Chapter 14 – Red Blood Cell: HEMOLYTIC ANEMIAS

Question 1

Hemolytic anemias share the following features

Answer 1

• • 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 hemoglobin

Question 2

Where does the physiologic destruction of senescent red cells takes place?

Answer 2

within mononuclear phagocytes,
which are abundant in the spleen, liver, and bone marrow.

Question 3

What triggers the physiologic destruction of senescent red cells takes place?

Answer 3

age-dependent changes in red cell surface proteins, which lead to their recognition and
phagocytosis.

Question 4

What is extravascular hemolysis?

Answer 4

[1] 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.

Question 5

What happens when there is a persistent extravascular hemolysis?

Answer 5

• *hyperplasia of phagocytes** manifested by varying
• *degrees of splenomegaly.**

Question 6

What is the general caused of extravascular hemolysis?

Answer 6

Extravascular hemolysis is generally caused by alterations that render the red cell less
deformable.

Question 7

What is required for RC to navigate the splenic sinusoids successfully?

Answer 7

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

Question 8

What makes the RC sequestration and phagocytosis within the cords?

Answer 8

Reduced deformability

makes this passage difficult, leading to red cell sequestration and phagocytosis within the cords

Question 9

Regardless of the cause, the principal clinical
features of extravascular hemolysis are

Answer 9

• (1) anemia,
• (2) splenomegaly,
• and (3) jaundice

Question 10

What is the reason for decrease in haptoglobin?

Answer 10

Some hemoglobin inevitably escapes from phagocytes, which leads to variable decreases in plasma
haptoglobin, an α2-globulin that binds free hemoglobin and prevents its excretion in the urine.

Question 11

Why do individuals with extravascular hemolysis benefit form splenectomy?

Answer 11

Because much of the pathologic destruction of red cells occurs in the spleen, individuals with
extravascular hemolysis often benefit from splenectomy.

Question 12

What is the cause of intravascular hemolysis?

Answer 12

Less commonly, intravascular hemolysis predominates.

Intravascular hemolysis of red cells may
be caused by mechanical injury, complement fixation, intracellular parasites (e.g., falciparum
malaria, Chapter 8 ), or exogenous toxic factors.

Causes of mechanical injury include trauma
caused by cardiac valves, thrombotic narrowing of the microcirculation, or repetitive physical
trauma (e.g., marathon running and bongo drum beating).

Complement fixation occurs in a
variety of situations in which antibodies recognize and bind red cell antigens.

Toxic injury is
exemplified by clostridial sepsis, which results in the release of enzymes that digest the red cell
membrane.

Question 13

Whatever the mechanism, intravascular hemolysis is manifested by :

Answer 13

• (1) anemia,
• (2) hemoglobinemia,
• (3) hemoglobinuria,
• (4) hemosiderinuria, and
• (5) jaundice.

Question 14

What is the reason for the red-brown color of urine in intravascular hemolysis?

Answer 14

The large amounts
of free hemoglobin released from lysed red cellsare promptlybound by haptoglobin, producing
a complex that is rapidly cleared by mononuclear phagocytes.

As serum haptoglobin is
depleted, free hemoglobinoxidizes to methemoglobin, which is brown in color.

The renal
proximal tubular cells reabsorb and catabolize much of the filtered hemoglobin and
methemoglobin,butsome passes out in the urine, imparting a red-brown color.

Iron released
from hemoglobin can accumulate within tubular cells, giving rise to renal hemosiderosis.

Question 15

What is the reason for jaundice in intravascular hemolysis?

Answer 15

Concomitantly, heme groups derived from hemoglobinhaptoglobin complexes are catabolized to
bilirubin within mononuclear phagocytes, leading to jaundice.

Question 16

Unlike in extravascular hemolysis,
________ is not seen intravascular hemolysis?

Answer 16

splenomegaly

Question 17

In all types of uncomplicated hemolytic anemias, the excess serum bilirubin is ____________

Answer 17

unconjugated.

The level of hyperbilirubinemia depends on the functional capacity of the liver and the rate of
hemolysis. When the liver is normal, jaundice is rarely severe.

Excessive bilirubin excreted by
the liver into the gastrointestinal tract leads to increased formation and fecal excretion of
urobilin ( Chapter 18 ), and often leads to the formation of gallstones derived from heme pigments.

Question 18

Certain changes are seen in hemolytic anemias regardless of cause or type.
Anemia and lowered tissue oxygen tension trigger the production of __________, which
stimulates erythroid differentiation and leads to the appearance of increased numbers of
erythroid precursors (normoblasts) in the marrow ( Fig. 14-1 ).

Answer 18

erythropoietin

Question 19

What results in the Compensatory
increases in erythropoiesis?

Answer 19

prominent reticulocytosis in the peripheral blood

Question 20

What is hemosiderosis?

Answer 20

The phagocytosis of red cells leads to hemosiderosis, which is most pronounced in the
spleen, liver, and bone marrow.

Question 21

Why does in chronic hemolysis formation of pigment gallstones can occur?

Answer 21

With chronic hemolysis, elevated biliary
excretion of bilirubin promotes the formation of pigment gallstones (cholelithiasis).

Question 22

Answer 22

FIGURE 14-1 Marrow smear from a patient with hemolytic anemia. The marrow reveals
greatly increased numbers of maturing erythroid progenitors (normoblasts).

Question 23

What is hereditary spherocytosis?

Answer 23

This inherited disorder is caused by intrinsic defects in the red cell membrane skeleton that
render red cells spheroid, less deformable, and vulnerable to splenic sequestration and destruction. [2]

The prevalence of HS is highest in northern Europe, where rates of 1 in 5000 are reported.

An autosomal dominant inheritance pattern is seen in about 75% of cases.

The
remaining patients have a more severe form of the disease that is usually caused by the
inheritance of two different defects (a state known as compound heterozygosity).

Question 24

The remarkable elasticity and durability of the normal red cell are attributable to what?

Answer 24

The remarkable elasticity and durability of the normal red cell are attributable to the physicochemical properties of its specialized membrane skeleton ( Fig. 14-2 ), which lies closely apposed to the internal surface of the plasma membrane

Question 25

What is the chief protein component of the RC skeloton?

Answer 25

Its chief protein component, spectrin,
consists of two polypeptide chains, α and β, which form intertwined (helical) flexible
heterodimers.

Question 26

What is the pathogenesis of hereditary spherocytosis?

Answer 26

HS is caused by diverse mutations that lead to an insufficiency of membrane skeletal
components

As a result of these alterations, the life span of the affected red cells is decreased
on average to 10 to 20 days from the normal 120 days. The pathogenic mutations most
commonly affect ankyrin, band 3, spectrin, or band 4.2, the proteins involved in the first of the
two tethering interactions, presumably because this complex is particularly important in
stabilizing the lipid bilayer.

Most mutations cause shifts in reading frame or introduce premature
stop codons, such that the mutated allele fails to produce any protein. The defective synthesis
of the affected protein reduces the assembly of the skeleton as a whole and results in a
decrease in the density of the membrane skeleton components. Compound heterozygosity for
two defective alleles understandably results in a more severe membrane skeleton deficiency.

Quick: Physiology

The “head” regions of spectrin dimers self-associate to form tetramers, while the “tails” associate with actin oligomers. Each actin oligomer can bind multiple spectrin tetramers, thus creating a two-dimensional spectrin-actin skeleton that is connected to the cell membrane by two distinct interactions.

The first, involving the proteins ankyrin and band 4.2, binds spectrin to the transmembrane ion transporter, band 3.

The second, involving protein 4.1, binds the
“tail” of spectrin to another transmembrane protein, glycophorin A.

Question 27

Describe how the shape of the RBCs of hereditory spherocytosis attained?

Answer 27

Young HS red cells are normal in shape, but the deficiency of membrane skeleton reduces the
stability of the lipid bilayer, leading to the loss of membrane fragments as red cells age in the
circulation.

The loss of membrane relative to cyt oplasm “forces” the cells to assume the smallest possible diameter for a given volume, namely, a sphere.

Question 28

What is the cardinal role of the spleen in hereditary spherocytosis?

Answer 28

The invariably beneficial effects of splenectomy prove that the spleen has a cardinal role in the premature demise of spherocytes

Question 29

Why does the spleen becomes the villain in hereditary spherocytosis?

Answer 29

In
the life of the portly inflexible spherocyte, the spleen is the villain.

Normal red cells must
undergo extreme deformation to leave the cords of Billroth and enter the sinusoids.

Because of
their spheroidal shape and reduced deformability, the hapless spherocytes are trapped in the
splenic cords, where they provide a happy meal for phagocytes.

The splenic environment also
somehow exacerbates the tendency of HS red cells to lose membrane along with K + ions and
H2O; prolonged splenic exposure (erythrostasis), depletion of red cell glucose, and diminished
red cell pH have all been suggested to contribute to these abnormalities ( Fig. 14-3 ).

After
splenectomy the spherocytes persist, but the anemia is corrected.

Question 30

Why does the splenic environment exacerbates the tendency of HS red cells to lose membrane?

Answer 30

The splenic environment also
somehow exacerbates the tendency of HS red cells to lose membrane along with K + ions and
H2O;

prolonged splenic exposure (erythrostasis), depletion of red cell glucose, and diminished
red cell pH have all been suggested to contribute to these abnormalities ( Fig. 14-3 ).

Question 31

Answer 31

FIGURE 14-3 Pathophysiology of hereditary spherocytosis.

