Red Cell Disorders

Question 1

Secondary hematopoietic organs which work at sever anemia

Answer 1

Liver-spleen-lymph nodes

Question 2

The compensatory response to bleeding or increased red cell destruction (hemolysis) can increase the production of red cells………….

Answer 2

Fivefold to eightfold

Question 3

The rise in marrow output is signaled by the appearance of increased numbers of newly
formed red cells …………

Answer 3

reticulocytes

Question 4

Mean cell volume (MCV)
Mean cell hemoglobin (MCH)
Mean cell hemoglobin concentration (MCHC)

Answer 4

Femtolitre
picograms
grams per deciliter

Question 5

plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels,
which are abnormal in…………. anemia

Answer 5

hemolytic

Question 6

the………….. test, which is used to detect antibodies or complement bound to red cells in suspected cases of antibody-mediated hemolytic anemia.

Answer 6

Coombs

Question 7

Adaptive changes mitigate the effects of mild to moderate anemia in otherwise
healthy persons but are less effective in those with……………and……………

Answer 7

increases in cardiac output
respiratory rate
red cell 2,3-diphosphoglycerate (DPG)
glycolytic pathway intermediate that enhances the release of O2 from hemoglobin.

compromised pulmonary or cardiac function

Question 8

Gallstones may be produced with

Answer 8

Chronic haemolytic anemia

Question 9

Anemia that stems from ineffective hematopoiesis (the premature death of marrow erythroid progenitors) is associated with inappropriate increases in …………………..with consequent damage to
endocrine organs and the heart.

Answer 9

iron absorption from the gut, which can lead to iron overload (secondary hemochromatosis)

Question 10

If blood loss exceeds ……………of blood 🩸 volume, the immediate threat is hypovolemic shock

If the patient survives, hemodilution begins at once and achieves its full effect within…………days;

erythropoietin level, which stimulates increased red cell production and reticulocytosis within a period of…………..days.

With chronic blood loss,………… stores are gradually depleted.

Answer 10

20%

2 to 3

5 to 7

iron

Question 11

Haemolytic anemia

Answer 11

1/erythroid hyperplasia and reticulocytosis are hallmarks of all hemolytic anemias.

2/The spleen contains large numbers of macrophages, responsible for the removal
of damaged or antibody-coated red cells from the circulation.

3/Findings that are relatively specific for extravascular hemolysis Hyperbilirubinemia and jaundice, splenomegaly , bilirubin-rich gallstones(pigment stones) and an increased risk of cholelithiasis

4/Intravascular hemolysis, is characterized by injuries (e.g., fixation of complement, or exposure to clostridial toxins or heat).

5/Findings that distinguish intravascular hemolysis from extravascular hemolysis include the presence of the following:Hemoglobinemia, hemoglobinuria, and hemosiderinuria, Loss of iron (cause not being recycled by macrophages).

6/A feature of both intravascular and extravascular hemolysis is decreased serum levels of haptoglobin, (a plasma protein that binds free hemoglobin) and is then removed from the circulation.

Question 12

Hereditary spheocytosis

Answer 12

1/Highly vulnerable to sequestration and destruction in the spleen.

2/Transmitted as an autosomal dominant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients.

3/caused by inherited defects in the membrane skeleton(spectrin protein).

4/Mutations that cause hereditary spherocytosis most frequently involve ankyrin, band 3, or spectrin.
5/The common feature of the pathogenic mutations is that they weaken vertical interactions between the membrane skeleton and intrinsic red cell membrane proteins.

6/Little cytoplasm is lost in the process and as a result the surface area-to volume ratio decreases progressively with time until the cells become spherical.

7/With splenectomy spherocytes persist, but the anemia is corrected.

Question 13

Morphology of Hereditary spherocytosis

Answer 13

1/On smears, spherocytes are dark red and lack central pallor.

2/Compensatory hyperplasia of red cell progenitors , in the marrow and an increase in red cell production.

3/Splenomegaly is more common and prominent in hereditary spherocytosis than in any other form of hemolytic anemia.

4/cholelithiasis, which occurs in 40% to 50% of patients.

Question 14

Clinical features of hereditary spherocytosis

Answer 14

1/splenomegaly, and jaundice.

2-red cells show increased osmotic fragilitywhen placed in hypotonic salt solutions, a characteristic that can help establish the diagnosis.

3/Splenectomy increases risk of serious bacterial infections, particularly in children. Partial splenectomy in children because still maintaining protection against sepsis./children may need second resection because the partially resected spleen eventually regains its size.

Question 15

Aplastic crisis in hereditary spherocytosis

Answer 15

1/The most severe of which are triggered by parvovirus B19 infection.

2/Erythroblasts, which undergo apoptosis during viral replication.

