Chapter 14 – Red Blood Cell: HEMOLYTIC ANEMIAS Flashcards
1
Q
Hemolytic anemias share the following features
A
- • 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
2
Q
Where does the physiologic destruction of senescent red cells takes place?
A
within mononuclear phagocytes,
which are abundant in the spleen, liver, and bone marrow.
3
Q
What triggers the physiologic destruction of senescent red cells takes place?
A
age-dependent changes in red cell surface proteins, which lead to their recognition and
phagocytosis.
4
Q
What is extravascular hemolysis?
A
[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.
5
Q
What happens when there is a persistent extravascular hemolysis?
A
- *hyperplasia of phagocytes** manifested by varying
- *degrees of splenomegaly.**
6
Q
What is the general caused of extravascular hemolysis?
A
Extravascular hemolysis is generally caused by alterations that render the red cell less
deformable.
7
Q
What is required for RC to navigate the splenic sinusoids successfully?
A
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
8
Q
What makes the RC sequestration and phagocytosis within the cords?
A
Reduced deformability
makes this passage difficult, leading to red cell sequestration and phagocytosis within the cords
9
Q
Regardless of the cause, the principal clinical
features of extravascular hemolysis are
A
- (1) anemia,
- (2) splenomegaly,
- and (3) jaundice
10
Q
What is the reason for decrease in haptoglobin?
A
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.
11
Q
Why do individuals with extravascular hemolysis benefit form splenectomy?
A
Because much of the pathologic destruction of red cells occurs in the spleen, individuals with
extravascular hemolysis often benefit from splenectomy.
12
Q
What is the cause of intravascular hemolysis?
A
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.
13
Q
Whatever the mechanism, intravascular hemolysis is manifested by :
A
- (1) anemia,
- (2) hemoglobinemia,
- (3) hemoglobinuria,
- (4) hemosiderinuria, and
- (5) jaundice.
14
Q
What is the reason for the red-brown color of urine in intravascular hemolysis?
A
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.
15
Q
What is the reason for jaundice in intravascular hemolysis?
A
Concomitantly, heme groups derived from hemoglobinhaptoglobin complexes are catabolized to
bilirubin within mononuclear phagocytes, leading to jaundice.
16
Q
Unlike in extravascular hemolysis,
________ is not seen intravascular hemolysis?
A
splenomegaly
17
Q
In all types of uncomplicated hemolytic anemias, the excess serum bilirubin is ____________
A
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.
18
Q
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 ).
A
erythropoietin
19
Q
What results in the Compensatory
increases in erythropoiesis?
A
prominent reticulocytosis in the peripheral blood
20
Q
What is hemosiderosis?
A
The phagocytosis of red cells leads to hemosiderosis, which is most pronounced in the
spleen, liver, and bone marrow.
21
Q
Why does in chronic hemolysis formation of pigment gallstones can occur?
A
With chronic hemolysis, elevated biliary
excretion of bilirubin promotes the formation of pigment gallstones (cholelithiasis).
22
Q
A
FIGURE 14-1 Marrow smear from a patient with hemolytic anemia. The marrow reveals
greatly increased numbers of maturing erythroid progenitors (normoblasts).
23
Q
What is hereditary spherocytosis?
A
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).
24
Q
The remarkable elasticity and durability of the normal red cell are attributable to what?
A
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
25
What is the chief protein component of the RC skeloton?
Its chief protein component, **spectrin,**
consists o**f two polypeptide chains, α and β**, which form **intertwined (helical) flexible
heterodimers.**
26
What is the pathogenesis of hereditary spherocytosis?
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.
27
Describe how the shape of the RBCs of hereditory spherocytosis attained?
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.
28
What is the cardinal role of the spleen in hereditary spherocytosis?
The invariably beneficial effects of splenectomy prove that the spleen has a cardinal role in the p**remature demise of spherocytes**
29
Why does the spleen becomes the villain in hereditary spherocytosis?
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.
30
Why does the splenic environment exacerbates the tendency of HS red cells to lose membrane?
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 ).
31
FIGURE 14-3 Pathophysiology of hereditary spherocytosis.
