Hemolytic Anemias (Hertz)

Question 1

Blood agar results

Answer 1

alpha strep– does’t hemolyze anything

beta strep– causes post strep glomerulophritis, rheumatic heart disease

Question 2

Hemolytic Anemia characteristics

Answer 2

Decrease in RBC’s 120 days lifespan

Reticulocytosis
(Erythropoietin elevation

Hemoglobin degradation products

Question 3

Types of Hemolysis

Answer 3

Intravascular: Acute, devastating; lysis and * destruction of red cells in the intravascular space

Extravascular: Chronic, enhancement or amplification of normal physiologic removal of red cells- not really hemolysis. Increased removal! Slow, not catastrophic
(most common form)

Question 4

Extravascular hemolysis leads to

Answer 4

Anemia, splenomegaly, and jaundice

Decreases in plasma haptoglobin

Question 5

Intravascular hemolysis

Answer 5

acute

hallmarks: hemoglobinuria, jaundice **

anemia, hemoglobinemia, hemosiderinuria,

Large amounts can cause renal failure, DIC

Causes: immunohemolytic destruction of red cells, complement mediated, malaria, severe osmotic stress

Question 6

critical lab test for intra/ extravascular hemolysis

Answer 6

decreased haptoglobin

Question 7

stuff going on in hemolytic anemia

Answer 7

hemosiderin
hemosiderosis
extramedullary hematopoiesis
pigment gallstones (cholelithiasis)

Question 8

osmotic fragility test

Answer 8

put RBCs in different concentrations of salt, see how much it takes to lyse them.

a test for hereditary spherocytosis

Question 9

black gallstones

Answer 9

are pigment stones– from bilirubin, not cholesterol

Question 10

Hereditary Spherocytosis

Answer 10

Hereditary spherocytosis (HS) is an inherited disorder caused by intrinsic defects in the red cell membrane skeleton that render red cells spheroid, less deformable, and vulnerable to splenic sequestration and destruction

HS is caused by diverse mutations that lead to an insufficiency of membrane skeletal components

The pathogenic mutations ** most commonly affect ankyrin, band 3, spectrin, or band 4.2, ** the proteins involved in one of the two tethering interactions, presumably because this complex is particularly important in stabilizing the lipid bilayer.

Question 11

Red cell membrane in hereditary spherocytosis

Answer 11

T 1/2 = 10-20 days! **

Young HS red cells are normal in shape, but the ** deficiency of membrane skeleton reduces the stability of the lipid bilayer, leading to the loss of membrane fragments as red cells age in the circulation.** The loss of membrane relative to cytoplasm “forces” the cells to assume the smallest possible diameter for a given volume, namely, a sphere.

Question 12

Clinical Features of hereditary spherocytosis

Answer 12

In two thirds of the patients the red cells are abnormally sensitive to osmotic lysis

HS red cells also have an increased mean cell hemoglobin concentration, due to dehydration caused by the loss of K+ and H2O.

The characteristic clinical features are anemia, splenomegaly, and jaundice

Question 13

classic diagnostic signs for hereditary spherocytosis

Answer 13

CBC and MCHC elevated

(review: Mean corpuscular hemoglobin concentration (MCHC) is the average concentration of hemoglobin in red blood cells. )

Question 14

parvovirus

Answer 14

shuts down red cells for 2 weeks (aplastic crisis)

Question 15

infectious mono –>

Answer 15

large spleen

hemolytic crisis

Question 16

what disease gives you the most giant spleen, curling all the way up into the pelvis?

Answer 16

polycythemia/ myeloproliferative disorders

Question 17

Holly Jowell bodies

Answer 17

spleen didn’t do its job of punching out the nucleus of the RBC (always seen in splenectomy pts)

Question 18

hereditary elliptocytosis outcome?

Answer 18

nothing! Clinically insignificant.

Question 19

Hemolytic Disease due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency

Answer 19

Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries and lead to hemolysis.

recessive X-linked- males at higher risk

Question 20

G6PD is responsible for

Answer 20

glutathione, which fights

free radicals, which damage blood cells

Question 21

evolutionary pressure for G6PD deficiency

and what are the most clinically significant variants of G6PD deficiency?

