11 Red Blood Cell Disorders

Erythropoiesis
Erythropoiesis is the production of RBCs in the bone marrow and is dependent on the
release of erythropoietin from the kidneys.
Erythropoiesis
Erythropoiesis is the production of RBCs in the bone marrow and is dependent on the
release of erythropoietin from the kidneys.
Erythropoiesis and erythropoietin (EPO)
EPO increases the O2carryin! capacity of blood by stimulatin! erythroid stem
cells to di"ide. Epoetin alfa# a form of EPO produced by recombinant $%&
technolo!y# is fre'uently abused by athletes to increase their ener!y le"el. (t
also is used in the treatment of anemia associated with renal failure# chronic
disease# and chemotherapy.
). *timuli for EPO release
o +ypo,emia# se"ere anemia# leftshifted O2bindin! cur"e (OBC)# hi!h altitude
2. (ncreased O2 content suppresses EPO release (e.!.# polycythemia "era).
-. Other sources of EPO
o Ectopic production by renal cell carcinoma and hepatocellular carcinoma
.. Peripheral blood markers of erythropoiesis
a. Reticulocytes are newly released RBCs from the bone marrow.
b. /hey are identified with supra"ital stains.
$etect threadlike R%& filaments in the cytoplasm
c. (n 2. hours# they become mature RBCs.
Reticulocyte count
). 0arker of effecti"e erythropoiesis (bone marrow response to anemia)
2. Reported as a percenta!e (normal# 1-2)
-. Percenta!e count is falsely increased in anemia.
a. (nitial percenta!e must be corrected for the de!ree of anemia.
b. Corrected reticulocyte count 3 (actual +ct4.5) 6 reticulocyte count# where .5
represents the normal hematocrit (+ct)
c. E,ample
i. +ct )52# reticulocyte count )72
ii. Corrected reticulocyte count is 82 ()54.5 6 )72 3 82)
.. Corrected reticulocyte count at or abo"e -2
a. 9ood bone marrow response to anemia (i.e.# effecti"e erythropoiesis)
b. E,ampleshemolytic anemia: after treatment of iron deficiency with iron
5. Corrected reticulocyte count below -2
a. Poor bone marrow response to anemia (i.e.# ineffecti"e erythropoiesis)
b. E,amplesuntreated iron deficiency: aplastic anemia
E,tramedullary hematopoiesis (E0+)
RBC# white blood cell (;BC)# and platelet production that occurs outside the bone
marrow
). Common sites of E0+ are the li"er and spleen.
2. Patho!enesis
a. (ntrinsic bone marrow disease (e.!.# myelofibrosis)
b. &ccelerated erythropoiesis (e.!.# se"ere hemolysis in sickle cell disease)
i. E,pands the bone marrow ca"ity
ii. Radio!raph of the skull shows a <haironend< appearance.
-. E0+ produces hepatosplenome!aly.
(n the fetus# hematopoiesis (blood cell formation) be!ins in the yolk sac and
subse'uently mo"es to the li"er and finally the bone marrow by the fifth to
si,th months of life.
Complete Blood Cell Count (CBC) and Other Studies
Components of a CBC
pa!e )=8
pa!e )=>
). +emo!lobin (+b)# +ct# RBC count
2. RBC indices# RBC distribution width (R$;)
-. ;BC count with a differential count# platelet count
.. E"aluation of the peripheral blood morpholo!y
Components of a CBC
pa!e )=8
pa!e )=>
). +emo!lobin (+b)# +ct# RBC count
2. RBC indices# RBC distribution width (R$;)
-. ;BC count with a differential count# platelet count
.. E"aluation of the peripheral blood morpholo!y
+b# +ct# and RBC counts
?etal RBCs containin! +b? are destroyed by splenic macropha!es o"er the
ensuin! 8 to = months. /he uncon@u!ated bilirubin deri"ed from the initial
destruction of fetal RBCs is responsible for physiolo!ic @aundice of the
newborn# which occurs - days from birth.
). ?actors affectin! the normal ran!e (reference inter"al)
a. %ewborns
i. %ewborns ha"e hi!her normal ran!es than do infants and children.
ii. +b? (2A42B !lobin chains) shifts the OBC to the left causin! the release
of EPO.
EPO causes an increase in +b# +ct# and RBC count.
iii. &fter birth# the +b drops from )7.5!4dC to ))!4dC (physiolo!ic anemia).
i". +b?containin! cells are replaced by RBCs containin! +b& (D=>2)# +b&2
(12.52)# and +b? (1)2).
b. *e, of the patient
0en ha"e hi!her normal ran!es due to increased testosterone
(stimulates erythropoiesis) and lack of cyclic bleedin!.
b. Pre!nancy
i. Pre!nant women ha"e lower normal ran!es than nonpre!nant women.
ii. /here is an increase in plasma "olume and RBC mass (i.e.# more RBCs
are produced).
Plasma "olume is twice !reater than RBC mass causin! a sli!ht
decrease in +b (dilutional effect).
2. Chan!es in thalassemia (i.e.# a !enetic !lobin chain disorder)
b. +b and +ct are decreased.
c. RBC count is increased (unknown mechanism).