32
What is the most specific morphologic finding of HS?
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**.
33
What are the other features of HS that are common to all hemolytic anemias?
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.
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.
35
How do you diagnose HS?
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.
36
What is the reason for the HS red cells have an **increased mean cell hemoglobin concentration?**
HS red cells also have an increased mean cell hemoglobin concentration , due to
dehydration caused by the loss of K + and H2O.
37
What are the characteristic clinical features of HS?
* anemia,
* splenomegaly, and
* jaundice .
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
39
The generally
stable clinical course of HS is sometimes punctuated by aplastic crises, usually triggered by an :
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.
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?
hereditary deficiency of glucose-6-phosphate dehydrogenase (G6PD) activity.
41
What is the function of G6PD?
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
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.
43
What type of hereditary disease is G6PD deficiency
recessive X-linked trait, placing males at higher risk for symptomatic disease.
44
Several hundred G6PD genetic variants are known, but most are harmless.
**Only two**
**variants, \_\_\_\_\_\_\_\_\_\_** cause most of the clinically significant
hemolytic anemias.
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
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.
46
What is the characteristic of G6PD?
The **episodic hemolysis** that is characteristic of G6PD deficiency is **caused by exposures that**
**generate oxidant stress.**
47
What is the most common triggers of episodic G6PD hemolysis?
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.
48
What are the oxidant drugs that trigger G6PD hemolysis?
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.
49
What is the most frequent cited food which generates oxidants when metabolized?
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. **
50
Oxidants cause both intravascular and extravascular hemolysis in G6PD-deficient individuals .
T or F
True
51
What are Heinz bodies?
Exposure of G6PD-deficient red cells to high levels of oxidants **causes the cross-linking of
reactive sulfhydryl groups**on**globin chains, which become denatured**and**form 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.
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.
53
What happens after 2 to 3 days of exposure of G6PD-deficient individuals to oxidants
**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.
54
Why is the episode of acute hemolysis in G6PD individuals self-limited?
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.
55
What is sickle cell disease?
Sickle cell disease is a **common hereditary hemoglobinopathy** that **occurs primarily in
individuals of African descent**
56
What is the biochemical structure of Hgb?
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).
57
What is the normal adult red cells composition?
**HbA (α2β2)**,
along with small amounts of **HbA2 (α2δ2)** and
**fetal hemoglobin (HbF; α2γ2).**
58
What is the cause of Sickle disease?
* *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!!!**
59
What is the epidemiology of Sickle Cell Disease?
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.
60
What is the pathogenesis of HbS?
**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.**
61
The presence of HbS underlies the major pathologic manifestations:
(1) chronic hemolysis,
(2) microvascular occlusions, and
(3) tissue damage.
62
Several variables affect the rate and degree
of sickling:
* 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
63
What is the reason why heterozygotes with sickle cell trait do not sickle except under conditions of profound hypoxia?
In heterozygotes with
sickle cell trait, abou**t 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.
64
Why are infants do not become symptomatic until they reach 5 or 6 months of age?
**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.
65
What is hereditary persistence of HbF?
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.
66
What is HbC?
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
67
What is HbSC disease?
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
68
Why does conditions that increase MCHC increase the disease severity?
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.
69
What conditions that increase MCHC increase the disease severity?
**intracellular dehydration**, which increases the MCHC, facilitates sickling.
70
What pH will increase the fraction of deoxygenated HbS at any given oxygen tension and augment the tendency for sickling?
. 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.**
71
How does transit time affect the sickling of cells?
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.
72
Sickling causes cumulative damage to red cells through what mechanisms?
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.
73
The severity of the hemolysis **correlates with the
percentage of irreversibly sickled cells,**which ar**e rapidly sequestered and removed by
mononuclear phagocytes (extravascular hemolysis).**
T or F
Sickled red cells are also mechanically
fragile, leading to some intravascular hemolysis as well.
74
FIGURE 14-7 Pathophysiology of sickle cell disease
75
What is the pathophysiology of the microvascular occlusions?
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
76
What is the appearance of full-blown sickle cell anemia?
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
77
What is the appearanc ef spleen in early childhood of patients with Sickle cell?