Answer 21

protects from malaria like sickle cell

Several hundred G6PD genetic variants are known, but most are harmless.

Two variants, designated G6PD− and G6PD Mediterranean, cause most of the clinically significant hemolytic anemias.

G6PD− is present in about 10% of American blacks; G6PD Mediterranean, as the name implies, is prevalent in the Middle East.

Question 22

G6PD hemolysis- what type? common triggers?

Which RBCs are more prone?

Answer 22

Both intra- and extravascular hemolysis

The episodic hemolysis that is characteristic of G6PD deficiency is caused by exposures that generate oxidant stress

• most common triggers: infections; oxygen-derived free radicals are produced by activated leukocytes
• other important initiators: drugs and certain foods

Because mature red cells do not synthesize new proteins, G6PD− or G6PD Mediterranean enzyme activities fall quickly to levels inadequate to protect against oxidant stress as red cells age. Thus, older red cells are much more prone to hemolysis than younger ones.

Question 23

Heinz bodies

Answer 23

dark inclusions within red cells that stain with crystal violet

precipitates of denatured globin.

As the splenic macrophages pluck out these inclusion, “bite cells” are produced.

Question 24

exposure of G6PD deficient folk to oxidants –>

Answer 24

Acute intravascular hemolysis, marked by anemia, hemoglobinemia, and hemoglobinuria, usually begins 2 to 3 days following exposure of G6PD-deficient individuals to oxidants.

The hemolysis is *greater in individuals with the highly unstable G6PD Mediterranean variant.

Because only older red cells are at risk for lysis, the episode is * self-limited, as hemolysis ceases when only younger G6PD-replete red cells remain (even if the patient continues to take the offending drug). The recovery phase is heralded by reticulocytosis*

Question 25

when should we test for G6PD deficiency?

Answer 25

10-20 days after the problem; all the lysed cells are the ones that might show the problem. Wait until new ones have been generated.

Question 26

newborn with anemia and jaundice is what until proven otherwise?

Answer 26

pyruvate kinase deficiency

cockleburr cells

Question 27

problem with the sickledex

Answer 27

a five-minute solubility test helpful in excluding sickle cell disease when negative, but impossible to separate sickle cell disease from trait.

positive if 10% Hb S is present.

Question 28

Hemoglobin electrophoresis and sickle cell

Answer 28

A- normal
AS- one of each (normal and sickle)- sickle trait
SS- sickle disease
AC- combo, a C variant

Question 29

Sickle Cell Disease

Answer 29

Sickle cell disease is a 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

Question 30

sickle cell disease vs trait

Answer 30

About 8% to 10% of African Americans, or roughly 2 million individuals, are heterozygous for HbS, a largely asymptomatic condition known as sickle cell trait.

The offspring of two heterozygotes has a 1 in 4 chance of being homozygous for the sickle mutation, a state that produces symptomatic sickle cell disease. In such individuals, almost all the hemoglobin in the red cell is HbS (α2βs2).

Question 31

Sickle cell evolutionary pressure?

Answer 31

This high frequency stems from protection afforded by HbS against falciparum malaria, (second one!)

It has been suggested that G6PD deficiency and thalassemias also protect against malaria by increasing the clearance and decreasing the adherence of infected red cells, possibly by raised levels of oxidant stress and causing membrane damage in the parasite-bearing cells

Question 32

Sickle Cell Disease

The major pathologic manifestations

Answer 32

Chronic hemolysis

Microvascular occlusions

Tissue damage

Question 33

pathogenesis of sickle cell disease

Answer 33

Stem from the tendency of HbS molecules to stack into polymers when deoxygenated.

Initially, this process converts the red cell cytosol from a freely flowing liquid into a viscous gel.

With continued deoxygenation HbS molecules assemble into long needle-like fibers within red cells, producing a distorted sickle or holly-leaf shape.

Question 34

variables affecting rate and degree of sicklling

Answer 34

[Hemoglobin S]
MCHC
Intracellular pH
Red cells transit time

Question 35

Interaction of HbS with the other types of hemoglobin in the cell

Answer 35

In heterozygotes with sickle cell trait, about *40% of the hemoglobin is HbS and the rest is HbA, which interferes with HbS polymerization. As a result, red cells in heterozygous individuals do not sickle except under conditions of profound hypoxia.

