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Hemolytic and Nutritional Anemias

Hemolytic and Nutritional Anemias. Bea Gepte, MD, MPH. The Red Blood Cell. No nucleus - better vessel for oxygen transport - loss of ability for protein synthesis - finite life span No mitochondria - cannot generate ATP through Kreb’s cycle

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Hemolytic and Nutritional Anemias

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  1. Hemolytic and Nutritional Anemias Bea Gepte, MD, MPH

  2. The Red Blood Cell • No nucleus - better vessel for oxygen transport - loss of ability for protein synthesis - finite life span • No mitochondria - cannot generate ATP through Kreb’s cycle - metobolism of glucose by anaerobic glycolysis (Embden-Meyerhof pathway) and pentose phosphate pathway

  3. The Red Blood Cell • Importance of ATP: 1. Maintenance of electrolyte gradients - accomplished by an energy (ATP)–dependent membrane mechanism, the cation pump 2. Initiation of energy production - ATP is required for the initial reaction of glycolysis involving phosphorylation of glucose to glucose-6-phosphate. 3. Maintenance of RBC membrane and shape - phospholipid structure of the RBC membrane - maintenance of the biconcave shape

  4. The Red Blood Cell • Importance of ATP: (Continued) 4.Maintenance of heme iron in the reduced (ferrous) form - Oxidative potentials within the RBC are inactivated - protection of RBCs from the effects of oxidation ultimately depends on NADPH and NADH 5. Maintenance of the levels of organicphosphates such as 2,3-diphosphoglycerate and ATP within the RBCs - have profound effects on oxygen affinity

  5. The Red Blood Cell Red Cell Life Span - the average life span for a neonatal RBC is 60–90 days, approximately ½ to⅔ that of an adult RBC 1. a rapid decline in intracellular enzyme activity and ATP 2. loss of membrane surface area by internalization of membrane lipids 3. decreased levels of intracellular carnitine 4. increased susceptibility of membrane lipids and proteins to peroxidation 5. increased mechanical fragility due to increased membrane deformability

  6. Hemolytic Anemias

  7. General Principles • Hemolysis is defined as the premature destruction of red blood cells (RBCs) - rate of destruction exceeds the capacity of the marrow to produce RBCs - RBC survival is shortened - erythropoietin is increased the stimulation of marrow activity heightened RBC production increased percentage of reticulocytes in the blood -The marrow can increase its output 2- to 3-fold acutely, with a maximum of 6- to 8-fold in long-standing hemolysis

  8. General Principles • The Reticulocyte Count and Reticulocyte Index Retic Count % X Observed Hct X 1 = Retic Index Actual Hct µ µ = maturation factor of 1–3 related to the severity of the anemia Hctµ 36 – 45 1 normal retic index= 1 26- 35 1.5 hemolysis = 2-3 or more 16 - 25 2 <15 2.5

  9. General Principles • General Consequences of Hemolysis 1. Erythroid hyperplasia resulting to the expansion of medullary spaces at the expense of the cortical bone 2. Increased biliary excretion of heme pigment derivatives and increased urinary and fecal urobilinogen 3. Gallstones composed of calcium bilirubinate may be formed in children as young as 4 yr of age 4. Elevations of serum unconjugated bilirubin and lactic dehydrogenase 5. Presence of free hemoglobin in the plasma and urine

  10. General Principles • Classification of Hemolytic Anemias 1. Cellular - resulting from intrinsic abnormalities of the membrane, enzymes, or hemoglobin 2. Extracellular - resulting from antibodies, mechanical factors, or plasma factors

  11. Hereditary Spherocytosis

  12. Epidemiology • Prevalence of approximately 1/5,000 in people of Northern European descent • Most common inherited abnormality of the red blood cell (RBC) membrane • 25% do not have a family history, mostly representing a new mutation

  13. Etiology PROTEIN BAND ON GEL GENE PROPORTION OF PATIENTS WITH HS INHERITANCE Ankyrin 2.1 ANK1 50–67% Dom and Rec Band 3 3 AE1 (SLC4A1) 15–20% Mostly Dom β Spectrin 2 SPTB 15–20% Dom α Spectrin 1 SPTA1 <5% Rec Protein 4.2 4.2 EPB42 <5% Rec

  14. Clinical Manifestations • Severe anemia and hyperbilirubinemia in the newborn period requiring phototherapy or exchange transfusions • Asymptomatic • Severe anemia with pallor, jaundice, fatigue, and exercise intolerance • Splenomegaly • Pigmentary (bilirubin) gallstones may form as early as age 4–5 yr • Susceptible to aplastic crisis

