HypERproliferative Anemias, Thalassemia, Sickle Cell Anemia, Blood Bank/Transfusion Medicine Flashcards
hypERproliferative anemias
key features
low Hb and HCt
elevated reticulocyte index
inc absolute reticulocyte count (reticulocyte % * total rbc)
anemia w/ appropriate/exaggerated EPO response but unable to fully compensate
2 major conditions leading to hyperproliferative anemias
- blood loss thru bleeding
2. functional “blood loss” via hemolytic anemia
Free plasma Hb released by intravascular hemolysis is bound by a Hb scavenging protein called ______
haptoglobin
haptoglobin levels during intravascular hemolysis
decreased
haptoglobin binds free Hb
extravascular hemolysis
in spleen or liver
congenital hemolysis causes
membrane disorders
spherocytosis
elliptocytosis
congenital hemolysis causes
enzyme disorders
G6PD deficiency
pyruvate kinase deficiency
congenital hemolysis causes
Hb disorders
Sickle cell anemia
Hb CC EE
acute hemolysis clinical pic
pallor fatigue dyspnea icterus jaundice splenomegaly dark urine
chronic hemolysis clinical pic
pigment gallstones skin ulcers aplastic crises (parvovirus, severe anemia, reticulocytopenia) CHF folic acid deficiency inc urine urobilinogen hemoglobinuria hemoglo binemia urine hemosiderin
hereditary spherocytosis
- most comm inherited membrane defect
- usu AD, some AR
- defects in spectrum, ankyrin, band 3, pallidin (band 4.2)
- effects on vertical interactions between membrane skeleton/lipid bilayer
- dec membrane deformability
- loss of membrane thru RES
- biconcave –> SPHERE
hereditary spherocytosis dx
suggestive
- inc reticulocyte count
- inc MCHC
- spherocytes on peripheral smear
hereditary spherocytosis dx
diagnostic
lower EMA binding (eosin-5-maleimide)
abnml osmotic fragility test
aplastic crises
due to a temporary drop in hematocrit and reticulocytopenia with inability of bone marrow production to compensate for spherocyte destruction in the RES
hereditary spherocytosis clinical pic
hyper hemolytic crises (inc anemia and jaundice due to infections)
aplastic crises
gallstones
splenomegaly
___ supplementation in hereditary spherocytosis is necessary
folic acid
hereditary elliptocytosis
- defective spectrin, protein 4.1, glycophorin C
- effects HORIZONTAL interactions between cytoskeletal proteins
- AD
- mild hemolytic anemia (milder than AS)
Which is characterized by a milder hemolytic anemia?
hereditary elliptocytosis or hereditary spherocytosis
hereditary elliptocytosis
G6PD deficiency
- XL, many mutations
- african variant (A-) is milder and only older rbc are env deficient
- mediterranean variant: all RBCs deficient
- comm cause of neonatal jaundice
hexose monophosphate shunt
G6P –> 6 phosphogluconate
prod NADPH, reduced glutathione
consequences of impaired pesos monophosphate shunt
- inc intracellular free radicals/peroxides
- oxidative membrane damage
- MetHgb
G6PD deficiency
dx
- acute intravascular hemolytic episodes –> hemoglobinemia
- ghost cells/bite cells
- Heinz bodies (oxidized Hb aggregates)
Heinz bodies
oxidized Hb aggregates
oxidant triggers in G6PD
sulfa drugs anti-malarial: chloroquine, primaquine nitrofurantoin aspirin misc drugs (pyridium) mothballs FAVA beans
common enzyme defect in embden-meyerhof pathway
pyruvate kinase
–> RBC hemolysis
pyruvate kinase deficiency
AR defective ATP production --> cell rigidity rbc hemolysis splenomegaly jaundice
dx: enzyme assay
tx: rbc transfusions/splenectomy
warm AI hemolytic anemia
IgG Abs (comm against Rh antigens) rbc agglutination @ warm temps
generally extravascular hemolysis with spleen removing Ab coated (opsonized) rbc
tx: underlying cause, immunosuppression, rbc transfusions if severe anemia, splenectomy
causes: idiopathic malignancy (lymphoma, multiple myeloma) rheumatologist disease drugs (methyl-dopa, quinidine, PCN)
cold AI hemolytic anemia
IgM Abs –> fixes COMPLEMENT on rbc surface
rbc agglutination in cold
hemolysis=intravascular and extravascular
tx: transfusion dep on sx, avoid cold exposure, warm blood prior to transfusion, steroids/splenectomy NOT effective, plasmapheresis, rituximab (modulate B cell activity), ID and tx underlying cause
causes:
idiopathic
infections (mycoplasma/EBV/HIV)
malignancy (lymphomas or solid tumors)
Ig fixes complement on rbc surface
cold AIHA
direct antiglobulin (Coombs) test
detects AutoAbs and/or complement on rbc surface
indirect antiglobulin (Coombs) test
detects Abs against rbc in serum
exp. alloAbs in hemolytic disease, transfusionrxns, autoAb in severe AIHA
splenectomy is effective in warm or cold AIHA?
