Hemoglobin disorders final
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Hemoglobin is composed of four subunits, each containing a heme group and globin protein. It transports oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs. Hemoglobin exists in tense and relaxed states that influence its affinity for oxygen. Abnormalities in hemoglobin synthesis or structure can result in hemoglobinopathies like sickle cell anemia or thalassemias. Sickle cell anemia is caused by a mutation replacing glutamic acid with valine in the beta globin chain, causing red blood cells to sickle and leading to anemia, pain crises and other complications. Thalassemias involve deficiencies in alpha or beta globin chain production causing anemia of varying severity
Hemoglobin disorders final
- 1. Hemoglobin Diseases GROUP 10 Reporters: Yang, Sheryl Ray Zagada, Timothy Zamora, Marvin Zapanta, Patricia Joyce
- 2. Hemoglobin 101 Yang, Sheryl Ray
- 3. Primary function of the Red blood cell is to manufacture hemoglobin, which in turn, transports oxygen to the tissues and carbon dioxide from tissues to the lungs. Hemoglobin molecule is composed of four subunits, each containing heme and globin Hemoglobin Synthesis
- 4. Protein component called globin Four molecules of the nitrogenous substance Protoporhpyrin IX Four Iron atoms at Ferrous (Fe+2) state that combine with Protoporphyrin IX to form four heme molecules One 2,3 Diphosphoglycerate (2,3 DPG) molecule as a sometime resident in the center of Hb unit Hemoglobin Synthesis Components of Hemoglobin
- 8. Produced on specific ribosomes in the cytoplasm of red blood cells. The globin in each hemoglobin molecule consists of four polypeptide chains which determine the type of hemoglobin formed. Globin Chains
- 9. Greek Designation Greek Name No. of Amino Acids Chromosome α Alpha 141 16 β Beta 146 11 δ Delta 146 11 γ Gamma 146 11 ε Epsilon 146 11 ζ Zeta 146 16 Globin Chains in Hemoglobin • Consist of varied sequences of amino acids – polypeptide chains
- 10. Hemoglobin Molecular structure Stage of life Proportion Newborns Proportion Adults Portland 2 Zeta + 2 Gamma Embryonic 0 0 Gower I 2 Zeta + 2 Epsilon Embryonic 0 0 Gower II 2 Alpha + 2 Epsilon Embryonic 0 0 Hb A1 2 Alpha + 2 Beta Newborn & Adult 20 97 Hb A2 2 Alpha + 2 Delta Newborn & Adult <0.5 2.5 Hb F (Fetal) 2 Alpha + 2 Gamma Newborn & Adult 80 <1 Normal Human Hemoglobin
- 12. T and R states of Hemoglobin • Hemoglobin exists in two major conformational states: Relaxed (R ) and Tense (T) • R state has a higher affinity for O2. • In the absence of O2, T state is more stable; when O2 binds, R state is more stable, so hemoglobin undergoes a conformational change to the R state. • The structural change involves readjustment of interactions between subunits. Tensed and Relaxed State
- 13. Tensed and Relaxed State
- 15. Iron in the ferrous state is required to convert protoporphyrin Ix to heme. Circumstances that cause reduction in the iron available for Hb synthesis or failure to incorporate iron into heme will cause anemia to develop. Iron Metabolism for Heme Synthesis
- 16. Most common cause of anemia Due to INCREASED PHYSIOLOGIC DEMANDS Rapid growth; infants, children Pregnancy, lactation Iron Deficiency Anemia * INADEQUATE INTAKE * Iron deficient diet * Inadequate absorption * CHRONIC BLOOD LOSS * Menstrual flow * Gastrointestinal bleeding * Regular blood donation * Chronic hemolysis
- 18. Hemoglobinopathy Conditions caused by qualitative structural abnormalities of the globin polypeptide chains that result from alteration of the DNA genetic code for those chains Hemoglobinopathies and Thalassemias
- 19. Thalassemias Conditions caused by quantitative abnormality in globin chain (i.e., reduced or no production). Hemoglobinopathies and Thalassemias
- 20. Sickle Cell Anemia Zamora, Marvin
- 21. Hgb S – most common abnormal hemoglobin - Normal glutamic acid at 6th position in the β chain is replaced by Valine Results in: - Altered solubility - Altered ability to withstand oxidation - Instability - Increased propensity for methemoglobin production - Increased or decreased oxygen affinity Sickle cell disease
- 22. Sickle cell anemia - Sickle cell disease (SCD) - Drepanocytosis - Hb SS - SS disease - Hemoglobin S - Homozygous
- 23. Sickle cell trait Is the heterozygous state of SCD One sickle gene and one normal hemoglobin gene (Hb AS) Usually have no symptoms
- 24. Overview Sickle cell disease is a general term for a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S) Erythrocytes becomes elongated and sickle shaped Removed from the circulation and destroyed at increasing rates, leading to anemia.