Question 32

What is the most specific morphologic finding of HS?

Answer 32

The most specific morphologic finding is spherocytosis, apparent on
smears as abnormally small, dark-staining (hyperchromic) red cells lacking the central zone of
pallor ( Fig. 14-4 ).

Spherocytosis is distinctive but not pathognomonic, since other forms of membrane loss, such as in autoimmune hemolytic anemias, also cause the formation of spherocytes.

Question 33

What are the other features of HS that are common to all hemolytic anemias?

Answer 33

Other features are common to all hemolytic anemias. These include:

• reticulocytosis,
• marrow erythroid hyperplasia,
• hemosiderosis,
• and mild jaundice.
• Cholelithiasis (pigment stones) occurs in 40% to 50% of affected adults.
• Moderate splenic enlargement is characteristic (500–1000 gm); in few other hemolytic anemias is the spleen enlarged as much or as consistently. Splenomegaly results from congestion of the cords of Billroth and increased numbers of phagocytes needed to clear the spherocytes.

Question 34

Answer 34

FIGURE 14-4 Hereditary spherocytosis (peripheral smear). Note the anisocytosis and
several dark-appearing spherocytes with no central pallor.

Howell-Jolly bodies (small dark
nuclear remnants) are also present in red cells of this asplenic patient.

Question 35

How do you diagnose HS?

Answer 35

The diagnosis is based on family history, hematologic findings, and laboratory evidence.

In two
thirds of the patients the red cells are abnormally sensitive to osmotic lysis when incubated in
hypotonic salt solutions, which causes the influx of water into spherocytes with little margin for
expansion.

HS red cells also have an increased mean cell hemoglobin concentration , due to
dehydration caused by the loss of K + and H2O.

Question 36

What is the reason for the HS red cells have an increased mean cell hemoglobin concentration?

Answer 36

HS red cells also have an increased mean cell hemoglobin concentration , due to
dehydration caused by the loss of K + and H2O.

Question 37

What are the characteristic clinical features of HS?

Answer 37

• anemia,
• splenomegaly, and
• jaundice .

Question 38

The severity of HS varies greatly.

In a small minority (mainly compound heterozygotes) HS presents at birth with marked jaundice and requires exchange transfusions.

In 20% to 30% of patients the disease is
so mild as to be virtually asymptomatic; here the decreased red cell survival is readily
compensated for by increased erythropoiesis.

In most, however, the compensatory changes are outpaced, producing a chronic hemolytic anemia of mild to moderate severity

Question 39

The generally
stable clinical course of HS is sometimes punctuated by aplastic crises, usually triggered by an :

Answer 39

acute parvovirus infection.

Parvovirus infects and kills red cell progenitors, causing red cell production to cease until an effective immune response commences, generally in 1 to 2 weeks.

Because of
the reduced life span of HS red cells, cessation of erythropoiesis for even short time periods leads to sudden worsening of the anemia.

Transfusions may be necessary to support the
patient until the immune response clears the infection.

Hemolytic crises are produced by
intercurrent events leading to increased splenic destruction of red cells (e.g., infectious
mononucleosis); these are clinically less significant than aplastic crises.

Gallstones, found in
many patients, can also produce symptoms. Splenectomy treats the anemia and its
complications, but brings with it the risk of sepsis.

Question 40

The red cell is vulnerable to injury by exogenous and endogenous oxidants.

Abnormalities in
the hexose monophosphate shunt or glutathione metabolism resulting from deficient or
impaired enzyme function reduce the ability of red cells to protect themselves against oxidative
injuries and lead to hemolysis.

What is the most important derangement of these enzyme derangement?

Answer 40

hereditary deficiency of glucose-6-phosphate dehydrogenase (G6PD) activity.

Question 41

What is the function of G6PD?

Answer 41

G6PD reduces
nicotinamide adenine dinucleotide phosphate (NADP) to NADPH while oxidizing glucose-6-
phosphate ( Fig. 14-5 ).

NADPH then provides reducing equivalents needed for conversion of oxidized glutathione to reduced glutathione, which protects against oxidant injury by catalyzing the breakdown of compounds such as H2O2 ( Chapter 1 ).
Anemias
1196

Question 42

Answer 42

FIGURE 14-5 Role of glucose-6-phosphate dehydrogenase (G6PD) in defense against
oxidant injury. The disposal of H2O2, a potential oxidant, is dependent on the adequacy of
reduced glutathione (GSH), which is generated by the action of the reduced form of
nicotinamide adenine dinucleotide (NADPH). The synthesis of NADPH is dependent on the
activity of G6PD. GSSG, oxidized glutathione.

Question 43

What type of hereditary disease is G6PD deficiency

Answer 43

recessive X-linked trait, placing males at higher risk for symptomatic disease.

Question 44

Several hundred G6PD genetic variants are known, but most are harmless.

Only two

variants, __________ cause most of the clinically significant
hemolytic anemias.

Answer 44

G6PD - and G6PD Mediterranean

G6PD - is present in about 10% of American blacks; G6PD Mediterranean, as the name implies, is prevalent in the Middle East. The high frequency of these variants in each population is believed to stem from a protective effect against Plasmodium falciparum
malaria

Question 45

G6PD variants associated with hemolysis result in misfolding of the protein, making it more
susceptible to proteolytic degradation.

Compared with the most common normal variant, G6PD B, the half-life of G6PD - is moderately reduced, whereas that of G6PD Mediterranean is more
markedly abnormal.

Because mature red cells do not synthesize new proteins, G6PD - or G6PD
Mediterranean enzyme activities fall quickly to levels inadequate to protect against oxidant
stress as red cells age. Thus, older red cells are much more prone to hemolysis than younger
ones.

Question 46

What is the characteristic of G6PD?

Answer 46

The episodic hemolysis that is characteristic of G6PD deficiency is caused by exposures that
generate oxidant stress.

Question 47

What is the most common triggers of episodic G6PD hemolysis?

Answer 47

The most common triggers are infections, in which oxygen-derived free
radicals are produced by activated leukocytes.

Many infections can trigger hemolysis; viral
hepatitis, pneumonia, and typhoid fever are among those most likely to do so.

The other
important initiators are drugs and certain foods.

Question 48

What are the oxidant drugs that trigger G6PD hemolysis?

Answer 48

The oxidant drugs implicated are numerous,
including antimalarials (e.g., primaquine and chloroquine), sulfonamides, nitrofurantoins, and
others.

Some drugs cause hemolysis only in individuals with the more severe Mediterranean
variant.

Question 49

What is the most frequent cited food which generates oxidants when metabolized?

Answer 49

The most frequently cited food is the fava bean, which generates oxidants when
metabolized. “

Favism” is endemic in the Mediterranean, Middle East, and parts of Africa where consumption is prevalent.

• *Uncommonly, G6PD deficiency presents as neonatal jaundice or a chronic low-grade hemolytic anemia in the absence of infection or known environmental
  triggers. **

Question 50

Oxidants cause both intravascular and extravascular hemolysis in G6PD-deficient individuals .

T or F

Answer 50

True

Question 51

What are Heinz bodies?

Answer 51

Exposure of G6PD-deficient red cells to high levels of oxidants causes the cross-linking of
reactive sulfhydryl groupsonglobin chains, which become denaturedandform membranebound
precipitates known as Heinz bodies.

These are seen as dark inclusions within red cells
stained with crystal violet( Fig. 14-6 ).

Heinz bodies can damage the membrane sufficiently to cause intravascular hemolysis.

Less severe membrane damage results in decreased red cell deformability. As inclusion-bearing red cells pass through the splenic cords, macrophages pluck
out the Heinz bodies.

As a result of membrane damage, some of these partially devoured cells retain an abnormal shape, appearing to have a bite taken out of them (see Fig. 14-6 ). Other
less severely damaged cells revert to a spherocytic shape due to loss of membrane surface
area.

Both bite cells and spherocytes are trapped in splenic cords and removed rapidly by
phagocytes.

Question 52

Answer 52

FIGURE 14-6 G6PD deficiency: effects of oxidant drug exposure (peripheral blood smear).
Inset, Red cells with precipitates of denatured globin (Heinz bodies) revealed by supravital
staining.

As the splenic macrophages pluck out these inclusions, “bite cells” like the one in
this smear are produced.

Question 53

What happens after 2 to 3 days of exposure of G6PD-deficient individuals to oxidants

Answer 53

Acute intravascular hemolysis, marked by anemia, hemoglobinemia, and hemoglobinuria ,
usually begins 2 to 3 days following exposure of G6PD-deficient individuals to oxidants.

The
hemolysis tends to be greater in individuals with the highly unstable G6PD Mediterranean
variant.

Question 54

Why is the episode of acute hemolysis in G6PD individuals self-limited?

Answer 54

Since only older red cells are at risk for lysis, the episode is self-limited, since
hemolysis ceases when only younger G6PD-replete red cells remain (even if administration of
an offending drug continues).

The recovery phase is heralded by reticulocytosis.

Question 55

What is sickle cell disease?

Answer 55

Sickle cell disease is a common hereditary hemoglobinopathy that occurs primarily in
individuals of African descent

Question 56

What is the biochemical structure of Hgb?

Answer 56

Hemoglobin, as you recall, is a
tetrameric protein composed of two pairs of globin chains, each with its own heme group.
Normal adult red cells contain mainly HbA (α2β2), along with small amounts of HbA2 (α2δ2) and
fetal hemoglobin (HbF; α2γ2).