warm
____ is considered a hapten – a non-pro- tein molecule that does not elicit an antibody response by itself but reacts with an antibody when bound to a carrier protein
penicillin
innocent bystander AIHA exp
Quinidine
AutoAb
AIHA exp
methyldopa, fludarabine
march hemoglobinuria
rbc damage via constant pounding
rbc hemolysis infectious causes
malaria
martonellosis
babesiosis
clostridium perfrinigens
____ toxin contains phospholipase that directly lyses rbc
clostridium
microangioapthic hemolysis
rbc membrane damage as rbc traverses abnml surfaces or fibrin network deposited on endothelium
smear: schistocytes
microangioapthic hemolysis causes
hemangioma artificial valves DIC TTP HUS
paroxysmal nocturnal hemoglobinuria
acquired clonal disorder of BM stem cells
mut in PIG-A gene
deficient synthesis of GPI membrane anchor
absence of GPI linked proteins (CD59, CD55 (DAF))
^rbc becomes sensitive to complement lysis
assoc w/ thromboses, aplastic anemia, muscle dystonia (bowel spasms), pulm HTN
Hgb
lg protein
2 alpha and two beta–> tetramer
each global chain covalently linked to heme moiety
heme
ferrous iron and protoprophyrin
most global synthesis occurs from which gene?
alpha 2
alpha globin, which chromosome?
16
beta global cluster, which chromosome?
11
expression of each globin cluster is regulated by
upstream locus control region (LCR)
when do alpha and gamma globin gene expression peak?
month 3 gestation
HbF
alpha2
gama 2
HbA
alpha 2
beta 2
HbA2
alpha 2
delta 2
__ globin gene is turned on at birth and persists at low level into adulthood
delta
__ globin gene expression is down regulated at birth and Hb F levels decline by _ mo
gamma
HbF declines by 6 mo.
Hb fxn
sequential binding of single O2 to each of 4 heme groups
- sigmoid, cooperativity
- lg O2 release w/ small dec in O2 tension
R shift –> inc O2 unloading
causes
low pH tissues
hyperthermia
inc tissue 2,3-BPG
low O2 affinity Hb (sickle Hb)
L shift –> inc O2 loading
high pH lungs (CO2 elimination)
high affinity Hb (HbF, Fe3+ Hb)
CO poisoning
hemoglobinopathy
alpha/beta globin mut that lead to structural or QUALITATIVE change in Hb
sickle gene, Hb C
thalassemia
QUANTITATIVE disorder of globin synthesis
mut in globin chains of Hb –> dec prod of globin chains from affected allele
thalassemia: deficient chain synthesis –> imbalance between alpha and B chains –>
precipitation of insoluble homo-tetramers of chain in xs
red cell hemolysis, dec rbc life span, ineffective erythropoises, microcytosis, Fe overload
most comm abnormality of Hb
thalassemia
clinical classification of alpha thalassemia
- hydrops fetalis
- HbH disease
- alpha thalassemia trait/minor
- alpha thalassemia minima (silent alpha thalassemia)
hydrops fetalis
deletion of 4 alpha globin genes, incompatible w/ life and designated (–,—)
HbH disease
deletion of 3 alpha globin genes (-alpha/–)
can be severe phenotype
alpha thalassemia trait/minor
deletion of 2 alpha globin genes
mild anemia
cis (aa/–) deletions on same haploid chromosome
trans (alpha-/alpha-) on alternate chromosomes
alpha thalassemia minima (silent alpha thalassemia)
deletion of 1 alpha globin gene (alpha-/alpha,alpha)
micocytosis but no anemia
deletion alpha-thalassemia mutations
deletions that remove all or part of the alpha globin gene cluster
deletions of 1 of the 2 alpha genes leave a functional gene on haploid chromosome
non-deletional alpha-thalassemia mutations
less common than deletion mut in alpha allele
point mutations that inactivate alpha globin
substitutions in alpha 2 globin termination codon (asia)