-. &nemia
d. $ecrease in +b# +ct# or RBC concentration
e. *i!n of an underlyin! disease rather than of a specific dia!nosis
f. Clinical findin!s
?ati!ue# dyspnea with e,ertion# inability to concentrate# diEEiness
RBC indices
). 0ean corpuscular "olume (0CF)
a. &"era!e "olume of RBCs
b. Gsed to classify anemia
0icrocytic (17H Im
-
)# normocytic (7H)HH Im
-
)# macrocytic (D)HH Im
-
)
2. 0ean corpuscular hemo!lobin concentration (0C+C)
a. &"era!e +b concentration in RBCs
b. $ecreased 0C+C
ii Correlates with decreased synthesis of +b (e.!.# microcytic anemias)
iii Central area of pallor is !reater than normal (called hypochromasia).
b. (ncreased 0C+C
ii Correlates with the presence of spherical RBCs (e.!.# hereditary
spherocytosis)
iii /here is no central area of pallor.
R$;
). Reflects "ariation in siEe of RBCs in the peripheral blood (anisocytosis)
2. (ncreased if RBCs are not uniformally the same siEe
o E,amplemi,ture of microcytic and normocytic cells
-. (ron deficiency
o Only microcytic anemia with an increased R$; due to a mi,ture of normocytic
and microcytic RBCs
Characteristics of mature RBCs
pa!e )=7
pa!e )==
). &naerobic !lycolysis
a. 0ain source of adenosine triphosphate (&/P)
b. Cactic acid is the end product of RBC metabolism.
2. Pentose phosphate pathway
a. *ynthesiEes !lutathione (9*+)# an antio,idant that neutraliEes hydro!en pero,ide
b. +ydro!en pero,ide is a product of o,idati"e metabolism.
-. 0ethemo!lobin reductase pathway
a. 0ethemo!lobin (met+b) refers to heme iron that is o,idiEed (?e
-J
).
0et+b cannot bind O2.
b. Reductase system con"erts iron to ferrous (?e
2J
) so that the RBCs can bind O2.
.. Cueberin!Rapaport pathway
a. *ynthesiEes 2#-bisphospho!lycerate (BP9)
b. Re'uired to ri!htshift the OBC (i.e.# release O2 to tissue)
5. 0ature RBCs lack mitochondria.
8. *enescent RBCs
a. Remo"ed by splenic macropha!es
b. End product of heme de!radation in macropha!es is uncon@u!ated bilirubin.
;BC count and differential
). )HHcell differential count subdi"ides leukocytes by percenta!e.
2. ?urther classifies neutrophils as se!mented or band neutrophils
Platelet count
Platelets are anucleate cells deri"ed from cytoplasmic buddin! of me!akaryocytes.
(ron studies
pa!e 2HH
pa!e 2H)
). *erum ferritin
a. ?erritin is the primary soluble iron stora!e protein.
i. Primary stora!e site is in the bone marrow macropha!es.
*ee shaded area in the small bo, in
ii. *erum le"els correlate with ferritin stores in the macropha!es.
iii. *ynthesis of ferritin in macropha!es increases in inflammation.
$ue to release of interleukin ) and tumor necrosis factorA
b. $ecreased serum ferritin
$ia!nostic of iron deficiency
b. (ncreased serum ferritin
i. &nemia of chronic disease (&C$)
ii. (ron o"erload disease
b. +emosiderin
i. (nsoluble de!radation product of ferritin
ii. $ecreased and increased le"els correlate with chan!es in ferritin stores
2. *erum iron
c. Represents iron bound to transferrin# the bindin! protein of iron
i. /ransferrin is synthesiEed in the li"er.
ii. *erum iron is the shaded area of the column in
%ote that the normal serum iron is )HH I!4dC.
d. $ecreased serum iron
i. (ron deficiency
ii. &C$
e. (ncreased serum iron
(ron o"erload diseases
ii *erum total iron bindin! capacity (/(BC)
a. *erum /(BC correlates with the concentration of transferrin.
i. +ei!ht of the column in correlates with serum transferrin and /(BC
ii. %ote that the normal /(BC is -HH I!4dC.
f. Relationship of transferrin synthesis with ferritin stores in macropha!es
i. $ecreased ferritin stores cause increased synthesis of transferrin
(ncrease in transferrin and /(BC is present in iron deficiency.
ii. (ncreased ferritin stores causes decreased synthesis of transferrin
$ecrease in transferrin and /(BC occurs in &C$ and iron
o"erload disease
-. (ron saturation (2)
!. Represents the percenta!e of bindin! sites on transferrin occupied by iron
i. (ron saturation (2) 3 serum iron4/(BC 6 )HH
ii. (n the normal 2 saturation is )HH4-HH 6 )HH or --2.
h. $ecreased percenta!e of iron saturation
i. (ron deficiency
ii. &C$
i. (ncreased percenta!e of iron saturation
(ron o"erload disease
+b electrophoresis
a. Primary use is to detect hemo!lobinopathies.
i. &bnormality in !lobin chain structure (e.!.# sickle cell disease)
ii. &bnormality in !lobin chain synthesis (e.!.# thalassemia)
b. /ypes of normal +b detected
i. +b& has 2A42K !lobin chains (=>2 in adults).
ii. +b&2 has 2A42L !lobin chains (22 in adults).
iii. +b? has 2A42B !lobin chains ()2 in adults).