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.
78
What is autosplenectomy?
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.
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.
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
81
FIGURE 14-10 “Autoinfarcted” splenic remnant in sickle cell disease.
82
What are the clinical features of sickle cella disease?
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.”**
83
What is Vaso-occlusive crises?
Vaso-occlusive crises, also called **pain**
* *crises,** are **episodes of hypoxic injury** and infarction that **cause severe pain in the affected**
* *region.**
84
What can act as triggers for sickle cell?
Although **infection, dehydration, and acidosis** (all of **which favor sickling)** can act as triggers, **in most instances no predisposing cause is identified**
85
What are the commonly involved sites in sickle disease?
* bones,
* lungs,
* liver,
* brain,
* spleen, and
* penis.
86
What is common in children with sickle cell disease?
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.
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?
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
88
What are the factors the proposed to stroke in sickle cell disease?
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.**
89
What is the most common cause of patient morbidity and mortality in sickle cell disease?
**occlusive crises**
alathou several other acute events complicate the course.
90
When does sequestratio crises occur?
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.
91
Where does Aplastic crises stem from?
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.**
92
In sickle cell what is responsible for a generalized impairment of growth d development?
Chronic hypoxia is responsible for a generalized impairment of growth and development, as well
as organ damage affecting spleen, heart, kidneys, and lungs.
93
What is the reason for patients of sickle cell disease to have hyposthenuria?
Sickling provoked by
**hypertonicity in the renal medulla causes damage that** eventually leads to **hyposthenuria** **(the
inability to concentrate urine)**, which**increases the propensity for dehydration and its attendant
risks.**
94
Why does Increased susceptibility to infection with encapsulated organisms is another threat to patients with sickle cell disease?
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**, and**completely 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.
95
there is great variation in the clinical manifestations of sickle cell
disease.
T or F
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
96
How to diagnose sickle cell disease?
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 as**metabisulfite**, which**induces 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.
97
What is the mainstay of treatment for sickle disease?
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.
98
What is Thalassemia syndrome?
The thalassemia syndromes are a **heterogeneous group** of disorders **caused by inherited
mutations**that**decrease the synthesis of adult hemoglobin, HbA (α2β2).**
99
What chromosome does the two α chains in HbA are encoded?
The two α chains in
HbA are encoded by an **identical pair of α-globin genes on chromosome 16**
100
To what chromosome do the β
chains are encoded?
while the two β
chains are encoded by a single β-globin gene on **chromosome 11**
101
What is the caused for β-Thalassemia?
β-Thalassemia is caused by
**deficient synthesis of β chains**,
102
What is deficient in α-thalassemia?
α-thalassemia is caused by deficient synthesis of **α
chains.**
103
What is the epidemiology of Thalassemia syndromes?
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
.
104
As with sickle cell disease and other common
inherited red cell disorders,Thalassemia prevalence seems to be explained by what?
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.
105
What is β-thalassemias?
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.
106
The causative mutation of β- Thalassemia s fall into two categories :
* (1) **β 0 mutations**
* (2) **β + mutations**
107
What is β 0 mutations?
β 0 mutationsβ 0 mutations
108
What is β + mutations?
characterized by reduced (but detectable) β-globin
synthesis.
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
* Splicing mutations
* Promoter region mutations
* Chain terminator mutations
110
What are the most common cause of β + -thalassemia
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.
111
Why are Promoter region mutations associated with β + -
thalassemia
These mutations reduce transcription by 75% to 80%. **Some normal β-globin is synthesized**; thus, these mutations are associated with β + -
thalassemia
112
What are the **most common cause of β 0 -thalassemia.**
Chain terminator mutations.
113
What are the Two subtypes of Chain terminator mutations?
* 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.
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.
115
Impaired β-globin synthesis results in anemia by two mechanisms
1. Ineffective erythropoiesis
2. Extravascular hemolysis
116
What is the reason for the underhemoglobinized hypochromic, microcytic red cells with subnormal oxygen transport capacity
The deficit in
HbA synthesis
117
What is the reason for the diminished survival of red
cells and their precursors
which results from the **imbalance in α- and β-globin synthesis.**
118
What is the reason why there are inclusions in β-thalassemia?
