Thalassemia Anemia - Hematology

Snapshot
A 22-year-old Vietnamese woman presents for a routine gyn exam. Her menstrual cycle is normal, and there is no evidence of other bleeding. Guaiac is negative. Her hemoglobin is at 11 (12-16), RBC is 5.8 (3.5-5.5), and an MCV of 70 (80-100) with a normal RDW of 10. WBC and platelets are normal. Hemoglobin electrophoresis shows an increase in the amount of Hgb A2, and Hgb F.
Introduction

Autosomal recessive disease caused by decreased production of hemoglobin may involve mutations in α (α-thalassemia) or β (β-thalassemia) globin gene There are 4 α genes (2 on each chromosome) and 2 β genes that make up three forms of Hgb Hgb A subunits: α,α,β,β 96-98% of adult hemoglobin Hgb A2 subunits: α,α,δ,δ present in trace amounts in adults. Hgb F subunits: α,α,γ,γ declines in the first year of life cannot bind 2,3 DPG so has a left-shifted curve α-thalassemia types 1 gene deletion is asymptomatic 2 gene deletion is associated with a mild anemia with RBC hyperplasia called α-thalassemia trait seen in Asians and Africans Asians more commonly have a deletion of two α genes on 1 chromosome (cis deletion) Africans more commonly have a deletion of 1 α gene from each chromosome (trans deletion) 3 gene deletion is associated with severe anemia 4 gene deletion is not compatible with life will cause hydrops fetalis β-thalassemia types 1 gene involvement called β-thalassemia minor chain may be truncated (β⁺) or deleted (β⁰) β/β⁺ is the most benign form may be caused by mutation in Kozak consensus sequence 2 gene involvement called β-thalassemia major β⁰/β⁰is the most severe form α,α,α,α hemoglobin present
Presentation
Symptoms α-thalassemia mild anemia in 2 gene deletion severe anemia in 3 gene deletion symptoms being at birth β-thalassemia minor form largely asymptomatic intermedia form hypochromic, microcytic anemia major form severe anemia symptoms begin after several months of life due to initial presence of HbF chipmunk facies secondary to extramedullary hematopoiesis in the skull Physical exam β-thalassemia major form hepatosplenomegaly due to chronic hemolysis, additionally exacerbated by extramedullary hematopoiesis in these organs
Evaluation
Peripheral smear 3 gene deletion α-thalassemia target, hypochromic, microcytic cells, with Heinz bodies from HbH β-thalassemia minor target, hypochromic, microcytic cells β-thalassemia major nucleated RBCs target, hypochromic, microcytic cells Hemoglobin gel-electrophoresis α-thalassemia trait normal 3 gene deletion α-thalassemia HbH (β,β,β,β) 4 gene deletion α-thalassemia Hb Barts (γ,γ,γ,γ) β-thalassemia minor ↑ HbA₂, HbF ↓ HbA β-thalassemia major ↑ HbA₂, HbF no HbA Imaging β-thalassemia major hair-on-end/crew cut appearance of the skull secondary to extramedullary hematopoiesis in the skull
Treatment
β-thalassemia major frequent transfusions required can cause iron overload and hemochromatosis

Prognosis, Prevention, and Complications
β-thalassemia major ↑ risk of B19-mediated aplastic crises Thalassemia trait protects against malaria