Microcytic Anemias
/ypes of microcytic anemias
). (ron deficiency (most common)
2. &nemia of chronic disease (&C$)
-. /halassemia (A and K)
4. *ideroblastic anemias (least common)
/ypes of microcytic anemias
). (ron deficiency (most common)
2. &nemia of chronic disease (&C$)
-. /halassemia (A and K)
.. *ideroblastic anemias (least common)
Patho!enesis
). $efects in the synthesis of +b
o +b 3 heme J !lobin chains
2. $efects in the synthesis of heme (i.e.# iron J protoporphyrin)
o (ron deficiency# &C$# sideroblastic anemias
-. $efects in the synthesis of !lobin chains (i.e.# A or K)
o A/halassemia and Kthalassemia (thal)
(ron deficiency anemia
Table 111! Causes o" #ron De"iciency Anemia
Classi"ication Causes Discussion
Blood loss 9astrointestinal loss 0eckel di"erticulum (in older children)
PG$ (most common cause in men 1 5H years old)
9astritis (e.!.# %*&($)
+ookworm infestation
Polyps4colorectal cancer (most common cause in adults D
5H years old)
0enorrha!ia 0ost common cause in women 1 5H years old
(ncreased utiliEation Pre!nancy4lactation
(nfants4children
$aily iron re'uirement is -..m! durin! pre!nancy and
2.5-.Hm! durin! lactation
(ron re'uired for tissue !rowth and e,pansion of blood
"olume
$ecreased intake (nfants4children
Elderly
0ost common cause of iron deficiency in youn! children
Restricted diets with little meat (lack of heme iron)
$ecreased
absorption
Celiac sprue &bsence of "illous surface in the duodenum
(ntra"ascular
hemolysis
0icroan!iopathic hemolytic
anemia
P%+
Chronic loss of +b in urine leads to iron deficiency
+b# hemo!lobin: %*&($# nonsteroidal antiinflammatory dru!: P%+# paro,ysmal nocturnal hemo!lobinuria: PG$# peptic ulcer
disease.
pa!e 2H2
pa!e 2H-
/he sta!es of iron deficiency in se'uence are as followsM absent iron stores:
decreased serum ferritin: decreased serum iron# increased /(BC# decreased
iron saturation (2): normocytic normochromic anemia: microcytic
hypochromic anemia.
). Epidemiolo!y
a. (t is the most common anemia.
b. Causes of iron deficiency
2. Patho!enesis
o $ecreased synthesis of heme
2. Clinical and laboratory findin!s
a. PlummerFinson syndrome
i. Caused by chronic iron deficiency
ii. Esopha!eal web (dyspha!ia for solids but not li'uids)
iii. &chlorhydria (absent acid in the stomach)
i". 9lossitis (inflammation of the ton!ue)# spoon nails (koilonychia)
b. Caboratory findin!s
i. $ecreased 0CF# serum iron# iron saturation (2)# ferritin (1-Hn!4mC)
ii. (ncreased /(BC# R$;
iii. 0icrocytic and normocytic cells with decreased central area of pallor
i". /hrombocytosis is a common findin! in chronic iron deficiency.
". Ceukocyte count is usually normal.
Eosinophilia occurs in hookworm infestations.
&nemia of chronic disease (&C$)
pa!e 2H-
pa!e 2H.
). Epidemiolo!y
a. 0ost common anemia in hospitaliEed patients
b. Common causes
i. Chronic inflammation (e.!.# rheumatoid arthritis# tuberculosis)
ii. &lcoholism (most common anemia)
iii. 0ali!nancy (most common anemia)
2. Patho!enesis
a. $ecreased synthesis of heme
b. (n some cases# there is a decrease renal production of EPO.
c. Ci"er synthesis and release of hepcidin
i. &ntimicrobial peptide
ii. &cute phase reactant released by the li"er in response to inflammation
iii. Enters macropha!es and pre"ents the release of iron to transferrin
i". ?erritin synthesis and iron stores increase in bone marrow macropha!es
-. Caboratory findin!s
a. $ecreased 0CF# serum iron# /(BC# and iron saturation (2)
b. (ncreased serum ferritin (D)HHn!4mC)
/halassemia (thal: A and K)
pa!e 2H.
pa!e 2H5
+b electrophoresis is normal# because all +b types re'uire A!lobin chains.
/he +b concentration is decreased: howe"er# the relati"e proportions of the
normal +bs remains the same.
%ormal K!lobin chain synthesis is desi!nated K: some K!lobin chain
synthesis is desi!nated K
J
: and# no K!lobin chain synthesis is desi!nated K
H
.
pa!e 2H5
pa!e 2H8
). Epidemiolo!y
a. &utosomal recessi"e disorders
b. A/hal is common in *outheast &sia and in black &mericans.
c. K/hal is common in black &mericans# 9reeks# and (talians.
2. Patho!enesis of Athal
a. $ecrease in A!lobin chain synthesis due to !ene deletions
?our !enes control A!lobin chain synthesis.
b. One !ene deletion produces a silent carrier.