Question 57

What is the normal adult red cells composition?

Answer 57

HbA (α2β2),

along with small amounts of HbA2 (α2δ2) and
fetal hemoglobin (HbF; α2γ2).

Question 58

What is the cause of Sickle disease?

Answer 58

• *point mutation** in the sixth
• *codon of β-globin** that leads to the replacement of a glutamate residue with a valine residue responsible for the disease

GV is sick!!!

Question 59

What is the epidemiology of Sickle Cell Disease?

Answer 59

About 8% to 10% of African Americans, or roughly 2 million individuals, are heterozygous for
HbS, a largely asymptomatic condition known as sickle cell trait.

The offspring of two
heterozygotes has a 1 in 4 chance of being homozygous for the sickle mutation, a state that
produces symptomatic sickle cell disease.

In such individuals, almost all the hemoglobin in the
red cell is HbS (α2β s 2). There are about 70,000 individuals with sickle cell disease in the
United States. In certain populations in Africa the prevalence of heterozygosity is as high as
30%. This high frequency probably stems from protection afforded by HbS against falciparum
malaria.

Question 60

What is the pathogenesis of HbS?

Answer 60

HbS molecules undergo polymerization when deoxygenated .

Initially the red cell cytosol
converts from a freely flowing liquid to a viscous gel as HbS aggregates form.

With continued
deoxygenation aggregated HbS molecules assemble into long needle-like fibers within red cells,
producing a distorted sickle or holly-leaf shape.

Question 61

The presence of HbS underlies the major pathologic manifestations:

Answer 61

(1) chronic hemolysis,
(2) microvascular occlusions, and
(3) tissue damage.

Question 62

Several variables affect the rate and degree
of sickling:

Answer 62

• Interaction of HbS with the other types of hemoglobin in the cell
• Mean cell hemoglobin concentration (MCHC).
• Intracellular pH.
• Transit time of red cells through microvascular beds

Question 63

What is the reason why heterozygotes with sickle cell trait do not sickle except under conditions of profound hypoxia?

Answer 63

In heterozygotes with
sickle cell trait, about 40% of the hemogtlobin is HbS and the rest is HbA, which
interferes with HbS polymerization.

As a result, red cells in heterozygous individuals do
not sickle except under conditions of profound hypoxia.

Question 64

Why are infants do not become symptomatic until they reach 5 or 6 months of age?

Answer 64

HbF inhibits the polymerization
of HbS even more than HbA; hence, infants do not become symptomatic until they reach
5 or 6 months of age, when the level of HbF normally falls.

Question 65

What is hereditary persistence of HbF?

Answer 65

However, in some individuals
HbF expression remains at relatively high levels, a condition known as hereditary persistence of HbF

in these individuals, sickle cell disease is much less severe.

Question 66

What is HbC?

Answer 66

Another
variant hemoglobin is HbC, in which lysine is substituted for glutamate in the sixth amino
acid residue of β-globin.

In HbSC cells the percentage of HbS is 50%, as compared with only 40% in HbAS cells.

Moreover, HbSC cells tend to lose salt and water and become dehydrated, which increases the intracellular concentration of HbS.

Both of these
factors increase the tendency for HbS to polymerize.

As a result, individuals with HbS
and HbChave asymptomatic sickling disorder (termed HbSC disease), but it is milder than sickle cell disease.

About 2% to 3% of American blacks are asymptomatic HbC heterozygotes, and about 1 in 1250 has HbSC disease

Question 67

What is HbSC disease?

Answer 67

Another variant hemoglobin is HbC, in which lysine is substituted for glutamate in the sixth amino
acid residue of β-globin.

In HbSC cells the percentage of HbS is 50%, as compared with only 40% in HbAS cells.

Moreover, HbSC cells tend to lose salt and water and become dehydrated, which increases the intracellular concentration of HbS.

*Both of these
factors increase the tendency for HbS to polymerize.*

As a result, individuals with HbS
and HbC have a symptomatic sickling disorder (termed HbSC disease), but it is milder than sickle cell disease.

About 2% to 3% of American blacks are asymptomatic HbC heterozygotes, and about 1 in 1250 has HbSC disease

Question 68

Why does conditions that increase MCHC increase the disease severity?

Answer 68

Mean cell hemoglobin concentration (MCHC).

• *Higher HbS concentrations** increase the
• *probability that aggregation and polymerization** will occur during any given period of deoxygenation.

Thus, intracellular dehydration, which increases the MCHC, facilitates sickling.

Conversely, conditions that decrease the MCHC reduce the disease severity.
This occurs when the individual is homozygous for HbS but also has coexistent α-
thalassemia, which reduces Hb synthesis and leads to milder disease.

Question 69

What conditions that increase MCHC increase the disease severity?

Answer 69

intracellular dehydration, which increases the MCHC, facilitates sickling.

Question 70

What pH will increase the fraction of deoxygenated HbS at any given oxygen tension and augment the tendency for sickling?

Answer 70

. A decrease in pH reduces the oxygen affinity of hemoglobin, thereby increasing the fraction of deoxygenated HbS at any given oxygen tension and
augmenting the tendency for sickling.

Question 71

How does transit time affect the sickling of cells?

Answer 71

Transit times in most normal microvascular beds are too short for significant aggregation of deoxygenated HbS to occur, and as a result sickling is
confined to microvascular beds with slow transit times.

Transit times are slow in the
normal spleen and bone marrow, which are prominently affected in sickle cell disease,
and also in vascular beds that are inflamed.

The movement of blood through inflamed tissues is slowed because of the adhesion of leukocytes and red cells to activated endothelial cells and the transudation of fluid through leaky vessels.

As a result, inflamed vascular beds are prone to sickling and occlusion.

Sickle red cells may express elevated levels of several adhesion molecules that have been implicated in binding to endothelial cells. [4] [5] [6]

There is also
evidence suggesting that sickle red cells induce some degree of endothelial activation, [7] which may be related to the adhesion of red cells and granulocytes, vasoocclusion– induced hypoxia, and other insults.

Question 72

Sickling causes cumulative damage to red cells through what mechanisms?

Answer 72

As HbS polymers grow, they herniate through the membrane skeleton and project from the cell ensheathed by only the lipid bilayer.

This severe derangement in membrane structure causes the influx of Ca [2] + ions, which induce the cross-linking of membrane proteins and activate an ion channel that permits the efflux of K + and H2O.

With repeated episodes of sickling, red cells become increasingly dehydrated, dense, and rigid ( Fig. 14-7 ).

Eventually, the most severely damaged
cells are converted to end-stage, nondeformable, irreversibly sickled cells, which retain a sickle
shape even when fully oxygenated.

The severity of the hemolysis correlates with the
percentage of irreversibly sickled cells, which are rapidly sequestered and removed by
mononuclear phagocytes (extravascular hemolysis). Sickled red cells are also mechanically
fragile, leading to some intravascular hemolysis as well.

Question 73

The severity of the hemolysis correlates with the
percentage of irreversibly sickled cells,which are rapidly sequestered and removed by
mononuclear phagocytes (extravascular hemolysis).

T or F

Answer 73

Sickled red cells are also mechanically
fragile, leading to some intravascular hemolysis as well.

Question 74

Answer 74

FIGURE 14-7 Pathophysiology of sickle cell disease

Question 75

What is the pathophysiology of the microvascular occlusions?

Answer 75

The pathogenesis of the microvascular occlusions, which are responsible for the most serious
clinical features, is less certain.

Microvascular occlusions are not related to the number of irreversibly sickled cells in the blood, but instead may be dependent upon more subtle red cell
membrane damage and other factors, such as inflammation, that tend to slow or arrest the
movement of red cells through microvascular beds (see Fig. 14-7 ).

Sickle red cells express higher than normal levels of adhesion molecules and are sticky.

Mediators
released from granulocytes during inflammatory reactions up-regulate the expression of
adhesion molecules on endothelial cells ( Chapter 2 ) and further enhance the tendency for sickle red cells to get arrested during transit throughthe microvasculature.

A possible role for
inflammatory cells is suggested by observations showing that the leukocyte count correlates
with the frequency of pain crises and other measures of tissue damage.

The stagnation of red
cells within inflamed vascular beds results in extended exposure to low oxygen tension, sickling,
and vascular obstruction.

Once started, it is easy to envision how a vicious cycle of sickling, obstruction, hypoxia, and more sickling ensues.

Depletion of nitric oxide (NO) may also play a
part in the vascular occlusions

. Free hemoglobin released from lysed sickle red cells can bind and inactivate NO, which is a potent vasodilator and inhibitor of platelet aggregation.

Thus,
reduced NO increases vascular tone (narrowing vessels) and enhances platelet aggregation,
both of which may contribute to red cell stasis, sickling, and (in some instances) thrombosis

Question 76

What is the appearance of full-blown sickle cell anemia?

Answer 76

the peripheral blood demonstrates variable
numbers of irreversibly sickled cells,reticulocytosis,and target cells, which result from red cell
dehydration ( Fig. 14-8 ).

Howell-Jolly bodies (small nuclear remnants) are also present in some red cells due to the asplenia (see below).

The bone marrow is hyperplastic as a result
of a compensatory erythroid hyperplasia.

Expansion of the marrow leads to bone resorption
and secondary new bone formation, resulting in prominent cheekbones and changes in the
skull that resemble a crew-cut in x-rays.