- 25. Overview An autosomal recessive inherited defect The disease is chronic and lifelong Lifespan average of 40 years.
- 26. Pathophysiology caused by a point mutation in the β-globin chain of hemoglobin glutamic acid valine at the 6th position *found on the short arm of chromosome 11.
- 31. Pathophysiology Sickling occurs when oxygen decreases at the tissue level – dissociation of oxygen from RBC Polymerization of Hgb molecules to crystals
- 32. Sickle cell crises Vasoocclusive crises - Increase in blood viscosity - restricts blood flow to an organ Hemolytic crises – acute accelerated drops in Hgb levels and RBCs break down at a faster rate. - common in patients with G6PD deficiency
- 33. Sickle cell crises Infectious crises - Abnormal splenic function - Depressed immune function - Streptococcus Pneumoniae is the major infectious agent among children
- 34. Sickle cell crises Aplastic crises - caused by infection and fever - Parvovirus B19 - Folate deficiency
- 35. Sickle cell crises Bone, joint and other crises: - Hand-foot syndrome or Dactylitis - Priapism - Gallstones
- 37. Sickle cell anemia Laboratory findings -severe anemia (Hgb 5-9 g/dl) -normocytic, normochromic RBC -aniso and poikilocytosis is present -with leukocytosis and thrombocytosis
- 38. Diagnosis Blood film appearance Screening tests for sickling Hemoglobin electrophoresis
- 39. Hemoglobin electrophoresis A (%) F (%) S (%) C (%) D (%) E (%) Degree of clinical abnormality Hemoglobinopathy Hb CC 1- 7 >90 Mild Hb AC 50-60 <2 40-50 None Hb SC 1-7 50 50 Mod - Severe Hb SS 1- 10 80-90 Severe Hb AS 55-70 <2 30-45 None/Mild Hb DD <2 95 None Hb AD 50-65 <2 35-50 None Hb EE 1-5 95 Mild Hb AE 60-80 20- 40 None
- 40. Treatment *Blood transfusion of PRBC *Administration of antisickling agents -Cyanate -Urea -Nitrogen mustard -zinc procaine hydrochloride, Citiedil, and piracetam *Bone marrow transplantation
- 42. THALASSEMIA SYNDROMES Each individual has 4 genes of hemoglobin ( HBA1, HBA2, HBB1,HBB2) (aa/aa)(bb/bb) Thalassemia is characterized by partial or total absence of one or more chains of hemoglobin (either α chain or β chain). Resulting to abnormal form of hemoglobin. Which leads to destruction of RBC leads to anemia It is a genetic disorder TYPES OF THALASSEMIA 1. α - thalassemia 2.β - thalassemia
- 44. THALASSEMIA DEMOGRAPHIC Southeast Asia and Meditteranian region CLINICAL PRESENTATION MINOR – mild anemia confused with iron deffeciancy INTERMEDIATE-moderate anemia MAJOR- severe anemia – hydrops fetalis intrauterine death
- 45. Alpha thalassemia Deletion of alpha- globin gene resuts to Children /Adult Excess beta globin – usually unstable and precipitate in cell Forms HEINZ BODY Fetal / new born Iincrease HYPOCHROMIC and MICROCYTIC RBC
- 46. ALPHA THALASSEMIA Involves the genes HBA1 and HBA2 Located at chromosome 16 Severity of disease depends on the number of genes defective or missing
