diagnostic hematology: disorders of hemoglobin and gammopathies
DESCRIPTION
Diagnostic Hematology: Disorders of Hemoglobin and Gammopathies. Muhammad Shoaib Khan GM Centre - 1. a globin. b globin. b globin. a globin. Hemoglobin structure. Hgb A tetramer. Development period. a cluster - chromosome 16. Globin chain component. % of adult Hgb. - PowerPoint PPT PresentationTRANSCRIPT
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Diagnostic Hematology:Disorders of Hemoglobin andGammopathies
Muhammad Shoaib KhanGM Centre - 1
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Hemoglobin structure
a globin globin
globin globin
Hgb A tetramer
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Globin chain synthesis cluster - chromosome 16
cluster - chromosome 11
Gower 1
Portland Embryonic
Gower II
F Fetal <1%
A2 1.5-3.5%Adult
A >95%
Glo
bin
chai
n
com
pone
nt
Hgb n
ame
Devel
opm
ent
per
iod
% o
f adu
lt H
gb
G A
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Thalassemia• Heterogenous group of disorders due to an imbalance of and
globin chain synthesis– thalssemia: -globin chain production decreased– thalassemia: globin chain production decreased
• The globin chains that are produced are normal
• Quantitative deficiency:– o thalassemia: No -globin chain is made– + thalassemia: decreased -globin chain is made
• With 4 genes and 2 genes there is wide phenotypic variation
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Incidence of Thalassemia
• ~100,000 patients with homozygous -thalassemia world-wide
• Found in Mediterranean countries, South Asia and Far East
• Prevalence in the United Sates is increasing due to population migration
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Alpha Thalassemia• Inadequate production of alpha chains• Hemoglobin analysis normal; can be detected by globin gene analysis• Absence of 1-2 alpha chains
– Common– Asymptomatic– Does not require therapy
• Absence of 3 alpha chains– Microcytic anemia (Hgb 7-10)– Splenomegaly
• Absence of 4 alpha chains– Hydrops fetalis (non-viable)
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chains Hgb (g/dl) MCV (fl) RDW
/ Normal Normal Normal
/- 12-14 75-85 Normal
-/- or - -/ 11-13 70-75
- -/- 7-10 50-60
- -/- - - - -
Laboratory Findings in Alpha Thalassemia
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Beta Thalassemia
Minor (Trait) / + or / ° 10-13
Intermedia +/+ 7-10
Major +/° or °/° < 7
ClinicalSyndrome Genotype Hemoglobin (g/dl)
Inadequate production of chains
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Beta Thalassemia - Hgb analysis
Minor (Trait) / + or / ° 90-94 3.5-8 1-10
Intermedia +/+ 5-60 2-8 20-80%Major +/° 2-10 1-6 >85
°/° 0 1-6 >94
ClinicalSyndrome Genotype A A2 F
Hemoglobin analysis: Increased levels of Hgb A2 and Hgb F
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Approach to Beta Thalassemia
• Screening/counseling
• RBC transfusion therapy
• Agents to increase hemoglobin F (Hydroxyurea)
• Bone marrow transplantation
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Clinical Presentations of Abnormal Hemoglobins
• Sickling disorder
• Thalassemia or microcytic anemia
• Cyanosis
• Erythrocytosis
• Hemolytic anemia
• Asymptomatic (screening or family study)
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Sickle Cell Disease
• Inherited as autosomal recessive• Point mutation in beta globin (6 Glu Val)• Gene occurs in 8% of African-Americans
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Relative Frequency of Hemoglobin Variants
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Screening for Sickle Cell Trait and Disease
• RBC lysate with concentrated phosphate buffer and sodium hydrosulfite
• Incubate 10-20 min
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Hemoglobin Electrophoresis: Methodology
• Separates hemoglobins on solid support media– Cellulose acetate (Alkaline gel)– Citrate agar (Acid gel)
• Inexpensive and quickly prepared
• Sharp resolution of major hemoglobin bands
• Electrophoretic variability based on charge
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QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
Hemoglobin electrophoresis
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Hemoglobin electrophoresis:Variants of sickle cell anemia
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Hemoglobin electrophoresis:Identification of abnormal hemoglobins
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High Pressure Liquid Chromatography (HPLC)
• Separates hemoglobins by a cation exchange column
• Resolution of various hemoglobins including Hgb F is excellent
• Procedure can be automated leading to reliable interpretation
• Hemoglobin fractions can be quantified
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HPLC: Normal Adult Hemoglobin
A1CA1C
AA00
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HPLC: Sickle cell trait