**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.
119
What is the proximal cause of
most red cell pathology in β-thalassemia?
membrane damage is the
120
What is the reason for the ineffective erythropoiesis in β-thalassemia
**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.**
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.
122
In severe β-thalassemia, ineffective erythropoiesis creates several additional problems.
What are these problems?
* 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
123
What is hepcidin?
hepcidin, a critical **negative regulator of iron absorption** (described later under iron deficiency anemia).
124
What happens when severe thalassemia occur leading to **Ineffective erythropoiesis suppresses the circulating levels of hepcidin?**
**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
125
Clinical classification of β-thalassemia is based on the severity of the anemia, which in turn
depends on the what?
```
genetic defect (β + or β 0 ) and the gene dosage (homozygous or
heterozygous).
```
126
What is β-thalassemia major?
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 .
127
What is β-thalassemia minor or β
-thalassemia trait?
Heterozygotes
with **one βthalassemia gen**e 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
128
What is β
-thalassemia intermedia?
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]
129
What does it says about the unusual forms of the β-thalassemia intermedia?
These unusual forms of the disease serve to emphasize **the cardinal role of unpaired α-globin chains
in the pathology.**
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.
131
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
β-THALASSEMIAS
* β- Thalassemia major
* β- Thalassemia intermedia
* β- Thalassemia minor
132
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
* Silent carrier
* α- Thalassemia trait
* HbH disease
* Hydrops fetalis
133
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
## Footnote
**β- Thalassemia
major**
* 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**
134
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
β- Thalassemia
intermedia
* 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**
135
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
β- Thalassemia
minor
* 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
136
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
Silent carrier
Genotype :-/α α/α
Clinical Features : Asymptomatic; no red cell
abnormality
Molecular Genetics :Mainly gene deletions
137
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
**Silent carrier**
* Genotype: -/α α/α
* Clinical Features: Asymptomatic; no red cell
abnormality
* Molecular Genetics: Mainly gene deletions
138
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
α-
Thalassemia
trait
* Genotype: -/- α/α (Asian)
* Clinical Features : Asymptomatic, like β-thalassemia minor
* Molecular Genetics: Mainly gene deletions
139
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
α- Thalassemia trait ( Black, African, Asian)
* Genotype: -/α -/α ( Black, African, Asian)
* Clinical Features: Asymptomatic like β-Thalassemia minor.
* Molecular Genetics: Mainly gene deletions
140
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
**HbH disease**
Genotype :**-/- -/α**
Clinical Features : **Severe; resembles β-
thalassemia intermedia**
Molecular Genetics: Mainly gene deletions
141
TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias
α-THALASSEMIAS
**Hydrops
fetalis**
* Genotype : **-/- -/-**
* Clinical Features :**Lethal in utero without
transfusions**
* Molecular Genetics: **Mainly gene deletions**
142
β-thalassemia major is most common where?
* Mediterranean countries,
* parts of Africa, and Southeast Asia.
143
What age does β-Thalassemia Major.manifest?
The anemia manifests **6 to 9 months after birth** as **hemoglobin synthesis switches from HbF to HbA.**
144
What happens to the hgb levels of untransfused patients in β-Thalassemia Major.
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.
145
What is the morphology of β-thalassemia major?
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 i**neffective erythropoiesi**s.
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.
146
What is the apperance of the Red cells of patients with β-thalassemia major?
**Target cells** (so
called **because hemoglobin collects in the cente**r of **the cell),** basophilic stippling, and
fragmented red cells are also common.
147
Why do inclusions of aggregated α chains in β-thalassemia major are not seen?
Inclusions of aggregated α chains are **efficiently
removed by the spleen** and not easily seen.
148
Why is the reticulocyte count is elevated, but it is lower
than expected for the severity of anemia in β-thalassemia major ?
because of the ineffective erythropoiesis.
149
Why are Variable
numbers of poorly hemoglobinized nucleated red cell precursors (normoblasts) are seen in
the peripheral blood of β-thalassemia major ?
as a result of **“stress**” erythropoiesis and **abnormal release from sites of
extramedullary hematopoiesis.**
150
What are the other major alterations involve in β-Thalassemia Major?
