Hemolytic Anemia Flashcards
hemolytic anemia occurs when ____ exceeds ____
common features?
rate of hemolysis exceeds rate of bone marrow RBC production
could be due to acute blood loss (would see symptoms/signs of low blood volume) or hemolysis
common features: HIGH reticulocytes (3x or more), shortened RBC lifespan, elevated EPO and erythropoiesis, clinical/laboratory evidence of RBC destruction
how can the high reticulocyte count seen in hemolytic anemia affect MCV?
reticulocytes are a bit larger than mature RBC (also are bluish and lack central pallor)
increase mean corpuscular volume (MCV)
splenic macrophages remove old/damaged RBC as they pass from ____ and _____
cords to sinusoids
changes in RBC surface proteins with age allow macrophages to bind
old RBC are also less flexible to fit through endothelial slits (spleen is like a filter)
unconjugated bilirubin from broken down RBC in spleen is very hydrophobic and toxic, so it circulates in plasma bound to ____
albumin, which takes it to liver for excretion (to bile, where it becomes conjugated to be water soluble)
[remember that RBC breakdown also releases iron, which is recycled]
hemolysis occurs when either 2 things occurs:
- extravascular: increased number of RBC are trapped in the spleen (cannot get through filter - endothelial slits) —> splenomegaly and increase in red pulp
- intravascular: RBC lyse within blood vessels
in hemolytic anemia due to increased number of RBC getting trapped in the spleen, what happens to the spleen and the liver?
splenomegaly and increased red pulp relative to white pulp
high amount of unconjugated bilirubin being taken to liver (carried by albumin) overwhelms liver, so there is an increase in unconjugated bilirubin in the blood, and increased conjugated bilirubin seen in the bile and intestine
increased unconjugated bilirubin in blood —> jaundice
in hemolytic anemia due to an increased number of RBC trapped in the spleen, there is an increase in unconjugated bilirubin (bound by albumin) in the blood. what clinical feature does this cause?
jaundice (icterus) - due to deposition of bilirubin in tissues (hyperbilirubinemia)
most noticiable in sclerae (eyes) - have high affinity for bilirubin
(total change in bilirubin must be at least 3mg/dL to detect a change)
in hemolytic anemia due to increased RBC being trapped in spleen, there is an increase in both unconjugated bilirubin (in the blood) and conjugated bilirubin (in bile and intestine). What do each of these cause
high unconjugated bilirubin in blood - causes jaundice (deposited in tissues)
high conjugated bilirubin in bile and intestines - causes gallstones
why is lactate dehydrogenase an important hemolytic marker?
lactate dehydrogenase - enzyme in anaerobic glycolysis (which is how RBC make ATP)
can leak out when RBC are broken down in spleen
*note that this enzyme is nonspecific for RBC, but very abundant in RBC
why is free hemoglobin toxic? what molecule in the body binds free hemoglobin and gets rid of it?
heme can be released from globin - consumes nitric oxide (NO) and causes oxidative damage to cells
haptoglobin (produced by liver) has high affinity for free hemoglobin and binds irreversibly —> confines hemoglobin to plasma and prevents heme release
*note that this consumes haptoglobin because binding is irreversible, so in splenic hemolysis, there will be a decrease in serum haptoglobin
when hemolysis is occurring in the spleen (lots of RBC getting trapped), describe how each of these are affected:
a. spleen size
b. unconjugated bilirubin
c. conjugated bilirubin
d. lactate dehydrogenase
e. serum haptoglobin
explain for each
a. spleen size: splenomegaly and more red pulp
b. unconjugated bilirubin: HIGH —> scleral icterus (jaundice)
c. conjugated bilirubin: HIGH (in bile and intestines)
d. lactate dehydrogenase: HIGH (abundant in RBC for anaerobic glycolysis)
e. serum haptoglobin: LOW (gets consumed from binding so much free hemoglobin)
when there are very high levels of lactate dehydrogenase and free hemoglobin in the blood, where is hemolysis likely occurring?
what protective protein will this deplete?
intravascularly
free hemoglobin (toxic) will exceed available haptoglobin (which binds free hemoglobin irreversibly) —> very low or absent haptoglobin and free hemoglobin in blood and urine
[remember that free hemoglobin causes oxidative damage and consumes nitric oxide —> vasoconstriction]
a patient with intravascular hemolysis complains of back/flank pain and dark urine - what is causing this?
