Hydroxyurea use in Sickle Cell disease: work in progressMatthew M. Heeney, MD Associate Chief – Hematology Director – Sickle Cell Program
Boston Children’s Hospital
SEPTEMBER 23-28, 2018
Faculty Disclosure
Personal financial interests in commercial entities that are relevant to my presentation(s) or other faculty roles:
Matthew M. Heeney, MD
• Astra Zeneca Consultant, Clinical Trial funding • Pfizer Clinical Trial funding • Micelle Biopharma Consultant, Clinical Trial funding • Novartis Consultant
Objective
– Qualitative disorders of hemoglobin • Sickle Cell disease • Other Hemoglobinopathies
– Quantitative disorders of hemoglobin • Thalassemias
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Hemoglobin
• Four globular proteins (globins) – 2 α-like globins – 2 β-like globins
• Four heme groups – One per globin chain – Reversibly bind O2 (CO2, NO)
• Hb synthesis must be balanced and coordinated
• All components are labile and toxic – globins, heme, iron
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Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
Globin Protein Synthesis
Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
Hemoglobin tetramers
• Hemoglobins are distinguished by globin composition:
% nl adult HbA α2β2 97-98% HbA2 α2δ2 2-3% HbF α2γ2 ≤2% HbS: α2βS
2 0% HbC: α2βC
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• Distribution of thalassemia & sickle cell disease mirror worldwide distribution of malaria prior to 20th century.
• Hypothesis (Haldane and others): heterozygous forms confer fitness - Thalassemia trait, sickle trait, G6PD etc.. protective against death from cerebral falciparum malaria. “Benefit” of trait outweighs homozygous risk.
Disorders of Hemoglobin
chains
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1910
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Chicago, Illinois
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Archives of Internal Medicine 1910. 6(5): 517-211
First description of sickle cell anemia in a West Indian dental student with “peculiar elongated and sickle-shaped” red blood cells.
1949
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Pasadena, CA
Pauling L et al. Sickle Cell, A Molecular Disease. Science. 110 (2865): 543–548.
Established sickle cell anemia as a genetic disease in which affected individuals have a different forms of hemoglobin in their blood
Vernon Ingram and J.A. Hunt working at MIT, discovers the single amino acid change that causes hemoglobin to sickle
Sickle cell anemia became the 1st genetic disorder whose molecular basis was known.
1956
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University of Cambridge
Ingram VM. A Specific Chemical Difference between Globins of Normal and Sickle-cell Anemia Hemoglobins" Nature. 178 (4537): 792–794
Epidemiology
Most common single gene disorder in African Americans 1/375 homozygous affected 1/12 are heterozygous carriers (~8%)
Also affects other ethnicities: India Middle East Hispanic
U.S. Prevalence: 80,000 – 120,000 U.S. Incidence: ~2000 live births annually
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Muntuwandi at en.wikipedia
Molecular Pathophysiology - Polymerization
The sickle mutation is a single amino acid substitution at position 6 of β globin.
Results in a hydrophobic region that is exposed in the deoxygenated state.
Adapted from Rotter MA et al. Biophys J. 2005 Oct;89(4):2677-84..
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Delay time
• Delay time: period during which Hb is deoxygenated, but not yet polymerized
• If passage through the capillaries exceeds the delay time, Hb will aggregate and initiate sickling.
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Polymerization leads to: • Distortion of cell shape • Damage to RBC membrane • Abnormal permeability • Irreversible sickling
Premature hemolysis = Anemia Impairment of RBC flow = Infarction
Hemolysis and Nitric Oxide depletion
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Adapted from Kato GJ et al. Blood Rev. 2007 Jan; 21(1): 37–47.
