Hemolytic anemias(2 of 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)

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

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

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 HbSthan 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

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

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

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

Elsevier. Kumar et al. Robbins basic pathology 9th

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

Please visit https://www.researchgate.net/figure/Skull-CT-bone-window-Emissary-vein-arrow_fig3_282562166 for references

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

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

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

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

Thalassemia, genetics

• The α chains are encoded by two α-globin genes…on chromosome 16

…while the β chains are encoded by a single β-globin gene located on

chromosome 11

Elsevier. Kumar et al. Robbins basic pathology 9th

Elsevier. Kumar et al. Robbins basic pathology 9th

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)

Visit http://imagebank.hematology.org/image/60310/target-cells for references

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

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

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