3/Until the immune response controls the infection (usually in 10–14 days), the marrow may be virtually devoid of red cell progenitors.
Because of the shortened life span of red cells in hereditary spherocytosis, a lack of red cell production, even for a few days, results in rapid worsening of the anemia.

4/ Blood transfusions may be needed.

Question 16

Sickle cell Anemia

Answer 16

1/Sickle cell anemia is the most common familial hemolytic anemia.

2/In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a protective effect against Plasmodium falciparum malaria.

Question 17

Pathogenesis of sckile cell Anemia

Answer 17

1/Tendency for deoxygenated HbS to self-associate into polymers.

2/On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2).
3/In patients with sickle cell anemia, HbA is completely replaced by HbS, whereas in heterozygous carriers, only about half is replaced.

4/HbS differs from HbA by having a valine residue instead of a glutamate residue
at the 6th amino acid position in β-globin.

5/The sickling of red cells initially is reversible on reoxygenation.

6/membrane distortion produced by each sickling episode leads to an influx of calcium,which causes the loss of potassium and water and also damages the membrane skeleton.

7/With time, this cumulative damage creates irreversibly sickled cells that rapidly undergo hemolysis.

8/The sickling of red cells has two major pathologic consequences:
A-chronic moderately severe hemolytic anemia.
B-vascular obstructions, which result in ischemic tissue damage and pain crises .

9-The mean life span of red cells in sickle cell anemia averages only 20 days (one-sixth of normal).

10-the severity of the hemolysis correlates with the fraction of irreversibly sickled cells that are present in the blood.

11-Vasoocclusion,result from superimposed factors such as infection, inflammation, dehydration, and acidosis, all of which enhance the tendency of sckiling.

Question 18

Three factors are particularly important in determining whether clinically significant polymerization of HbS occurs in patients:

Answer 18

1-The intracellular levels of hemoglobins other than HbS:-
A-HbA, interacts only weakly with deoxygenated HbS
ex/ In heterozygotes approximately 40% of Hb is HbS remainder is HbA/have little tendency sickle in vivo/Such persons are said to have sickle cell trait.

B-Due to that (HbF) interacts weakly with HbS/ newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months.

C-Hemoglobin C (HbC), ( lysine residue instead of the normal glutamic acid) HbC has a greater tendency to aggregate with HbS and as a result HbS/HbC compound heterozygotes have a symptomatic sickling disorder called HbSC disease.

2-Tissues that are most susceptible to obstruction by sickling are those in which blood flow is normally sluggish, such as the spleen and the bone marrow.

3-Sickling may occur in other microvascular beds in the face of factors that retard the passage of red cells, particularly inflammation/slows blood flow by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels.

4-sickle red cells have a greater tendency to adhere to endothelial cells .

Question 19

Morphology of sckile cell anemia

Answer 19

1/In peripheral smears,elongated, spindled, or boat-shaped irreversibly sickled red
cells are evident.

2/Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver,and renal tubules.

3/There is a compensatory hyperplasia of erythroid progenitors in the marrow. The cellular proliferation in the marrow often causes bone resorption /secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a “crewcut” in radiographs.

4-Extramedullary hematopoiesis may appear in the liver and spleen.

5-In children there is moderate splenomegaly /chronic splenic erythrostasis produces hypoxic damage and infarcts, which with time reduce the spleen to a useless nubbin of fibrous tissue/autosplenectomy, is complete by adulthood.

6-Vascular congestion, thrombosis, and infarction can affect any organ, including the bones, liver, kidney, retina, brain,lung, and skin.The bone marrow is particularly prone to ischemia because of its sluggish blood flow and high rate of metabolism.

7-Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction.

8-hemosiderosis and pigment gallstones are common.

Question 20

Clinical features of sckile cell anemia

Answer 20

1-From its onset, the disease runs an unremitting course punctuated by sudden crises.

2-Homozygous sickle cell disease usually is asymptomatic until 6 months of age when the shift from HbF to HbS is complete.
3-most patients have hematocrits of 18% to 30% (normal range, 38%–48%).

4-chronic hemolysis is associated with hyperbilirubinemia and compensatory reticulocytosis.

5-vasoocclusive crises, which are associated with pain and often lead to tissue damage and significant morbidity and mortality.
A-Hand-foot syndrome, resulting from infarction of bones in the hands and feet, is the most common presenting symptom in young children.
B-Acute chest syndrome, in which sluggish blood flow in inflamed lung (e.g., an area of pneumonia) leads to sickling within hypoxemic pulmonary beds. This exacerbates pulmonary dysfunction, creating a vicious circle of worsening pulmonary and systemic hypoxemia, sickling, and vaso-occlusion.
may also be triggered by fat emboli emanating from infarcted bone.