Manwani D and Frenette PS Blood. 2013:122(24):3892-3898
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Vaso-occlusion
Genotype Characteristics Hb SS “Sickle cell anemia”
Anemia : Hb 7 - 9 g/dL Smear: Irreversibly sickled cells Electrophoresis: Hb S, Hb F
Hb SC Anemia: Hb 9 - 11 g/dL Smear: Sickle and target cells Electrophoresis: Hb S and Hb C
Hb S/β0 thalassemia Anemia: Hb 7 - 9 g/dL Smear: Microcytosis with sickle and target cells Electrophoresis: Hb S, Hb F
Hb S/β+ thalassemia Anemia: Hg > 10 g/dL Smear: Microcytosis with sickle and target cells Electrophoresis: Hb S, Hb F, and small %Hb A
Sickle cell genotypes
Smear: Irreversibly sickled cells
Hb SC
Electrophoresis: Hb S and Hb C
Hb S/(0 thalassemia
Smear: Microcytosis with sickle and target cells
Electrophoresis: Hb S, Hb F
Hb S/(+ thalassemia
Electrophoresis: Hb S, Hb F, and small %Hb A
Vaso-occlusion • Pain episodes / “crises” • Acute chest syndrome • Avascular necrosis • Splenic sequestration
(mostly in children)
Chronic Hemolysis • Cholelithiasis • Folate deficiency • Cardiomegaly • High-output heart failure • Liver disease from iron
overload (with repeated transfusions)
Primary pathological processes in SCD
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AA SS
Infection in SCD
• Clinical syndrome of – Fever, – Respiratory symptoms (e.g. hypoxia, tachypnea) – New pulmonary infiltrate
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Acute chest syndrome (ACS)
• 2nd most common cause of hospitalization. • Most common cause of death in sickle cell anemia. • Increased mortality with poorly controlled asthma • Prevent atelectasis
– Control chest pain, incentive spirometry
• O2 and trial of bronchodilators • Often associated with atypical organisms (e.g.
chlamydia, mycoplasma). – Empiric broad-spectrum antibiotics + macrolide
• Simple or exchange transfusion may be life-saving
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Stroke
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Stroke
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Stroke Risk Assessment Transcranial Doppler ultrasound (TCD) is a
reproducible, non-invasive technique to predict 1° stroke risk in children
< 170 cm/sec “Normal” 170 – 199 cm/sec “Conditional” > 200 cm/sec “Abnormal”
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R.R. of stroke with Abnormal TCD = 44
(95% CI = 5.5 - 346)
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Effect of chronic transfusion on 2° stroke probability.
Effect of chronic transfusion on 1° stroke rate in an asymptomatic patients with elevated TCD. (“STOP” Trial)
Incident rate of stroke in SS children living in California (CA), before and after publication of the STOP Trial
Effect on stroke rate of discontinuing chronic transfusion in asymptomatic patients with elevated TCD from STOP Trial. (“STOP2” Trial)
Adapted from: Platt OS. Hematology 2006.. 2006:54-57 (ASH Education Book 2006)
Acute Transfusion therapy
• Goal – maximize O2-carrying capacity • Post –transfusion Hb should not exceed 10-11 g/dL
• Transfuse phenotypically matched blood for minor antigens C, E and Kell
• Allo-sensitization should be reassessed 1-3 months after episodic transfusions
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Chronic transfusion therapy
Risks • Iatrogenic Fe overload • Allo-sensitization • Unknown Infectious Risk
Perioperative management of SCD • Preoperative period
– Admit to hospital 12 to 24 hours before surgery for hydration. – Treat obstructive lung disease with bronchodilators. – Simple transfusion to a Hb 10-11g/dL except for minor operations.
• Intraoperative period – Maintain oxygen therapy with pulse oximetry. – Maintain hydration. – Prevent hypothermia. – Monitor blood loss and replace blood when necessary.
• Postoperative period – Pulse oximetry, IV fluids, incentive spirometry. – Monitor for development of acute chest syndrome.
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• Sickle cell phenotype only occurs after ~ 6months of age
• Hemoglobin F levels are inversely correlated with disease severity / mortality
• Biochemical evidence that gamma globin disrupts sickle globin polymerization
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Hydroxyurea
• The only FDA approved agent for sickle cell disease. • Old drug – New indication.
• first synthesized in 1869 • anti-neoplastic since the 1960’s • mechanism of action unclear. • ribonucleotide reductase inhibitor.
• Mechanism • ↑ Hemoglobin F • ↓ HbS polymerization and hemolysis • ↑ Hemoglobin • ↓ White Blood Cells (“Side-Effect”?)