- 47. Alpha (+) thalassemia: -deletion of I or more alpha globin gene If 1 gene = silent carrier If 2 genes = alpha trait (thalassemia minor) If 3 genes = H hemoglobin (thalassemia intermedia) Alpha (0) thalassemia If 4 genes = Bart hemoglobin (thalassemia major) ALPHA THALASSEMIA
- 48. 3 normal gene (-a/aa) Normal patient Silent Carrier/ Alpha thalassemia minima/ alpha thalassemia – 2 trait
- 49. 2 normal gene (aa/--) – cis form (-a/-a) – trans form Clinically normal Minimal anemia Decrease MCV and MCH Alpha thalassemia trait/ alpha thalassemia minor/ alpha thalassemia – 1 trait
- 50. Only 1 normal alpha-globin gene (-a/--) Increase ratio beta globin : alpha globin Sensitive to oxidative stress RBC prone to hemolyze Hemoglobin H / HbH disease
- 51. All 4 alpha globin gene is deleted (--/--) Most severe case Hydrops fetalis Bart’s Hemoglobin/ alpha (0) thalassemia
- 52. BETA THALASSEMIA Β thalassemia will not manifest at birth since predominant is Hgb F. production of B chain will occur only at 3 – 6 months after birth Involves the gene HBB1 and HBB2 Located at chromosome 11 Severe transfusion dependent anemia
- 53. BETA THALASSEMIA TYPE OF BETA THALASEMIA Homozygous beta thalassemia ( thalassemia major, cooley’s anemia, Meditteranean anemia) - severe life long -all beta gene mutated -severe anemia Heterozygous beta thalassemia (thalassemia minor) -one normal beta chain and 1 abnormal beta chain -mild anemia
- 54. THALASSEMIA LAB DIAGNOSTICS Peripheral Blood Smear -Target cells, Heinze bodies, basophilic strippling, nucleated RBC Reticulocyte – increased Decreased osmotic fragility Iron storage disease
- 55. As blood glucose enters the erythrocytes it glycosylates the ε-amino group of lysine residues and the amino terminals of hemoglobin. RBC life span – 120 days HbA1c and Diabetes
- 57. HbA1c Normal/abnormal Blood glucose level via meter 4.0 - 6.0% Normal for those without diabetes 3 – 8mmol/L 6.1 – 7.0% Target range for those with diabetes 4 – 8mmol/L 7.1 – 8.0% High 8 – 11mmol/L 8.1 – 9.0% Too high 11 – 14mmol/L Greater than 9.1% Very high 15mmol/L and above HbA1c and Diabetes
- 59. Laboratory Experiment: Hgb Determination Zagada, Timothy
- 60. Cyanmethemoglobin method A method used for hemoglobin determination The reagent hemolyzes the erythrocytes which releases the hemoglobin into the solution. REACTIVE INGREDIENTS: -potassium cyanide and potassium ferricyanide.
- 61. Principle in Cyanmethemoglobin method When blood is mixed with a solution containing potassium ferricyanide and potassium cyanide, the potassium ferricyanide oxidizes iron to form methemoglobin. The potassium cyanide then combines with methemoglobin to form cyanmethemoglobin Hgb(Fe++) K3Fe(CN)6 Methemoglobin(Fe+++) KCN Cyanmethemoglobin
- 62. Procedure Hgb Reagent (5ml) Mix well. Stand for 3 min Read at spectrophotometer +20ul blood sample (EDTA whole blood)
- 63. PURPOSE OF EDTA EDTA (ethylenediaminetetraacetic acid) is the most commonly used anticoagulant in evacuated tubes. EDTA reduces platelet activation by protecting the platelets during contact with the glass tube that may initiate platelet activation.