Extramedullary hematopoiesis can also appear. The
increased breakdown of hemoglobin can cause pigment gallstones and hyperbilirubinemia

Question 77

What is the appearanc ef spleen in early childhood of patients with Sickle cell?

Answer 77

In early childhood, the spleen is enlarged up to 500 gm by red pulp congestion, which is
caused by the trapping of sickled red cells in the cords and sinuses ( Fig. 14-9 ).

With time,
however, the chronic erythrostasis leads to splenic infarction, fibrosis, and progressive
shrinkage, so that by adolescence or early adulthood only a small nubbin of fibrous splenic
tissue is left; this process is called autosplenectomy ( Fig. 14-10 ).

Infarctions caused by
vascular occlusions can occur in many other tissues as well, including the bones, brain, kidney, liver, retina, and pulmonary vessels, the latter sometimes producing cor pulmonale.

In adult patients, vascular stagnation in subcutaneous tissues often leads to leg ulcers; this
complication is rare in children.

Question 78

What is autosplenectomy?

Answer 78

With time,
however, the chronic erythrostasis leads to splenic infarction, fibrosis, and progressive
shrinkage, so that by adolescence or early adulthood only a small nubbin of fibrous splenic
tissue is left; this process is called autosplenectomy ( Fig. 14-10 ).

Infarctions caused by
vascular occlusions can occur in many other tissues as well, including the bones, brain,
kidney, liver, retina, and pulmonary vessels, the latter sometimes producing cor pulmonale.

In adult patients, vascular stagnation in subcutaneous tissues often leads to leg ulcers; this
complication is rare in children.

Question 79

Answer 79

FIGURE 14-8 Sickle cell disease (peripheral blood smear).

• A, Low magnification shows sickle cells, anisocytosis, and poikilocytosis.
• B, Higher magnification shows an irreversibly sickled cell in the center.

Question 80

Answer 80

FIGURE 14-9 A, Spleen in sickle cell disease (low power). Red pulp cords and sinusoids
are markedly congested; between the congested areas, pale areas of fibrosis resulting
from ischemic damage are evident. B, Under high power, splenic sinusoids are dilated and
filled with sickled red cells

Question 81

Answer 81

FIGURE 14-10 “Autoinfarcted” splenic remnant in sickle cell disease.

Question 82

What are the clinical features of sickle cella disease?

Answer 82

Sickle cell disease causes a moderately severe hemolytic anemia (hematocrit 18% to 30%) that
is associated with reticulocytosis, hyperbilirubinemia, and the presence of irreversibly sickled
cells. Its course is punctuatedby a variety of “crises.”

Question 83

What is Vaso-occlusive crises?

Answer 83

Vaso-occlusive crises, also called pain

• *crises,** are episodes of hypoxic injury and infarction that cause severe pain in the affected
• *region.**

Question 84

What can act as triggers for sickle cell?

Answer 84

Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances no predisposing cause is identified

Question 85

What are the commonly involved sites in sickle disease?

Answer 85

• bones,
• lungs,
• liver,
• brain,
• spleen, and
• penis.

Question 86

What is common in children with sickle cell disease?

Answer 86

In children, painful bone crises are
extremely common and often difficult to distinguish from acute osteomyelitis

These frequently
manifest as the hand-foot syndrome or dactylitis of the bones of the hands or feet, or both.

Question 87

What is a particularly dangerous type of vaso-occlusive crisis involving the lungs, which typically presents with fever, cough, chest pain, and pulmonary infiltrates?

Answer 87

Acute chest syndrome

Pulmonary inflammation (such as may be induced by a simple infection) causes blood flow to
become sluggish and “spleenlike,” leading to sickling and vaso-occlusion.

This compromises
pulmonary function, creating a potentially fatal cycle of worsening pulmonary and systemic
hypoxemia, sickling, and vaso-occlusion.

Other forms of vascular obstruction, particularly
stroke, can take a devastating toll.

Factors proposed to contribute to stroke include the
adhesion of sickle red cells to arterial vascular endothelium and vasoconstriction caused by the
depletion of NO by free hemoglobin

Question 88

What are the factors the proposed to stroke in sickle cell disease?

Answer 88

Factors proposed to contribute to stroke include the

• *adhesion of sickle red cells t**o arterial vascular endothelium and vasoconstriction caused by the
• *depletion of NO by free hemoglobin.**

Question 89

What is the most common cause of patient morbidity and mortality in sickle cell disease?

Answer 89

occlusive crises
alathou several other acute events complicate the course.

Question 90

When does sequestratio crises occur?

Answer 90

Sequestration crises occur in children with
intact spleens.

Massive entrapment of sickle red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock.

These complications may be fatal in several cases.
Survival from sequestration crises and the acute chest syndrome requires treatment with exchange transfusions.

Question 91

Where does Aplastic crises stem from?

Answer 91

Aplastic crises stem from the infection of red cell progenitors by
parvovirus B19, which causes a transient cessation of erythropoiesis and a sudden worsening
of the anemia.

Question 92

In sickle cell what is responsible for a generalized impairment of growth d development?

Answer 92

Chronic hypoxia is responsible for a generalized impairment of growth and development, as well
as organ damage affecting spleen, heart, kidneys, and lungs.

Question 93

What is the reason for patients of sickle cell disease to have hyposthenuria?

Answer 93

Sickling provoked by
hypertonicity in the renal medulla causes damage that eventually leads to hyposthenuria (the
inability to concentrate urine), whichincreases the propensity for dehydration and its attendant
risks.

Question 94

Why does Increased susceptibility to infection with encapsulated organisms is another threat to patients with sickle cell disease?

Answer 94

Increased susceptibility to infection with encapsulated organisms is another threat.

This is due
in large part to altered splenic function, which is severely impaired in children by congestion
and poor blood flow, andcompletely absent in adults because of splenic infarction.

Defects of
uncertain etiology in the alternative complement pathway also impair the opsonization of
bacteria.

Pneumococcus pneumoniae and Haemophilus influenzae septicemia and meningitis,
common causes of death, particularly in children, can be reduced by vaccination and
prophylactic antibiotics.

Question 95

there is great variation in the clinical manifestations of sickle cell
disease.

T or F

Answer 95

True

It must be emphasized that there is great variation in the clinical manifestations of sickle cell
disease. Some individuals are crippled by repeated vaso-occlusive crises, whereas others have
only mild symptoms. The basis for this wide range in disease expression is not understood

Question 96

How to diagnose sickle cell disease?

Answer 96

The diagnosis is suggested by the clinical findings and the presence of irreversibly sickled red
cells and is confirmed by various tests for sickle hemoglobin.

In general, these involve mixing a
blood sample with an oxygen-consuming reagent,such asmetabisulfite, whichinduces sickling
of red cells if HbS is present.

Hemoglobin electrophoresis is also used to demonstrate the presence of HbS and exclude other sickle syndromes, such as HbSC disease.

Prenatal
diagnosis is possible by analysis of fetal DNA obtained by amniocentesis or chorionic biopsy.

Question 97

What is the mainstay of treatment for sickle disease?

Answer 97

The outlook for patients with sickle cell disease has improved considerably over the last 10 to
20 years. About 90% of patients survive to age 20, and close to 50% survive beyond the fifth
decade.

A mainstay of treatment is an inhibitor of DNA synthesis, hydroxyurea, which has
several beneficial effects.

These include :

• (1) an increase in red cell HbF levels, which occurs by unknown mechanisms; and
• (2) an anti-inflammatory effect, which stems from an inhibition of white cell production. These activities (and possibly others [9] ) are believed to act in concert to decrease crises related to vascular occlusions in both children and adults.

Question 98

What is Thalassemia syndrome?

Answer 98

The thalassemia syndromes are a heterogeneous group of disorders caused by inherited
mutationsthatdecrease the synthesis of adult hemoglobin, HbA (α2β2).

Question 99

What chromosome does the two α chains in HbA are encoded?

Answer 99

The two α chains in
HbA are encoded by an identical pair of α-globin genes on chromosome 16

Question 100

To what chromosome do the β
chains are encoded?

Answer 100

while the two β
chains are encoded by a single β-globin gene on chromosome 11

Question 101

What is the caused for β-Thalassemia?

Answer 101

β-Thalassemia is caused by
deficient synthesis of β chains,

Question 102

What is deficient in α-thalassemia?

Answer 102

α-thalassemia is caused by deficient synthesis of α
chains.

Question 103

What is the epidemiology of Thalassemia syndromes?

Answer 103

Thalassemia syndromes are endemic in the Mediterranean basin,
the Middle East, tropical Africa, the Indian subcontinent, and Asia, and in aggregate are among
the most common inherited disorders of humans

.

Question 104

As with sickle cell disease and other common
inherited red cell disorders,Thalassemia prevalence seems to be explained by what?

Answer 104

the protection they
afford heterozygous carriers against malaria. [3]

Although we will discuss the thalassemia
syndromes with other inherited forms of anemia associated with hemolysis, it is important to
recognize that the defects in globin synthesis that underlie these disorders also impair red cell
production and contribute to the pathogenesis of these disorders.

Question 105

What is β-thalassemias?

Answer 105

The β-thalassemias are caused by mutations that diminish the synthesis of β-globin chains.

The clinical severity varies because of heterogeneity in the causative mutations.

We will begin
our discussion with the molecular lesions in β-thalassemia and then relate the clinical variants
to specific underlying molecular defects.

