Anemia: Blood Loss/Hemolytic Anemia Flashcards
Severely anemic patients may develop fatty changes in their ______ (3) due to hypoxia.
liver, kidney or myocardium
2 types of hemolytic anemia
- intravascular
- extravascular
acute blood loss is mainly due to the loss of _____ and can lead to CV collapse → shock → death.
intravascular volume
(presentation depends on rate of hemorrhage & whether bleeding is internal or external)
Hemodilution
during acute blood loss → volume is restored by intravascular shift (water from interstitial fluid → vasculature → dilutes blood)
Hemodilution and a lowering of the hematocrit. The reduction in oxygenation due to acute blood loss triggers → EPO → stimulates erythroid progenitors (CFU-E) in the marrow.
EPO
Iron is recaptured during acute blood loss if RBCs ______ versus bleeding ______ which → iron loss.
- extravasate from vessels into tissues
- into the gut or out of the body
Early recovery from acute blood loss is often accompanied by _____.
thrombocytosis
Increased renal secretion of EPO → increased erythrocyte progenitors. What is their appearance early on? Later?
- Early: normocytic, normochromic RBC
- Later: ⇡ marrow production → reticulocytosis → macrocytic w/ polychromatophilic cytoplasm
Chronic blood loss only leads to anemia if the ______ or when iron reserves are depleted.
rate of loss exceeds the regenerative capacity of marrow
Age-dependent changes of RBC surface proteins triggers MF to destroy them in the ________ (3).
liver, spleen and bone marrow
Elevated EPO → elevated _____.
erythropoiesis
In all hemolytic anemias there is an increase in _____ (3).
- erythroid precursors
- hemosiderin
- reticulocytosis
Severe hemolytic anemia → extramedullary _____.
hematopoiesis (liver & spleen)
uncomplicated, chronic anemia → elevated ______.
unconjugated bilirubin (liver excretes bilirubin into GI = gallstones)
Most hemolytic anemias are _______ (intravascular/extravascular).
extravascular
(premature RBCs phagocytosis in spleen → splenomegaly)
In extravascular hemolytic anemia the RBC membranes are less deformable making them more likely to be sequestered by spleen → get stuck in ______ → MF destroy them in _____.
- sinusoids
- splenic cords
Intravascular hemolysis: causes (4)
- mechanical injury
- complement fixations
- intracellular parasites (malaria)
- toxins
Which toxic factor → intravascular hemolysis?
clostridial species (have enzymes that destroy RBCs)
What 2 findings are present in both intra- and extra-vascular hemolysis?
- jaundice
- anemia
Findings of extravascular hemolysis will demonstrate _______; while intravascular hemolysis will have _______ (3).
- increased plasma haptoglobin
- hemoglobinemia, hemoglobinuria, hemosiderinuria
(both present w/jaundice & anemia)
Why is there an increase in plasma haptoglobin in extravascular hemolysis?
hemoglobin escaping phagocytosis → binding to a2-globulin
Decreased haptoglobin in intravascular hemolysis → ______ (unique diagnostic feature/finding)
methemoglobin (red-brown urine)
Why do patients with intravascular hemolysis have renal hemosiderosis?
released iron accumulates inside the tubule cells
(iron is stored as hemosiderin in renal cells)
Hereditary spherocytosis
Parvovirus can cause aplastic crisis in which two inherited forms of hemolytic anemia?
- HS
- Sickle cell
(destroys RBC progenitors → compensatory erythropoiesis is outpaced → aplastic crisis)
What is a hemolytic crisis in patients with hereditary spherocytosis?
increased splenic RBC destruction
(ex: infectious mono)
Hereditary spherocytosis is due to which 2 _________ mutations.
- spectrin
- ankyrin
(mutations → destabilizes lipid bilayer)
spectrin
main membrane skeletal protein (alpha & beta chains) of RBC
ankyrin
binds spectrin to band 4.2 and band 3 (“tethering”)
Young HS RBCs are described as ______
normal shape
(they shed fragments as they age)
As the HS RBC ages and becomes less deformable →______ → MF destroy them.
splenic trapping & prolonged splenic exposure → erythrostasis
HS inheritance
75% AD
(heterozygotes are born jaundiced and require transfusions)
HS is diagnosed by _______ (2).
- osmotic lysis: more sensitive when incubated in hypotonic salt solution
- increased MCHC due to loss of K+/H2O → dehydration → increased [Hgb]
HS is treated by splenectomy. _____ is fixed but _____ remains. Also increases the risk of _____.
- anemia
- spherocytosis
- infection
HS clinical features include: anemia, splenomegaly, ______ (2).
- jaundice
- gallstones
G6PD causes _________ (intravascular/extravascular) hemolysis.
both
Function of G6PD
- reduce NAPD → NAPDH
- oxidize glucose-6-phosphate
Inherited variants of G6PD lead to misfolded proteins → making the enzyme more susceptible to ______.
proteolytic degradation
What are 2 morphologic characteristics of G6PD Deficiency?
- Bite cells (aka degmacytes)
- Heinz bodies
(“blister cells” may also be seen: Hb collects on one side of the cell leaving the other clear)
Howell-Jolly bodies are seen in both ______ & _____.
- HS
- Sickle cell
Heinz bodies are membrane-bound precipitants formed by ______.
denatured globin
(caused by increased oxidants → dark inclusions - crystal violet stain)
Heinz bodies can lead to a loss of ______ & intravascular hemolysis.
deformability
Why are spherocytes seen in G6PD Deficiency?
MF “pluck out” or “take a bite” out of RBCs to remove the Heinz bodies. This leads to bite cells (aka degmacytes) or spherocytes if they are less severely damaged by this.
