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Lecture 14

Thalassemia/Hemoglobinopathies

QuestionAnswer
What are the globin genes found on chromosome 16? Alpha globin gene and zeta globin gene
When is the alpha globin genes expressed during embryologic development? 10th week of conception. Prior to that, the zeta globin genes are expressed.
What are the globin chains that form Hb Gower 1? 2 zeta chains and 2 epsilon chains
What are the globin chains that form Hb Gower 2? 2 alpha chains and 2 epsilon chains
What are the globin chains that form Hb F? 2 alpha chains and 2 gamma chains
What are the globin chains that form Hb A2? 2 alpha chains and 2 delta chains
What are the globin chains that form Hb A? 2 alpha chains and 2 beta chains
What percentage of hemoglobin is HbS in patients with Sickle cell trait? 40 to 45%
What hemoglobin trait only develop sickle cell crises only in association with severe hypoxia? Sickle cell trait (HbAS)
(T or F) Patients with sickle cell trait have impaired growth, behavior, and educational achievement. Additionally, patients have shorter life expectancy and increased frequency of hopsitalization. False. Growth, behavior, and educaiton achievement are normal, as are life expectancy and frequency of hospitalization.
What is the clinical significance of Hb C trait (HbAC) Potential for offspring of these individuals to inherit Hb C in combination with HbS thus have a sickling disorder.
What is the etiology of Sickle Cell Anemia (HbSS)? Substitution of valine for glutamic acid at the 6th residue of the beta-globin chain due to a single base pair mutation (A to T) in beta globin gene sequence.
Microscopic findings on peripheral blood smear in sickle cell anemia (1) Normochromic, normocytic RBC (2) Sickle forms of RBCs (3) Howell-Jolly bodies
Microscopic findings on peripheral blood smear for Sickle/beat Thalassemia anemia (1) Microcytic RBCs with poly chromatophilia (2) Target cells (3) Basophilic stippling (4) Sickle forms of RBCs
What determines the severity of disease in Sickle/beta Thalassemia patients? The severity is proporitonate to the amount of HbA produced and therefore is determined by the inheritance which beta globin gene is inherited: either no beta globin produced or decreased amount of normal beta globin produced.
What is the severity of anemia in Hb SC disease? Mild to moderate anemia with Hb 1 to 2 g/dL below lower limit of normal for age and gender.
Microscopic findings of Hb SC disease on peripheral blood smear (1) Normochromic, normocytic RBC (2) Target cells
What are the findings for Hb SC disease on hemoglobin electrophoresis? 50% Hb S and 50% Hb C
What type of ocular complications can occur in Hb SC and Sickle/beta Thalassemia disease? (1) Proliferative retinopathy (2) retinal detachment (3) glaucoma following an anterior chamber bleed.
What is the etiology of Sickle Cell Anemia (HbSS)? Substitution of valine for glutamic acid at the 6th residue of the beta-globin chain due to a single base pair mutation (A to T) in beta globin gene sequence.
What makes a RBC sickle? The conformational change that occurs with oxygen release exposes the mutated amino acid [#6 Glu to Val], which can bind to another Hb S molecule.
What factors lower the oxygen affinity of hemoglobin? (1) Acidosis (2) Increased temp (3) 2,3-bisphosphoglycerate (2,3-DPG)
What factors increase the tendency a RBC to sickle? (1) Increased temp (fever, increased environment temp) (2) Dehydration
What is the effect of Hb F on sickling of RBCs? Hb F inhibits poymerization with Hb S, preventing sickling.
What pharmacologic agent increases Hb F in RBCs? Hydroxyurea
What is the effect of Hb S polymerization on a RBC? Hb S polymer formation increases RBC rigidity, damges the RBC membrane, increases water loss from the RBC, and causes changes to the RBC cell surface molecules that increase the adherence to endothelium. The result is a poorly flexible, sitcky cell.
What is the effect of Hb S polymerization on a RBC? Hb S polymer formation increases RBC rigidity, damges the RBC membrane, increases water loss from the RBC, and causes changes to the RBC cell surface molecules that increase the adherence to endothelium. The result is a poorly flexible, sitcky cell.
How does Hb S polymerization cause end organ damage? Sickled cells are rigid and sticky causes veno-occlusive disease resulting in ischemia and infarction of organs, namely, the spleen and kidneys.
What is the typical age of autoinfarction of the spleen in Sickle Cell Anemia patients? 24 months
What type of organisms are asplenic patients suspectible to? Encapsulated organisms: S. penumonia, H. influenza, and N. meningoccous
(T or F) Pulmonary hypertension is poor prognostic factor in sickle cell diseae. True. Pulmonary hypertension in adults with sickle cell disease identifies a group with a high risk of death within 5 years of diagnosis of pulmonary hypertension.
Explain the association between RBC lysis and pulmonary hypertension in sickling diseases. Hb S polymerization causes RBC lysis. The free Hb from lysed cells decreases plasma nitric oxide (NO). NO is a mjaor mediator of vascular relaxation. Decreased NO along with other mechanisms of lung injury results in pulmonary hypertension.