Question 106

The causative mutation of β- Thalassemia s fall into two categories :

Answer 106

• (1) β 0 mutations
• (2) β + mutations

Question 107

What is β 0 mutations?

Answer 107

β 0 mutationsβ 0 mutations

Question 108

What is β + mutations?

Answer 108

characterized by reduced (but detectable) β-globin
synthesis.

Question 109

Sequencing of β-thalassemia genes has revealed more than 100 different causative
mutations, mostly consisting of point mutations. Details of these mutations and their effects are
found in specialized texts. Figure 14-11 gives a few illustrative examples

Answer 109

• Splicing mutations
• Promoter region mutations
• Chain terminator mutations

Question 110

What are the most common cause of β + -thalassemia

Answer 110

Splicing mutations

Most of
these mutations lie within introns, while a few are located within exons.

Some of these mutations destroy the normal RNA splice junctions and completely prevent the
production of normal β-globin mRNA, resulting in β 0 -thalassemia.

Others create an
“ectopic” splice site within an intron.

Because the flanking normal splice sites remain,
both normal and abnormal splicing occurs and some normal β-globin mRNA is made,
resulting in β + -thalassemia.

Question 111

Why are Promoter region mutations associated with β + -
thalassemia

Answer 111

These mutations reduce transcription by 75% to 80%. Some normal β-globin is synthesized; thus, these mutations are associated with β + -
thalassemia

Question 112

What are the most common cause of β 0 -thalassemia.

Answer 112

Chain terminator mutations.

Question 113

What are the Two subtypes of Chain terminator mutations?

Answer 113

• The most common type creates a new stop codon within an exon;
• the second introduces small insertions or deletions that shift the mRNA reading frames (frameshift mutations; see Chapter 5 ).

Both block translation and prevent the synthesis of any functional β-globin.

Question 114

Answer 114

FIGURE 14-11 Distribution of β-globin gene mutations associated with β-thalassemia.
Arrows denote sites where point mutations giving rise to β 0 or β + thalassemia have been
identified.

Question 115

Impaired β-globin synthesis results in anemia by two mechanisms

Answer 115

1. Ineffective erythropoiesis
2. Extravascular hemolysis

Question 116

What is the reason for the underhemoglobinized hypochromic, microcytic red cells with subnormal oxygen transport capacity

Answer 116

The deficit in
HbA synthesis

Question 117

What is the reason for the diminished survival of red
cells and their precursors

Answer 117

which results from the imbalance in α- and β-globin synthesis.

Question 118

What is the reason why there are inclusions in β-thalassemia?

Answer 118

Unpaired α chains precipitate within red cell precursors, forming insoluble inclusions.

T hese
inclusions cause a variety of untoward effects, but membrane damage is the proximal cause of
most red cell pathology.

Question 119

What is the proximal cause of
most red cell pathology in β-thalassemia?

Answer 119

membrane damage is the

Question 120

What is the reason for the ineffective erythropoiesis in β-thalassemia

Answer 120

Many red cell precursors succumb to membrane damage and undergo apoptosis.

In severe β-thalassemia, it is estimated that 70% to 85% of red cell precursors suffer
this fate, which leads to ineffective erythropoiesis.

Those red cells that are released from the
marrow also bear inclusions and membrane damage and are prone to splenic sequestration
and extravascular hemolysis.

Question 121

Answer 121

FIGURE 14-12 Pathogenesis of β-thalassemia major. Note that the aggregates of unpaired
α-globin chains, a hallmark of the disease, are not visible in routinely stained blood smears.
Blood transfusions are a double-edged sword, diminishing the anemia and its attendant
complications, but also adding to the systemic iron overload.

Question 122

In severe β-thalassemia, ineffective erythropoiesis creates several additional problems.

What are these problems?

Answer 122

• Erythropoietic drive in the setting of severe uncompensated anemia
• *leads to massive erythroid** hyperplasia in the marrow and extensive extramedullary hematopoiesis.
• The e xpanding mass of red cell precursors erodes the bony cortex, impairs bone growth, and produces skeletal abnormalities (described later).
• Extramedullary hematopoiesis involves the liver, spleen, and lymph nodes, and in extreme cases produces extraosseous masses in the thorax, abdomen, and pelvis. The metabolically active erythroid progenitors steal nutrients from other tissues that are already oxygen-starved, causing severe cachexia in untreated patients
• Another serious complication of ineffective erythropoiesis is the excessive absorption of dietary iron. Ineffective erythropoiesis suppresses the circulating levels of hepcidin, a critical negative regulator of iron absorption (described later under iron deficiency anemia). Low levels of hepcidin and the iron load of repeated blood transfusions inevitably lead to severe iron overload unless preventive steps are taken. Secondary injury to parenchymal organs, particularly the iron-laden liver, often follows and sometimes induces secondary hemochromatosis

Question 123

What is hepcidin?

Answer 123

hepcidin, a critical negative regulator of iron absorption (described later under iron deficiency anemia).

Question 124

What happens when severe thalassemia occur leading to Ineffective erythropoiesis suppresses the circulating levels of hepcidin?

Answer 124

Low levels of hepcidin and the iron load of repeated blood transfusions inevitably lead to severe iron overload unless preventive steps are taken.

Secondary injury to parenchymal organs,
particularly the iron-laden liver, often follows and sometimes induces secondary
hemochromatosis

Question 125

Clinical classification of β-thalassemia is based on the severity of the anemia, which in turn
depends on the what?

Answer 125

genetic defect (β + or β 0 ) and the gene dosage (homozygous or
heterozygous).

Question 126

What is β-thalassemia major?

Answer 126

In general, individuals with two β-thalassemia alleles (β + /β + , β + /β 0 , or β 0 /
β 0 ) have a severe, transfusion-dependent anemia called β-thalassemia major .

Question 127

What is β-thalassemia minor or β
-thalassemia trait?

Answer 127

Heterozygotes
with one βthalassemia gene and one normal gene (β + /β or β 0 /β) usually have a mild
asymptomatic microcytic anemia.

This condition is referred to as β-thalassemia minor or β
-thalassemia trait

Question 128

What is β
-thalassemia intermedia?

Answer 128

A third genetically heterogeneous variant of moderate severity is called β
-thalassemia intermedia.

This category includes milder variants of β + /β + or β + /β 0 - thalassemia and unusual forms of heterozygous β-thalassemia.

Some patients with β-
thalassemia intermedia have two defective β-globin genes and an α-thalassemia gene defect,
which lessens the imbalance in α- and β-chain synthesis.

In other rare but informative cases,
individuals have a single β-globin defect and one or two extra copies of normal α-globin genes
(stemming from a gene duplication event), which worsens the chain imbalance. [10]

Question 129

What does it says about the unusual forms of the β-thalassemia intermedia?

Answer 129

These unusual forms of the disease serve to emphasize the cardinal role of unpaired α-globin chains
in the pathology.

Question 130

The clinical and morphologic features of β-thalassemia intermedia are not
described separately but can be surmised from the following discussions of β-thalassemia major
and β-thalassemia minor.

Question 131

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

β-THALASSEMIAS

Answer 131

• β- Thalassemia major
• β- Thalassemia intermedia
• β- Thalassemia minor

Question 132

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

Answer 132

• Silent carrier
• α- Thalassemia trait
• HbH disease
• Hydrops fetalis

Question 133

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

β- Thalassemia
major

Answer 133

• Genotype :Homozygous β- thalassemia (β 0 / β 0 , β + /β + , β 0 / β + )
• Clinical Features: Severe; requires blood
  transfusions
• Molecular Genetics: Mainly point mutations that lead to defects in the transcription, splicing,
  or translation of β-globin mRNA

Question 134

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

β- Thalassemia
intermedia

Answer 134

• Genotype :Variable (β 0 /β + , β + /β + , β 0 /β, β + /β)
• Clinical Features: Severe but does not require regular blood transfusions
• Molecular Genetics: Mainly point mutations that lead to defects in the transcription, splicing,
  or translation of β-globin mRNA

Question 135

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

β- Thalassemia
minor

Answer 135

• Genotype: Heterozygous β- thalassemia (β 0 /β, β + /β)
• Clinical Features: Asymptomatic with mild or absent anemia; red cell abnormalities seen
• Molecular Genetics: Mainly point mutations that lead to defects in the transcription, splicing,
  or translation of β-globin mRNA

Question 136

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

Silent carrier

Answer 136

Genotype :-/α α/α

Clinical Features : Asymptomatic; no red cell
abnormality

Molecular Genetics :Mainly gene deletions

Question 137

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

Silent carrier

Answer 137

• Genotype: -/α α/α
• Clinical Features: Asymptomatic; no red cell
  abnormality
• Molecular Genetics: Mainly gene deletions

Question 138

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

α-
Thalassemia
trait

Answer 138

• Genotype: -/- α/α (Asian)
• Clinical Features : Asymptomatic, like β-thalassemia minor
• Molecular Genetics: Mainly gene deletions

Question 139

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

α- Thalassemia trait ( Black, African, Asian)

Answer 139

• Genotype: -/α -/α ( Black, African, Asian)
• Clinical Features: Asymptomatic like β-Thalassemia minor.
• Molecular Genetics: Mainly gene deletions

Question 140

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

HbH disease

Answer 140

Genotype :-/- -/α

Clinical Features : Severe; resembles β-
thalassemia intermedia

Molecular Genetics: Mainly gene deletions

Question 141

TABLE 14-3 – Clinical and Genetic Classification of Thalassemias

α-THALASSEMIAS

Hydrops
fetalis

Answer 141

• Genotype : -/- -/-
• Clinical Features :Lethal in utero without
  transfusions
• Molecular Genetics: Mainly gene deletions

Question 142

β-thalassemia major is most common where?