Distinct features of G6PD deficiency
episodic hemolysis caused by oxidative stress: toxin, fava beans, infection
Drugs that may trigger episodic hemolysis in patients w/G6PD deficiency (2)
- antimalarials: primaquine, chloroquine
- sulfonamides
______ is seen during the recovery phase of hemolytic episodes in patients w/ G6PD deficiency.
reticulocytosis
Which variant of G6PD deficiency has more severe bouts of intravascular hemolysis due to oxidative stress? Why?
Mediterranean variant
markedly reduced half-life of G6PD → marked intravascular hemolysis with oxidative stress
(African variant has a mildly reduced half life)
Patients w/G6PD deficiency will have hemolytic episodes 2-3 days after exposure to oxidants → acute intravascular hemolysis. What are the key findings?
hemoglobinuria
(no signs of chronic hemolysis i.e. splenomegaly or cholelithiasis)
Sickle cell disease is a common hereditary hemoglobinopathy that is caused by a point mutation in _____ , which leads to _______.
- beta-globin
- polymerization of deoxygenated Hgb
Inheritance of Sickle cell disease is _______ .______ have sickle cell trait.
- Autosomal recessive
- heterozygotes for HbS (“AS”, nl: “AA”)
_______% of African-Americans = heterozygous for HbS. Trait protective against ______.
- 8-10
- falciparum malaria
In Sickle Cell Disease, polymerized deoxy-Hgb causes RBC distortion (“sickle cell”), which causes _______ and _______.
- hemolytic anemia
- microvascular obstruction → ischemic tissue damage.
Normal adult RBCs = mainly _______ (type of hemoglobin). In Sickle cell, there is a point mutation in beta-globin which replaces ______ → _____ residue. *Different mutation (lysine residue) causes HbC variant;
- HbA (α2β2)
- glutamate → valine (HbS)
(HbC is glutamate → lysine; can be compound HbS/HbC (HbSC disease)
How is the RBC membrane shape distorted in Sickle Cell Disease?
HbS molecules “stack” into polymers when deoxygenated → membrane defects = distorted shape.
Low O2 and decreased intracellular pH promote sickling. Why?
Low pH → reduced O2 affinity → more deoxygenated Hb
Interaction of HbS with other types of Hgb (i.e. heterozygotes) can be either inhibit or enhance HbS polymerization. Which inhibit and which enhance?
- Inhibit polymerization: HbF & HbA
- Enhance: HbC (causes dehydration of cell → increasing [HbS])
(concomitant alpha-thalassemia also inhibits polymerization)
Decreased RBC transit through the ______ (3) increases the risk of occlusion in sickle cell disease.
- spleen
- bone marrow
- inflamed tissues
2 mechanisms of damage in sickle cell disease?
- RBC dehydration
- microvascular occlusion
How does RBC dehydration → hemolysis in sickle cell diseaes?
HbS stabs through membrane → influx of Ca2+→ activation of K+/H2O efflux
How does RBC dehydration cause extravascular hemolysis triggered in sickle cell disease? Intravascular?
- Extravascular: repeated RBC dehydration → sickled cells destroyed by MF
- intravascular: mechanically fragle
Describe the microvascular occlusions that occur in sickle cell disease
vasoconstriction or inflammation slows RBC movement in vascular beds → extended exposure to low O2 increases sickling → occlusion → ischemia → hypoxia/sickle cycle
(free Hgb from lysed cells also binds/inactivates NO which normally inhibits platelet aggregation)
How is sickle cell anemia diagnosed?
metabisulfite (O2-consuming agent) + blood sample → induces sickling
(positive for trait and disease)
2 prominent phenotypes of patients with sickle cell disease
- “crewcut skull” on XR
- Chipmunk facies (prominent cheekbones)
Target cells (from RBC dehydration) and Howell-Jolly bodies indicate which hemolytic disease?
sickle cell
Howell-Jolly bodies are small nuclear remnants due to asplenia (enlarged spleen early in disease; red pulp congestion) eventually leads to ______
splenic infarct & fibrosis → autosplenectomy
Describe the vaso-occlusive/pain crisis of sickle cell disease.
hypoxic injury/infarct → severe pain in bones, lungs, liver, brain, spleen, penis
what is the most common cause of death in adult sickle cell patients? children?
- adults: vaso-occlusive/pain crisis
- children: infection H. flu
What are 3 common syndromes caused by vaso-occlusive/pain crisis?
- hand-foot syndrome : dactylitis of hands/feet
- acute chest syndrome
- priapism
(stroke, retinopathy, blindness)
What is sequestration crisis (seen in sickle cell patients)?
massive entrapment of sickled cells in spleen → rapid splenomegaly → hypovalemia → shock
Chronic effects of sickle cell disease (2)
- renal injury: hyposthenuria (inability to concentrate urine)
- Infection: encapsulated organisms (H. flu, P. pneumo) → septicemia, meningitis
sickle cell : tx
hydroxyurea (DNA synthesis inhibitor)
(increases HbF (a2g2) & decreases inflammation)
“Autoinfarcted” splenic remnant in sickle cell disease
Spleen in sickle cell disease (low power). Red pulp cords and sinusoids are markedly congested; between the congested areas, pale areas of fibrosis resulting from ischemic damage are evident
Splenic sinusoids dilated and filled with sickled red cells
_____ is a quick calculation to rule in HS.
MCHC/MCV >0.36
Polyspecific antibody
specific to more than 1 antigen (anti-human Ig)
(screening test used to do Coombs testing: Anti-IgM, IgG, CD3)