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MultiCenter Study of Hydroxyurea (MSH) (1992-1995) • Adults • ↑ Hemoglobin F; ↓ Hemolysis & Anemia; ↓ white blood cells
• ↓ pain crises by 40%; ↓ acute chest syndrome by 50%; ↓ transfusions by 50%
MSH Follow-Up (1996-2001) • 40% reduction in mortality after 9 years of follow-up
MSH Follow-Up (1996-2010) • after 17.5 years of follow-up
Steinberg MH et al. Am J Hematol 2010;85: 403–408.
Charache S et al. N Engl J Med 1995;332:1317-1322.
Steinberg MH et al JAMA. 2003;289(13):1645-1651
MSH Follow-up – Cumulative Mortality
Steinberg MH et al. Am J Hematol 2010;85: 403–408.
Who should get Hydroxyurea?
Indications: a) HbSS, HbSβ0 + ?? HbSC. b) Frequent pain crises? c) Acute chest syndrome?
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https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-disease-report.pdf
• Hydroxyurea • Folate • Consideration of chronic transfusion
• Renal and cardiac follow-up • Management of iron burden • Routine eye examination
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Complications of SCA
chronic end organ damage
Investigative therapies - sickle cell disease • HbF induction with new agents • Shift oxygen dissociation curve
– Small molecule allosteric modifier • Interference with endothelial/selectin adhesion
– Anti-selectin • Reverse endothelial/vascular dysfunction
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Zaidi AU, Heeney MM. Pediatr Clin North Am. 2018 Jun;65(3):445-464.
Sickle cell trait
• Present in about 8% of African Americans • Diagnosed by hemoglobin electrophoresis • Generally clinically silent
– isosthenuria generally develops with age – occasional hematuria 2 to papillary necrosis – ?sudden death upon profound dehydration/exertion
• No restrictions indicated for general activity • Screening requirement for NCAA athletes
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• High O2 affinity: familial erythrocytosis
• Low O2 affinity: familial cyanosis
• M-hemoglobins: familial cyanosis
• Amino acid residues of globin oxidize and precipitate too readily
• Form inclusions (Heinz bodies) that damage erythrocyte membrane.
• May see abnormal “smeared” band on electrophoresis • Cause hemolytic anemia • Patients often benefit from splenectomy.
• e.g. Hb Koln; Hb Hasharon; Hb Zurich
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Decreased O2 affinity: • Hb Kansas
Diagnosis: • May be ‘silent’ on
electrophoresis.
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P50 • P50 describes the affinity
of a given Hb for oxygen. • P50 is the PO2 at which the
Hb is 50% saturated with oxygen.
• As the P50 ↓, oxygen affinity ↑.
• Hb A 26.5 mmHg • Hb F 20 mmHg • Hb S 34 mmHg
Methemoglobinemia I
• Methemoglobin: – Oxidation of hemoglobin iron from ferrous Fe2+ to ferric Fe3+
– Methemoglobin levels normally maintained at <3% by methemoglobin reductase (NADH-dehydratase)
• Methemoglobinemia results in increased O2 affinity, poor tissue oxygen delivery, and cyanosis.
• Congenital methemoglobinemias – M-hemoglobins: globin mutations – Inherited defects in the methemoglobin reductase
• Toxic methemoglobinemia – Nitrites, trinitrotoluene, aniline
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• Diagnosis of methemoglobinemia – Unexplained cyanosis with normal PaO2
– Characteristic absorption peaks at 630 and 502 nm – Pulse oximetry gives inaccurate reading of 85% for blood with 100%
methemoglobin – Blood is brownish color
• Treatment – Methemoglobin levels >30%, patients start to have symptoms of
oxygen deprivation – M hemoglobins and deficiencies of reductase usually do not need
treatment. Can use oral methylene blue for cyanosis. – Emergency treatment: methylene blue 1-2 mg/kg IV infused rapidly,
repeat at 1 mg/kg after 30 minutes if necessary
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Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
Thalassemia: an international problem
Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
• The most common global genetic disorder.
• Thalassemia trait: >240 million people
• Thalassemia intermedia syndromes:
• Homozygous /compound heterozygous thalassemia syndromes:
Hundreds of thousands • ~ 1,000 in N America
What are thalassemia syndromes?
