Alya Putri Khairani | 130110110220
Alya Putri Khairani | 130110110220D1
HEMOLYTIC ANEMIAHemolytic anemias share the following features:
Premature destruction of red cells and a shortened red cell life
span below the normal 120 days Elevated erythropoietin levels and a
compensatory increase in Erythropoiesis Accumulation of hemoglobin
degradation products released by red cell breakdown derived from
hemoglobinThe physiologic destruction of senescent red cells takes
place within mononuclear phagocytes, which are abundant in the
spleen, liver, and bone marrow. This process appears to be
triggered by age dependent changes in red cell surface proteins,
which lead to their recognition and phagocytosis. In the great
majority of hemolytic anemias the premature destruction of red
cells also occurs within phagocytes, an event that is referred to
as extravascular hemolysis
Extravascular hemolysis is generally caused by alterations that
render the red cell less deformable. Extreme changes in shape are
required for red cells to navigate the splenic sinusoids
successfully. Reduced deformability makes this passage difficult,
leading to red cell sequestration and phagocytosis within the
cords. Regardless of the cause, the principal clinical features of
extravascular hemolysis are (1) anemia, (2) splenomegaly, and (3)
jaundice
Less commonly, intravascular hemolysis predominates.
Intravascular hemolysis of red cells may be caused by mechanical
injury, complement fixation, intracellular parasites (e.g.,
falciparum malaria, or exogenous toxic factors. Whatever the
mechanism, intravascular hemolysis is manifested by (1) anemia, (2)
hemoglobinemia, (3) hemoglobinuria, (4) hemosiderinuria, and (5)
jaundice. The large amounts of free hemoglobin released from lysed
red cells are promptly bound by haptoglobin, producing a complex
that is rapidly cleared by mononuclear phagocytes
MORPHOLOGYCertain changes are seen in hemolytic anemias
regardless of cause or type. Anemia and lowered tissue oxygen
tension trigger the production of erythropoietin, which stimulates
erythroid differentiation and leads to the appearance of increased
numbers of erythroid precursors(normoblasts) in the marrow.
Compensatory increases in erythropoiesis result in a prominent
reticulocytosis in the peripheral blood. The phagocytosis of red
cells leads to hemosiderosis, which is most pronounced in the
spleen, liver, and bone marrow. If the anemia is severe,
extramedullary hematopoiesis can appear in the liver, spleen, and
lymph nodes. With chronic hemolysis, elevated biliary excretion of
bilirubin promotes the formation of pigment gallstones
CLASSIFICATIONHemolytic Anemias may be classified as follow:(1)
Intracorpuscular defectsa) Hereditary defects Defects in the red
cell membrane Enzyme defects Hemoglobinopathies Thalassemia
syndromeb) Acquired defects Paroxysmal nocturnal hemoglobinuria(2)
Extracorpuscular defectsa) Immune Hemolytic Anemiab) Infectionc)
Exposure to chemicals and toxinsd) Exposure to physical agentse)
Microangiopathic and macroangiopathic hemolytic anemiasf) Splenic
sequestrationg) General systemic disorders
APPROACH TO DIAGNOSIS1. Tests Reflecting Increased Red Cell
Destruction Serum Unconjugated Bilirubin>3-4mg/dL catabolism of
heme from red cells phagocytosed by reticuloendothelial system
Serum Haptoglobin very sensitive rapid clearance by
reticuloendothelial system of a complex formed between liberated Hb
and circulatory Haptoglobin Others: Spectroscopic examination and
Dipstick to detect hemoglobinemia, hemoglobinuria,
hemosiderinuria2. Tests Reflecting Increased Red Cell Production
Reticulocyte Count (Romanowsky Stain) elevated (showing
compensatory bone marrow response)If there is anemia, reticulocytes
may leave the bone marrow prematurely and mature in the circulation
for longer than the normal maturation time of 1 day - RPI Index
(Reticulocyte Production Index):
Hereditary Defects of the Red Cell MembraneStructures of RBC
membrane to deform and regain its original biconcave disc shape is
determined by three factors:1. Cell surface area-to-volume ratio2.