HbF inhibits the polymerization of HbS even more than HbA; hence, infants do not become symptomatic until they reach * 5 or 6 months of age, when the level of HbF normally falls.

In * HbSC red cells the percentage of HbS is 50%, as compared with only 40% in HbAS cells. As a result, individuals who are compound heterozygotes for HbS and HbC have a symptomatic sickling disorder (termed HbSC disease), but it is milder than sickle cell disease

Question 36

Mean cell hemoglobin concentration (MCHC) and Sickle cell disease

Answer 36

Higher HbS concentrations increase the probability that aggregation and polymerization will occur during any given period of deoxygenation. Thus, intracellular dehydration, which increases the MCHC, facilitates sickling

Question 37

Intracellular pH

and sickle cell

Answer 37

A decrease in pH reduces the oxygen affinity of hemoglobin, thereby increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling

Question 38

Transit time of red cells through microvascular beds and sickle cell

Answer 38

Transit times in most normal microvascular beds are too short for significant aggregation of deoxygenated HbS to occur, and as a result sickling is confined to microvascular beds with slow transit times.
Blood flow is sluggish in the normal spleen and bone marrow, which are prominently affected in sickle cell disease, and also in vascular beds that are inflamed.

The movement of blood through inflamed tissues is slowed because of the adhesion of leukocytes to activated endothelial cells and the transudation of fluid through leaky vessels.

Question 39

sickle cells clogging up the spleen cause

Answer 39

auto infarction

Question 40

Clinical Features

of sickle cell disease

Answer 40

Sickle cell disease causes a moderately severe hemolytic anemia (hematocrit 18% to 30%) that is associated with reticulocytosis, hyperbilirubinemia, and the presence of irreversibly sickled cells

Question 41

Sickle cell crises

Answer 41

• Vaso-occlusive crises,

In children, painful bone crises

• Acute chest syndrome
• Sequestration crises

aplastic crises

hyposthenuria

increased susceptiility to infection with encapsulated organisms

Question 42

• Vaso-occlusive crises (sickle)

Answer 42

also called pain crises, are episodes of hypoxic injury and infarction that cause severe pain in the affected region.

Question 43

painful bone crises (sickle)

Answer 43

in children, are extremely common and often difficult to distinguish from acute osteomyelitis. These frequently manifest as the *hand-foot syndrome or dactylitis of the bones of the hands or feet, or both.

Question 44

acute chest syndrome

Answer 44

is a particularly dangerous type of vaso-occlusive crisis involving the lungs, which typically presents with fever, cough, chest pain, and pulmonary infiltrates.

(sickle cell)

Question 45

sequestration crises (sickle cell)

Answer 45

occur in children with intact spleens. Massive entrapment of sickle red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock

Both sequestration crises and the acute chest syndrome may be fatal and sometimes require prompt treatment with exchange transfusions

Question 46

aplastic crises (sickle cell)

Answer 46

Aplastic crises stem from the infection of red cell progenitors by parvovirus B19, which causes a transient cessation of erythropoiesis and a sudden worsening of the anemia

Chronic hypoxia is responsible for a generalized impairment of growth and development

Question 47

hyposthenuria in sickle cell

Answer 47

Sickling provoked by hypertonicity in the renal medulla causes damage that eventually leads to hyposthenuria (the inability to concentrate urine)

Question 48

sickle cell susceptibility to pathogens

Answer 48

Increased susceptibility to infection with encapsulated organisms is another threat

Defects of uncertain etiology in the * alternative complement path­way also impair the opsonization of bacteria. Pneumococcus pneumoniae and Haemophilus influenzae septicemia and meningitis are common, particularly in children, but can be reduced by vaccination and prophylactic antibiotics.

Question 49

prognosis for sickle cell

Answer 49

The outlook for patients with sickle cell disease has improved considerably over the past 10 to 20 years.

About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade.

A mainstay of treatment is an inhibitor of DNA synthesis, * hydroxyurea, which has several beneficial effects. These include (1) an increase in red cell HbF levels, which occurs by unknown mechanisms; and (2) an antiinflammatory effect, which stems from an inhibition of leukocyte production