Thalassemia, Hemoglobinopathies, Unstable Hgb Variants Flashcards
What are normal hemoglobin percentages in adults (HbA, HbA2, and HbF)?
- HbA = α2B2, 95-98%
- HbA2 = α2δ2, 2-3%
- HbF = α2γ2, 0.8-2%
HbA = α2β2
Distinguish thalassemia from hemoglobinopathy
Thalassemia is a quantitative hemoglobinopathy characterized by genetic mutations that lead to decreased or absent production of one or more globin chains. Hemoglobinopathies refer to qualitative defects in that result in structural abnormalities of the globin chain.
It results in a relative excess of the complementary chain.
What type(s) of thalassemia would result in a normal hemoglobin electrophoresis?
Hemoglobin electrophoresis would be expected to be normal in silent carriers of alpha thal (-α/αα) and in alpha thal trait (–/αα or -α/-α) because Hgb electropheresis measures relative amounts of types of hemoglobin (and not actual amounts)
It does not measure the actual amounts.
What is the genotype and phenotype for a silent carrier of alpha thalassemia? What would Hgb electrophoresis show?
Silent carrier of alpha thalassemia:
Genotype: -α/αα
Phenotype: normal
Hgb electrophoresis: normal
What is genotype and phenotype for alpha thal trait? What would Hgb electrophoresis show?
Alpha thal trait:
Genotype: –/αα (cis, more common in Asian descent) or -α/-α (trans, more common in Africa/European descent)
Phenotype: microcytosis +/- mild anemia
Hgb electrophoresis: normal
It is associated with Hb Barts (γ4) which has a very high O2 affinity.
What is the genotype and phenotype for HbH disease? What would Hgb electrophoresis show?
HbH disease (AKA “deletional HbH)
Genotype: a-/–
Phenotype: Hb H refers to B4 tetramers that can precipitate and cause hemolysis, anemia of varying severity, may require transfusions
Hgb electrophoresis: abnormal, extra band for Hgb H
What is the genotype and phenotype for Hb constant spring? What would Hgb electrophoresis show?
Hgb constant spring (AKA “non-deletional HbH)
Genotype: ααcs / - -
Phenotype: more severe than HbH disease
Hgb electrophoresis: abnormal, structural alpha globin chain termination that makes abnormal Hgb component that is detectable on electrophoresis
What is the genotype of hydrops fetalis (AKA Hb Barts)?
Hydrops fetalis
Genotype: –/–
Phenotype: most severe, Hgb Barts refers to y4 tetramers with very high O2 affinity and no delivery to tissue. Incompatible with life, requires intrauterine transfusions and HSCT
What are common genotypes (and phenotypic severity) of B-thal minor? What would Hgb electrophoresis show?
Genotypes: β/β0, β/β+, β+/β+
Phenotype: typically mild anemia and microcytosis MCV 70s, elevated RBC count, not transfusion dependent
Hgb electrophoresis: HbA2 slightly elevated (4-8%), proportionally to HbA decrease
What are common genotypes (and phenotypic severity) of B-thal major? What would Hgb electrophoresis show?
Genotypes: β0/β0, β0/β+
Phenotype: severe, transfusion-dependent anemia. Alpha tetramers precipitate and cause intramedullary hemolysis, iron overload
Hgb electrophoresis: α4 tetramers and absence or relative deficiency of Hgb A
What are the common complications of iron overload in transfusion-dependent thalassemia?
Common complications include:
* Diabetes mellitus
* Hypothyroidism
* Hypogonadism
* Liver cirrhosis
* Cardiac issues (iron deposition, LV dysfunction)
What is route of administration of deferasirox (Exjade, Jadenu), targeted iron removal site, and common side effects?
Route: oral suspension
Iron removal site: liver>cardiac
Adverse effects: GI, rash, elevated creatinine and LFTs, GI bleeding
What are novel therapies for thalassemia?
- Gene therapy (Beti-cel lentiviral vector and Exa-cel CRISPR-Cas9 editing)
- Luspatercept: enhances late-state erythropoiesis and reduces RBC transfusion burden
- Mitapivat: pyruvate kinase activator
What is the target Hgb in patients with transfusion-dependent thalassemia and what are complications of lower Hgb in this populations?
Maintain pre-transfusion Hgb 10
Common complications include:
- pulmonary HTN
- RV dysfunction
- VTE
- Osteoporosis
- Liver cirrhosis
- Cholelithiasis
- Splenomegaly
- Leg ulcers
- extramedullary hematopoiesis
What is route of administration of deferiprone (Ferriprox), targeted iron removal site, and common side effects?
Route: oral tablets
Iron removal site: cardiac >liver
Adverse effects: agranulocytosis, GI, arthralgia
What is route of administration of deferoxamine (Desferal), targeted iron removal site, and common side effects?
Route: IV infusion, subcutaneous
Iron removal site: liver >cardiac
Adverse effects: vision changes, hearing loss, skin reaction, allergy
What is the pathophysiology of Hb S (switch in which amino acids?)
glutamate (charged) -> valine (hydrophobic) in β chain –> less soluble, polymerization and sickling
What is the expected Hgb electrophoresis in sickle cell trait (S-β) and phenotype?
Hgb Electrophoresis: Hgb S 35%, Hgb A 60%
Phenotype: normal, may have renal manifestations, coagulopathy
How does the Hgb electrophoresis of sickle cell trait (S-β) differ from sickle-beta thal trait (S-β+)?
Sickle cell trait: S-β Hgb Electrophoresis: Hgb S 35%, Hgb A 60%, Hgb A2 4%
Sickle cell trait/ B thal trait S-β+ Hgb Electrophoresis: Hgb S 60%, Hgb A 35%, Hgb A2 4%
What is Hgb Lepore and how is this diagnosed on Hgb electrophoresis?
Hgb Lepore is a variant produced from fusion of delta and beta globin genes
Hgb electrophoresis: migrates with Hgb S on alkaline gel (except patient does not have sickling). Hgb A is decreased due to decreased synthesis of beta chains ~50%, Hgb F usually increased
How do you distinguish Hgb C on peripheral smear?
Oxyhemoglobin C leads to crystallization and formation of target cells and rectangular crystals on peripheral smear
What hemoglobin variant is referred to as “thalassemic hemoglobinopathy” and where is this most prevalent. How do you distinguish this on Hgb electrophoresis?
Hgb E is thalassemic hemoglobinopathy where mutation leads to decreased rate of beta chain synthesis.
>80% in SE Asia, esp in Indian subcontinent
Hgb electrophoresis: remember that on standard alkaline pH, E co-migrates with C and A2
What are the diagnostic criteria for acute chest syndrome for sickle cell disease?
Defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms (ie., hypoxia, dyspnea)
Indications for exchange transfusion in sickle cell disease
- acute chest syndrome
- acute stroke (and chronic exchange for secondary prevention)
- priapism
- multiorgan failure