  15. Laboratory Findings • reticulocytosis • indirect hyperbilirubinemia • Increased MCHC 36–38 g/dL • spherocytes usually account for >15–20% of the cells when hemolytic anemia is present • Erythroid hyperplasia is evident in the marrow aspirate or biopsy • Marrow expansion may be evident on routine Xray • Gallstones on UTZ

  16. Diagnosis • The diagnosis of hereditary spherocytosis usually is established clinically from the blood film, which shows many spherocytes and reticulocytes, from the family history, and from splenomegaly. • osmotic fragility test -nonspecific -normal test result also may be found in 10–20% of patients • cryohemolysis test • osmotic gradient ektacytometry • eocin-5-maleimide test • DNA analysis

  17. Differential Diagnosis • Isoimmune hemolytic disease of the newborn - due to ABO and RH incompatibility - detection of antibody on an infant's RBCs using a direct antiglobulin (Coombs) test • Autoimmune hemolytic anemias - evidence of previously normal values for hemoglobin, hematocrit, and reticulocyte count • Rare causes of spherocytosis: - thermal injury, clostridial septicemia with exotoxemia, and Wilson disease

  18. Treatment • Splenectomy (recommended after age 5–6 yr) Indications: 1. severe anemia 2. reticulocytosis 3. hypoplastic or aplastic crises 4. poor growth 5. cardiomegaly • Partial splenectomyalso may be useful in children younger than age 5 yr and can provide some increase in hemoglobin and reduction in the reticulocyte count, with potential maintenance of splenic phagocytic and immune function.

  19. Treatment • Supportive Care 1. Folic Acid 1mg/day 2. Vaccination prior to splenectomy: -pneumococcus -meningococcus -Haemophilus influenzae type b, 3.Prophylactic oral penicillin V - age <5 yr, 125 mg twice daily - age 5 yr through adulthood, 250 mg twice daily

  20. Pyruvate Kinase Deficiency

  21. Pyruvate Kinase Deficiency • Homozygous for an autosomal recessive gene • Marked reduction in RBC PK or production of an abnormal enzyme with decreased activity. Decreased ATP RBCs cannot maintain the potassium and water content the cells become rigid life span is considerably reduced.

  22. Etiology • Defect in the human PKLR gene located on chromosome 1q21 • 133 mutations are reported in this structural gene, which codes for a 574–amino acid protein that forms a functional tetramer

  23. Clinical Manifestations • Severe neonatal hemolytic anemia - jaundice and anemia - kernicterus has been reported • mild, varies in severity, with hemoglobin values ranging from 8–12 g/dL • associated with some pallor, jaundice, splenomegaly • well-compensated hemolysis first noted in adulthood - Not transfusion dependent • Severe form of the disease found among the Amish of the Midwestern United States.

  24. Laboratory Findings • Polychromatophilia and mild macrocytosis elevated reticulocyte count. • Spherocytes are uncommon, but a few spiculated pyknocytes are found. • Normal non-incubated osmotic fragility • Diagnosis relies on demonstration of a marked reduction of RBC PK activity or an increase in the Michaelis-Menten dissociation constant (Km) for its substrate, phosphoenolpyruvate.

  25. Treatment • Exchange transfusions may be indicated for hyperbilirubinemia in newborns • Transfusions of packed RBCs are necessary for severe anemia or for aplastic crises • Splenectomy for patients with recurrent and severeanemia 5–6 yr of age (not curative)

  26. G6PD Deficiency

  27. G6PD Deficiency • Most important disease of the hexose monophosphate pathway • Responsible for 2 clinical syndromes: - Episodic hemolytic anemia induced by infections, certain drugs or, rarely, fava beans, and - Spontaneous chronic nonspherocytic hemolytic anemia • Affects more than 400 million people worldwide • “Balanced Polymorphism” - evolutionary advantage of resistance to falciparum malaria in heterozygous females that outweighs the small negative effect of affected hemizygous males

  28. Etiology • X-Linked • Inheritance of any of a large number of abnormal alleles of the gene responsible for the synthesis of the G6PD protein • Milder disease is associated with mutations near the amino terminus of the G6PD molecule, and chronic nonspherocytic hemolytic anemia is associated with mutations clustered near the carboxyl terminus

  29. Inheritance of G6PD Deficiency (X)Y – Deficient, Symptomatic (X)(X) – Deficient, Symptomatic (X)X – Carrier

  30. Episodic or Induced Hemolytic Anemia • Considerable variation in the defect is noted among various racial groups Example: The enzyme activity of RBCs containing the variant enzyme (G6PD B-) in Americans of European descent is very low, often <1% of normal. A 3rd common mutant enzyme with markedly reduced activity (G6PD Canton) occurs in approximately 5% of the Chinese population. • More than 100 distinct enzyme variants of G6PD are associated with a wide spectrum of hemolytic disease.