Other major alterations involve the bone marrow and spleen.
151
What is striking in the untransfused patient β-Thalassemia Major
there is a striking expansion of hematopoietically active marrow.
152
What is the reason for the crew-cut” appearance on x-ray of β-Thalassemia Major?
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 ).
153
What is the reason for the enlargement of the spleen, liver and lymphnodes in β-Thalassemia Major patients?
**Both phagocyte hyperplasia**
and e**xtramedullary hematopoiesis contribute to enlargement of the spleen, which can weig**h
as much as 1500 gm.
The **liver and the lymph node**s can also be enlarged by **extramedullary
hematopoiesis.**
154
What are the two manifestation of iron overload in β-Thalassemia Major patients?
**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.**
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
156
What is the clinical course of β-thalassemia major?
The clinical course is **brief unless blood transfusions are given.**
157
Why do Untreated children of β-Thalassemia Major suffer from growth retardation and die at an early age?
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.
158
What are the complications contributed by blood transfusions in β-Thalassemia Major?
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.
159
What is the only therapy offering a cure and is being used increasingly for β-Thalassemia Major?
**Bone marrow
transplantation**
Prenatal
diagnosis is possible by molecular analysis of DNA.
160
How can survival in the third devade possiblefor β-Thalassemia Major?
## Footnote
**With transfusions and iron chelation**
161
Which is more common β-Thalassemia minor or major?
β-Thalassemia minor
162
What is **β-Thalassemia minor?**
* 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**
163
What is the apperance of the peripheral blood smear of β-Thalassemia Minor?
* red cell abnormalities,
* including **hypochromia, microcytosis,**
* basophilic stippling, and target cells.
164
165
What is revealed in the Hemoglobin electrophoresis of β-Thalassemia Minor?
**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.
166
Recognition of β-thalassemia trait is important for two reasons:
* (1) **differentiation from the hypochromic microcytic anemia of iron deficiency** and
* (2) **genetic counseling**.
167
Recognition of β-thalassemia trait is important fort the: differentiation **from the
hypochromic microcytic anemia of iron deficiency, how will you do that?**
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).
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?
The **increase in HbA2** is
diagnostically useful,
169
What is the pathophysiology of α-thalassemias?
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.**
170
As in β-thalassemias, the
anemia stems both from what?
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
171
What is hemoglobin Barts?
In newborns with α-thalassemia,
excess unpaired γ-globin chains form γ4 tetramers known as *hemoglobin **B**arts*
**B** for **Bata**
172
What is HbH?
whereas in
older **children and adults** **excess β-globin chain**s form **β4 tetramers** known as **HbH.**
**Hapatan!**
173
Why are α-Thalassemias less severe than β-thalassemias?
* *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.
174
What is the most common cause of
reduced α-chain synthesis?
A variety of
**molecular lesions give rise to α-thalassemi**a, but **gene deletio**n is the most common cause of
reduced α-chain synthesis.
175
What is the Silent Carrier State of α-Thalassemia
This is associated with the **deletion of a single α-globi**n gene, which **causes a barely detectable
reduction in α-globin chain synthesi**s.
These individuals are completely asymptomatic, but they
**have slight microcytosis.**
176
What is thepathophysio of α-Thalassemia Trait?
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 f**rom each of the **two chromosomes (α/—α α/—α)**
177
In the α-Thalassemia Trait what is more common in Asian populations?
(α/α α/α),
178
In the α-Thalassemia Trait what is more common in regions of Africa. ?
(α/—α α/—α)
179
Why is symptomatic α-thalassemia is relatively common in Asian populations and rare in black African populations?
**Both genotypes produce similar quantitative** **deficiencies of α-globin** and are **clinically identical,**
but **have different implications for the children of affected individual**s, who **are at risk of clinically
significant α-thalassemia (HbH disease or hydrops fetalis)**only when**at 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.
180
What is the clinical picture in α-thalassemia trait?
**identical to that described for β-thalassemia minor**, that is, **small red cells (microcytosis),** **minimal
or no anemia,**and**no abnormal physical signs**.
