1. Hemolytic anemias (2 of 2)
Ali Al Khader, M.D.
Faculty of Medicine
Al-Balqa’ Applied University

2. Sickle Cell Anemia
The most common familial hemolytic anemia in the world
Sickle cell anemia is the prototypical (and most prevalent) hemoglobinopathy
Mutation in the β-globin gene that creates sickle hemoglobin (HbS)
Normal hemoglobins are tetramers composed of two pairs of similar chains
The normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2)

3. Sickle Cell Anemia, cont’d
HBS is caused by substitution of valine for glutamic acid at the sixth amino acid residue of beta-globin
In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced
In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria
In the United States, approximately 8% of blacks are heterozygous for HbS, and about 1 in 600 have sickle cell anemia

4. Sickle Cell Anemia, cont’d
On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6
…these polymers distort the red cell, which assumes an elongated
crescentic, or sickle, shape
The sickling is initially reversible with reoxygenation…However, repeated sickling will cause influx of calcium
…the cytoskeleton will be affected…irreversibly sickled cells
…rapidly hemolyzed

5. Sickle Cell Anemia, cont’d
3 most important factors for sickling:
1-Presence of hemoglobins other than HbS
…sickle cell trait: 40% HbS and the remainder is HbA…less sickling
…HbC…lysine instead of glutamic acid
…Because HbC has a greater tendency to aggregate with HbS
than does HbA, HbS/HbC compound heterozygotes have a
symptomatic sickling disorder called HbSC disease
…HbF interacts weakly with HbS, so 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

6. Sickle Cell Anemia, cont’d
2-The intracellular concentration of HbS …The polymerization of deoxygenated HbS is strongly concentration- dependent…so: -red cell dehydration, which increases the Hb concentration, facilitates sickling -if coexistent alpha-thalassemia (decreased concentration): less sickling -HbS trait (less HbS)…no sickling

7. Sickle Cell Anemia, cont’d
3-The transit time for red cells through the microvasculature …sluggish circulation (e.g., spleen, bone marrow)…more sickling …inflammation (more adhesiveness and slowing)…more sickling ***The clinical sequelae: Chronic hemolytic anemia (life span nearly 20 days) + Microvascular obstruction…ischemic tissue damage and pain crises

8. Sickle Cell Anemia, cont’d
Vaso-occlusion does not correlate with the number of irreversibly sickled cells and therefore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells

9. Sickle Cell Anemia, of the consequences:
Hypoxia-induced fatty changes in the heart, liver, and renal tubules
Severe chronic hemolytic anemia
Extramedullary hematopoiesis
Compensatory hyperplasia of erythroid progenitors in the marrow
…this will cause bone resorption and secondary new bone formation
…prominent cheekbones
…crewcut appearance on x-rays
Splenomegaly (extravascular
hemolysis)…then autosplenectomy
(complete by adulthood)
Not specific…more known in thalassemia major

10. Sickle Cell Anemia, consequences, cont’d
Vascular congestion, thrombosis, and infarction
…any organ: bones, liver, kidney, retina, brain, lung, and skin
Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction
As with the other hemolytic anemias, hemosiderosis and gallstones are common
Aplastic crisis if superimposed B19 infection…severe but self-limited
Susceptibility to infection by encapsulated bacteria…due to splenic problems
Susceptibility to Salmonella osteomyelitis

11. Sickle Cell Anemia & the Acute Chest Syndrome
…can be triggered by pulmonary infections or fat emboli from infarcted
marrow
…a lung infection with sluggish circulation will induce sickling and this
will exacerbate the hypoxia and lung damage more and more
(vicious circle)
The acute chest syndrome and stroke are the two leading causes of ischemia-related death in sickle cell patients

12. Sickle Cell Anemia, diagnosis and treatments
Electrophoresis: demonstration of HbS
Prenatally: by analyzing fetal DNA by amniocentesis or biopsy of chorionic villi
Penicillin for prophylaxis
Hydroxyurea

13. Thalassemia
Mutations that decrease the synthesis of α- or β-globin chains
…the result: deficiency of Hb and additional red cell changes due to
the relative excess of the unaffected globin chain
Autosomal recessive
Mutations that cause thalassemia are particularly common among populations in Mediterranean, African, and Asian regions in which malaria is endemic…so they are protective against malaria

14. Thalassemia, genetics
The α chains are encoded by two α-globin genes…on chromosome 11
…while the β chains are encoded by a single β-globin gene located on
chromosome 16

17. β-thalassemia minor and α-thalassemia trait
The abnormalities are confined to the peripheral blood
In smears the red cells are small (microcytic) and pale (hypochromic), but regular in shape
Often seen are target cells, cells with an increased surface area-to-volume ratio that allows the cytoplasm to collect in a central, dark-red “puddle”
β-thalassemia minor diagnosis by electrophoresis: reduced level of HbA (α2β2) and an increased level of HbA2 (α2δ2)

18. β-thalassemia major
Peripheral blood smears show marked microcytosis, hypochromia, poikilocytosis, and anisocytosis
Nucleated red cells (normoblasts) are also seen that reflect the underlying erythropoietic drive
The ineffective erythropoiesis and hemolysis result in a striking hyperplasia of erythroid progenitors, with a shift toward early forms
The expanded erythropoietic marrow may completely fill the intramedullary space of the skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities
Prominent splenomegaly, hepatomegaly, and lymphadenopathy

19. β-thalassemia major, cont’d
Ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia reminiscent of that seen in cancer patients
Unless steps are taken to prevent iron overload, over the span of years severe hemosiderosis develops
Diagnosis: by electrophoresis: increased HbF and nearly absent HbA
…HbA2 level may be normal or increased
…Similar but less profound changes are noted in patients affected by β-
thalassemia intermedia

20. β-Thalassemia intermedia and HbH disease
Peripheral smear findings that lie between the two extremes
Also associated with splenomegaly, erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β- thalassemia major
HbH disease can be diagnosed by detection of β4 tetramers by electrophoresis

21. Thank You