free hemoglobin - directly toxic to tubules (causing kidney pain) and consumes NO (causing vasoconstriction)
hemoglobin levels exceed available haptoglobin
*plasma can appear red/pink, urine can appear brown/red, urine dipstick will test + for blood
chronic intravascular hemolysis can lead to renal _____
explain why
intravascular hemolysis —> renal hemosiderin
this occurs because free hemoglobin (very high in intravascular hemolysis) is toxic to renal tubules
will present with back/flank pain and brown/red urine
in intravascular hemolysis, describe how each of these is affected:
a. spleen size
b. unconjugated bilirubin
c. lactate dehydrogenase
d. serum haptoglobin
e. hemoglobinuria
f. hemosiderin
a. spleen size: normal
b. unconjugated bilirubin: HIGH —> scleral icterus (jaundice)
c. lactate dehydrogenase: VERY HIGH!
d. serum haptoglobin: VERY LOW
e. hemoglobinuria: HIGH
f. hemosiderin: HIGH (renal)
if hemolytic anemia is intrinsic to RBC, most cases are ____
if hemolytic anemia is extrinsic to RBC, most cases are ____
intrinsic to RBC - likely inherited (defect in RBC)
extrinsic to RBC - likely acquired
what are 3 general issues with RBC that could cause intrinsic/inherited hemolytic anemia?
issue with:
1. RBC membrane structure
2. enzyme function
3. hemoglobin structure
hereditary spherocytosis - cause, outcome
AD inheritance, mutation in spectrin, ankyrin, or Band 3 cytoskeletal proteins (causing loss of protein)
RBC lifespan reduced from 120d to 20d
spherocytes: small cells, lack central pallor, trapped in spleen, high concentration of hemoglobin within RBC (mean corpuscular hemoglobin concentration/ MCHC)
causes inherited/intrinsic hemolytic anemia
an increase in what is indicative of the presence of spherocytes?
increased MCHC: mean corpuscular hemoglobin concentration (avg hgb concentration per RBC)
(spherocytes are small due to membrane loss but contents are not changed)
spherocytes are less flexible and get trapped in spleen —> extravascular hemolysis (phagocytosed)
what specific type of anemia does this likely indicate:
- anemia with high reticulocyte count
- jaundice due to high unconjugated bilirubin
- splenomegaly due to RBC trapping
- pigment gallstones due to high conjugated bilirubin in bile
- increased MCHC
- negative direct Coomb’s test
hereditary spherocytosis: AD mutation in spectrin/ankyrin/Band3, causes extravascular (in the spleen) hemolytic anemia
*note that you must exclude autoimmune hemolytic anemia, which can also cause spherocytosis (via direct Coomb’s test)
if you’re considering hereditary spherocytosis for a patient, what must you exclude, and what test will you use?
hereditary spherocytosis: AD mutation in spectrin/ankyrin/Band 3 that causes extravascular hemolytic anemia
must exclude autoimmune hemolytic anemia with direct Coomb’s test (detects antibodies or complement bound to RBC), as this can also cause spherocytosis
what are 2 confirmatory tests for hereditary spherocytosis, which is an intrinsic extravascular hemolytic anemia?
- osmotic fragility test (old method): spherocytes can’t handle as much water (lower osmolarity)
[*note that thalassemia would have opposite result - more surface area, so can handle more water] - eosin-50maleimide flow cytometry (new method): binds RBC membrane protein Band 3 —> low in spherocytes
hereditary spherocytosis can be treated with _____ to correct chronic hemolysis
what will be seen in peripheral smear after?
treat with splenectomy —> Howell-Jolly bodies can be detected in peripheral smear following (RBC have a dark dot in them - remnants of nuclei that are usually removed by spleen)
glucose-6-phosphate dehydrogenase deficiency results in….
glucose-6-dehydrogenase is needed in hexose monophosphate shunt to produce NADPH, which produces glutathione (antioxidant, protects cells from oxidative damage)
G-6-PD deficiency: XLR trait (males higher risk), prevalent in patients with ancestors from areas where malaria is endemic —> protein misfolding and premature RBC destruction
Glucose-6-dehydrogenase deficiency produces what kind of anemia?
decrease G6PD —> decrease NADPH (via HMP, hexose monophosphate pathway) —> decrease glutathione —> more ROS
——> episodic hemolytic anemia, both intra- and extra- vascular
Heinz bodies and bite cells visible (hemoglobin precipitates)
what are the clinical features of G-6-PD deficiency?
triggering event causes oxidant exposure (food, drugs, infection)
oxidant leads to Hgb precipitation —> hemolysis 2-3 days later —> jaundice, anemia, dark urine, maybe back pain (kindeys)
increased LDH, decreased haptoglobin, increased unconjugated bilirubin, hemoglobinuria
bite cells and Heinz bodies seen
episodes are self-limited
what test is used to diagnose glucose-6-phosphate dehydrogenase deficiency?
fluorescent spot screening test: directly measures G6PD levels, must test after acute hemolytic episode
no fluorescent = no enzyme