HbA2 levels are normal or low.
181
What is the pathophysiology of Hemoglobin H Disease?
This is **caused by deletion of three α-globin genes.**
182
Hemoglobin H Disease is most common in what population?
Asian
Hb**Hazel**
183
What is the pathophysio of Hemoglobin H Disease?
With only **one normal α-globin gene**, the s**ynthesis of α chains is
markedly reduced**, and**tetramers of β-globin,**called**HbH**, form.**HbH has an extremely high
affinity for oxyge**n and**therefore is not useful for oxygen delivery**, leading to**tissue 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.**
184
Why do **HbH** has moderately severe anemia resembling **β- thalassemia intermedia.**
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.
185
What is the most severe form of α-thalassemia?
Hydrops Fetalis
186
Why is Hydrops Fetalis the most severe form of α-thalassemia?
This most severe form of α-thalassemia is caused by d**eletion 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**.
187
Survival in early development in Hydrops Fetalis is due to what?
Survival in early development is **due to the
expression of ζ chains**, an**embryonic globin**that**pairs with γ chains to form a functional ζ2γ2 Hb
tetramer.**
188
Whe do signs of fetal distress become evident in Hydrops Fetalis?
**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.
189
What are the clinical features of Hydrops Fetalis?
The **fetus shows severe pallor**, **generalized
edema**, and**massive 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
190
What is Paroxysmal nocturnal hemoglobinuria (PNH)?
is a **disease that results from acquired mutations**
in the **phosphatidylinositol glycan complementation gro**up **A gene (PIGA)**, an enzyme that is
**essential for the synthesis of certain cell surface proteins**
191
What is the incidence rate of PNH?
PNH has an incidence of 2 to 5 per
million in the United States.
192
PNH is rare but why does it fascinates hematologists?
_only hemolytic anemia_ caused by an ***acquired genetic defect***.
193
What is the pathophysiology of PNH?
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.
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?
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 a**utoimmune 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.
195
What is the deficiency in PNH blood cells?
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.
196
What is the most important deficient GPI-linked proteins in PNH blood cells?
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**
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**
True
198
Why do of Red cells in PNH manifests as intravascular
hemolysis?
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.
199
What is the explanation why 25% of cases of PNH occurs paroxysmal and nocturnal?
The **tendency for red cells to lyse at night** is explained by a
**slight decrease in blood pH during sleep,** which i**ncreases the activity of complement**
200
What is the rate of anemia in PNG?
**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.
201
What is the leading cause of disease-related death in individuals with PNH?
Thrombosis .
About 40% of
patients suffer from **venous thrombosis**, often involving the hepatic, portal, or cerebral veins.
202
What contributes to the prothrombotic state PNH?
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]
203
Why do About 5% to 10% of patients eventually develop acute myeloid leukemia or a myelodysplastic syndrome in PNH patients?
, possibly **because hematopoietic stem cells have
suffered some type of genetic damage**
204
How to diagnose PNH?
**flow cytometry**, which provides a **sensitive means for detecting red cells
that are deficient in GPI-linked proteins such as CD59** ( Fig. 14-14 ).
205
What are the therapeutic approches to PNH?
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 infection**s (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.
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.
207
What are Immunohemolytic Anemia?
Hemolytic anemias in this category are caused by **antibodies that bind to red cells**, leading to
**their premature destructio**n.
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
208
Immunohemolytic anemia can be
classified based on the characteristics of the responsible\_\_\_\_\_\_\_
antibody
209
TABLE 14-4 -- Classification of Immunohemolytic Anemias
* 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
210
The diagnosis of immunohemolytic anemia requires ?
the **detection of antibodies and/or complement on red cells from the patient.**
211
What is the process for detection of antibodies and/or complement on red cells from the patient.
This is done using the **direct Coombs antiglobulin
test**
212
What is direct Coombs antiglobulin
test?
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 is**easily
appreciated visually as clumping.**
213
What is the Indirect Cooms antiglobulin test?
In the indirect Coombs antiglobulin test, the patient's serum is
**tested for its ability to agglutinate commercially available red cell**s 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.
