shaped central pallor not as flexible Shortened survival time

4.3.5. Paroxysmal nocturnal hemoglobinuria (PNH) frequently in young adults acquired intrinsic defect of the RBC membrane RBCs hypersensitive to complement C3 binding Defect

4.3.6. Hemosiderinuria is also present

4.3.7. Platelets and neutrophils may also be hypersensitive to complement, and therefore low in count.

4.3.8. Laboratory tests useful in the diagnosis of PNH include the following sucrosehemolysistest(i.e.,sugar-watertest) is basedontheprinciple that sucrose provides a medium of low ionic strength and promotes the binding of complement to RBCs. Patients who have PNH demonstrate a higher degree of hemolysis with this procedure. The acidified serum test (i.e., Ham test)

4.4. Hemolysis caused by RBC metabolic disorders

4.4.1. Glucose-6-phosphatedehydrogenase(G6PD)deficiencies inherited as a sex linked trait. highest incidence is among African and Mediterranean cultures. Two genetic isoenzyme variations Type A Type B Favism Pyruvate kinase (PK) deficiency

4.5. Acquired extrinsic hemolysis

4.5.1. Causes Physical forces Heat from extensive burns Cardiovascular disease and prostheses

4.5.2. Microangiopathic hemolytic anemia moderate RBC fragmentation can result as a secondary manifestation of the following conditions 1) Chronic hypertension (2) Thrombotic thrombocytopenic purpura (3) Disseminated carcinoma (4) DIC

4.5.3. Immune hemolytic anemias result from immunoglobulin binding to the RBC membrane and splenic removal of the cells. Autoimmune hemolytic anemia (AIHA) associated with warm antibodies hemolytic anemiawithapositivedirectantiglobulin test (i.e., Coombs’ test) Cold antibodies