Chapter - 23 Rodak Intrinsic Defect

Chapter 23
Intrinsic Defects Leading

to Increased Erythrocyte Destruction
Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc.

Chapter Overview
 Red blood cell (RBC) membrane abnormalities
 RBC membrane structure and function
 Hereditary RBC membrane abnormalities
 Mutations that alter membrane structure
 Mutations that alter membrane transport proteins
 Acquired membrane defect―paroxysmal nocturnal
hemoglobinuria
 RBC enzymopathies
 Glucose-6-phosphate dehydrogenase (G6PD)
deficiency
 Pyruvate kinase (PK) deficiency
Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 2
RBC Membrane Abnormalities
 Classification based on morphology
 Hereditary spherocytosis
 Hereditary elliptocytosis
 Hereditary stomatocytosis
 Hereditary xerocytosis
 Hereditary pyropoikilocytosis

Hereditary Spherocytosis
Figure 23-1 Peripheral blood film for the patient in the case
study (×500). (From Carr JH, Rodak BF: Clinical hematology
atlas, ed 3, Philadelphia, 2009, Saunders.)

study Table 23-1sobrang importante
 Hereditary spherocytosis with polychromasia: defects in
protein
 Mode of inheritance: 75% autosomal dominant
 Incidence: worldwide; 1 in 3,000 in NE
 Pathophysiology
• Primary defect
• Structural abnormalities
 Clinical features: splenomegaly, jaundice and anemia
 Clinical classifications
Continued
RBC Membrane
Abnormalities─cont’d
 Hereditary spherocytosis
 Laboratory features
• Blood smear morphology
• Complete blood count and indices
• Reticulocyte count
• Bone marrow
• Hemolytic indicators
• Osmotic fragility test
• Autohemolysis test
• Miscellaneous tests
Continued
Tests Reflecting Increased Red Cell
Production
Reticulocyte Production Index
(RPI) – corrects the hematocrit to
a normal value of 45% and takes
into account the maturation time
at a particular hematocrit

Osmotic Fragility Test

Curve

Autohemolysis Test
 When normal RBCs
are incubated in
their own plasma,
hemolysis takes
place
 Normal: 5%
hemolysis after 48
hr
 HS: 10-50%

SDS-PAGE
 Identifies protein
deficincies

Ektacytometer
 Laser-diffraction visvometer that measures
osmotic gradient deformability profile
 Patient is incubated with eosin-5’-maleimide
and measure of fluorescence in a flow
cytometer

Hypertonic Cryohemolysis Test
 Cells from HS 370C 0 0C
patients are 10 mins 10 mins
particularly sensitive
to cooling at 0o C in
hypertonic solutions
 Incubated with 0.7
mol/L sucrose
 Normal: 3-15%
hemolysis
 HS: >20%
hemolysis
RBC Membrane
 Hereditary spherocytosis
 Therapy and outcome: vaccine; splenectomy
 Differential diagnosis
• Immune hemolytic anemia
• Heinz body hemolytic anemia

 Hereditary elliptocytosis
 History and mode of inheritance: autosomal dominant
 Pathophysiology
• Cell membrane defect due to gene mutations in which the
defective protein disrupt the horizontal linkages in the
protein cytoskeleton and weaken the mechanical stability of
the membrane
• Becomes elliptical after exposure to shear stress
• Damaged RBC trapped in the spleen
• Heterozygous for mutation
• Homozygous for mutation
Continued
RBC Membrane
 Hereditary elliptocytosis (HE)
 Clinical features
• Three types
 Common HE: 90% asymptomaticc
 Spherocytic HE
 Southeast Asia ovalocytosis: mutation in band 3
 Laboratory findings
 Common HE
• Clinical features
• Laboratory featuresL low MCV <50 fl
• Ethnic distribution
Continued
Subtypes
HPP Leach Phenotype

 Decreased thermal  Lack Gerbich antigen,
stability glycoprotein C and

 Marked RBC glycoprotein D
fragmentation upon  Defect in the interaction
heating between GPC and protein
 Severe form of HE 4.1R

Hereditary Elliptocytosis
Figure 23-6 Red blood cell morphology in hereditary elliptocytosis

(peripheral blood, ×1000). (From Carr JH, Rodak BF: Clinical
hematology atlas, ed 3, Philadelphia, 2009, Saunders.)

