Hemolytic anemias (2 of 2) - PowerPoint Presentation

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Hemolytic anemias(2 of 2)

Ali Al Khader, M.D.

Faculty of Medicine

Al-Balqa’ Applied University

Email: ali.alkhader@bau.edu.jo

Sickle Cell AnemiaThe most common familial hemolytic anemia in the worldSickle cell anemia is the prototypical (and most prevalent)

hemoglobinopathy

M

utation

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’dHBS is caused by substitution of valine for glutamic acid at the sixth amino acid residue of beta-globinIn 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’dOn 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’d3 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

Sickle Cell Anemia, cont’d2-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’d3-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’dVaso-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 tubulesSevere chronic hemolytic anemiaExtramedullary hematopoiesisCompensatory 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’dVascular congestion, thrombosis, and infarction …any organ: bones, liver, kidney, retina, brain, lung, and skinPriapism, 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 treatmentsElectrophoresis: demonstration of HbSPrenatally: by analyzing fetal DNA by amniocentesis or biopsy of chorionic villiPenicillin for prophylaxis Hydroxyurea

ThalassemiaMutations 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

M

utations

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, geneticsThe 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 traitThe 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 majorPeripheral 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 deformitiesProminent splenomegaly, hepatomegaly, and lymphadenopathy

β-thalassemia major, cont’dIneffective 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 diseasePeripheral smear findings that lie between the two extremesAlso

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

Thank You