  31. Clinical Manifestations • Hemolysisdevelop 24–48 hr after a patient has ingested a substance that has oxidant properties or infection • Favism - vicine and convicine hydrolyzed to divicine and isouramil producing hydrogen peroxide and other reactive oxygen products. The degree of hemolysis varies with the inciting agent, the amount ingested, and the severity of the enzyme deficiency.

  32. Laboratory Findings • Abrupt fall in hemoglobin and hematocrit • Tea colored urine • Unstained or supravital preparations of RBCs reveal Heinz bodies (precipitated hemoglobin) • fragmented and polychromatophilic cells (5–15%)

  33. Diagnosis • Direct measurement of enzyme activity: - affected persons is ≤10% of normal • Screening tests: - decoloration of methylene blue - reduction of methemoglobin - fluorescence of NADPH • G6PD variants also can be detected by electrophoretic analysis. • DNA analysis

  34. Treatment • Prevention of hemolysis constitutes the most important therapeutic measure. • Supportive therapy may require blood transfusions.

  35. Chronic Nonspherocytic Hemolytic Anemia • Caused by enzyme variants, particularly those defective in quantity, activity, or stability • Gene defects located primarily in the region of the NADP binding site near the carboxyl terminus of the protein • Impairment of the regeneration of GSH as an oxidant “sump” • Manifest as pallor, jaundice, splenomegaly requiring regular transfusions

  36. Thalassemia

  37. Epidemiology • 3% of the world's population carries genes for β-thalassemia • 5–10% of the population carries genes for α-thalassemia in Southeast Asia • In the U.S., an estimated 2,000 individuals have β-thalassemia.

  38. Pathophysiology • An imbalance in α- and β-globin chain production • In bone marrow, thalassemic mutations disrupt the maturation of red blood cells, resulting in ineffective erythropoiesis

  39. Pathophysiology • In β-thalassemias, there is an excess of α-globin chains relative to β- and γ-globin chains • α-globin tetramers (α4) are formed, and these inclusions interact with the red cell membrane and shorten red cell survival • The γ-globin chains are produced in increased amounts, leading to an elevated Hb F (α2γ2) • The δ-globin chains are also produced in increased amounts, leading to an elevated Hb A2(α2δ2) in β-thalassemia.

  40. Pathophysiology • In α-thalassemia, there are relatively fewer α-globin chains and an excess of β- and γ-globin chains. • These excess chains form Bart's hemoglobin (γ4) in fetal life and Hb H (β4) after birth. • Prenatally, a fetus with α-thalassemia may become symptomatic because Hb F requires sufficient α-globin gene production, whereas postnatally, infants with β-thalassemia become symptomatic because Hb A requires adequate production of β-globin genes

  41. HOMOZYGOUS β-THALASSEMIA (THALASSEMIA MAJOR, COOLEY ANEMIA) • Severe anemia requiring regular transfusions (6 months of life) • Classic findings: typical facies (maxillary hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures, marked hepatosplenomegaly, and cachexia • Spleen may become so enlarged that it causes mechanical discomfort and secondary hypersplenism • Hemosiderosis

  42. Laboratory Findings • Severe hypochromic anemia • Numerous nucleated red cells • Microcytosis

  43. Treatment • Blood Transfusion - promotes general health and well-being and avoids the consequences of ineffective erythropoiesis • Chelation - Measurement of the iron level by liver biopsy is the standard method for accurately determining the iron store • Bone marrow transplantation has cured >1,000 patients who have thalassemia major - Most success has been in children younger than 15 yr of age without excessive iron stores and hepatomegaly who have HLA-matched siblings

  44. α-THALASSEMIA • Deletion of 1 α-globin gene (silent trait) - No alterations are noted in the mean corpuscular volume and mean corpuscular hemoglobin. - Individuals with this deletion are usually diagnosed after the birth of a child with a 2-gene deletion, or Hb H (β4) - Newborn period: <3% Bart's hemoglobin is observed - common in African-Americans.

  45. α-THALASSEMIA • Deletion of 2 α-globin genes/α-thalassemia trait - present as a microcytic anemia - hemoglobin analysis is normal, except during the newborn period, when Bart's hemoglobin is commonly <8%, but >3% - distinguished from IDA by history and trial tx of iron

  46. α-THALASSEMIA • Deletion of 3 α-globin genes: Hb H disease - during the newborn period, the Bart's hemoglobin level is commonly >25% - at least 1 parent must have α-thalassemia trait - definitive diagnosis of Hb H disease requires DNA analysis Transfusion is not commonly used for therapy because the range of hemoglobin is 7.0–11.0 g/dL, with a mean corpuscular volume of 51–73 fl.

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