- 64. RESULTS 0 5 10 15 20 25 Group 6 Group 7 Group 8 Group 9 Group 10 Hgb g/dL 17.9 15.57 19.5 17.74 22 Hgbconcentration Hgb concentration per sample Normal: Male: 13-18 g/dL Female: 12-16 g/dL
- 65. SOURCES OF ERRORS Technical Error - Pipeting - Use of dirty, scratched or unmatched cuvettes - Use of deteriorated reagents - Incorrectly calibrated spectrophotometer
- 66. SOURCES OF ERRORS Physiologic Error - Turbidity in the mixture causes falsely elevated values Turbidity maybe caused by: Lipemia Extremely high leukocyte counts Easily precipitated Globulins
- 67. Factors that affect Hemoglobin Increased Hemoglobin kidney releases too much erythropoietin People living in high altitudes Anabolic steroid Smoking Dehydration Polycythemia vera
- 68. Factors that affect Hemoglobin Decreased Hemoglobin -Vitamin-deficiency Anemia deficiency of vitamin B12 or folate -Bleeding Blood volume is replaced more quickly than red blood cells, leading to a lower concentration of hemoglobin -Kidney Disease results in lower levels of erythropoietin -Pregnancy -Blood Disorders
Editor's Notes
- #61: a compound formed by combination of hydrocyanic acid with methemoglobin1. measures all forms of hemoglobin except sulfhemoglobin2. can be easily standardized3. cyanmethemoglobin reagent (also called Drabkin's solution) is very stable
- #62: In alkaline mediumThe CYANMETHEMOGLOBIN REAGENT contains a surfactant to promote rapid hemolysis and to accelerate formation of cyanmethemoglobin.The Ferrous ions (Fe2+) of the hemoglobin molecules are oxidized by potassium ferricyanide to ferric ions (Fe3+). This oxidation results to the formation of methemoglobin. All hemoglobin derivatives are converted to cyanmethemoglobin except sulfhemoglobin.
- #63: The potassium cyanide then combines with methemoglobin to form cyanmethemoglobin, which is a stable color pigment read photometrically at a wave length of 540nm.When measured spectrophotometrically at 540nm. The absorbance of cyanmethemoglobin follow Beer-Lamberts Law and is directly proportional to the concentration of hemoglobin in the blood.
- #64: It inhibits the clotting process by removing calcium from the blood.The calcium activates protein kinase C, which, in turn, activates phospholipase A2 (PLA2). PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulantmicroparticles or microvesicles shed from them.
- #65: Women: 12.1 to 15.1 gm/dlMen: 13.8 to 17.2 gm/dlChildren: 11 to 16 g/dlPregnant women: 11 to 12 g/dl
- #68: Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells.The blast cells no longer stop producing red cells when too many cells are already present.This causes excess production of red blood cells in the same manner that a breast tumor causes excess production of a specific type of breast cell. It usually causes excess production of white blood cells and platelets as well. When the body is dehydrated, The contraction of the plasma volume results in the appearance of an elevated hemoglobin concentration, or hemoconcentration which can raise the hemoglobin concentration by 10–15%.-kidney releases too much erythropoietin.Anabolic steroid used to enhance body building, can also stimulate red blood cell production. Smoking drops the level of oxygen in the lungs, so to balance out the deficiency, the body raises levels of hemoglobin. The only condition of elevated hemoglobin that is due to the production of defective red blood cells, but not subject to the control of tissue oxygen drive, is polycythemia vera
- #69: Both of these (B12 and Folic acid) are essential for the synthesis of DNA, because each in a different way is required for the formation of thymidine triphosphate, one of the essential building blocks of DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, failure of nuclear maturation and cell division.