Not associated with anemia
c. /he combination of two !ene deletions is called Athal trait.
ii 0ild anemia with an increased RBC count
iii Black &merican type
&ssociated with a loss of one !ene on each chromosome (A4 A4)
iiii &sian type
&ssociated with a loss of both !enes on the same chromosome
(4 A4A)
(ncreased risk for de"elopin! more se"ere types of Athal
ivi $ecreased 0CF# +b# and +ct
vi (ncreased RBC count
vii %ormal R$;# serum ferritin# and +b electrophoresis
viii /here is no treatment.
b. /he combinations of three !ene deletions is called +b+ (four Kchains) disease.
ii *e"ere hemolytic anemia
E,cess Kchain inclusions cause macropha!e destruction of the
RBCs.
iii +b electrophoresis detects +b+.
c. /he combination of four !ene deletions is called +b Bart (four Bchains) disease.
ii (ncompatible with life
iii +b electrophoresis shows an increase in +b Bart.
2. Patho!enesis of Kthal
a. $ecrease in K!lobin chain synthesis
ii 0ild anemia is most often due to $%& splicin! defects.
iii *e"ere anemia is due to a nonsense mutation with formation of a stop
codon.
Premature termination of K!lobin chain synthesis or absent K
!lobin chain synthesis.
b. %ormal synthesis of A# L# B!lobin chains.
c. K/hal minor (K4K
J
)
ii 0ild microcytic anemia
iii 0ild protecti"e effect a!ainst falciparum malaria
RBC life span is shorter than normal.
iiii $ecreased 0CF# +b# and +ct
ivi (ncreased RBC count
vi %ormal R$; and serum ferritin
vii +b electrophoresis
$ecreased +b& (2A42K)
(ncreased +b&2 (2A42L) and +b? (2A42B)
viii /here is no treatment.
d. K/hal ma@or (CooleyNs anemia: K
H
4K
H
)
ii *e"ere hemolytic anemia
RBCs with Achain inclusions are remo"ed by macropha!es in
the spleen.
Causes an increase in uncon@u!ated bilirubin
RBCs with Achain inclusions under!o apoptosis in the bone
marrow (ineffecti"e erythropoiesis).
iii E,tramedullary hematopoiesis
iiii (ncreased R$; and reticulocytes
ivi +b electrophoresis
No synthesis of +b&
(ncrease in +b&2 and +b?
vi Con!term transfusion re'uirement
$an!er of iron o"erload (called hemosiderosis)
*ideroblastic anemia
pa!e 2H7
/ubular dama!e by lead produces ?anconiNs syndrome. /he syndrome
includes pro,imal renal tubular acidosis (loss of bicarbonate in urine)#
aminoaciduria# phosphaturia# and !lucosuria.
). Epidemiolo!y
a. Chronic alcoholism (most common cause)
b. Pyrido,ine ("itamin B8) deficiency
c. Cead (Pb) poisonin!
2. Patho!enesis
a. $efect in heme synthesis within the mitochondria
b. (ron accumulates in the mitochondria formin! rin!ed sideroblasts
c. (rono"erload type of anemia
(ncrease in iron stores in the bone marrow macropha!es
-. Chronic alcoholism
a. &lcohol is a mitochondrial to,in.
$ama!es heme biosynthetic pathways in the mitochondria
b. *ideroblastic anemia occurs in -H2 of hospitaliEed chronic alcoholics.
.. Pyrido,ine deficiency
a. Fitamin B8 is a cofactor for Laminole"ulinic acid synthase.
Ratelimitin! reaction of heme synthesis
b. 0ost common cause of deficiency is isoniaEid ((%+) therapy.
(%+ is used in the treatment of tuberculosis.
5. Cead (Pb) poisonin!
a. Epidemiolo!y
ii Pica (abnormal cra"in!) for eatin! leadbased paint
Common cause of childhood lead poisonin! in inner cities
iii Pottery painter
Pbbased paints are commonly used for decoration.
iiii ;orkin! in a battery or ammunition factory
b. Pb denatures enEymesM
ii ?errochelatase (heme synthase)
(ron cannot bind with protoporphyrin to form heme.
(ncrease in protoporphyrin# which is pro,imal to the enEyme block
iii &minole"ulinic acid (&C&) dehydrase
Causes an increase in L&C&# which is pro,imal to the enEyme
block
iiii Ribonuclease
Ribosomes cannot be de!raded and persist in the RBC.
Produces coarse basophilic stipplin!
c. Clinical and laboratory findin!s
ii &bdominal colic with diarrhea
Pb is "isible in the !astrointestinal tract on plain abdominal
radio!raphs.
iii Encephalopathy in children
L&C& dama!es neurons# increases "essel permeability (cerebral
edema)# and causes demyelination.
iiii 9rowth retardation in children
Pb deposits in the epiphysis of !rowin! bone.
Radio!raphs show increased density in the epiphyses.
ivi Peripheral neuropathy in adults
E,amplefootdrop (peroneal ner"e palsy)
vi %ephroto,ic dama!e to pro,imal renal tubules
vii (ncreased whole blood and urine Pb le"els
Best screen and confirmatory test for Pb poisonin!