214
Classification of Immunohemolytic Anemias
* 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)
215
What is the most common form of immunohemolytic anemia?
Warm Antibody Type
216
What is the Warm Antibody Type of immunohemolytic anemia?
* 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.
217
What is the Most causative antibodies In Warm Antibody Immunohemolytic Anemias?
IgG class; less commonly, IgA antibodies are culpable.
218
What type of hemolysis is Warm Antibody Immunohemolytic Anemias?
**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
219
Why does Warm Antibody Type of Immunohemolytic Anemias has Moderate splenomegaly due to hyperplasia of splenic phagocytes is usually seen
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
220
As with other autoimmune disorders, the **cause of primary immunohemolytic anemia of Warm Antibody Type i**s what?
I
unknown
221
n many cases, the antibodies of immunohemolytic anemia of Warm Antibody Type is directed against what?
Rh blood group antigens.
222
The
mechanisms of drug-induced immunohemolytic anemia of Warm Antibody Type are better understood.
Two different
mechanisms have been described.
* Antigenic drugs.
* Tolerance-breaking drugs
223
What are Antigenic drugs?
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 cephalosporin**s, 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.
224
What are your Tolerance-breaking drugs?
These drugs, o**f 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.
225
What is the Cold Agglutinin Type of immunohemolytic anemia i
```
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.
226
Cold agglutinin antibodies sometimes appear
transiently following certain infections, such as with what?
* 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.
227
Where does Chronic cold agglutinin immunohemolytic anemia occurs?
occurs in **association with certain
B-cell neoplasms**or as**an idiopathic condition.**
228
What is the pathophysio of Cold Agglutinin Type?
.
Clinical symptoms result from **binding of IgM to red cells in vascular beds where the temperature
may fall below 30°C, s**uch as in**exposed fingers, toes, and ears.**
**IgM binding agglutinates red
cells**and**fixes complement rapidly**.
As the blood recirculates and warms, **IgM is released,
usually before complement-mediated hemolysis can occu**r.
However, the **transient interaction
with IgM is sufficient to deposit sublytic quantities of C3b, a**n**excellent opsonin, which leads to
the removal of affected red cells by phagocyte**s 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.
229
What are the clinical symptoms of Cold Agglutinin Type?
Vascular obstruction caused by agglutinated red cells results in **pallor, cyanosis, and Raynaud phenomeno**n ( Chapter 11 ) in body parts exposed to cold
temperature.
230
What are Cold hemolysins?
are autoantibodies responsible for an u**nusual entity known as paroxysmal
cold hemoglobinuria.**
This **rare disorder causes substantial,** sometimes **fatal, intravascular**
**hemolysis and hemoglobinuria**.
231
What are the autoantibodies of cold hemolysins?
**IgGs that bind to the P blood group**
antigen on the red cell surface [14] i**n cool, peripheral regions of the body.**
232
When does the Complementmediated
lysiof cold hemolysins occurs??
**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.**
233
What is the treatment for Cold hemolysin type?
**Treatment of warm antibody immunohemolytic anemia** centers on the r**emoval of initiating
facto**rs (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***
234
What is The most significant hemolysis caused by trauma to red cells?
is seen in individuals ***with cardiac
valve prostheses***and**microangiopathic disorders**
235
Which is more implicated artificial mechanical cardiac valves or bioprosthetic porcine valves as Hemolytic Anemia Resulting from Trauma to Red Cells?
**Artificial mechanical cardiac valves are more
frequently implicated** than are bioprosthetic porcine valves
236
What is the pathophysio of the most significant hemolysis caused by trauma to red cells is seen in individuals with cardiac valve prostheses?
The hemolysis **stems from shear
forces produced by turbulent blood flow and pressure**gradients across damaged valves.
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?
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
238
Regardless of the
cause, **traumatic damage leads to the appearance of what?**
* **red cell fragments(schistocytes),**
* **“burr** in blood smears **cells,”**
* **“helmet cells,”**
* **and “triangle cells”**
239
FIGURE 14-15 Microangiopathic hemolytic anemia. A peripheral blood smear from a person
with hemolytic-uremic syndrome shows several fragmented red cells