Answer 142

• Mediterranean countries,
• parts of Africa, and Southeast Asia.

Question 143

What age does β-Thalassemia Major.manifest?

Answer 143

The anemia manifests 6 to 9 months after birth as hemoglobin synthesis switches from HbF to HbA.

Question 144

What happens to the hgb levels of untransfused patients in β-Thalassemia Major.

Answer 144

In
untransfused patients, hemoglobin levels are 3 to 6 gm/dL.

The red cells may completely lack HbA (β 0 /β 0 genotype) or contain small amounts (β + /β + or β 0 /β + genotypes).

The major red
cell hemoglobin is HbF,which is markedly elevated. HbA2 levels are sometimes high but more
often are normal or low.

Question 145

What is the morphology of β-thalassemia major?

Answer 145

Blood smears show severe red cell abnormalities, including marked variation in size (anisocytosis) and shape (poikilocytosis), microcytosis, and hypochromia.

Target cells (so
called because hemoglobin collects in the center of the cell), basophilic stippling, and
fragmented red cells are also common.

Inclusions of aggregated α chains are efficiently
removed by the spleen and not easily seen.

The reticulocyte count is elevated, but it is lower
than expected for the severity of anemia because of the ineffective erythropoiesis.

Variable
numbers of poorly hemoglobinized nucleated red cell precursors (normoblasts) are seen in
the peripheral blood as a result of “stress” erythropoiesis and abnormal release from sites of
extramedullary hematopoiesis.

Question 146

What is the apperance of the Red cells of patients with β-thalassemia major?

Answer 146

Target cells (so
called because hemoglobin collects in the center of the cell), basophilic stippling, and
fragmented red cells are also common.

Question 147

Why do inclusions of aggregated α chains in β-thalassemia major are not seen?

Answer 147

Inclusions of aggregated α chains are efficiently
removed by the spleen and not easily seen.

Question 148

Why is the reticulocyte count is elevated, but it is lower
than expected for the severity of anemia in β-thalassemia major ?

Answer 148

because of the ineffective erythropoiesis.

Question 149

Why are Variable
numbers of poorly hemoglobinized nucleated red cell precursors (normoblasts) are seen in
the peripheral blood of β-thalassemia major ?

Answer 149

as a result of “stress” erythropoiesis and abnormal release from sites of
extramedullary hematopoiesis.

Question 150

What are the other major alterations involve in β-Thalassemia Major?

Answer 150

Other major alterations involve the bone marrow and spleen.

Question 151

What is striking in the untransfused patient β-Thalassemia Major

Answer 151

there is a striking expansion of hematopoietically active marrow.

Question 152

What is the reason for the crew-cut” appearance on x-ray of β-Thalassemia Major?

Answer 152

In the bones of the face and
skull the burgeoning marrow erodes existing cortical bone and induces new bone formation,
giving rise to a “crew-cut” appearance on x-ray ( Fig. 14-13 ).

Question 153

What is the reason for the enlargement of the spleen, liver and lymphnodes in β-Thalassemia Major patients?

Answer 153

Both phagocyte hyperplasia
and extramedullary hematopoiesis contribute to enlargement of the spleen, which can weigh
as much as 1500 gm.

The liver and the lymph nodes can also be enlarged by extramedullary
hematopoiesis.

Question 154

What are the two manifestation of iron overload in β-Thalassemia Major patients?

Answer 154

Hemosiderosis and secondary hemochromatosis, the two manifestations of iron overload (
Chapter 18 ), occur in almost all patients.

The deposited iron often damages organs, most
notably the heart, liver, and pancreas.

Question 155

Answer 155

FIGURE 14-13 Thalassemia: x-ray film of the skull showing new bone formation on the
outer table, producing perpendicular radiations resembling a crewcut

Question 156

What is the clinical course of β-thalassemia major?

Answer 156

The clinical course is brief unless blood transfusions are given.

Question 157

Why do Untreated children of β-Thalassemia Major suffer from growth retardation and die at an early age?

Answer 157

from the effects of
anemia.

In those who survive long enough, the cheekbones and other bony prominences are
enlarged and distorted.

Hepatosplenomegaly due to extramedullary hematopoiesis is usually
present.

Question 158

What are the complications contributed by blood transfusions in β-Thalassemia Major?

Answer 158

Although blood transfusions improve the anemia and suppress complications related to
excessive erythropoiesis, they lead to complications of their own.

Cardiac disease resulting from
progressive iron overload and secondary hemochromatosis ( Chapter 18 ) is an important
cause of death, particularly in heavily transfused patients, who must be treated with iron
chelators to prevent or reduce this complication.

With transfusions and iron chelation, survival
into the third decade is possible, but the overall outlook remains guarded.

Question 159

What is the only therapy offering a cure and is being used increasingly for β-Thalassemia Major?

Answer 159

Bone marrow
transplantation

Prenatal
diagnosis is possible by molecular analysis of DNA.

Question 160

How can survival in the third devade possiblefor β-Thalassemia Major?

Answer 160

With transfusions and iron chelation

Question 161

Which is more common β-Thalassemia minor or major?

Answer 161

β-Thalassemia minor

Question 162

What is β-Thalassemia minor?

Answer 162

• more common than β-thalassemia major
• affects the same ethnic groups
• Most patients are heterozygous carriers of a β + or β 0 allele.
• usually asymptomatic
• Anemia, if present, is mild

Question 163

What is the apperance of the peripheral blood smear of β-Thalassemia Minor?

Answer 163

• red cell abnormalities,
• including hypochromia, microcytosis,
• basophilic stippling, and target cells.

Question 165

What is revealed in the Hemoglobin electrophoresis of β-Thalassemia Minor?

Answer 165

increase in HbA2 (α2δ2) to 4% to 8% of the total
hemoglobin (normal, 2.5% ± 0.3%), which is a reflection of an elevated ratio of δ-chain to β-
chain synthesis.

HbF levels are generally normal or occasionally slightly increased.

Question 166

Recognition of β-thalassemia trait is important for two reasons:

Answer 166

• (1) differentiation from the hypochromic microcytic anemia of iron deficiency and
• (2) genetic counseling.

Question 167

Recognition of β-thalassemia trait is important fort the: differentiation from the
hypochromic microcytic anemia of iron deficiency, how will you do that?

Answer 167

Iron deficiency
can usually be excluded through measurement of :

• serum iron,
• total iron-binding capacity, and
• serum ferritin (as described later under iron deficiency anemia).

Question 168

What is useful in the diagnosis particularly in individuals (such as women of childbearing age) who are at risk for both β-thalassemia trait and iron deficiency?

Answer 168

The increase in HbA2 is
diagnostically useful,

Question 169

What is the pathophysiology of α-thalassemias?

Answer 169

The α-thalassemias are caused by inherited deletions that result in reduced or absent
synthesis of α-globin chains.

Normally, there are four α-globin genes, and the severity of α- thalassemia depends on how many α-globin genes are affected.

Question 170

As in β-thalassemias, the
anemia stems both from what?

Answer 170

a lack of adequate hemoglobin and the effects of excess unpaired non-α chains (β, γ, and δ), which vary in type at different ages

Question 171

What is hemoglobin Barts?

Answer 171

In newborns with α-thalassemia,
excess unpaired γ-globin chains form γ4 tetramers known as hemoglobin Barts

B for Bata

Question 172

What is HbH?

Answer 172

whereas in
older children and adults excess β-globin chains form β4 tetramers known as HbH.

Hapatan!

Question 173

Why are α-Thalassemias less severe than β-thalassemias?

Answer 173

• *Since free β and γ chains are more soluble than free α chains** and form fairly stable homotetramers,
• *hemolysis and ineffective erythropoiesis** are less severe than in β-thalassemias.

Question 174

What is the most common cause of
reduced α-chain synthesis?

Answer 174

A variety of
molecular lesions give rise to α-thalassemia, but gene deletion is the most common cause of
reduced α-chain synthesis.

Question 175

What is the Silent Carrier State of α-Thalassemia

Answer 175

This is associated with the deletion of a single α-globin gene, which causes a barely detectable
reduction in α-globin chain synthesis.

These individuals are completely asymptomatic, but they
have slight microcytosis.

Question 176

What is thepathophysio of α-Thalassemia Trait?

Answer 176

This is caused by the deletion of two α-globin genes from a single chromosome (α/α α/α), or the
deletion of one α-globin gene from each of the two chromosomes (α/—α α/—α)

Question 177

In the α-Thalassemia Trait what is more common in Asian populations?

Answer 177

(α/α α/α),

Question 178

In the α-Thalassemia Trait what is more common in regions of Africa. ?

Answer 178

(α/—α α/—α)

Question 179

Why is symptomatic α-thalassemia is relatively common in Asian populations and rare in black African populations?

Answer 179

Both genotypes produce similar quantitative deficiencies of α-globin and are clinically identical,
but have different implications for the children of affected individuals, who are at risk of clinically
significant α-thalassemia (HbH disease or hydrops fetalis)only whenat least one parent has the
α/—α haplotype.

As a result, symptomatic α-thalassemia is relatively common in Asian populations and rare in black African populations.

