SDL 6: hereditary spherocytosis and sickle cell disease

anemia when hematopoiesis cannot match pace of RBC destruction, jaundice, cholelithiasis, reticulocytosis

manifestations of hemolysis

-first converted to unconjugated bilirubin within macrophages in the reticuloendothelial system

-then taken up by hepaatocytes and conjugated

what happenns to the heme of lysed cells?

reticuloendothelial system

system composed of tissue macrophages in the spleen, liver, bone marrow and lymph nodes, and their blood- borne counterparts, monocytes

-aka the mononuclear phagocyte system

extravascular hemolysis

Destruction of red blood cells outside of a blood vessel like the spleen, and sometimes the liver

cells of reticuloendotheliail system

-similar to physiologic removal of senescent RBCs

in extravascular hemolysis, RBCs are cleared from circulation by

splenomegaly

main consequence of chronic extravascular hemolysis

intravascular hemolysis

hemolysis associated with cell membrane damage by autoantibodies, microorganisms, direct trauma, shear stress, or toxins

hemoglobinemia, decreased plasma haptoglobin, hemoglobinuria, and hemosiderinuria.

the principle features of intravascular hemolysiis

Fenton reaction

reaction of free hemoglobin promoting formation of hydroxyl radicals---> oxidative tissue damage

spleen and liver macrophages

haptoglobin hemoglobin complex is removed by

Hemosiderin

an iron-storage protein primarily made in times of iron overload secondary to intravascularr hemolysis

no

is splenomegaly associated with intravascular hemolysis?

severe

extramedullary hematopoiesis is a sign of ______ annemia

iron containing pigment hemosiderin, particularly in the spleen, liver, and bone marrow

phagocytosis of red cells leadsd to the accumulation of

pigment gallstones

gallstone type associated with chronic hemolysis

Hereditary spherocytosis

an inherited disorder caused by mutations in the genes encoding erythrocyte membrane protein

hereditary spherocytosis

the most common hereditary hemolytic anemia in people of northern European descent

ANK1, encoding ankyrin

most common gene mutation of hereditary spherocytosis

autosomal dominant

inheritance of hereditary spherocytosis

microvesicles

-splenic sequestration also promotes the spheres

young spherocytosis cell's destabilized lipid bilayer sheds membrane fragments which form ______ which reduces RBC surface area, making spheroid

splenectomy

procedure that removes the primary 'graveyard' for spherocytes and, thus, eliminates anemia and hyperbilirubinemia.

seen in other disorders associated with membrane loss, such as in autoimmune hemolytic anemia.

besides HS, what other anemias are associated with spherocytes?

reticulocytosis, marrow erythhroid hyperplasia, hemosiderosis, mild jaundice, sometimes cholelithiasis and moderate splenomegaly

-large range of clinical presentatoni

features common to hereditary spherocytosis

-normal or slightly low

must take into account the combined presence of spherocytes (with a low MCV) and reticulocytes (with an increased MCV)

MCV associated with hereditary spherocytosis

increased MCHC

most helpful red cell index in diagnosis hereditary spherocytosis

elevated LDH, unconjugated bilirubiin, and decreased haptoglobin

main three tests for hemolysis

Eosin-5-maleimide binding test

flow cytometric test based on interaction between fluorescent dye EMA and band 3 protein; great test for HS

-lower in HS

osmotic fragility test

if Eosin-5-maleimide binding test results are equivocal, whaat test is done for herediatry spherocytosis diagnosis?

determined by measuring the degree of hemolysis in hypotonic saline solution

how to perform an osmotic fragility test

Fresh normal red cells start to hemolyze at 0.5% NaCl and hemolysis is complete at 0.3% NaCl.

at what tonicity do normal red cells hemolyze?

0.5%

red cell osmotic fragiliity is considered to be increased if hemolysis occurs at NaCl concentration higher than

good

-no specific treatment, treat complications of gallstones

-may rerquire blood traansfusion, EPO, and splenectomy in severe cases

prognosis of hereditary spherocytosis

sickle cell disease

common hereditary hemoglobinopathy caused by a point mutation in β-globin that promotes the polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage.

the second half of the first year of life, when fetal Hb falls

at what at is SCD clinically apparent?

point mutation in the sixth codon of β- globin that leads to the replacement of a glutamate residue with a valine residue

mutation associated with SCD

autosomal recessive

-heterozygosity---> asymptomatic sickle cell trait

inheritance of HbS

Sickle cell trait

-polymerization contributes to sickling

40% of the hemoglobin is HbS and the rest is HbA, which interferes with HbS polymerization

HbF>HbA

Hemoglobin types that interfere with polymerization of HbS

Hemoglobin C

hemoglobin of Lysine is substituted for Glutamic Acid at the 6th position on the Beta chain.

HbSC disease

heterozygous for HbbC and HbS---> symptomatic sickling disorder

end-stage, nondeformable, irreversibly sickled cells, which retain a sickle shape even when fully oxygenated.

the most severely damaged sickled cells are converted to

-chronic hemolytic anemia (mean lifespan 20 days)

-widespread microvascular obstrructiton---> ischemic tissue crisis

what are the two major consequences that arise from sickling of red cells

free radicas and oxidative damage

reperfusion of ischemic tissue due to SCA generates

damaged erythrocytes release free hemoglobin into the plasma, which strongly bind to nitric oxide, causing functional nitric oxide deficiency and contributing to the development of vasculopathy.

how is SCA associated with functional nitric oxide deficiency?

irreversibly sickled cells, reticulocytosis, and target cells

-howell jolly bodies

findings of peripheral blood smear of SCA pt

howell-jolly bodies

small nuclear remnant RBCs due to asplenia

-associated with SCA

Autosplenectomy

the gradual fibrosis and dysfunction of the spleen secondary to SCA

dactylitis

a special manifestation of an acute pain crisis in young children in which the hands or feet are swollen, tender, and erythematous.

encapsulated organisms

children with SCD are at an increased risk of infection from _______ organisms due to functional asplenia

salmonella

children with SCD are at an increased risk of osteomyelitis by what causitive organism?

aplastic crisis

complication of children with SCD who get parvovirus B19

sudden onset of acute anemia (pallor), and splenomegaly and may present as sudden circulatory collapse due to the rapid sequestration of circulating red cells in the spleen.

signs of acute splenic sequestration crisis

acute chest syndrome

acute pulmonary process that occurs exclusively in pts with SCD

-presence of new pulmonary infiltrate that involves at least one complete lung segment

leukocyte count is elevated with predominance of nneutrophils

-platelets increased

WBC of pt with SCD

low

ESR associated with SCD

Howell-Jolly bodies

this finding indicates the pt is asplenic

gel electrophoresis process

diagnosis of SCD is confirmed by

sickle trait

heterozygous state with 35-45% of hemoglobin being HbS, 50-60% is HbA and <3.5% is HbA2 on electrophoresis

sickle cell disease

85-90% of hemoglobin being HbS, 2-15% HbF and <3.5% HbA2 on electroporesis

cardiac and infectious

primarry cause of death among pts with SCD

hydroxyurea (myelosuppressive agent)

-raises the level of HbF and generates NO

the only effective drug proven to reduce the frequency of painful episodes