2. Caboratory findin!s in sideroblastic anemias
a. (ncreased serum iron# iron saturation (2)# and ferritin
b. $ecreased 0CF and /(BC
c. Rin!ed sideroblasts are present in a bone marrow aspirate.
3. *ummary table of microcytic anemias
Table 11$! %aboratory &indin's in Microcytic Anemias
Test
#ron
De"iciency
Anemia o" Chronic
Disease
(Thal)*Thal
Minor
%ead
+oisonin'
0CF
*erum iron %ormal
/(BC %ormal
Percent saturation %ormal
*erum ferritin %ormal
R$; %ormal %ormal %ormal
RBC count
+b electrophoresis %ormal %ormal A/halassemiaM
normal
K/halM +b&# +b&2#
+b?

Rin!ed sideroblasts %one %one %one Present

Coarse basophilic
stipplin!
%one %one %one Present
+b# hemo!lobin: 0CF# mean corpuscular "olume: R$;# red blood cell distribution width: /(BC# total ironbindin! capacity.
Macrocytic Anemias
0acrocytic anemias are most often caused by folate or "itamin B)2 deficiency.
Fitamin B
)2
metabolism
pa!e 2H7
pa!e 2H=
). Present in meat# e!!s# and dairy products
2. Parietal cells synthesiEe intrinsic factor ((?) and hydrochloric acid.
-. 9astric acid con"erts pepsino!en to pepsin.
o Pepsin frees "itamin B)2 from in!ested proteins.
.. ?ree "itamin B)2 is bound to Rbinders synthesiEed in the sali"ary !lands.
5. Pancreatic enEymes in the duodenum clea"e off the Rbinders.
o Fitamin B)2 binds to (? to form a comple,.
8. Fitamin B)2(? comple, is reabsorbed in the terminal ileum.
>. Fitamin B)2 binds to transcobalamin (( and is secreted into plasma.
o $eli"ered to metabolically acti"e cells or stored in the li"er (8= year supply).
Causes of "itamin B
)2
deficiency
Table 11,! Causes o" -itamin B1$ De"iciency
Classi"ication Causes Associated &actors
$ecreased intake Pure "e!an diet
0alnutrition
Breastfed infants of pure "e!ans may de"elop deficiency
0ay occur in elderly patients
0alabsorption (ntrinsic factor
9astric acid
(ntestinal
reabsorption
&utoimmune destruction of parietal cells (i.e.# pernicious anemia)
Cannot acti"ate pepsino!en to release "itamin B)2
CrohnNs disease or celiac disease in"ol"in! terminal ileum
(destruction of absorpti"e cells)
Bacterial o"er!rowth (bacterial utiliEation of a"ailable "itamin B)2)
?ish tapeworm
Chronic pancreatitis (cannot clea"e off Rbinder)
(ncreased
utiliEation
Pre!nancy4lactation $eficiency is more likely in a pure "e!an
?olate metabolism
). Present in !reen "e!etables and animal proteins
o (n the form of poly!lutamates
2. Con"erted to mono!lutamates by intestinal con@u!ase
o (ntestinal con@u!ase is inhibited by phenytoin.
-. 0ono!lutamates are reabsorbed in the @e@unum.
a. Con"erted to methyltetrahydrofolate# the circulatin! form of folate
b. Reabsorption is blocked by alcohol and oral contracepti"es.
2. /here is only a - to .month supply of folate in the li"er.
Causes of folate deficiency
Table 11.! Causes o" &olate De"iciency
Classi"ication Causes Comment and Associated &actors
$ecreased intake 0alnutrition
(nfants4elderly
Chronic alcoholics
9oatNs milk
$ecreased intake most common cause of folate deficiency
0alabsorption Celiac disease
Bacterial o"er!rowth
$eficiency usually occurs in association with other "itamin
deficiencies (fat and water soluble)
$ru! inhibition 5?luorouracil
0ethotre,ate#
trimethoprimsulfa
Phenytoin
Oral contracepti"es#
alcohol
(nhibits thymidylate synthase
(nhibit dihydrofolate reductase
(nhibits intestinal con@u!ase
(nhibit uptake of mono!lutamate in @e@unum
&lcohol also inhibits the release of folate from the li"er.
(ncreased
utiliEation
Pre!nancy4lactation
$isseminated mali!nancy
*e"ere hemolytic anemia
(ncreased utiliEation of folate in $%& synthesis
Patho!enesis of macrocytic anemia in folate and "itamin B
)2
deficiency
pa!e 2H=
pa!e 2)H
). (mpaired $%& synthesis
a. $elayed nuclear maturation
i. Causes a block in cell di"ision leadin! to lar!e# nucleated hematopoietic
cells
ii. Enlar!ed cells are called me!aloblasts.
b. &ffects all rapidly di"idin! cells
E,amplesRBCs# leukocytes# platelets# intestinal epithelium
b. Cellular R%& and protein synthesis continue unabated.
Cytoplasmic "olume continues to e,pand.
ii (neffecti"e erythropoiesis
a. 0e!aloblastic precursors outside the bone marrow sinusoids are pha!ocytosed
by macropha!es.
b. 0e!aloblastic precursors under!o apoptosis causin! pancytopenia.