What is the mean RBC survival in sickle cell disease? 15 to 20 days
How do you calculate absolute reticulocyte count? Absolute reticulocyte count = reticulocyte % x RBC number
It is a complication of Sickle cell disease where a large proportion of RBC mass is trapped in the spleen. It often occurs infecitons or vaso-occlusive events and is considered a medical emergency. Acute splenic sequestration
What is the most common viral infection responsible for aplastic events in sickle cell disease? Parvovirus B19 infection
What is the most common nutritional deficiencies in sickle cell disease? (1) Folate (2) Iron (3) Zinc
What is the most common site of acute pain in sickle cell disease? Bone marrow - Deep bone pain
What is dactylitis? It is the painful swelling of hands and feet. It ocurs in children < 2 years old.
What is the leading cause of death in sickle cell disease? Acute an chronic pulmonary disease
Clinical manifestations of Acute Chest Syndrome in sickle cell disease (1) new infiltrate on CXR (2) chest pain (3) respiratory distress (4) fever (5) cough (6) abnormal lung ausculation
At what age are sickle cell disease patients at risk for strokes? After age one
What type of strokes predominate in sickle cell disease children ages 2 to 10? Thrombotic strokes
What type of strokes predominate in sickle cell disease adults 20 years and older? Hemorrhagic strokes
What percentage of sickle cell disease children have had strokes by age of 10? 7%. An additional 20% of children have had thrombotic strokes of small vessels, but without stroke symptoms.
What percentage of sickle cell disease children have had strokes by age of 20? 11%
What is priapism? It is the painful, persistent erection of the penis.
What factors make the spleen particularly vulnerable to infarction by Hb SS cells? (1) Prolonged RBC transit time (2) Decreased pH of hte spleen (3) Possible differences in the spleen's endothelium (4) Higher oxygen demand of the spleen
What is the most common bacteremia in sickle cell disease children < 6 years of age? S. penumoniae and H. influenzae and UTI due to E. coli
Wha is the most common cause of bacteremia in sickle cell disease adults? S. pneumoniae, H. flu, E. coli (UTIs), Staph. aureus, other gram negative rods, and Salmonella
What is the cause of decreased left ventricular function and congestive heart failure in sickle cell disease? Chronic high output in response to anemia and to tissue hypoxemia.
(T or F) The frequency of myocardial infarction is increased in sickle cell disease. False. The frequency of myocardial infarction is not increased in sickle cell disease.
What type of stones are responsible for cholelithiasis in sickle cell disease? Cholestrol stones and bile acid stones
Definition of isosthenuria Inability to concentrate urine
What are the complications of the liver associated with cell disease? Infarcts and abscess formation. Frequent transfusions increases the risk for transfusion transmitted hepatitis.
What are the complications of the kidneys associated with sickle cell disease? Isosthenuria, hematuria, nephrotic and nephritic syndrome, and chronic renal failure
What are the complications of the gall bladder associated with sickle cell disease? Cholelithiasis and acute cholangitis
What is the lifetime risk for hip avascular necrosis in sickle cell disease? 10%
What is the radiographic finding of the vertebral bodies characteristic of sickle cell disease? Biconcave or "fish mouth" vertebrae
What complication of sickle cell disease results in inefficient painful gait? Avascular necrosis of the femoral head
What screening test is available for strokes in sickle cell patients? Measurement of the velocity in cerebral arteries have produced marked decrease in the frequency of stroek in children with Hb SS.
(T or F) Decreased velocity in cerebral arteries is a risk of CNS infarcts among 2 to 15 year olds with sickle cell disease. False. The risk of CNS infarct among 2 to 15 year olds is associated with increased velocity in cerebral arteries.
(T or F) Weight is affected more than height in sickle cell disease. True. People with sickle disease consume more calories in inverse proportion to their Hb level due to increased cardiac activity and red blood cell production.
What is the sequelae of recurrent priapism secondary to sickle cell disease? Impotence
What hemoglobin disorder has both qualitative and quantitative features? Hemoglobin E
What are the qualitative and quantitative features of Hemoglobin E disorder? Qualitative change: change in amino acid from Glu to Lys Quantitative change: activation of a cryptic mRNA splice site resulting in decreased utilization of the normal splice site. This causes decreased mRNA stability and thus decreased production.
What population is the hemoglobin E disorder mutation seen? People of SE Asian ancestry
Microscopic findings of Hb EE on peripheral blood smear (1) Hypochromic, microcytic RBCs (2) Prominent target cells (3) Occaasional basophilic stippling
Microscopic findings of Hb E/beta Thalassemia on peripheral blood smear 1) Hypochromic, microcytic RBCs (2) Prominent target cells (3) Occaasional basophilic stippling (4) Nucleated RBCs
What infection prophylaxis is used in Sickle Cell Disease patients? Penicillin between the age of 3 months to 5 years old and immunization aganist Pneumococcus, H. flu, and meningicoccus, and yearly influenza in addition to the standard immunizations.
