Red Cell Path Ch 14 Flashcards
Features of hemolyic anemias
1) premature destruction of RBCs and shortened lifespan
2) elevated erythropoitin level/erythropoisis
3) accumulation of hemoglobin degredation products
extravascular hemolysis
premature destruction of RBCs within phagocytes
clinical features of extravascular hemolysis
1) anemia
2) splenomegaly
3) jaundice
what is the fxn of alpha2-globulin
binds free hemoglobin and prevents its excretion in urine
intravascular hemolysis causes
mechanical injury, complement fixation, intracellular parasites, exogenous toxic factors
clinical features of intravascular hemolysis
1) anemia
2) hemoglobinemia
3) hemoglobinuria
4) hemosiderinuria
5) jaundice
hapatoglobin
binds free hemoglobin, produces a complex that is cleared by macrophages
what occurs when serum hepatoglobin is used up/depleted
free hemoglobin oxidizes to methemoglobin (brown in color)
what is true about bilirubin in uncomplicated hemolytic anemias
unconjugated
cholelithiasis
pigmented gallstones
hereditary spherocytosis (HS)
intrinsic defects in red cell membrane skeleton that render cells spheroid, less deformable, and vulnerable to destruction
where is hereditary spherocytosis prevalent
northern europe (1/5000); autosomal dominant 75% of time and compound heterozygosity 25%
spectrin components
2 polypeptide chains (alpha and beta) form intertwined flexible heterodimers
how is spectrin attached to membrane
1) proteins ankyrin and band 4.2 bind spectrin to transmembrane ion transporter
2) protein 4.1 binds tail of spectrin to another transmembrane protein glycophorin A
what is the lifespan of RBCs with HS
10-20 days
what genetic defect are most common in HS
ankyrin, band 3, spectrin, or band 4.2; they stabilize lipid bilayer
good treatment option for HS
splenectomy
red cell morphology in HS
small, dark-staining, lack central zone of pallor, spherocytosis
MCHC in HS
increased due to dehydration caused by loss of K+ and water
how often is HS asymptomatic
20-30%; usually compensation outpaces and mild/moderate chonic hemolytic anemia occurs
aplastic crisis in HS
generally triggered by acute parvovirus infection
what does parvovirus affect
infects and kills red cell progenitors ceasing production until immune response fixes; RBC producation back 1-2 weeks
what affects do red cell enzyme disfunctions have
reduced ability for RBCs to protect themselves against oxidative injuries and lead to hemolysis
Most important RBC enzyme derangement
glucose-6-phosphate dehydrogenase (G6PD); reduces NADP to NADPH while oxidizing glucose-6-phosphate
What does NADPH do in RBCs
converts oxidized glutathione to reduced glutathione, which protects against oxidant injury
How is G6PD inherited
X-linked
G6PD- is present in what ethinic group
10% american blacks
G6PD-mediterranean is present where
middle east
episodic hemolysis characteristic of G6PD
triggered by infections; oxygen-derived free radicals produced by leukocytes; food/drugs can also trigger (fava bean)
Heinz bodies morphology
dark inclusions within red cells stained with crystal violet
Heinz bodies cause
G6PD deficient exposed to oxidants; cross-linking of reactive sulhydryl groups on globon chains, which become denatured and form membrane bound precipitates
Heinz bodies effect
damage membrane to cause intravascular hemolysis
bite cells
phagocytes in spleen remove/’bite’ heinz bodies out of red cells
how long after oxidant exposure do hemolysis, anemia, hemogloburea/emia occur
2-3 days
why isn’t splenomegaly seen in G6PD abnormalities
hemolytic episodes are intermitent
sickle cell mutation
point mutation in 6th codon of B-globin; glutamate replaced with valine
How common is sickle cell
8-10% of african americans are heterozygous
Pathogenesis of sickle cell
HbS undergo polymerization when deoxygenated causing
1) chronic hemolysis
2) microvascular occlusions
3) tissue damage
variables affecting rate/degree of sickling
1) interaction of HbS with other types of hemoglobin
2) MCHC
3) intracellular pH
4) transit time of RBCs
why don’t infants become syymptomatic until 5-6 months of age
HbF inhibits polymizeration of HbS more than HbA
HbC
lysine substituted for glutamate in 6th aa of B-globin
HbSC pathology
tend to lose salt and water and become dehydrated increasing intracellular concentration of HbS; milder than HbSS
carrier frequency of HbC
2-3% american blacks heterozygous; 1/1250 have HbSC disease
example of MCHC decrease helping reduce severity of HbS
HbS plus coexistant alpha-thalassemia (reduces Hb synthesis and leads to milder disease)
Where are transit times slow in microvascular beds
spleen and bone marrow (also inflammation areas); increases likelyhood of sickling
what occurs with repeated incidences of sickling in a RBC
dehydrated, dense, and rigid
other properties of sickel red cells
express higher than normal adhesion molcules and are sticky
What can free hemoglobin do to NO
bind and inactivate, enhancing vasoconstriction and platelet aggregation
what are target cells
RBCs that results from dehydration
what are howell-jolly bodies
small nuclear remnants; present due to asplenia
what does bone marrow expansion cause
leads to bone reabsorption and secondary new bone formation, resulting in prominent cheekbones and chnges in skull that resemble a crew-cut on x-ray
autosplenectomy
process of chronic erythrostasis leading to splenic infarction, fibrosis, and progressive shrinkage
vaso-occlusive crises (pain crises)
episode of hypoxic injury and infarction that cause severe pain in affected region
what are pain crises in sickle cell difficult to distinguish from in children
acute osteomyelitis
acute chest syndrome
pain crisis in lungs (fever, cough, chest pain, pulmonary infiltrates)
most common cause of patient morbidity and mortality in sickle cell
vaso-occlusive crises
sequestration crises
massive entrapment of sickled cells leading to rapid spleen enlargement, hypovolemia, and sometimes shock
aplastic crises
infection with parvovirus B19 which infect RBC progenitors; causes cessation of erythropoiesis
mainstay treatment for sickle cell anemia
hydroxyurea (inhibitor of DNA synthesis) - increase HgF, anti-inflammatory (inhibit WBCs)
where are alpha chain genes located from hemoglobin
identical pair on chromosome 16
where are beta chain genes located from hemoglobin
single copy on chromosome 11
mutations causing B-thalassemias
1) splicing mutation
2) promotor region mutations
3) chain terminator mutations
Two mechanisms of anemia in B-thalssemias
1) deficit in HbA produces hypochromatic, microcytic RBCs 2) diminsihed survival of RBCs and their precursors due to alpha-beta imbalance
proximal cause of red cell pathology in B-thalessemia
membrane damage due to imbalance btwn alpha and beta chains in HbA
extramedullary hemotopoitic sites
liver, spleen, lymph nodes; sometimes thorax, abdomen, and pelvis in extreme cases
Ineffective erythropoisis suppresses circulating levels of what, causing what?