Question 180

What is the clinical picture in α-thalassemia trait?

Answer 180

identical to that described for β-thalassemia minor, that is, small red cells (microcytosis), minimal
or no anemia,andno abnormal physical signs.

HbA2 levels are normal or low.

Question 181

What is the pathophysiology of Hemoglobin H Disease?

Answer 181

This is caused by deletion of three α-globin genes.

Question 182

Hemoglobin H Disease is most common in what population?

Answer 182

Asian

HbHazel

Question 183

What is the pathophysio of Hemoglobin H Disease?

Answer 183

With only one normal α-globin gene, the synthesis of α chains is
markedly reduced, andtetramers of β-globin,calledHbH, form.HbH has an extremely high
affinity for oxygen andtherefore is not useful for oxygen delivery, leading totissue hypoxia
disproportionate to the level of hemoglobin.

Additionally, HbH is prone to oxidation, which
causes it to precipitate out and form intracellular inclusions that promote red cell sequestration
and phagocytosis in the spleen.

The result is a moderately severe anemia resembling β- thalassemia intermedia.

Question 184

Why do HbH has moderately severe anemia resembling β- thalassemia intermedia.

Answer 184

Additionally, HbH is prone to oxidation, which
causes it to precipitate out and form intracellular inclusions that promote red cell sequestration
and phagocytosis in the spleen.

The result is a moderately severe anemia resembling β- thalassemia intermedia.

Question 185

What is the most severe form of α-thalassemia?

Answer 185

Hydrops Fetalis

Question 186

Why is Hydrops Fetalis the most severe form of α-thalassemia?

Answer 186

This most severe form of α-thalassemia is caused by deletion of all four α-globin genes.

In the
fetus, excess γ-globin chains form tetramers (hemoglobin Barts) that have such a high affinity
for oxygen that they deliver little to tissues.

Question 187

Survival in early development in Hydrops Fetalis is due to what?

Answer 187

Survival in early development is due to the
expression of ζ chains, anembryonic globinthatpairs with γ chains to form a functional ζ2γ2 Hb
tetramer.

Question 188

Whe do signs of fetal distress become evident in Hydrops Fetalis?

Answer 188

third trimester of pregnancy.

In the past, severe tissue anoxia led to death in utero or shortly after birth; with intrauterine
transfusion many such infants are now saved.

Question 189

What are the clinical features of Hydrops Fetalis?

Answer 189

The fetus shows severe pallor, generalized
edema, andmassive hepatosplenomegaly similar to that seen in hemolytic disease of the
newborn ( Chapter 10 ).

There is a lifelong dependence on blood transfusions for survival, with the associated risk of iron overload. Bone marrow transplantation can be curative

Question 190

What is Paroxysmal nocturnal hemoglobinuria (PNH)?

Answer 190

is a disease that results from acquired mutations
in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is
essential for the synthesis of certain cell surface proteins

Question 191

What is the incidence rate of PNH?

Answer 191

PNH has an incidence of 2 to 5 per
million in the United States.

Question 192

PNH is rare but why does it fascinates hematologists?

Answer 192

only hemolytic anemia caused by an acquired genetic defect.

Question 193

What is the pathophysiology of PNH?

Answer 193

Recall that proteins are anchored
into the lipid bilayer in two ways.

Most have a hydrophobic region that spans the cell membrane; these are called transmembrane proteins.

The others are attached to the cell membrane
through a covalent linkage to a specialized phospholipid called glycosylphosphatidylinositol
(GPI).

In PNH, these GPI-linked proteins are deficient because of somatic mutations that
inactivate PIGA.

PIGA is X-linked and subject to lyonization (random inactivation of one X chromosome in cells of females; Chapter 5 ).

As a result, a single acquired mutation in the
active PIGA gene of any given cell is sufficient to produce a deficiency state.

Because the
causative mutations occur in a hematopoietic stem cell, all of its clonal progeny (red cells, white
cells, and platelets) are deficient in GPI-linked proteins. Typically the mutant clone coexists with
the progeny of normal stem cells that are not PIGA deficient.

Question 194

most normal individuals harbor small numbers of bone marrow cells with PIGA mutations identical to those that cause PNH.

What is the reason for this?

Answer 194

It is hypothesized that these cells increase in
numbers (thus producing clinically evident PNH) only in rare instances where they have a
selective advantage,such as in the setting of autoimmune reactions against GPI-linked
antigens. [12] Such a scenario might explain the frequent association of PNH and aplastic
anemia, a marrow failure syndrome (discussed later) that has an autoimmune basis in many
individuals.

Question 195

What is the deficiency in PNH blood cells?

Answer 195

PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity:

• (1) decay–accelerating factor, or CD55;
• (2) membrane inhibitor of reactive lysis, or CD59; and
• (3) C8 binding protein.

Question 196

What is the most important deficient GPI-linked proteins in PNH blood cells?

Answer 196

membrane inhibitor of reactive lysis, or CD59;

Of these factors, the most important is CD59, a potent inhibitor of C3 convertase that prevents the spontaneous activation of the alternative complement pathway

Question 197

In PNH Red cells, platelets, and granulocytes deficient in these GPI-linked factors are abnormally
susceptible to lysis or injury by complement.

T or F

Answer 197

True

Question 198

Why do of Red cells in PNH manifests as intravascular
hemolysis?

Answer 198

which is caused by the C5b-C9 membrane attack complex.

The hemolysis is
paroxysmal and nocturnal in only 25% of cases; chronic hemolysis without dramatic hemoglobinuria is more typical.

Question 199

What is the explanation why 25% of cases of PNH occurs paroxysmal and nocturnal?

Answer 199

The tendency for red cells to lyse at night is explained by a
slight decrease in blood pH during sleep, which increases the activity of complement

Question 200

What is the rate of anemia in PNG?

Answer 200

anemia is variable but usually mild to moderate in severity.

The loss of heme iron in the urine
(hemosiderinuria) eventually leads to iron deficiency, which can exacerbate the anemia if
untreated.

Question 201

What is the leading cause of disease-related death in individuals with PNH?

Answer 201

Thrombosis .

About 40% of
patients suffer from venous thrombosis, often involving the hepatic, portal, or cerebral veins.

Question 202

What contributes to the prothrombotic state PNH?

Answer 202

Dysfunction of platelets due to the absence of certain GPI-linked proteins contributes to the
prothrombotic state, as does the absorption of NO by free hemoglobin (as discussed under
sickle cell disease). [13]

Question 203

Why do About 5% to 10% of patients eventually develop acute myeloid leukemia or a myelodysplastic syndrome in PNH patients?

Answer 203

, possibly because hematopoietic stem cells have
suffered some type of genetic damage

Question 204

How to diagnose PNH?

Answer 204

flow cytometry, which provides a sensitive means for detecting red cells
that are deficient in GPI-linked proteins such as CD59 ( Fig. 14-14 ).

Question 205

What are the therapeutic approches to PNH?

Answer 205

Several therapeutic
approaches are available, none of which is entirely satisfactory.

• Infusion of a monoclonal antibody inhibitor of C5a greatly reduces the hemolysis but exposes patients to an increased risk of serious or fatal meningococcal infections (as is true of individuals with inherited complement defects).
• Immunosuppressive drugs are sometimes beneficial for those with evidence of marrow aplasia. The only cure is bone marrow transplantation.

Question 206

Answer 206

FIGURE 14-14

Paroxysmal nocturnal hemoglobinuria (PNH).

A, Flow cytogram of blood from a normal individual shows that the red cells express two phosphatidylinositol glycan (PIG)
–linked membrane proteins, CD55 and CD59, on their surfaces.
B, Flow cytogram of blood from a patient with PNH shows a population of red cells that is deficient in both CD55 and CD59. As is typical of PNH, a second population of CD55+/CD59+ red cells that is derived
from residual normal hematopoietic stem cells is also present.

Question 207

What are Immunohemolytic Anemia?

Answer 207

Hemolytic anemias in this category are caused by antibodies that bind to red cells, leading to
their premature destruction.

Although these disorders are commonly referred to as autoimmune hemolytic anemias, the designation immunohemolytic anemia is preferred because in some instances the immune reaction is initiated by an ingested drug

Question 208

Immunohemolytic anemia can be
classified based on the characteristics of the responsible_______

Answer 208

antibody

Question 209

TABLE 14-4 – Classification of Immunohemolytic Anemias

Answer 209

• WARM ANTIBODY TYPE (IgG ANTIBODIES ACTIVE AT 37°C)
  
  • Primary (idiopathic)
    Secondary
    Autoimmune disorders (particularly systemic lupus erythematosus)
    Drugs
    Lymphoid neoplasms
• COLD AGGLUTININ TYPE (IgM ANTIBODIES ACTIVE BELOW 37°C)
  
  • Acute (mycoplasmal infection, infectious
    mononucleosis)
  • Chronic
  • Idiopathic
  • Lymphoid neoplasms
• COLD HEMOLYSIN TYPE (IgG ANTIBODIES ACTIVE BELOW 37°C)
  
  • Rare; occurs mainly in children following viral infections

Question 210

The diagnosis of immunohemolytic anemia requires ?

Answer 210

the detection of antibodies and/or complement on red cells from the patient.

Question 211

What is the process for detection of antibodies and/or complement on red cells from the patient.

Answer 211

This is done using the direct Coombs antiglobulin
test

Question 212

What is direct Coombs antiglobulin
test?