C-Stroke, which sometimes occurs in the setting of the acute chest syndrome.
Stroke and the acute chest syndrome are the two leading causes of ischemia-related death.

D- Proliferative retinopathy, that can lead to loss of visual acuity and blindness.

E-Another acute event, aplastic crisis, is caused by a sudden decrease in red cell production. this usually is triggered by the infection of erythroblasts by parvovirus B19 and, although severe, is self-limited.
6-Both children and adults with sickle cell disease are functionally asplenic, making them
susceptible to infections caused by encapsulated bacteria, such as pneumococci.

7-In the earlier childhood phase of splenic enlargement, congestion caused by trapped sickled red cells apparently interferes with bacterial sequestration and killing; hence, even children with enlarged spleens are at risk for the development of fatal septicemia.

9-Predisposed to Salmonella osteomyelitis.
10-In homozygoussickle cell disease, irreversibly sickled red cells are seen in routine peripheral blood smears. In sickle cell trait, sickling can be induced in vitro by exposing cells to marked hypoxia.
11-The diagnosis is confirmed by electrophoretic demonstration of HbS.

12-Prenatal diagnosis of sickle cell anemia can be performed by analyzing fetal DNA obtained by amniocentesis or biopsy of chorionic villi.

Question 21

Treatments of sickle cell anemia

Answer 21

1/prophylactic treatment with penicillin to prevent pneumococcal infections, especially in children younger than age 5.

2/hydroxyurea, (inhibitor of DNA synthesis)/ Hydroxyurea reduces pain crises andm-
A-increase levels of HbF;
B-Anti-inflammatory effect because of the inhibition of white cell production.
C- 👆red cell size, which👇the intracellular hemoglobin concentration;
D-its metabolism to NO,a potent vasodilator and inhibitor of platelet aggregation.

3/Allogeneic bone marrow transplantation, which is potentially curative.

Question 22

Thalassemias

Answer 22

1/Inherited disorders caused by mutations in globin genes that decrease the synthesis of α- or β-globin. Which results in a deficiency of Hb/red cell damage caused by precipitates of unpaired “normal” globin chains.

2/The mutations are particularly common in regions in which malaria is endemic.

3/As with HbS, it is hypothesized that globin mutations associated with thalassemia protect against falciparum malaria.

Question 23

Pathogenesis of Thalassemias (beta)

Answer 23

1/Autosomal codominant conditions.

2/Persons inheriting one abnormal allele have β-thalassemia minor (also known as β-thalassemia trait), which is asymptomatic or mildly symptomatic.

3/Most people inheriting any two β0 and β+alleles have β-thalassemia major.

4/Occasionally, persons inheriting at least one β+allele have a milder disease termed β-thalassemia
intermedia

5/The most common mutations lead to abnormal RNA splicing, whereas others fall in the β-globin gene promoter or coding regions.

6/small (microcytic), poorly hemoglobinized (hypochromic) red cells.

7/Accumulation of unpaired α-globin chains, which form toxic precipitates that severely damage the membranes of red cells and erythroid precursors.

8/A high fraction of erythroid precursors die by apoptosis /ineffective erythropoiesis, and the few red cells that are produced have a shortened life span.

9/Ineffective hematopoiesis is associated with an inappropriate increase in the absorption of dietary leads to iron overload due to inappropriately low hepcidin, which is a negative regulator of iron absorption.

Question 24

Alpha thalassemias

Answer 24

1/Caused mainly by deletions involving one or more of the α-globin genes.( The severity of the disease is proportional to the number of α-globin genes that are deleted).

2/loss of a single α-globin gene produces a silent-carrier state,
whereas deletion of all four α-globin genes is lethal in utero
With loss of three α-globin genes there is a relative excess of β-globin or (early in life) γ-globin chains.

3/Excess β-globin and γ-globin chains form relatively stable β4 and γ4 tetramers known as HbH
and Hb Bart, respectively,which cause less membrane damage than the free α-globin chains that are found in β-thalassemia.

4/Ineffective erythropoiesis is less pronounced in α-thalassemia.

5/Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues.

Question 25

Morphology of Thalassemias

Answer 25

1/β-thalassemia minor and α-thalassemia trait, in which abnormalities are confined to the peripheral blood. In smears the red cells are small (microcytic) (hypochromic), but regular in shape. Often seen are target cells with an increased surface area-to-volume ratio that allows the cytoplasm to collect in a central, dark-red “puddle.”

2/On the other end of the spectrum, in β-thalassemia major peripheral blood smears show marked microcytosis, hypochromia, poikilocytosisg(variation in cell shape), and anisocytosis (variation in cell size).
3/Nucleated red cells (normoblasts) are also seen that reflect the underlying erythropoietic drive.

4/β-Thalassemia intermedia and HbH disease are associated with peripheral smear findings that
lie between these two extremes.