HbH
adults
beta tetramers precipitate in rbc, inc affinity
can’t release O2 to tissues
Hb Barts
gamma tetramers in utero
can’t release O2 to tissues
hydrops fetalis
hydrops fetalis
abnormal accumulation of fluid in multiple fetal compartments, including around the heart, lungs, abdominal cavity, skin
Hb Bart’s
beta thalassemia major
Cooley’s anemia
- very severe
- transfusion dependency
- homozygous, complete loss of beta globin gene expression
beta thalassemia intermedia
moderately severe
not transfusion dependent
mut of both globin alleles but quantity of normal HbA prod is greater than Thal major
beta thalassemia minor
clinically mild/silent
mut of single beta Thal allele
beta thalassemia mutations
point mutations that down-reg/abolish either transcription of globin genes/translation of globin mRNA
beta thalassemia pathophysio
b-globin chain deficiency
–> xs of alpha globin chains –> inc minor Hb species –> alpha tetramers precipitate in rbc precursors, damaging cell membranes –> INEFFECTIVE ERYTHROPOIESIS
peripheral hemolysis –> splenomegaly from work hypertrophy
complications of beta-thalassemia major
-severe anemia
-chronic hemolysis
-bone deformities (inc BM space) includes frontal bossing/cortical thinning
-hepatosplenomegaly
-infection risk
transfusion Fe overload w end organ damage
-high output HF
combined hemoglobinopathy and thalassemia
> 50 mut that can result in a variant non-A Hb and thalassemia phenotype
- Hb Constant Spring
- delta/beta fusion (lepore hemoglobins)
Hb E
one of the most common mutations worldwide
HbE=variant Hb, activates cryptic mRNA splice site –> reduced synthesis of beta-E globin chain –> thalassemia phenotype
AE (E trait) –> resistance to plasmodium falciparu
Indian subcontinent, SE China, Thailand, Laos, Cambodia, Malaysia, Sri Lanka
Thalassemia dx - CBC
- low Hb and HCt
- low MCV or microcytosis ABSOLUTE REQ
- high rbc (>1/3Hb val)
absolute requirement of thalassemia dx
low MCV or mirocytosis
Thalassemia dx - smear
small, hypo chromic rbc
polychromasia (inc reticulocytosis), basophilic stippling
variable cell shape (poiklocytosis, rbc fragments, target cells)
Fe studies - Thalassemia
WNL
basophilic stippling
hemolytic anemias
rRNA deposits from toxic injury or globin chain deposition
Hb electophoresis for dx of thalassemia
thalassemia=quantitative disorder so Hb bands migrate at normal rate thru gel
HbH=
beta-thalassemia=HbA2 and HbF inc bc xs
Hb electophoresis
alpha-thalassemia
HbA only
Hb electophoresis
HbH
fast migrating band of tetramers of beta (HbH) plus HbA
Hb electophoresis
beta-thalassemia
HbA2 and HbF inc bc xs alpha chains form tetramers w/ delta and gamma globin chains
HPLC for thalassemia dx
separates Hb on basis of hydrophobicity
RELIABLY QUANTITATES HbA2 and HbF fractions in beta thalassemia
beta thalassemia major tx
supportive
- rbc transfusion from birth
- folic acid
- Fe chelation
- hepatitis vaccination
- endocrine replacement
disease modifying
- BM transplant
- gene therapy
sickle cell disease
AD co-dominance
-single base pair substitution in beta-globin gene of Hb
(A–>T, glutamic acid –> valine)
HbS
variant Hb (biochemical change)
sickle cell trait
most benign
- HbA protects cells from assuming sickle shape
- NO anemia, hemolysis, pain crises
- risk of splenic infarct
- risk of sudden death w/ extreme dehydration/hyperthermia
- hyphema
- isothenuria, hematuria, pyelonephritis (preg)
- medullary CA of kidney
sickle cell trait - primary clinical impact
child-bearing
sickle cell disease manifests at what age?