Blood, Plasma, Serum	Reference Range
ALT	8-20 U/L
Amylase, serum	25-125 U/L
AST	8-20 U/L
Bilirubin, serum (adult) Total // Direct	0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca²⁺)	8.4-10.2 mg/dL
Cholesterol, serum	Rec: < 200 mg/dL
Cortisol, serum	0800 h: 5-23 μg/dL //1600 h: 3-15 μg/dL 2000 h: ≤ 50% of 0800 h
Creatine kinase, serum	Male: 25-90 U/L Female: 10-70 U/L
Creatinine, serum	0.6-1.2 mg/dL
Electrolytes, serum
Sodium (Na⁺)	136-145 mEq/L
Chloride (Cl^-)	95-105 mEq/L
Potassium (K⁺)	3.5-5.0 mEq/L
Bicarbonate (HCO₃^-)	22-28 mEq/L
Magnesium (Mg²⁺)	1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)
24-28 wks // 32-36 wks	30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks	40-220 ng/mL // 80-350 ng/mL
Ferritin, serum	Male: 15-200 ng/mL Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma	Male: 4-25 mIU/mL Female: premenopause: 4-30 mIU/mL midcycle peak: 10-90 mIU/mL postmenopause: 40-250
pH	7.35-7.45
PCO₂	33-45 mmHg
PO₂	75-105 mmHg
Glucose, serum	Fasting: 70-110 mg/dL 2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation	Fasting: <5 ng/mL Provocative stimuli: > 7ng/mL
Immunoglobulins, serum
IgA	76-390 mg/dL
IgE	0-380 IU/mL
IgG	650-1500 mg/dL
IgM	40-345 mg/dL
Iron	50-170 μg/dL
Lactate dehydrogenase, serum	45-90 U/L
Luteinizing hormone, serum/plasma	Male: 6-23 mIU/mL Female: follicular phase: 5-30 mIU/mL midcycle: 75-150 mIU/mL postmenopause 30-200 mIU/mL
Osmolality, serum	275-295 mOsmol/kd H₂O
Parathyroid hormone, serume, N-terminal	230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C)	20-70 U/L
Phosphorus (inorganic), serum	3.0-4.5 mg/dL
Prolactin, serum (hPRL)	< 20 ng/mL
Proteins, serum

Hematologic	Reference Range
Bleeding time	2-7 minutes
Erythrocyte count	Male: 4.3-5.9 million/mm³ Female: 3.5-5.5 million mm³
Erythrocyte sedimentation rate (Westergren)	Male: 0-15 mm/h Female: 0-20 mm/h
Hematocrit	Male: 41%-53% Female: 36%-46%
Hemoglobin A1c	≤ 6 %
Hemoglobin, blood	Male: 13.5-17.5 g/dL Female: 12.0-16.0 g/dL
Hemoglobin, plasma	1-4 mg/dL
Leukocyte count and differential
Leukocyte count	4,500-11,000/mm³
Segmented neutrophils	54%-62%
Bands	3%-5%
Eosinophils	1%-3%
Basophils	0%-0.75%
Lymphocytes	25%-33%
Monocytes	3%-7%
Mean corpuscular hemoglobin	25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration	31%-36% Hb/cell
Mean corpuscular volume	80-100 μm³
Partial thromboplastin time (activated)	25-40 seconds
Platelet count	150,000-400,000/mm³
Prothrombin time	11-15 seconds
Reticulocyte count	0.5%-1.5% of red cells
Thrombin time	< 2 seconds deviation from control
Volume
Plasma	Male: 25-43 mL/kg Female: 28-45 mL/kg
Red cell	Male: 20-36 mL/kg Female: 19-31 mL/kg

Cerebrospinal Fluid	Reference Range
Cell count	0-5/mm³
Chloride	118-132 mEq/L
Gamma globulin	3%-12% total proteins
Glucose	40-70 mg/dL
Pressure	70-180 mm H₂O
Proteins, total	< 40 mg/dL

Sweat	Reference Range
Chloride	0-35 mmol/L
Urine
Calcium	100-300 mg/24 h
Chloride	Varies with intake
Creatinine clearance	Male: 97-137 mL/min Female: 88-128 mL/min
Estriol, total (in pregnancy)
30 wks	6-18 mg/24 h
35 wks	9-28 mg/24 h
40 wks	13-42 mg/24 h
17-Hydroxycorticosteroids	Male: 3.0-10.0 mg/24 h Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total	Male: 8-20 mg/24 h Female: 6-15 mg/24 h
Osmolality	50-1400 mOsmol/kg H₂O
Oxalate	8-40 μg/mL
Potassium	Varies with diet
Proteins, total	< 150 mg/24 h
Sodium	Varies with diet
Uric acid	Varies with diet
Body Mass Index (BMI)	Adult: 19-25 kg/m²