Viscoelastic properties of membrane, which depend on the structural
and functional integrity of the membrane skeleton3. The cytoplasmic
viscosity, which is determined primarily by Hb
The hereditary Hemolytic Anemia due to red cell membrane protein
defects may be classified according to the morphological
abrnotmality of the red cells. Four main groups are delineated:(1)
Hereditary Spherocytosis (HS)(2) Hereditary Elliptocytosis (HE) and
morphologically related disorders(3) Hereditary Stomatocytosis(4)
Hereditary Xerocytosis
To gain insight into the pathogenesis and to enable a
correlation of the genotype with the observed morphological
phenotype, it is useful to divide the interaction between the red
cell membrane components into 2 categories:Vertical
interactionsBetween membrane skeleton and the bilayer and mainly
involve Spectrin-Ankyrin-Band 3 associationsHorizontal
interactionsBetween components of the membrane skeleton and include
Spectrin dimer self-association and Spectrin-Actin-Protein 4.1
complex formation
Hereditary Spherocytosis
HS is characterized by osmotically fragile, spherical red cells,
and is the most common hereditary anemia in people of northern
European origin. The underlying molecular defects in HS are
heterogenous and several genetic loci have been implicated. In the
vast majority of cases, the resulting protein abnormalities are
quantitative with decreased amount of the membrane proteins
involved in vertical interaction between the bilayer and the
skeleton which there are defects (protein deficiencies) in
Spectrin, Ankyrin, Band 3, Protein 4.2
PATHOPHYSIOLOGYThe fundamental expression of the membrane defect
in HS is a loss of surface area of red cell, resulting in a
decreased surface-to-volume ratio. This is morphogically as
Spherocytosis, although it should be noted that the majority of HS
cells are spherostomatocytic rather than truly spherocytic. Such
cells tolerate less swelling than normal red cells and are
osmotically fragile. The decrease in surface-to-volume ratio also
makes the cells less deformable than normal
CLINICAL MANIFESTATIONThe classic presenting features of
patients with HS are the triad of jaundice, anemia, and enlarged
spleen, but many patients do not show all of these signs. The age
at presentation can vary from within a day or two after birth to
old age, and sometimes the condition is diagnosed only during
family studies or investigation for other reason
CLINICAL LABORATORY FINDINGS For Extravascular Hemolysis:
Hyperbilirubinemia found in half of the patients and Haptoglobins
are variably reduced For Intravascular Hemolysis: Hemoglobinemia,
Hemoglobinuria, or Hemosiderinuria do not occur Mean Corpuscular
Hemoglobin Concentration (MCHC) is elevated, probably reflects mild
cellular dehydration Morphology hallmark: Spherocyte
PROGNOSISAfter Splenectomy, RBC survival improves dramatically,
enabling most patients with HS to maintain a normal Hb level
Hereditary Elliptocytosis
HE is a group of disorder found in all race groups and
characterized by the presence of elliptical red cells in the
peripheral blood. HE syndrome is heterogenous in terms of
inheritance, clinical manifestation, and underlying molecular
defects
Three major clinical and morphological phenotypes have been
delineated: Common HE, including HPP; Spherocytic HE; and Southeast
Asian Ovalocytosis
CLINICAL LABORATORY FINDINGSPhenotypesHemolysisMorphologyMost
Common Defects
Common HEAsymptomaticcElliptocytesImpaired Spectrin Tetramer
formation or Protein 4.1 deficiency
HE with infantile PoikilocytosisModerately severe up to age 2
yearsElliptocytesPoikilocytesImpaired Spectrin Tetramer formation
or Protein 4.1 deficiency
HPPSevereMicrospherocytesPoikilocytesFew ElliptocytesImpaired
Spectrin Tetramer formation and Spectrin deficiency
SAOAsymptomaticLarge Ovalocytes9-amino acid deletion in Band
3
PATHOPHYSIOLOGY
CLINICAL MANIFESTATIONMost patients are asymptomatic and do not
have any obvious physical signs. Patients with clinically
significant hemolysis have splenomegaly, pallor, scleral icterus,
and (in rare cases) leg ulcers
Hereditary Stomatocytosis and Hereditary Xerocytosis