6mo
sickle cell disease modifiers
tissue oxygenation status
pH
HbF levels
co-inheritance of other Hb gene abnml
heterozygous inheritance of HbS offers some protection against
malaria
SCD epidemiology
African Amer
Hispanic Amer
Sickle trait epidemiology
8% african-amer
sickle cell pathophys
–> RBC hemolysis
RBC deoxy –> polymerization of HbS (dec solubility) at low O2 tension –> rbc membrane damage
cellular dehydration –> inc cell [HbS], Ca activated K+ (Gardos) channels –> deoxygenation-induced Na-K pump –> oxidative membrane damage –> K loss –> RBC hemolysis
sickle cell pathophys
–> vasoocclusion/pain
sickle rbc adhere to vascular endothelium –> activation of coag/inflamm –> inc blood viscosity –> occlusion in microvasculature –> no scavenging by release of free intravascular Hb –> tissue ischemia, PAIN
HbS hemolysis, intravascular or extravascular?
both intravascular or extravascular
rbc survival in sickle disease
shortened to 10-16 days
epo can’t fully compensate in severe hemolysis
vasocclusive phenomena in sickle cell disease
rigid banana shaped cells
sickle disease
labs
Hb- low wbc/platelets-normal or elevated MCV: -normal-low in HbSS -low in sickle-thalassemia (S-beta thal)
classic markers of (intrinsic) hemolysis
- elevated reticulocyte count
- low haptoglobin (binds free Hb)
- elevated total/indirect bilirubin
- elevated LDH
sickle solubility test
deoxygenated HbS is insoluble in presence of concentrated phosphate buffer solution –> forms a turbid suspension
used as screening test (can’t distinguish btwn genotypes)
Hb electrophoresis to dx sickle disease
on cellulose acetate (alkaline pH), Hb migrates from - to +
fast>slow
HbA>HbF>HbS>HbC
citrate agar (acid pH)
separates HbS from HbD and HbG, and separates HbC from HbA2 and HbE
HPLC
sep Hb based on hydrophobicity
allows quantification of HbS
sickle cell complications
multi-organ effects
- chronic hemolytic anemia
- chronic pain syndrome
- chronic leg ulcers
- endocrinopathies (growth retardation, hypOgonadism)
- bone disease (dactylics, AVN, osteomyelitis)
- ocular (proliferative retinopathy, retinal detachment)
- sensorineural hearing loss
- pregnancy: PERILOUS, HIGH MORBIDITY/MORTALITY
- pulmonary (ACS, pulmonary HTN)
- cardiac (high output HF)
- stroke/renal a occlusion
- renal (proteinuria, sickle nephropathy, renal fail, acute papillary necrosis)
- infections
- priapism (sustained penile erection)
- pigment gall stones
acute sickle cell crises
acute pain (vasoocclusive) crisis
hemolytic crisis
aplastic crisis (erythroid aplasia, often via parvovirus B19)
sequestration crisis (pooling of erythrocytes in spleen w/ acute splenomegaly/shock-like state)
acute dactylics in SCD
often first sx of SCD babies
presents 6-18 mo as HbF dec
acute chest syndrome
most common lung complication in sickle disease
freq cause of death in adults
new pulm infiltrate, pleuritic CP, fever >38.5, dyspnea/tachypnea/wheezing/cough
repeated episodes –> pulm HTN, R HF (cor pulmonale)
unclear etiology, pulm infarct/pulm fat embolism/infectious pneumonia –> 1/2 of cases
cause of pulm HTN in sickle cell disease
NO scavenging by free Hb chains in serum –> inc vascular tone in pulm bed
sickle vasculopathy
hemolytic anemia –> free Hb in circulation (potent inhibitor of all NO bioactivity –> EC dysfuction, NO resistance)
ferric heme = toxic to endothelium
inc endothelin-1 prod (vasoconstriction)
stroke in SCD
- ischemic infarcts
2. hemorrhagic stroke (adults over 29, formation of MOYAMOYA vessels in brain
intracranial hemorrhage in SCD tx
aggressive hydration,RBC transfusion/exchange
Nimodipine
neurosurgery - evacuation; aneurysm repair as needed
acute pain crisis tx in SCD
narcotics/non-narcotics
fluids
O2 support for hypoxia
low threshold for abx
incentive spirometer
acure chest syndrome in SCD
O2 support abx inhaled bronchodilators, incentive spirometer transfusion mechanical ventilation inhaled NO hydrocyurea
hydroxyurea
anti-neoplastic