&nemia# neutropenia# and thrombocytopenia
Fitamin B
)2
and folate in $%& synthesis
?olate deficiency is the most common cause of increased serum
homocysteine le"els in the Gnited *tates. +omocysteine dama!es endothelial
cells leadin! to "essel thrombosis.
). Fitamin B)2 remo"es the methyl !roup from methyltetrahydrofolate (%
5
methyl?+.).
a. Produces tetrahydrofolate (?+.)
b. 0ethylB)2 transfers the methyl !roup to homocysteine to produce methionine.
c. $eficiency of folate or "itamin B)2 increases plasma homocysteine.
2. /hymidylate synthase con"erts deo,yuridine monophosphate (dG0P) to deo,ythymidine
monophosphate (d/0P).
o /hymidylate synthase is inhibited by 5fluorouracil.
2. $ihydrofolate reductase con"erts dihydrofolate (?+2) to ?+..
o $ihydrofolate reductase is inhibited by methotre,ate and trimethoprim
sulfametho,aEole.
Fitamin B
)2
in oddchain fatty acid metabolism
pa!e 2)H
pa!e 2))
). Propionyl Co& is con"erted to methylmalonyl Co&.
2. 0ethylmalonyl Co& is con"erted to succinyl Co&.
o Fitamin B)2 is a cofactor for methylmalonyl Co& mutase.
-. Fitamin B)2 deficiency causes an increase in propionyl and methylmalonyl Co& and their
correspondin! acids.
o Propionyl Co& replaces acetyl Co& in neuronal membranes resultin! in
demyelination.
Clinical findin!s in "itamin B
)2
deficiency
). ?indin!s in pernicious anemia
a. &chlorhydria (lack of !astric acid) due to destruction of parietal cells
i. 0aldi!estion of food
ii. +yper!astrinemia due to loss of acid inhibition of !astrin
b. &ntibodies associated with pernicious anemia
i. &ntibodies directed a!ainst the proton pump in parietal cells
ii. &ntibodies that block bindin! of "itamin B)2 to (?
0ost specific test for pernicious anemia
iii. &ntibodies that pre"ent bindin! of "itamin B)2(? comple,es to ileal
receptors
c. &ntibody destruction of parietal cells causes chronic atrophic !astritis of the body
and fundus.
(ncreased incidence of !astric adenocarcinoma
ii *mooth# sore ton!ue with atrophy of papillae
ii %eurolo!ic disease
a. Peripheral neuropathy with sensorimotor dysfunction
b. Posterior column dysfunction
$ecrease in "ibratory sensation and proprioception (@oint sense)
c. Cateral corticospinal tract dysfunction with spasticity
d. $ementia
Caboratory findin!s in "itamin B
)2
deficiency
). $ecreased serum "itamin B)2
2. (ncreased serum homocysteine and methylmalonic acid (=52 of cases)
-. Peripheral blood findin!s
a. Pancytopenia
b. O"al macrocytes
c. +yperse!mented neutrophils
0ore than fi"e nuclear lobes
.. Bone marrow findin!s
o 0e!aloblastic nucleated cells with primiti"e open (lacy) chromatin pattern
2. *chillin! test localiEes some of the causes of "itamin B)2 deficiency
i. GtiliEes oral administration of radioacti"e "itamin B)2
ii. Reabsorption of radioacti"e "itamin B)2
(ndicates dietary deficiency of "itamin B)2 (e.!.# pure "e!an)
iii. Reabsorption of radioacti"e "itamin B)2 after administration of (?
(ndicates pernicious anemia# where there is a lack of (?
i". Reabsorption of radioacti"e "itamin B)2 after administration of antibiotics
(ndicates bacterial o"er!rowth with destruction of "itamin B)2(? comple,
". Reabsorption of radioacti"e B)2 after administration of pancreatic e,tract
(ndicates chronic pancreatitis with lack of enEymes to clea"e off Rbinder
Clinical findin!s in folate deficiency
). *imilar to "itamin B)2 deficiency with the exception of neurolo!ic disease.
2. (ncreased risk for open neural tube defects in the fetus
o $ue to decreased maternal intake of folate prior to conception
Caboratory findin!s in folate deficiency
pa!e 2)2
pa!e 2)-
). Peripheral blood and bone marrow findin!s are similar to "itamin B)2 deficiency.
2. $ecreased serum folate and RBC folate (best screenin! test)
(t is important to distin!uish folate from "itamin B)2 deficiency. Pharmacolo!ic
doses of folate can correct the hematolo!ic findin!s in both folate and "itamin
B)2 deficiency: howe"er# neurolo!ic disease is not corrected.
Comparison table of "itamin B
)2
and folate deficiency
Table 11/! Clinical and %aboratory &indin's in -itamin B1$ and &olate
De"iciencies
%aboratory)Clinical
&indin'
+ernicious
Anemia
Other -itamin B1$
De"iciencies
&olate
De"iciency
&chlorhydria Present &bsent &bsent
&utoantibodies Present &bsent &bsent
Chronic atrophic !astritis Present &bsent &bsent
9astric carcinoma risk %one %one
+yperse!mented neutrophils Present Present Present
0ean corpuscular "olume
%eurolo!ic disease Present Present %one
Pancytopenia Present Present Present
Plasma homocysteine
*erum !astrin le"el %ormal %ormal
Grine methylmalonic acid %ormal
0ormocytic Anemias1 Corrected Reticulocyte Count or #nde2 Belo3 ,4
&nemias under this classification include acute blood loss# early iron deficiency or anemia
of chronic disease (&C$)# aplastic anemia# and chronic renal failure.
