Hemolytic Anemias (Hertz) Flashcards
Blood agar results
alpha strep– does’t hemolyze anything
beta strep– causes post strep glomerulophritis, rheumatic heart disease
Hemolytic Anemia characteristics
Decrease in RBC’s 120 days lifespan
Reticulocytosis
(Erythropoietin elevation
Hemoglobin degradation products
Types of Hemolysis
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)
Extravascular hemolysis leads to
Anemia, splenomegaly, and jaundice
Decreases in plasma haptoglobin
Intravascular hemolysis
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
critical lab test for intra/ extravascular hemolysis
decreased haptoglobin
stuff going on in hemolytic anemia
hemosiderin
hemosiderosis
extramedullary hematopoiesis
pigment gallstones (cholelithiasis)
osmotic fragility test
put RBCs in different concentrations of salt, see how much it takes to lyse them.
a test for hereditary spherocytosis
black gallstones
are pigment stones– from bilirubin, not cholesterol
Hereditary Spherocytosis
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.
Red cell membrane in hereditary spherocytosis
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.
Clinical Features of hereditary spherocytosis
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
classic diagnostic signs for hereditary spherocytosis
CBC and MCHC elevated
(review: Mean corpuscular hemoglobin concentration (MCHC) is the average concentration of hemoglobin in red blood cells. )
parvovirus
shuts down red cells for 2 weeks (aplastic crisis)
infectious mono –>
large spleen
hemolytic crisis
what disease gives you the most giant spleen, curling all the way up into the pelvis?
polycythemia/ myeloproliferative disorders
Holly Jowell bodies
spleen didn’t do its job of punching out the nucleus of the RBC (always seen in splenectomy pts)
hereditary elliptocytosis outcome?
nothing! Clinically insignificant.
Hemolytic Disease due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency
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
G6PD is responsible for
glutathione, which fights
free radicals, which damage blood cells
evolutionary pressure for G6PD deficiency
and what are the most clinically significant variants of G6PD deficiency?
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.
G6PD hemolysis- what type? common triggers?
Which RBCs are more prone?
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.
Heinz bodies
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.
exposure of G6PD deficient folk to oxidants –>
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*
when should we test for G6PD deficiency?
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.
newborn with anemia and jaundice is what until proven otherwise?
pyruvate kinase deficiency
cockleburr cells
problem with the sickledex
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.
Hemoglobin electrophoresis and sickle cell
A- normal
AS- one of each (normal and sickle)- sickle trait
SS- sickle disease
AC- combo, a C variant
Sickle Cell Disease
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
sickle cell disease vs trait
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).
Sickle cell evolutionary pressure?
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
Sickle Cell Disease
The major pathologic manifestations
Chronic hemolysis
Microvascular occlusions
Tissue damage
pathogenesis of sickle cell disease
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.
variables affecting rate and degree of sicklling
[Hemoglobin S]
MCHC
Intracellular pH
Red cells transit time
Interaction of HbS with the other types of hemoglobin in the cell
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
Mean cell hemoglobin concentration (MCHC) and Sickle cell disease
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
Intracellular pH
and sickle cell
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
Transit time of red cells through microvascular beds and sickle cell
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.
sickle cells clogging up the spleen cause
auto infarction
Clinical Features
of sickle cell disease
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
Sickle cell crises
- Vaso-occlusive crises,
In children, painful bone crises
- Acute chest syndrome
- Sequestration crises
aplastic crises
hyposthenuria
increased susceptiility to infection with encapsulated organisms
- Vaso-occlusive crises (sickle)
also called pain crises, are episodes of hypoxic injury and infarction that cause severe pain in the affected region.
painful bone crises (sickle)
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.
acute chest syndrome
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)
sequestration crises (sickle cell)
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
aplastic crises (sickle cell)
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
hyposthenuria in sickle cell
Sickling provoked by hypertonicity in the renal medulla causes damage that eventually leads to hyposthenuria (the inability to concentrate urine)
sickle cell susceptibility to pathogens
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.
prognosis for sickle cell
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