Hereditary Pyropoikilocytosis
Figure 23-7A&B A, Morphology of red blood cells in hereditary pyropoikilocytosis before incubation. B, Morphology after 1 hour at 45° C (peripheral
blood, ×500).

Hereditary Stomatocytosis
Figure 23-8 Red blood cell morphology in hereditary stomatocytosis (peripheral blood,
×1000).

 Overhydrated Hereditary stomatocytosis

 Inheritance: autosomal dominant pattern
 Pathophysiology
• Ion movement: excessive permeable to Na+ and K+
• Water movement: more water enters the cell
• Structural defect: RHAg protein
 Clinical features: moderate to severe hemolytic
anemia
 Laboratory features: macrocytes, reduced K+ and
increased Na+
 Acquired stomatocytosis: drying artifact in Wright’s
 Rhnull Copyright
disease: absence of Rh membrane proteins
© 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 23
RBC Cation Permeability and
Volume
 Hereditary xerocytosis: a.k.a. dehydrated
hereditary stomatocytosis
 Inheritance: autosomal dominant
 Pathophysiology
• Ion movement: excessive parmeability to K+
• Water movement: water is loss from the cell
• Structural defect: abnormal gene 16q 23-24
 Clinical features: mild to moderate anemia,
reticulocytosis, jaundice, splenomegaly, fetal loss,
hydrops fetalis and neonatal hepatitis
 Laboratory features: elevated MCHC Continued
Acanthocytosis (spur cells)
 Spicules: irregular vary in width and length
 Pathophysiology
• Membrane defect: spur cell anemia (defect in lipid
component i.e. excess free cholesterol due to abnormal
lipoproteins
• Related disorders: Neuroacanthocytosis (neurologic
impairment)
 Abetaliproteinemia: MTP gene mutation
 McLeod Syndrome: mutation in KX gene
 Chorea acanthocytosis: defect inVPA13A
 Other causes
• McLeod blood group
• In(Lu) gene
• Malnutrition
• VitaminCopyright
E deficiency
© 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 25
Paroxysmal nocturnal
hemoglobinuria (PNH)
 History and etiology
 Acquired clonal stem cell mutation that lack
glycosylphosphatidylinositol (GPI)-anchored proteins
such as CD55 and CD59
 Role of complement
 Pathophysiology
 Main defect: mutation in PIG-A gene
 Subpopulations of cells
• PNH-I: normal CD55 and CD 59, little or no hemolysis
• PNH-II: partial deficiency; relatively resistant to hemolysis
• PNH-III: sensitive to hemolysis
Paroxysmal Nocturnal
Hemoglobinuria
 Clinical findings
 Onset: young adulthood
 Age most at risk: childhood and advanced age
 Laboratory findings
 Degree of anemia: mild to severe
 25 % positive for hemoglobinuria/hemoglobinemia
 Hepatic Vein Thrombosis: Budd-Chiari
 Cell counts: increased reticulocytes
 Classification of anemia: chronic intravascular
hemolysis due to hemosiderinuria
 Bone marrow evaluation: erythroid hyperplasia Continued
Paroxysmal Nocturnal
Hemoglobinuria─cont’d
 Special diagnostic tests
 Urine hemosiderin
 Sugar water test
 Ham test
 Surface markers (flow cytometers -> deficiency of
CD59, CD55, CD24, and CD15
 Therapy and prognosis
 Eculizumab -> monoclonal ab that binds with C5
 Supportive
 Median survival rate: 10 years