What is the chance of having offspring with sickle cell anemia if both parents have Hb AS? 25%
What antenatal diagnostic tools are available for sickle cell disease screening? DNA analysis of featl cells obtained by CVS or aminocentesis
What is the first line of thearpy for mild/moderate acute pain in sickle cell disease? NSAIDs
What are the risks of frequent transfusions? (1) transfusion transmitted infections (2) alloimmunization (3) iron overload
Indications for blood transfusion in sickle cell disease (1) acute worsening of anemia (2) severe acute chest syndrome (3) splenic sequestration (4) persistent priapism (5) new onset neurologic deficits (6) prior to general anesthesia
What is the genetic abnormality associated for majority of alpha Thalassemia disorders? More than 80% of patients with alpha Thalassemia the gene abnormality is deletion of the gene.
What population carries the alpha Thalassemia trait with deletion of the alpha globin gene on the same chromsome 16s? Southern Asians
What are the clinically significant alpha Thalassemias? Hb H disease with deletion or mutation of 3 of the 4 alpha globin genes and Hydrops fetalis with deletion of all 3 alpha globin genes.
Microscopic findings of Hb H disease on peripheral blood smear? (1) Microcytic, hypochromic RBCs (2) Target cells (3) Heinz bodies
What is the difference in presentation between the two different genotypes (deletion vs. mutation) of Hb H disease? The mutation type is associated with earlier age of symptoms, more severe anemia, a bigger spleen, and greater risk for RBC transfusion.
What types of Hb is found in RBCs in Hydrops fetalis? Hb Barts, Hb H, or Hb Portland
What is the clinical significance of (--/alpha alpha) genotype of alpha Thalassemia? Parents with (--/alpha alpha) can pass on a two gene deletion with one chromosome 16. If their partner also endows the offspring with (alpha - ) or (- -) genotype then Hb H or hydrops fetalis occurs.
What are the genetic alterations that result in the beta Thalassemia phenotype? (1) Point mutations (2) Premautre stop signal (3) Alterations of the regulatory regions
What is the genotype of Cooley's anemia? Homozygous mutations in beta globin genes or 2 different beta Thalassemia mutations
When do the clinical manifestations of Cooley's Anemia first appear? After the age of 4 months when the switch from gamma globin to beta globin nears completion.
Pathophysiology of severe anemia of Cooley's Anemia? (1) ineffective erythropoiesis due to erythrocyte destruction within the bone marrow (2) Shortened life span of circulating RBCs due to the unstable alpha-globin monomers causing membrane damage.
Clinical manifestations of untreated Cooley's Anemia? (1) Failure to thrive (2) Slower rate of development (3) Skeletal abnormalities (4) Hepatosplenomegaly (5) Death before age of 5
Microscopic findings of Cooley's Anemiaon peripheral blood smear (1) Microcytosis with variation in size and shape of RBCs (2) Target cells (3) Tear drop cells (4) Cigar-shaped cells
What are the Hb electrophoresis findings for Cooley's Anemia? Large amounts of Hb F, variable amounts of Hb A, depending on the nature of the mutation. Hb A2 is typically increased - this findings is diagnostic of beta Thalassemia.
Therapy for beta Thalassemia (1) RBC transfusion to maintain Hb > 9 g/dL (2) Bone marrow transplantation
What pharmacologic agents are available for prevention of iron overload due to transfusions? (1) Parenteral desferoxamide (Desferal) (2) oral deferasirox (Exjade)
Definition of beta Thalassemia intermedia Patients with beta Thal of moderate severity regardless of genotype who require at least intermittent transfusion for health and normal growth.
What situation can a beta Thalssemia patient have normal HbA2 levels? Patients with beta Thal who become iron deficient usually have an normal level of HbA2 which increases after iron repletion.
Microscopic findings of /beta Thalassemia minor on peripheral blood smear (1) Microcytic, hypochromic cells (2) occasional target cells (3) cigar-shaped cells (4) basophilic stippling
(T or F) Over 400 structurally different Hb variants have been discovered, but less than 1/3 of these mutant Hb are associated with significant clinical manifestations. True.
What are the advantage of isoelectric focusing (IEF)? (1) Larger number of samples can be run at one time (2) the resolution (ability to separate Hb bands) is greater
What techniques can be used to distinguish HbA2 from HbE on Hb electrophroesis? isoelectric focusing (IEF) and High pressure liquid chromatography (HPLC)
What is metabisulfite? An oxygen-consuming reagent used to induce sickling of RBCs.
(T or F) The sickle preparation test is the diagnostic test of choice for diagnosing sickling diseases. False. Sickle prep is only appropriate in the Emergency Room setting where rapid detection of Hb S is necessary. It must be always be confirmed by Hb electrophroesis, isoelectric focusing, or high pressure liquid chromatography.
What are the disadvantages of the Sickle Preparation Test? It is not accurate for children < 1 yo and will not detect other variants Hb with potential to sickle in combination with Hb S.
Created by: UVAPATH4