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HPLC:Sickle cell anemia (Hgb SS)
A 2
Hb F
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HPLC:Hgb SC disease
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Monoclonal Gammopathies
• Laboratory evaluation of gammopathies
• Diseases associated with gammopathies
• Common clinical syndromes
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Clinical indications for the evaluation of immunoglobulins
• Normochromic normocytic anemia
• Nephrotic syndrome in a non-diabetic patient
• Osteolytic lesions
• Lymphadenopathy
• Non-ischemic heart failure
• Elevated total serum protein
• Hypercalcemia
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Free light chains
• Have been detected in urine for >50 years *• Polyclonal antibody against free LC• Purified so no cross-reactivity and does not bind to intact
immunoglobulin• Bound to latex beads - detected by a variety of techniques
(turbidity)
* Korngold and Lapiri Cancer: (1956) 9:262-272
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Representative sensitivity levels
Kappa Lambda
SPEP 500-2000 mg/L 500-2000mg/L
IFE 150-500 mg/L 150-500 mg/L
Free light chains 1.5 mg/L 3.0 mg/L
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Comparison of FLC measurements in serum and urine in healthy individuals
0
1
10
100
0.1 1 10 100
FLC (mg/L)
_ F
LC
(m
g/L
)
Normal serumNormal urine
FLC (mg/L)
F
LC
(m
g/L
)
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Serum free light chains
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
FLC (mg/L)
F
LC
(m
g/L
)
Normal sera
κ LCMM
λ LCMM
IIMM
High pIgG
AL Amyloidosis
Renal impairment
NSMM
IFE Sensitivity
SPE Sensitivity
F
LC
(m
g/L
)
Composite Figure of serum free light chain concentrations in various diseases
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Potential uses of serum free light chains
• Sensitive marker for diagnosing monoclonal lymphoproliferative diseases
• ratio may be a prognostic marker for MGUS
• Useful marker in non-secretory myeloma or patients with only Bence-Jones proteinuria
• Marker to follow disease
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Lymphoproliferative Disorders Commonly Associated with a Monoclonal Gammopathy
• Monoclonal gammopathy of undetermined significance (MGUS)
• Multiple myeloma• Waldenstroms macroglobulinemia• Amyloidosis
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Monoclonal Gammopathies of Undetermined Significance (MGUS)
• Commonly found on serum protein electrophoresis• Occurs in ~2% of persons > 50 years of age• Characteristics
– Low serum monoclonal protein concentration (<3 g/dl)– Less than 5% plasma cells in bone marrow– Little or no monoclonal protein in urine– Absence of lytic bone lesions– No anemia, hypercalcemia, or renal insufficiency
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“Benign Monoclonal Gammopathy” Course of MGUS in 241 Patients
Median follow-up 22 years
Group Description No. % 1 No substantial increase of serum 46 19 or urine monoclonal protein (benign) 2 Monoclonal protein ≥3.0g.dl but 23 10 no myeloma or related disease 3 Died of unrelated causes 113 47 4 Development of myeloma, 59 24 amyloidosis or related disease Total 241 100
N Engl J Med 2002;346:564-9 (Updated)Am J Med 1978; 64:814-26
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Patterns of Monoclonal Protein Increase
Multiple myelomaPattern No. patients (%)
Stable with sudden increase 19 (25%)Stable with gradual increase 9 (12%)Gradual increase 9 (12%)Sudden increase 11 (15%)Stable 10 (13%)Indeterminate 17 (23%)
N Engl J Med 2002:346; 564-9
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Summary:(MGUS)
• Monoclonal proteins rarely disappear spontaneously (<5%)
• MGUS is a risk factor for multiple myeloma and related disorders
• Risk of progression to multiple myeloma or related disorders is increased with higher initial monoclonal protein levels
• Risk of progression is ~1 % per year
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Multiple Myeloma: Incidence and Etiology
• 13,000 cases/year in USA• Median age - 65 yrs.• Incidence in African-Americans is two-fold other
ethnic groups• Familiar clusters are rare• Environmental/occupational exposures have been
implicated
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Multiple Myeloma: Clinical Manifestations
• Bone pain/skeletal involvement• Fatigue/anemia• Renal insufficiency• Hypercalcemia• Neurologic symptoms• Infections
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Laboratory evaluation
CBC with peripheral smear Chemistry panel (Include calcium and creatinine) SPEP/UPEP (immunofixation electrophoresis) Urinalysis/24 hr urine for protein Bone marrow exam Skeletal survey LDH and 2-microglobulin Serum viscosity
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Peripheral smear: Plasma cell