5/The anatomic changes in β-thalassemia major are profound in degree.
A-Ineffective erythropoiesis/hyperplasia of erythroid progenitors.
B-The expanded erythropoietic marrow may completely fill the intramedullary space of the skeleton, invade the bony cortex/ impair bone growth, and produce skeletal deformities.
C-Extramedullary hematopoiesis and hyperplasia of mononuclear phagocytes result in prominent splenomegaly, hepatomegaly,and lymphadenopathy.
D-The ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia.
E-severe hemosiderosis develops

6/HbH disease andβ-thalassemia intermedia are also associated with splenomegaly,erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β-thalassemia major.

7/In diagnosis of β-thalassemia major ,Hb electrophoresis shows a profound reduction or absence of HbA and increased levels of HbF. The HbA2 level may be normal or increased.

8/The diagnosis of β-thalassemia minor is made by Hb electrophoresis,which typically shows a reduced level of HbA (α2β2) and an increased level of HbA2 (α2δ2).

9/HbHdisease can be diagnosed by detection of β4 tetramers by electrophoresis.

Question 26

Clinical features of Thalassemias

Answer 26

1/β-Thalassemia trait and α-thalassemia trait are typically asymptomatic/mild microcytic hypochromic anemia.
2/β-Thalassemia major are sustained by blood transfusions, which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis . With transfusions alone, survival into the second or third decade is possible
cardiac dysfunction from secondary hemochromatosis develops and often is fatal in the second or third decade of life.

Question 27

Glucose-6-Phosphate Dehydrogenase Deficiency

Answer 27

1/Abnormalities affecting enzymes responsible for the synthesis of glutathione GSH leave red
cells vulnerable to oxidative injury and hemolysis.

2/the most common is (G6PD) deficiency.

3/G6PD A− has a normal enzymatic activity but a decreased half-life.

Question 28

Pathogenesis of G6PD deficiency

Answer 28

1/Transient episodes of intravascular hemolysis caused by exposure to an environmental factor (usually infectious agents or drugs) that produces oxidant stress.

2/incriminated drugs include antimalarials (e.g., primaquine), sulfonamides, nitrofurantoin,
phenacetin, aspirin (in large doses), and vitamin K derivatives.

3/oxidants are free to attackother red cell components including globin chains/Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, which can damage the red cell membrane so severely .

4/Other cells with lesser damage lose their deformability and suffer further injury when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating ((bite cells)) . Such cells become trapped on recirculation to the spleen and are destroyed by phagocytes(extravascular hemolysis).

Question 29

Clinical Features of G6PD deficiency

Answer 29

1/Hemolysis typically develops 2 or 3 days after drug exposure and is of variable severity.

2/Because G6PD is X-linked/males .

3/By contrast, random inactivation of one X chromosome in heterozygous females creates two populations of red cells, one normal and the other G6PD-deficient. /هاوزالبوون

4/Most carrier females are unaffected except for those with a large proportion of deficient red cells (a chance situation known as unfavorable lyonization).

5/In the case of the G6PD A−variant, it is mainly older red cells that are susceptible to lysis/ the marrow compensates for the anemia ,the hemolysis abates even if the drug exposure continues.

6/In other variants such as G6PD Mediterranean, found mainly in the Middle East, the enzyme
deficiency and the hemolysis that occur on exposure to oxidants are more severe.

Question 30

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 30

1/stems from acquired mutations in PIGA a gene required for the synthesis of phosphatidylinositol
glycan (PIG), which serves as a membrane anchor for many proteins.

2/PIGA is X-linked .

3/The pathogenic mutations in PNH occur in an early hematopoietic progenitor that is
capable of giving rise to red cells, leukocytes, and platelets.

4/Red cells derived from PIGA-deficient precursors are inordinately sensitive to lysis by the complement C5b-C9 membrane attack complex.

5/Leukocytes share the same deficiency but are less sensitive to complement than are red cells.

6/Complement fixation is enhanced by the decrease in blood pH that accompanies sleep (owing to CO2 retention).

7/The most feared complication of PNH is thrombosis, which often occurs within abdominal vessels such as the portal vein and the hepatic vein.

8/Treatment with Eculizumab ,binds C5 and inhibits the assembly of the C5b–C9 membrane attack complex, greatly lessens the incidence of thrombosis as well as the degree of
intravascular hemolysis.
Eculizimab has no effect on early stages of complement fixation, and treated patients continue to have varying degrees of extravascular hemolysis

9/because of the deposition of C3b on red cell surfaces , Loss of C5b-C9 activity in patients receiving Eculizimab poses a risk for Neisseria infections, particularly meningococcal sepsis; thus, all treated patients must be vaccinated against N. meningococcus