&cute blood loss
). Epidemiolo!y
a. E,ternal blood loss (e.!.# peptic ulcer)
0ay result in iron deficiency
b. (nternal blood loss (e.!.# ruptured abdominal aortic aneurysm)
2. Clinical and laboratory findin!s
-. Re'uires 5 to > days before a reticulocyte response is obser"ed
Early iron deficiency or &C$
). &nemia is normocytic before it becomes microcytic.
o &C$ is microcytic in only )H2 to -H2 of cases.
2. *erum ferritin is most useful in distin!uishin! the two anemias.
&plastic anemia
Table 115! Causes o" Aplastic Anemia
Classi"icationE2amples and Discussion
(diopathic &ppro,imately 5H>H2 of cases are idiopathic
$ru!s 0ost common known cause of aplastic anemia
$oserelated causes are usually re"ersible (e.!.# alkylatin! a!ents)
(diosyncratic reactions are fre'uently irre"ersible (e.!.# chloramphenicol)
Chemical a!ents /o,ic chemicals in industry and a!riculture (e.!.# benEene# insecticides$$/# parathion)
(nfection 0ay in"ol"e all hematopoietic cell lines (pancytopenia) or erythroid cell line alone (pure
RBC aplasia)
E,amplesEBF: C0F: par"o"irus: non&# nonB hepatitis (most common)
Physical a!ents ;holebody ioniEin! radiation (therapeutic or nuclear accident)
0iscellaneous /hymoma (may be associated with pure RBC aplasia)
Paro,ysmal nocturnal hemo!lobinuria
C0F# cytome!alo"irus: EBF# EpsteinBarr "irus: RBC# red blood cell.
pa!e 2)-
pa!e 2).
). Causes
2. Patho!enesis
a. &nti!enic alteration of multipotent myeloid stem cells
Causes /cell acti"ation and release of cytokines that suppress stem
cells
b. $efecti"e or deficient stem cells (ac'uired or hereditary)
-. Clinical findin!s
a. ?e"er due to infection associated with neutropenia
b. Bleedin! due to thrombocytopenia
c. ?ati!ue due to anemia
.. Caboratory findin!s
a. Pancytopenia
b. Reticulocytopenia
c. +ypocellular bone marrow
5. Complete reco"ery occurs in less than )H2 of cases.
Chronic renal failure (CR?)
). Patho!enesis
o $ecreased synthesis of EPO (most common cause)
2. Caboratory findin!s
a. %ormocytic anemia
b. Presence of burr cells (i.e.# RBCs with an undulatin! membrane)
c. Platelet dysfunction
i. /hrombocytopenia
ii. $efect in platelet a!!re!ation that is re"ersible with dialysis
Prolon!ed bleedin! time
0ormocytic Anemias1 Corrected Reticulocyte Count at or Abo6e ,4
&nemias include the hemolytic anemias due to defects within the RBC (intrinsic) or
factors outside the RBC (e,trinsic).
Patho!enesis of hemolytic anemias
pa!e 2).
pa!e 2)5
+apto!lobin is an acute phase reactant that combines with +b to form a
comple, that is pha!ocytosed and de!raded by macropha!es causin! a
decrease in serum hapto!lobin. /he amount of +b in the comple,es is so
small that uncon@u!ated bilirubin is not si!nificantly increased.
). (ntrinsic or e,trinsic hemolytic anemias
a. (ntrinsic refers to a defect in the RBC causin! the anemia.
E,amplesmembrane defects# abnormal +b# enEyme deficiency
b. E,trinsic refers to factors outside the RBC causin! hemolysis.
E,amplesstenotic aortic "al"e# immune destruction
2. 0echanisms of hemolysis
a. E,tra"ascular hemolysis
ii RBC pha!ocytosis by macropha!es in the spleen (most common site)
and li"er
iii Reasons for pha!ocytosis
RBCs coated by (!9 with or without C-b
&bnormally shaped RBCs (e.!.# spherocytes# sickle cells)
iiii (ncrease in serum uncon@u!ated bilirubin
End product of macropha!e de!radation of +b
ivi (ncreased serum lactate dehydro!enase (C$+) from hemolyEed RBCs.
b. (ntra"ascular hemolysis
ii +emolysis occurs within blood "essels.
iii Causes of hemolysis
EnEyme deficiency (e.!.# deficiency of !lucose8phosphate
dehydro!enase)
Complement destruction (e.!.# (!0mediated hemolysis)
0echanical dama!e (e.!.# calcific aortic "al"e stenosis)
iiii (ncreased plasma and urine +b
ivi +emosiderinuria
Renal tubules con"ert iron in +b into hemosiderin.
vi $ecreased serum hapto!lobin
vii (ncreased serum C$+ from hemolyEed RBCs.