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Bone marrow aspirate: Plasma cell infiltrate
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Diagnostic Criteria for Multiple Myeloma
Major criteria I. Bone marrow plasmacytosis > 30% II. Histologic diagnosis of plasmacytoma III. Serum paraprotein IgG > 3.5 g/dl or IgA > 2.0 g/dl
Minor criteria a. Bone marrow plasmacytosis 10-30% b. Serum paraprotein less than major criteria c. Osteolytic lesion d. Hypogammaglobulinemia
One major criteria and one minor criteria Minor criteria a + b and one other
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Waldenstroms MacroglobulinemiaIncidence and clinical features
• 1,500 cases/year in USA• Median age -, 63 yrs• Presenting symptoms
– Weakness and fatigue 44%
– Hemorrhagic manifestations 44%
– Weight loss 23%
– Neurologic symptoms 11%
– Visual disturbances 8%
– Raynauds phenomenon 3%
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Waldenstroms Macroglobulinemia:Clinical Features
• Tumor infiltration– Bone marrow 90%– Splenomegaly 38%– Lymphadenopathy 30%
• Circulating IgM– Hyperviscosity syndrome 15-20%– Cryoglobulinemia 5-15%– Cold agglutinin disease 5-10%– Bleeding disorders 10%
• Tissue IgM– Neuropathy 10-20%
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Amyloidosis: Classification and Biochemical Composition
• Primary amyloidosis– Immunoglobulin light chain (AL)
• Secondary amyloidosis– Amyloid A protein (AA)– Synthesized by liver as an acute phase reactant
• Hereditary amyloidosis– Transthyretin-derived amyloid (ATTR)
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Primary Amyloidosis: Clinical Features• Nephropathy
– Renal function loss 80– Proteinuria 75
• Cardiomyopathy– Heart failure 40-50
• Neuropathy– Polyneuropathy 36– Orthostatic hypotension 26– Carpal tunnel syndrome 8
• Enteropathy– Hepatomegaly 57– Macroglossia 32– Diarrhea ± Malabsorption 8
% involved
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Primary Amyloidosis: Histopathology
H&E Congo Red
Tongue(Macroglossia)
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Primary amyloidosisKey points
1. Suspect amyloidosis when a patient has unexplained:Nephrotic range proteinuria with or without renal insufficiencyCardiomyopathy manifested by fatigue or CHFPeripheral neuropathyHepatomegaly
2. Pursue diagnosis if:A monoclonal protein is detected in serum or urine
3. Confirm diagnosis with Congo red stain of:Bone marrowSubcutaneous fatOther affected tissue
4. Perform echocardiogram to assess prognosis
5. Begin systemic treatment
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Common clinical syndromesassociated with monoclonal gammopathies
• Bleeding disorders
• Hyperviscosity
• Cryoglobulinemia
• Peripheral neuropathy
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Hemostatic defects associated withMonoclonal proteins
Effect on hemostasis Assay
Inhibition of platelet aggregation PFA; Bleeding time
Inhibition of fibrin polymerization Thrombin time
Acquired von Willebrand disease VWF activity and antigen
Acquired factor X deficiency Factor X activity
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Acquired factor X deficiency
• Low factor X levels (<50%)• Severe bleeding with activity <10%• Associated with amyloidosis• Factor X binds to amyloid deposits in tissues• Treatment
– Underlying amyloidosis– Splenectomy– Large volumes of FFP/plasma exchange
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Hyperviscosity syndrome
• Associated with Waldenstroms macroglobulinemia (15-20% of patients)• Measure serum viscosity (normal <1.8)• Clinical syndrome of hyperviscosity occurs >4.0• Symptoms
– Headaches
– Other neurologic symptoms (dizziness, mental status changes
– Blurry vision
– Easy bleeding
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Cryoglobulinemia
• Type I (monoclonal) cryoglobulin• Associated with any lymphoproliferative disorder
– Waldenstroms macroglobulinemia 10-20%
• Symptoms– Raynaud phenomenon– Purpura– Renal insufficiency – Arthralgia
• Blood handling is difficult– Collect blood in 37° C tube– Transport and centrifuge at 37° C– Chill serum to 4° C for 48 hrs– Assay for cryoglobulin
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Peripheral smear: Cryoglobulinemia
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Neuropathies associated withmonoclonal protein disorders
• Associated with any lymphoproliferative disease
• Target antigens are occasionally identified (MAG; myelin associated glycoprotein)
• Symmetric, distal, sensory or sensorimotor
• May simulate CIDP (Chronic inflammatory demyelinating polyneuropathy)
• Associated with any class of monoclonal protein
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Summary
• Lymphoproliferative disorders associated with monoclonal proteins are common
• Diagnosis may be difficult
• Treatment requires identification of underlying disease and any associated clinical syndromes