shown to decrease the frequency of vasoocclusive crises and acute chest syndrome, reduce the transfusion requirement, decrease chronic pain, and improve survival
MOA:
- inc HbF
- inc Hb
- dec wbc, platelets
- attenuates hemolysis
- improves QOL, survival
AVOID IN PREGNANCY
ischemic stroke risk management risk SCD
chronic exchange transfusion if velocity >200 m/s
no drug therapy
indications for rbc transfusion in SCD
acute chest syndrome
stroke prophylaxis
complications: Fe overload
L-glutamine
SCD management
dec intracellular oxidante stress
dec pain crises
after collection of whole blood from donor, _____ is completed, then further separation
LEUKODEPLETION
reduced risk of alloimmunization, CMV infection, febrile transfusion rxns
blood bank TTD
HIV Hep B/C Human T-lymphotrophic Virus (HTLV) types I & II Trypanosoma cruzi (Chagas) West Nile virus
shelf life of rbc, platelets
rbc=42d
platelets=5d
*req constant agitation
most common antigens (ABO)
O>A>B>AB
ABO Abs
naturally occurring
present at birth in absence of transfusion
mix of IgM and IgG against A or B
Rh blood group
D, C, E, c, e
newborn hemolytic disease
Rh- (D-) mother is exposed to Rh+ (D+) and development anti-D Abs (IgG) which can cross placenta
hemolysis, anemia, CHF in fetus –> hydrops fetalis and fetal death
prevention: Anti-D Ig (binds any circulating fetal RBCs that are Rh+ to prevent the mother from making Abs to these RBCs)
in addition to mom developing antibody to D antigen, also see
Rh incompatibility due to E antigen
direct Coombs test
determines whether there is IgG or IgM coating the patient’s RBCs by adding antihuman Abs to a patient’s RBCs
indirect Coombs test
starts with the patient’s serum
RBCs with known antigens are added to the patient’s serum
Anti-human Its added to solution
clumping=pt’s serum contains Ig against antigens on donor RBCs
indications for transfusion of platelets
prophylactically w/ -severe thrombocytopenia (platelet count <10,000)
-bleeding
platelet compatibility rules
platelets do not need to be transfused according to rules of ABO or Rh compatibility
Alloimmunization to ___ antigens can cause refractoriness to platelet transfusions
HLA
fresh frozen plasma contains
coagulation proteins needed for thrombus formation/fibrinolysis
also Abs (need to transfuse according to ABO compatibility)
indications for FFP transfusion
deficiencies of coagulation proteins w/ unavailable specific concentrates/unknown specific fx deficiency
emergent reversal of warfarin (interferes w/ vitamin K salvage)
precipitate left after thawing FFP
cryoprecipitate
cryoprecipitate components
VIII
vW antigen
XIII
fibrinogen
primary use of cryoprecipitate in transfusion
bleeding pt w/ low fibrinogen
2 types of VIII concentrates
- plasma derived (contains vWF)
- recombinant (does NOT contain vWF, no risk of viral transmission)
-used prophylactically in hemophilia A to prevent bleeds
prothrombin complex concentrates
FEIBA
KCENTRA
use: rapid control of bleeding in patients on vitamin K antagonists or in patients with hemophilia AND those w/ acquired inhibitors to specifc factors
risk of thrombosis
FEIBA
factor VIII, IX, X, proteins C/s
albumin
used as volume expander in critically ill patients w/ hypOalbuminemia/capillary leak
cotroversial/expensive
IVIG
replacement of IgG in immunicomprimised patients
-ITP, Kawasak
recombinant factor VIIa
used to treat hemophilia pts w/ bleeding who have inhibitors to VIII or IX, or congenital VII deficiency
leukodepletion renders blood product “ CMV ____ “
leukodepletion renders blood product “ CMV SAFE “
“CMV negative” blood
only blood donated from a donor known to be CMV negative
transfusion-related acute lung injury (TRALI)
dyspnea, hypoxia, tachycardia, fever, hypOtension
non-cariogenic pulmonary edema
tx: supportive care
dx of exclusion
transfusion-associated circulatory overload (TACO)
occurs in pt w/ pre-existing congestive HF
dyspnea, tachycardia, HTN, vol overload