This is a heterogenous group of rare disorders characterized by
alterations in the permeability of the red cell membrane to
cations.Hereditary Stomatocytosis : Hydrocytosis, which the red
cells are swollenHereditary Xerocytosis: The cells are markedly
dehydratedETIOLOGY AND PATHOPHYSIOLOGYHereditary StomatocytosisThe
basic abnormality of Stomatocytic red cells is a marked increase in
the passive permeability of Sodium into the cell and of Potassium
out of the cell. The defect in Sodium permeability is greater than
that for Potassium. Although the Sodium-Potassium pump is
stimulated by the influx of Sodium, it cannot cope with the influx
and the total cation content of the cell increases, with resultant
water influx and formation of Hydrocytes. Because of the influx of
the water, Stomatocytes have an increase volume with a decreased
surface-to-volume ratio and the attendant consequences of decreased
rec dell deformability and susceptibility to splenic
sequestration
Hereditary XerocytosisRed cells from patients with Hereditary
Xerocytosis have an increased efflux of Potassium that approximates
Sodium influx. Although the Sodium-Potassium pump is stimulated by
the influx of Sodium, it is insufficient to correct the loss of
Potassium. Irreversible Potassium and total cation loss occurs with
resultant dehydration and formation of Xerocytes
CLINICAL LABORTORY FINDINGS Stomatocytes : Red cells with a
cenral slit or stoma. On scanning electron microscopy, the cells
have a bowl-like appearance Xerocytes : Target cells are present,
reflecting the greater surface-to-volume ratio of these cells MCV
in both HS and HX is elevated MCHC is increased in HX and decreased
in HS
Hereditary Enzyme DeficienciesGlucose-6-Phosphate Dehydrogenase
Deficiency
G6PD deficiency is transmitted by a mutant gene located on the X
chromosome. The gene encoding G6PD has been mapped to the Xq28
region in humans
CLINICAL MANIFESTATIONSThe majority of G6PD-deficients are
asymptomatic most of the time and go through life without ever
being aware of their genetic trait. Symptoms of the disorder are
related to the severity of the hemolytic episode. 2 or 3 days after
the administration of the offending drug (ex:/ Napthalene &
TNT), the erythrocyte count decreases, along with the Hemoglobin
content
LABORATORY TESTING A fall in Hb and Ht Hemoglobinuria Heinz
bodies in erythrocytes Elevated serum Bilirubin levels Markedly
decreased or absent Haptoglobin levels
PATHOGENESIS
Pyruvate Kinase Deficiency
PK deficiency is inherited as an autosomal recessive trait, but
true homozygotes are rare and are restricted to children of
consanguineous parents. The common mode of inheritance is that of
double heterozygosity; that is, when 2 mutant variants of the PK
enzyme are simultaneously inherited from each parent
PATHOGENESIS
CLINICAL MANIFESTATIONThe severity of the hemolytic disease
associated with PK defiency varies from mild to severe, depending
on the properties of the mutant enzymes. True homozygotes are
anemic and jaundiced at birth and may require repeated transfusions
during life. Less severely affected patients may come to clinical
attention later in childhood or early adulthood because of anemia,
jaundice, or an enlarged spleen
LABORATORY TETSINGThe peripheral blood smears of patients with
PK deficiency typically show a normochromic, normocytic anemia with
varying degrees of Reticuocytosis. Accelerated erythropoiesis may
result in Polychromasia, Poikilocytosis, Anisocytosis, and
nucleated red blood cells. Both the Hb and Ht levels are decreased
from normal. The serum usually has a moderate increase in
unconjugated bilirubin, and the Haptoglobin level is decreased or
absent
Methemoglobin Reductase Deficiency
HemoglobinopathiesThe majority of hemoglobinopathies result from
-chain abnormalities. Some individuals with -chain abnormalities
present with abnormal physical properties resulting in clinical
disease. Most hemoglobinopathies arise from a single amino acid
substitution that represent a molecular alteration. The abnormality
was demostrated by electrophoresis to be located in the protein
portion of hemoglobin molecule.