RBC ENZYMOPATHIES

G6PD-> protect the cell from oxidative stress
 Inheritance: X-linked recessive

 Hemizygotes or partial; homozygotes or heterozygotes
 Classes of G6PD deficiencies
• Class I: severe -> CNSHA
• Class II: severe deficiency, no CNSHA; G6PD-Mediterranean
• Class III: moderate (10 to 60% def), no CNSHA; G6PD-A- &
G6PD-Canton
• Class IV: normal enzyme activity (60 to150%) with no hemolysis;
G6PD-B and G6PD-A+
• Class V: increased enzyme activity with greater than 150%, not
clinically relevant
Continued
RBC Enzymopathies─cont’d
 G6PD
 Variants of G6PD
• G6PD-B
• G6PD-A+
• G6PD-A
• G6PD-A
• G6PD-Med
• G6PD-Mahidol
• G6PD-Canton
Continued
 G6PD
 Pathophysiology
• Role in hexose monophosphate shunt: G6PD reduced
NADPH and oxidizing G6PD
• Mechanism for Heinz body formation: oxidized hb
 Hemolytic process
• (1) AHA (2) neonatal jaundice (3) CNSHA
• Associated clinical syndromes due to oxidative stress
 Drug induced
 Infection induced
 Fava bean induced
 Neonatal jaundice
 Chronic nonspherocytic hemolytic anemia
 Plasmodium falciparum
Continued
 Normal until offending drug is taken (II and III)
 Induced conditions (infection and favism)
 Laboratory findings
 Classification of anemia: hemolytic;
normocytic/normochromic
 Wright-stained blood smear: anisocytosis,
poikilocytosis, spherocytosis and schistocytosis
 Confirming presence of Heinz bodies: Crystal violet
 Reticulocyte count: 30%
 Blood cell counts: WBC slightly elevated; platelet
varies
 Chemistry test results: based on reduction of NADP to
NADPH by change in absorbance at 340 nm
Continued
 G6PD
 Therapy and prognosis: preventing the most common
manifestations of HA and neonatal jaundice
 Differential diagnosis: Class II and III must be
differentiated against other drug induced HA
Continued
PK Deficiency
 Pathophysiology
 Function of PK: conversion of PEP to pyruvate
forming ATP
 Cell parameters affected: decreased RBC lifespan
 Infants: severe anemia
 Adults: fully compensated hemolytic process
 Role of 2,3-disphosphoglycerate (2,3-BPG) -> shifts
the Hb-O2 dissociation curve and decreases the O2
affinity of cell Continued
 Glycolytic pathway deficiencies

 PK deficiency
• Laboratory findings
 Classification of anemia: hemolytic anemia
 Reticulocyte count: high (800 x 109 /L); sequestered in spleen
 Blood smear evaluation: anisocytosis, polychromasia and
poikilocytosis with burr cells or echinocytes
 Chemistry test results
 PK activity in white blood cell (WBC) versus RBC
Continued
 Glycolytic pathway deficiencies

 PK deficiency
• Therapy and prognosis: splenectomy
• Differential diagnosis -> must be differentiated with other
hemogloninopathies and HS

Talking Points
 What are the hereditary defects based on RBC
morphology classification?
 What are the laboratory findings in HE?
 What is the autohemolysis test? What does it
mean to have glucose correction?
 What is the cell morphology in xerocytosis?
 Which G6PD variant is found at higher
incidence in the African-American population?
 What are Heinz bodies? How are they detected
and confirmed?

Chapter - 23 Rodak Intrinsic Defect

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Chapter 23

Intrinsic Defects Leading

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc.

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 3

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 6

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HPP Leach Phenotype

stability glycoprotein C and

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 19

Figure 23-6 Red blood cell morphology in hereditary elliptocytosis

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 20

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 21

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 22

 Overhydrated Hereditary stomatocytosis

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 28

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 29

 Inheritance: X-linked recessive

 Glycolytic pathway deficiencies

 Glycolytic pathway deficiencies

Copyright © 2012, 2007, 2002, 1995 by Saunders, an imprint of Elsevier Inc. 37

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