Answer 212

in which the patient’s red cells are mixed with sera containingantibodies that are specific
for human immunoglobulin or complement.

If either immunoglobulin or complement is present
on the surface of the red cells, the multivalent antibodies cause agglutination,which iseasily
appreciated visually as clumping.

Question 213

What is the Indirect Cooms antiglobulin test?

Answer 213

In the indirect Coombs antiglobulin test, the patient’s serum is
tested for its ability to agglutinate commercially available red cells bearing particular defined
antigens.

This test is used to characterize the antigen target and temperature dependence of
the responsible antibody.

Quantitative immunological tests to measure such antibodies directly
are also available.

Question 214

Classification of Immunohemolytic Anemias

Answer 214

• WARM ANTIBODY TYPE (IgG ANTIBODIES ACTIVE AT 37°C)
• COLD AGGLUTININ TYPE (IgM ANTIBODIES ACTIVE BELOW 37°C)
• COLD HEMOLYSIN TYPE (IgG ANTIBODIES ACTIVE BELOW 37°C)

Question 215

What is the most common form of immunohemolytic anemia?

Answer 215

Warm Antibody Type

Question 216

What is the Warm Antibody Type of immunohemolytic anemia?

Answer 216

• most common form
• About 50% of cases are idiopathic (primary); the others are related to a predisposing condition (see Table 14-4 ) or exposure to a drug.

Question 217

What is the Most causative antibodies In Warm Antibody Immunohemolytic Anemias?

Answer 217

IgG class; less commonly, IgA antibodies are culpable.

Question 218

What type of hemolysis is Warm Antibody Immunohemolytic Anemias?

Answer 218

The red cell hemolysis is mostly extravascular.

IgG-coated red cells bind to Fc
receptors on phagocytes, which remove red cell membrane during “partial” phagocytosis.

As in
hereditary spherocytosis, the loss of membrane converts the red cells to spherocytes, which
are sequestered and removed in the spleen. Moderate splenomegaly due to hyperplasia of
splenic phagocytes is usually seen

Question 219

Why does Warm Antibody Type of Immunohemolytic Anemias has Moderate splenomegaly due to hyperplasia of splenic phagocytes is usually seen

Answer 219

IgG-coated red cells bind to Fc
receptors on phagocytes, which remove red cell membrane during “partial” phagocytosis.

As in hereditary spherocytosis, the loss of membrane converts the red cells to spherocytes, which
are sequestered and removed in the spleen.

Moderate splenomegaly due to hyperplasia of
splenic phagocytes is usually seen

Question 220

As with other autoimmune disorders, the cause of primary immunohemolytic anemia of Warm Antibody Type is what?

I

Answer 220

unknown

Question 221

n many cases, the antibodies of immunohemolytic anemia of Warm Antibody Type is directed against what?

Answer 221

Rh blood group antigens.

Question 222

The
mechanisms of drug-induced immunohemolytic anemia of Warm Antibody Type are better understood.

Two different
mechanisms have been described.

Answer 222

• Antigenic drugs.
• Tolerance-breaking drugs

Question 223

What are Antigenic drugs?

Answer 223

Antigenic drugs.

In this setting hemolysis usually follows large, intravenous doses of the
offending drug and occurs 1 to 2 weeks after therapy is initiated.

These drugs,
exemplified by penicillin and cephalosporins, bind to the red cell membrane and are
recognized by anti-drug antibodies.

Sometimes the antibodies bind only to the drug, as
in penicillin-induced hemolysis.

In other cases, such as in quinidine-induced hemolysis,
the antibodies recognize a complex of the drug and a membrane protein.

The
responsible antibodies sometimes fix complement and cause intravascular hemolysis, but more often they act as opsonins that promote extravascular hemolysis within phagocytes.

Question 224

What are your Tolerance-breaking drugs?

Answer 224

These drugs, of which the antihypertensive agent α-
methyldopa is the prototype, induce in some unknown manner the production of antibodies against red cell antigens, particularly the Rh blood group antigens

. About
10% of patients taking α-methyldopa develop autoantibodies, as assessed by the direct
Coombs test, and roughly 1% develop clinically significant hemolysis.

Question 225

What is the Cold Agglutinin Type of immunohemolytic anemia i

Answer 225

This form of immunohemolytic anemia is caused by **IgM antibodies that bind red cells avidly at
low temperatures (0°–4°C).**[14]

It is less common than warm antibody immunohemolytic anemia, accounting for 15% to 30% of cases.

Cold agglutinin antibodies sometimes appear
transiently following certain infections, such as with Mycoplasma pneumoniae, Epstein-Barr
virus, cytomegalovirus, influenza virus, and human immunodeficiency virus (HIV).

In these
settings the disorder is self-limited and the antibodies rarely induce clinically important
hemolysis.

Chronic cold agglutinin immunohemolytic anemia occurs in association with certain
B-cell neoplasms or as an idiopathic condition.

Question 226

Cold agglutinin antibodies sometimes appear
transiently following certain infections, such as with what?

Answer 226

• Mycoplasma pneumoniae,
• Epstein-Barr virus,
• cytomegalovirus,
• influenza virus, and
• human immunodeficiency virus (HIV)

In these
settings the disorder is self-limited and the antibodies rarely induce clinically important
hemolysis.

Question 227

Where does Chronic cold agglutinin immunohemolytic anemia occurs?

Answer 227

occurs in association with certain
B-cell neoplasmsor asan idiopathic condition.

Question 228

What is the pathophysio of Cold Agglutinin Type?

.

Answer 228

Clinical symptoms result from binding of IgM to red cells in vascular beds where the temperature
may fall below 30°C, such as inexposed fingers, toes, and ears.

IgM binding agglutinates red
cellsandfixes complement rapidly.

As the blood recirculates and warms, IgM is released,
usually before complement-mediated hemolysis can occur.

However, the transient interaction
with IgM is sufficient to deposit sublytic quantities of C3b, anexcellent opsonin, which leads to
the removal of affected red cells by phagocytes in the spleen, liver, and bone marrow. The
hemolysis is of variable severity.

Vascular obstruction caused by agglutinated red cells results in pallor, cyanosis, and Raynaud phenomenon ( Chapter 11 ) in body parts exposed to cold
temperature.

Question 229

What are the clinical symptoms of Cold Agglutinin Type?

Answer 229

Vascular obstruction caused by agglutinated red cells results in pallor, cyanosis, and Raynaud phenomenon ( Chapter 11 ) in body parts exposed to cold
temperature.

Question 230

What are Cold hemolysins?

Answer 230

are autoantibodies responsible for an unusual entity known as paroxysmal
cold hemoglobinuria.

This rare disorder causes substantial, sometimes fatal, intravascular
hemolysis and hemoglobinuria.

Question 231

What are the autoantibodies of cold hemolysins?

Answer 231

IgGs that bind to the P blood group
antigen on the red cell surface [14] in cool, peripheral regions of the body.

Question 232

When does the Complementmediated
lysiof cold hemolysins occurs??

Answer 232

when the cells recirculate to warm central regions, since the complement
cascade functions more efficiently at 37°C.

Most cases are seen in children following viral
infections; in this setting the disorder is transient, and most of those affected recover within 1
month.

Question 233

What is the treatment for Cold hemolysin type?

Answer 233

Treatment of warm antibody immunohemolytic anemia centers on the removal of initiating
factors (i.e., drugs); when this is not feasible,immunosuppressive drugs and splenectomy are
the mainstays. [15]

Chronic cold agglutinin immunohemolytic anemia caused by IgM antibodies
is more difficult to treat

Question 234

What is The most significant hemolysis caused by trauma to red cells?

Answer 234

is seen in individuals with cardiac
valve prosthesesandmicroangiopathic disorders

Question 235

Which is more implicated artificial mechanical cardiac valves or bioprosthetic porcine valves as Hemolytic Anemia Resulting from Trauma to Red Cells?

Answer 235

Artificial mechanical cardiac valves are more
frequently implicated than are bioprosthetic porcine valves

Question 236

What is the pathophysio of the most significant hemolysis caused by trauma to red cells is seen in individuals with cardiac valve prostheses?

Answer 236

The hemolysis stems from shear
forces produced by turbulent blood flow and pressuregradients across damaged valves.

Question 237

What is the pathophysio of the most significant hemolysis caused by trauma to red cells is seen in individuals with cardiac valve prosthesesMicroangiopathic hemolytic anemia?

Answer 237

Microangiopathic hemolytic anemia is most commonly seen with disseminated intravascular
coagulation, but it also occurs in thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic
syndrome (HUS),malignant hypertension,systemic lupus erythematosus, and disseminated
cancer.
The common pathogenic feature in these disorders is a microvascular lesion that
results in luminal narrowing, often due to the deposition of fibrin and platelets.

These vascular
changes produce shear stresses that mechanically injure passing red cells. Regardless of the
cause, traumatic damage leads to the appearance of red cell fragments (schistocytes), “burr
cells,” “helmet cells,” and “triangle cells” in blood smears

Question 238

Regardless of the
cause, traumatic damage leads to the appearance of what?

Answer 238

• red cell fragments(schistocytes),
• “burr in blood smears cells,”
• “helmet cells,”
• and “triangle cells”

Question 239

Answer 239

FIGURE 14-15 Microangiopathic hemolytic anemia. A peripheral blood smear from a person
with hemolytic-uremic syndrome shows several fragmented red cells