• Hereditary anemias caused by mutation/deletion of one or more α or β globin genes. – α thalassemia caused by a defect in α globin gene(s) – β thalassemia caused by a defect in β globin gene(s)
• Imbalanced expression of α and β globin leads to: – Decreased functional hemoglobin, resulting in anemia – Excess of α or β globins, cause membrane toxicity and
intramedullary hemolysis of erythroid precursors
• Anemia results in erythroid drive with “ineffective erythropoiesis” that stimulates increased iron absorption.
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Thalassemia syndromes
• Any imbalance of the “perfect” 4:2 ratio of α to β globin • β globin to α globin protein ratio determines severity
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Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
β-Thalassemias Quantitative Disorders of Hemoglobin
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mRNA
β+-thalassemia: Mutations cause defects in splicing or mRNA expression • Still allows some normal processing
β0-thalassemia: Nonsense mutations in coding region, partial gene deletions • No normal processing of mRNA
IVS IVS
β-Thalassemia Mutations
Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
Primary defect: Deficient synthesis of β-globin Consequence: Excess α-globin precipitates in erythroid cells
Bone marrow SpleenBlood
• Anemia • Hypochromic red cells
• Mild anemia and indirect hyperbilirubinemia • Microcytosis, hypochromia and poikilocytosis; RBC
stippling, target cells. • Increased HbA2 (>3.5%) or (rarely) HbF • Normal serum iron. • No clinical sequelae.
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• Marked marrow expansion – Cortical thinning/Osteoporosis fractures.
• Iron overload (Transfusional/Absorption) – Hepatic cirrhosis. – Cardiac cardiac failure, arrhythmia. – Endocrine
• Pancreas diabetes. • Thyroid hypothyroidism, growth failure. • Pituitary delayed puberty, gonadal failure.
• Extramedullary hematopoiesis/Hepatosplenomegaly • Hemolysis
β-Thalassemia Bone changes
• Anemia / Ineffective erythropoiesis – Chronic monthly transfusion to keep Hb > 10g/dL – Novel HbF inducers (e.g. HDAC inhibitors – Differentiating agents (e.g. TGF-β ligand trap - Luspatercept)
• Complications of transfusion – Endocrinopathies
• Vitamin D • Osteoclast inhibitors (e.g. bisphosphonates)
– Iron Overload • No physiologic way for the body to reduce iron. • Chelation therapy
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Typical Dose (mg/kg/day)
Route SC or IV infusion Oral tablet Tablet for oral
suspension
sprinkles
Dosing frequency Over 8 - 24 hours 3 times daily Once daily
Adverse Effects Local reactions Audiologic
Ophthalmologic Bone abnormalities
enzymes
+++ ++
Weekly blood count monitoring
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Adapted from Kwiatkowski JL, Ann N Y Acad Sci. 2016 Mar;1368(1):107-14
Goals of Chelation
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• Maintain a “safe” level of iron – Prophylaxis: Prevent excess iron accumulation – Treatment
• Remove excess stored iron • Reverse iron-related organ dysfunction
• Detoxify iron through binding to non-transferrin bound, labile iron – Continuous chelator exposure is optimal
Adapted from: Kwiatkowski JL, Hematology Am Soc Hematol Educ Program. 2011;2011:451-8.
Parameter
Cardiac T2*
≥ 20 ms
≥ 20 ms
Ware, Kwiatkowski, Pediatric Clin N A, 2013
Unacceptably high Intensify chelation Consider combination chelation
Acceptable Continue current
Unacceptably high Intensify chelation Consider combination chelation
Moderately high Intensify chelation
Survival by Availability of Chelation Therapy
Adapted from Borgna-Pignatti et al. Haematologica. 2004;89:1187.
30 Age (y)
Years
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Monitoring Iron/Chelation Status
• Serum ferritin – Advantages -Can be measured with every visit, widely available. – Disadvantages -Loose correlation with liver (body) iron.
-Inaccurate with inflammation, abnormal liver fxn.
• Liver biopsy – Disadvantages -Invasive.
• MRI – Can interrogate many organs (liver, heart, pancreas, etc.) – Hepatic R2 or R2* Obtain annually, reported as mg/g dry weight liver.