At the molecular level, a single-base DNA substitution in the
corresponding triplet codon produces one amino acid change (common
cuase of hemoglobinopathy). Other molecular changes that are more
rare include: multiple-base substitutions, production of long/short
subunits, and the occurrence of fusion subunits
CLASSIFICATION
More inclusive method of classification (5 major
categories):Abnormal hemoglobins without clinical
significanceAggregating hemoglobinsUnbalanced synthesis of
hemoglobin (thalassemia)Unstable hemoglobinsHemoglobins with
abnormal heme function
ThalassemiaThalassemia is a blood disorder passed down through
families (inherited) in which the body makes an abnormal form of
hemoglobin, the protein in red blood cells that carries oxygen. The
disorder results in excessive destruction of red blood cells, which
leads to anemia.
Causes, incidence, and risk factorsHemoglobin is made of two
proteins: Alpha globin and beta globin. Adult hemoglobin (HbA) is a
tetramer composed of two chains and two chains encoded by a pair of
functional -globin genes on chromosome 16 and a single -globin gene
on chromosome 11. Thalassemia occurs when there is a defect in a
gene that helps control production of one of these proteins.There
are two main types of thalassemia: Alpha thalassemia Occurs when a
gene or genes related to the alpha globin protein are missing or
changed (mutated). The most common cause of reduced -chain
synthesis is deletion of -globin genes. Occur most commonly in
persons from southeast Asia, the Middle East, China, and in those
of African descent. Beta thalassemia Occurs when similar gene
defects affect production of the beta globin protein. Classified
into two categories:(1) 0-thalassemia, associated with total
absence of -globin chains in the homozygous state(2) +-thalassemia,
characterized by reduced (but detectable) -globin synthesis in the
homozygous state. Impaired -globin synthesis results in anemia by
two mechanisms. The deficit in HbA synthesis produces
"under-hemoglobinized," hypochromic, microcytic red cells with
subnormal oxygen transport capacity. A more important factor is
diminished survival of red cells and their precursors, resulting
from the imbalance in - and -chain synthesis. Occur in persons of
Mediterranean origin, and to a lesser extent, Chinese, other
Asians, and African Americans.There are many forms of thalassemia.
Each type has many different subtypes. Both alpha and beta
thalassemia include the following two forms: Thalassemia major
(must inherit the defective gene from both parents to develop this
syndrome) Thalassemia minor (occurs if receive the defective gene
from only one parent. Persons with this form of the disorder are
carriers of the disease and usually do not have symptoms).
Thalassemia minor is much more common than thalassemia major.
SymptomsThe most severe form of alpha thalassemia major causes
stillbirth (death of the unborn baby during birth or the late
stages of pregnancy).Children born with thalessemia major (Cooley's
anemia) are normal at birth, but develop severe anemia during the
first year of life.Other symptoms can include: bone deformities in
the face, fatigue,growth failure, shortness of breath, and yellow
skin (jaundice).Persons with the minor form of alpha and beta
thalassemia have small red blood cells (which are identified by
looking at their red blood cells under a microscope), but no
symptoms.
Clinical and Genetic Classification of ThalassemiasClinical
NomenclatureGenotypeDiseaseMolecular Genetics
-Thalassemias
Thalassemia majorHomozygous 0-thalassemia (0/0)Severe; requires
blood transfusionsRare gene deletions in 0/0Defects in
transcription, processing, or translation of -globin mRNA
Homozygous +-thalassemia (+/+)
Thalassemiaintermedia0/Severe, but does not require regular
blood transfusions
+/+
Thalassemia minor0/Asymptomatic with mild or absent anemia; red
cell abnormalities seen
+/
-Thalassemias
Hydropsfetails-/- -/-Lethal in utero without transfusionsMainly
gene deletions
HbH disease-/- -/Severe; resembles -thalassemiaintermedia
-Thalassemia trait-/- / (Asian)Asymptomatic, like -thalassemia
minor
-/ -/ (black African)
Silent carrier-//Asymptomatic; no red cell abnormality
Signs and testsA physical exam may reveal a swollen (enlarged)
spleen.A blood sample will be taken and sent to a laboratory for
examination. Red blood cells will appear small and abnormally
shaped when looked at under a microscope. A complete blood count
(CBC) reveals anemia. A test called hemoglobin electrophoresis
shows the presence of an abnormal form of hemoglobin.A test called
mutational analysis can help detect alpha thalassemia that cannot
be seen with hemoglobin electrophoresis.