DONE BY : RaSHA RAKAN & Bushra Saleem

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

Abnormality is in the Hb

• 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 The beta subunit has the amino acid valine at position 6 instead of the glutamic acid that is normally present

• 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

Through the ages the generations with HbS a result of homozygote sickle cell anemia survived the endemic 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

sickling (which means looking like a sickle because HbS is abnormal, they bind to one another and polymerize, and thus elongate the cell and cause damage to the cell membrane) It has 2 types :

A. Reversible

B. Irreversible

• On deoxygenation O2 , HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6 Attacks happen in high altitude, infection, pretty much anything that causes hypoxia

…these polymers distort the red cell, which assumes an elongated

crescentic, or sickle, shape

• The sickling is initially reversible the binding of HbS relieved with reoxygenation and the RBC goes back to its normal shape …However, repeated sickling will cause influx of calcium

…the cytoskeleton will be affected…irreversibly sickled cells preminant

…rapidly hemolyzed

Sickle Cell Anemia, cont’d • 3 most important factors for sickling:

1-Presence of hemoglobins other than HbS

• sickle cell trait carriers : 40% HbS and the remainder is HbA…less sickling

• HbC…lysine instead of glutamic acid a rare hemoglobinopathy compound heterozygous :when people have heterozygote HbC and heterozygote HbS at the same time is a very bad thing …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

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 because the problem in thalassemia is the decreasing of Hb

-HbS trait (less HbS)…no sickling

Sickle Cell Anemia, cont’d

3-The transit time how much the strength/velocity of RBCs movements in the vessels for red cells through the microvasculature The slower (more stasis) the more the sickling

…sluggish circulation (e.g., spleen, bone marrow)…more sickling because they are trapped and slow in these organs

…inflammation (more adhesiveness and slowing)…more sickling because it increases the adhesiveness of RBCs thus stasis

***The clinical sequelae: Chronic hemolytic anemia (life span nearly 20 days) Extravascular hemolysis

+ Microvascular obstruction…ischemic tissue damage and pain crises

The clinical sequelae

Reversible and irreversible sickling are the main cause of the complications that happen with those patients 1. Ischemia in organs : in reversible sickling, RBCs mechanically block the capillaries of many organs, and therefor patients will have pain crisis

2. Extravascular hemolysis: with time when the reversible sickling turns into irreversible, RBCs will be trapped in the spleen, and splenic macrophages destroy them to cause extravascular hemolysis as we mentioned before

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

Sickle Cell Anemia, of the consequences:

• Hypoxia-induced fatty changes in the heart, liver, and renal tubules

• Severe chronic hemolytic anemia

• Extramedullary hematopoiesis general feature og hemolytic anemia

• Compensatory hyperplasia of erythroid progenitors in the marrow degradation (تحلل) of bone followed by reactive bone formation that will cause abnormalities in bone

…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

the spleen is in danger of ischemia, and therefore fibrosis

Sickle Cell Anemia, consequences, cont’d

• Vascular congestion, thrombosis, and infarction

…any organ: bones, liver, kidney, retina, brain, lung, and skin

• Priapism continuous erection of the penis, another frequent problem, can lead to penile fibrosis and erectile dysfunction

• As with the other hemolytic anemias, hemosiderosis and gallstones all hemolytic anemia 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 even though Salmonella isn’t a major cause of osteomylitis

Sickle Cell Anemia & the Acute Chest Syndrome

…can be triggered by :

1.pulmonary infections

2.fat emboli from infarcted marrow

…a lung infection with sluggish circulation will induce sickling and this

will exacerbate the hypoxia and lung damage slow RBCs because of inflammation

ischemia in the lung more and more

(vicious circle)

• The acute chest syndrome and stroke ischemia in the brain are the two leading causes of ischemia-related death in sickle cell patients

Sickle Cell Anemia, diagnosis and treatments Diagnosis:

• Electrophoresis of the serum: demonstration of HbS

• Prenatally: by analyzing fetal DNA by amniocentesis through amniotic fluid

• or biopsy of chorionic villi

Treatment:

• Penicillin for prophylaxis from encapsulated bacteria because they have problems in spleen

• 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(that’s why it occurs a lot there)

Thalassemia, genetics

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

( there are2 alleles α from the mother and 2 alleles α from father )

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

chromosome 11 (there Is 1 allele β from the mother and 1 allele β from father )

• There are 2 types of thalassemia (α, β) , the mutation that happened in globin chain gene depend on how much mutated alleles and the type of the mutation: when β mutated it’s not deletion but it’s changing pair to another, but when α mutated it’s deletion.

• In β thalassemia mutated allele could cause decreasing or stopping the production :

• β0 β0 stop production, β+ β+ decrease production (major)

• β0 β, β+ β (minor)

• In α there is 2 genes: if 1 mutated gene silent , 2 mutated genes “ both from mother or father , or one from mother and one from father” α thalassemia trait – asymptomatic, like minor-, 4 genes mutated fetus died in uterus (hydrops fetalis).

• If there is 3 mutated genes “ when α deleted β accumulate in bad way – HbH disease- that resemble β TH intermedia that is severe anemia but don’t need for frequent blood transfusion like β TH major.

• This is case of β TH major : β globin reduced, α globin accumulates.

• That cause changes in the membrane affects the passing through spleen and cause extravascular hemolysis, these cells and their precursors (erythroblast) are abnormal so they exposed to early apoptosis in B.M called (ineffective erythropoiesis) this is lead to

• 1-increase iron absorption in GI and cause hemosiderosis (because of decreasing in histidine that prevents iron absorption + that because of recurrent transfusion).

• 2-hemolytic anemia.

• 3- erythrocytes hyperplasia if it’s severe it’ll cause bone degeneration followed by abnormal formation of bones “crewcut x-rays”.