• LIC > 15 mg/g dry weight predict poor prognosis
– Cardiac T2* -Obtain annually, reported in ms (lower is worse) • < 20 ms predicts increased risk of arrhythmias/cardiac failure • < 6 ms predicts high risk cardiac failure in next year
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St. Pierre et al, Blood 2005;105:855; Wood, Blood 2005 106:1460; Saliba AN et al, J Blood Med. 2015; 6: 197–209.
Hepatic and Cardiac Iron by T2* MRI
Andy Powell, MD - Boston Children’s Hospital
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β-Thalassemia genotypes/phenotype
β Thalassemia Intermedia Syndromes
• Wide phenotypic variability. • “Strong” β+ allele(s) may allow patient to be
transfusion independent. • But brisk and ineffective erythropoiesis persists with
all the end-organ damage similar to thalassemia major, but later than in life (e.g. growth failure, osteoporosis, exuberant iron absorption, etc.).
• Some of the sickest North American thalassemia patients are adults with thalassemia intermedia.
Normal β-globin
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• βE is a mutated β globin that is both mildly unstable and produced at decreased rate because of a splicing defect.
Hemoglobin E - A Special Case
• HbE trait (βNβE): mild microcytosis, no anemia • HbE disease (βE βE): + microcytosis, mild anemia • HbE/beta-thalassemia (β0 βE): thalassemic phenotype
(intermedia or major)
• HbE trait is present in 15-30% of the population in regions of Laos, Cambodia, Vietnam, and southern China
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• Reduction of ineffective erythropoiesis – JAK2 inhibitors and TGF-β ligand traps
• Decrease iron overload – hepcidin agonists, erythroferrone inhibitors
• Reduction of Oxidative stress – activators of Foxo3, inhibitors of HO-1
• Gene therapy – Introduce normal or interfering globins
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Makis A et al. Am J Hematol. 91:1135–1145, 2016.
α-Thalassemia Quantitative Disorders of Hemoglobin
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• Primary defect: Deficient synthesis of α-globin. • Consequence: Excess β-globin leads to formation of
β globin tetramers (β4 = HbH). • HbH is relatively unstable & soluble, but under
certain conditions (e.g. oxidant stress, older RBCs) HbH precipitates leading primarily to extravascular hemolysis in the spleen.
• Concentrated in Southeast Asia, Malaysia, & southern China.
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Nathan and Oski's Hematology of Infancy and Childhood, 7th Ed.
• α-thalassemia is most frequently a result of deletions involving one or both α globin genes.
• Less commonly caused by non-deletional defects.
Genotype Lab feature Severity
α-thalassemia trait α-/α- or αα/-- ↓ MCV, ↓MCH, minimal anemia
1+
Hb H disease α-/-- ↓↓ - ↓↓↓ MCV and MCH, hemolytic anemia (7-10g/dL), mild jaundice, Hb Barts/HbH
2+
4+
α-Thalassemia
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partly clarified
α-Thalassemia Diagnosis
• Silent carrier state (- α / α α) can only easily be diagnosed in newborn period by presence (1–2%) of HbBarts (γ4)on Newborn screen and RBC indices and Hb electrophoresis are normal in the adult.
• α-thalassemia trait (- - /αα or - α / - α) show greater increase (5– 6%) of HbBarts on Newborn screen and microcytic hypochromic RBC indices, with normal HbA2 and HbF in the adult.
• HbH Disease (- - / - α) microcytic hypochromic anemia Hb (7-10g/dL), reduced (<2%) HbA2 and variable amounts of HbH (up to 30%)
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α-Thalassemia Management
• Silent carriers and α-thalassemia trait generally do not need any treatment.
• HbH disease management is influenced by its marked phenotypic variability. – Most individuals with HbH disease are clinically well and
require no treatment. – Avoid oxidant drugs (same as G6PD deficiency). – Hemolytic or aplastic crises may require transfusion
support.
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LCR ε Gγ Aγ δ β
Chr 11
Chr 16
Hb A: α2β2 Hb A2: α2δ2 Hb F: α2γ2 Hb S: codon 6 β-globin mutation Hb C: different codon 6 β-globin mutation Hb E: β-globin splice variant - thal equivalent Hb H: β4 Hb Barts: γ4
Unstable: Heinz body hemolytic anemia High O2 affinity: familial erythrocytosis Low O2 affinity: familial cyanosis M-hemoglobins: familial cyanosis
Sickle cell genotypes: SS SC SD S/β thal
Genotype Lab feature Severity
α-thal trait α-/α- or αα/-- ↓MCV 1+
Hb H disease α-/-- Hemolysis, HbH 2+
Hydrops fetalis --/-- Hb Barts 4+
Genotype Lab feature Severity
β-thal intermedia
β-thal major β0/β0 Severe anemia 4+
β-thalassemia
α-thalassemia
severe anemia, bone changes and endocrinopathies. These complications can be limited by adequate transfusions and chelation therapy.