hepcidin, a negative regulator of iron absorption, causing excessive absorption of dietary iron
what is clinical classification of B-thalessemia based on
genetic defect (B0 B+) and gene dosage (homo vs heterozygote)
when does anemia from B-thalassemia minor manifest
6-9 months after birth
anisocytosis
marked variation in size
poikilocytosis
marked variation in shape
B-thalessemia histology
anisocytosis, poikilocytosis, microcytic, hypochromatic
reticulocytes in B-thalessemia major
elevated, but lower than expected for degree of anemia due to impaired erythropoisis
B-thalesemmia minor blood smear findings
hypochromia, microcytosis, basophilic stippling, target cells, mild erythroid hyperplasia in bone marrow
gamma-globin chains in excess form
gamma tetramers known as hemoglobin Barts; occurs in newborns with alpha-thalsemmia
excess B-globin chains form
tetramers known as HbH; occurs in older children and adults with alpha-thalassemia
why are alpha-thalassemias less severe than B
gamma and beta chains more soluble and form stable tetramers
silent carrier state
1/4 alpha genes deleted; barely detectable reduction in a-globin synthesis; asymptomatic, but may have microcytosis
alpha-thalassemia trait
2/4 alpha genes deleted (both on one chromosome - asian, one on each chromosome - africa)clinically similar to B-thalassemia minor - microcytosis, minimal anemia
hemoglobin H disease
3/4 alpha genes deleted; HgH has high affinity for O2 and prone to oxidation - precipitates out and forms intracellular inclusions that promote RBC sequestration; similar to B-thalassemia intermediate
Hydrops fetalis
4/4 alpha genes deleted; fetal distress evident by 3rd trimester; infants has extreme pallor, generalized edema, massive hepatosplenomegaly; dependent on transfussions
paroxysmal nocturnal hemoglobinuria (PNH)
results from aquired mutations in phosphatidylinositol glycan omplementation group A (PIGA); X-linked
What does PIGA do
enzyme essential for synthesis of certain cell surface proteins
PNH incidence
2 to 5 per million in US
what is deficiency in PNH
GPI-linked proteins deficient because of somatic mutations that inactivate PIGA
lyonization
random inactivation of one X chromosme in females
3 proteins PNH blood cells are deficient in
1) decay-accelerating factor/CD55
2) membrane inhibitor of reactive lysis/CD59
3) C8 binding protein
most important deficient protein in PNH
CD59; potent inhibitor of C3 convertase that prevents spontaneous activation of the alternative complement pathway
intravascular hemolysis in PNH cause by
C5b-C9 membrane attack complex; paroxysmal and noctural in 25%; generally chronic hemolysis without dramatic hemoglobinuria
why would red cells in PNH tend to lyse at night
slight decrease in blood pH, increases activity of complement
leading cause of death in PNH
thrombosis (40%); dysfxn of platelets due to absence of certain GPI-linked proteins and absorption of NO by free hemoglobin
immunohemolytic anemia
caused by antibodies that bind red cells leading to premature destruction
how are immunohemolytic anemias classified
by characteristics of reponsible antibody
warm antibody type
most common form of immunohemolytic anemia; 50% idiopathic; generally IgG
drug-induced immunohemolytic anemia mechanisms
1) antigenic drugs - bind red cells, recognized by anti-druf antibodies
2) tolerance-breaking drugs - unknown
cold agglutinin type
caused by IgM antibodies (15-30% cases); follows some infections; rarely associated with clinically significant hemolysis
cold agglutinin type cause
IgM released, transient interaction with IgM deposits sublytic quantities of C3b (excellent opsonin), red cells phagocytized in liver, spleen, and bone marrow
cold agglutinin clinical appearance
pallor, cyanosis, Raynaud phenomenon
cold hemolysin type
autoantibodies responsible for paroxysmal cold hemoglobinuria; IgGs bind P blood group antigen on RBC surface
most common cases of cold hemolysin type are seen
in children following viral infection
most significant hemolysis caused by trauma
cardiac valve protheses and microangioplastic disorders
what is hemolysis in microangioplastic disorders caused from
microvascular lesion that results in narrowing in lumin; generally due to deposition of fibrin and platelets
histology of RBCs hemolysed by trauma
apprearance of RBC fragments (schistocytes), ‘burr’ cells, ‘helmet’ cells, and ‘triangle’ cells