• Qualitative disorders disorders of globin synthesis are Hemoglobinopathies – Production of abnormal globin proteins which can be
unstable, have altered O2 affinity or other presentations.
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Acknowledgements
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Supplemental References • Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005; 353:1135-46.
Galanello R, Cao A. Alpha Thalassemia. Genet Med. 2011; 13:83–88. • Neufeld, EJ. Update on Iron Chelators in Thalassemia. Hematology Am Soc Hematol
Educ Program. 2010: 451-455. Brittenham, GM. Iron-Chelating Therapy for Transfusional Iron Overload. N Engl J Med 2011; 364:146-156. Marsella M et al. Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Hematol Oncol Clin North Am. 2014 Aug;28(4):703-27.
• Steinberg MH, Nagel RL. Unstable Hemoglobins, Hemoglobins with Altered Oxygen Affinity, Hemoglobin M, and Other Variants of Clinical and Biological Interest. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of Hemoglobin - Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press; 2009. p. 589-606. Globin Gene Server - HbVar Database (http://globin.cse.psu.edu/)
• Management of Sickle Cell Disease (http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf).Yawn BP et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48
hemoglobin, distortion of erythrocyte shape, and unfavorable rheological properties leading to vaso-occlusion.
• Leukocytes, platelets, coagulation cascade also contribute to VOC.
• Hypoxia-Reperfusion leads to endothelial activation, inflammatory state and further VOC.
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Dover GJ, Heeney MM. Sickle Cell Disease. Nathan and Oski’s Hematology of Infancy and Childhood. 2008; 949-1014 Platt OS. Sickle cell anemia as an inflammatory disease. J Clin Invest. 2000 August 1; 106(3): 337–338.
Black LV, Smith WR. Are Systemic Corticosteroids an Effective Treatment for Acute Pain in Sickle Cell Disease? ASH Education Book 2010:416-41
• SCD patients have chronically elevated levels of multiple inflammatory mediators
• This milieu is attractive for use of anti-inflammatories / corticosteroids
Background • Acute chest syndrome (ACS)
– 1. New CXR infiltrate 2. Fever 3. Pulmonary symptom(s) – Significant cause of morbidity and a leading cause of mortality.
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Vichinsky EP et al . Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Jun 22;342(25):1855-65
Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005 Oct;19(5):857-79
• Etiology is multifactorial – Infectious (bacterial, atypical bacteria, viral) – Infarctive (VOC, atelectasis) – Inflammatory (asthma, fat embolism)
• Asthma and ACS – higher prevalence of airway hyper-responsiveness and obstructive
lung disease than expected. Overlapping or co-morbid conditions? – Trial of bronchodilators often recommended in ACS.
Nordness ME, et al. Asthma is a risk factor for ACS and cerebral vascular accidents in children with sickle cell disease. Clin Mol Allergy. 2005; 3: 2. Field JJ, DeBaun MR. Asthma and sickle cell disease: two distinct diseases or part of the same process? ASH Education Program. 2009:45-53.
Matthew M. Heeney, MDAssociate Chief – HematologyDirector – Sickle Cell ProgramBoston Children’s Hospital
Slide Number 2
Disorders of Hemoglobin
Sickle cell disease
Dichotomization of Pathophysiology?
Slide Number 22
Slide Number 23
Sickle cell genotypes
Infection in SCD
Acute Transfusion therapy
Chronic transfusion therapy
Hydroxyurea
Sickle cell trait
Other hemoglobin variants
Methemoglobinemia I
Methemoglobinemia II
Properties of Chelators
Goals of Chelation
Survival Proportional to Chelation Adherence
Monitoring Iron/Chelation Status
β Thalassemia Intermedia Syndromes
Investigative therapies - β Thalassemia