+ereditary spherocytosis
). Patho!enesis
a. &utosomal dominant disorder
b. (ntrinsic defect with e,tra"ascular hemolysis
c. 0embrane protein defect results in the loss of RBC membrane and spherocyte
formation.
i. 0utation in ankyrin is the most common defect.
ii. 0utation in band 2# spectrin (A and K)# or band - account for other
defects.
d. (ncreased permeability of spherocytes to sodium
$ue to membrane defect and dysfunctional %a
J
4O
J
&/Pase pump
ii Clinical findin!s
a. Paundice due to increased uncon@u!ated bilirubin
b. (ncreased incidence of calcium bilirubinate !allstones
$ue to increased concentration of con@u!ated bilirubin in bile
c. *plenome!aly
d. &plastic crisis
0ay occur in children especially after a "iral infection (e.!.# par"o"irus)
ii Caboratory findin!s
a. %ormocytic anemia with spherocytosis
b. (ncreased 0C+C
c. (ncreased RBC osmotic fra!ility
i. (ncreased permeability of spherocytes to sodium and water
ii. *pherocytes rupture in mildly hypotonic salt solutions.
2. /reatment is splenectomy
o *pherocytes remain in the peripheral blood.
+ereditary elliptocytosis
). Patho!enesis
a. &utosomal dominant disorder
b. $efecti"e spectrin and band ..)
2. Clinical findin!s
a. 0a@ority ha"e no anemia or a mild hemolytic anemia
b. *plenome!aly
-. Caboratory findin!s
a. Elliptocytes !reater than 252 of RBCs in peripheral blood
b. (ncreased osmotic fra!ility
.. /reatment is splenectomy in symptomatic patients
Paro,ysmal nocturnal hemo!lobinuria (P%+)
pa!e 2)8
pa!e 2)>
). Patho!enesis
a. &c'uired membrane defect in multipotent myeloid stem cells
i. 0utation causes loss of the anchor for decay acceleratin! factor ($&?).
ii. %ormally $&? neutraliEes complement attached to RBCs# neutrophils#
and platelets.
b. (ntra"ascular complementmediated lysis of RBCs# neutrophils# and platelets
Occurs at ni!ht# because respiratory acidosis enhances complement
attachment to these cells
ii Clinical findin!s
a. Episodic hemo!lobinuria
0ay cause iron deficiency
b. (ncreased incidence of "essel thrombosis (e.!.# hepatic "ein)
$ue to the release of a!!re!atin! a!ents from destroyed platelets
c. (ncreased risk for de"elopin! acute myelo!enous leukemia
ii Caboratory findin!s
a. *creenin! test is the sucrose hemolysis test (su!ar water test).
*ucrose enhances complement destruction of RBCs.
b. Confirmatory test is the acidified serum test (+am test).
&cidified serum acti"ates the alternati"e pathway causin! hemolysis.
c. Peripheral blood findin!s
i. %ormocytic anemia with pancytopenia
0icrocytic if iron deficiency de"elops from hemo!lobinuria
ii. $ecreased leukocyte alkaline phosphatase
b. $ecreased serum hapto!lobin
c. (ncreased serum4urine +b
*ickle cell anemia
pa!e 2)7
pa!e 2)=
pa!e 2)=
pa!e 22H
). Epidemiolo!y
a. &utosomal recessi"e disorder
b. 0ost common hemo!lobinopathy in black &mericans
c. +eteroEy!ote condition (sickle cell trait# +b&*) has no anemia.
Present in 72 to )H2 of black &mericans
d. +omoEy!ous condition (+b**) produces anemia.
e. Protecti"e a!ainst Plasmodium falciparum malaria
2. Patho!enesis
a. Predominantly e,tra"ascular hemolysis of sickle cells
b. 0issense point mutation
*ubstitution of "aline for !lutamic acid at si,th position of K!lobin chain
c. Causes of sicklin!
ii +b* molecules a!!re!ate and polymeriEe into lon! needlelike fibers
RBCs assume a sickle or boatlike shape
iii *ickle +b (+b*) concentration !reater than 8H2 is the most important
factor for sicklin!.
+b* concentration is too low in +b&* to produce sicklin! in the
peripheral blood.
iiii (ncrease in deo,yhemo!lobin increases the risk for sicklin!.
&cidosis (causes O2 release from RBCs)
Folume depletion (intracellular dehydration causes an increase in
concentration of deo,yhemo!lobin)
+ypo,emia (decrease in arterial PO2 decreases O2 saturation of
+b)
b. Re"ersible and irre"ersible sicklin!
ii (nitial sicklin! is re"ersible with administration of o,y!en.
iii Recurrent sicklin! causes irre"ersible sicklin! due to membrane dama!e.
iiii (rre"ersibly sickled cells ha"e increased adherence to endothelial cells in
the microcirculation.
0icro"ascular occlusions ("asoocclusi"e crises) produce
ischemic dama!e.
c. +b? pre"ents sicklin!.
ii (ncreased +b? at birth pre"ents sicklin! in +b** for 5 to 8 months.
iii +ydro,yurea increases the synthesis of +b?.
d. Oey patholo!ic processes in +b**
ii *e"ere hemolytic anemia
iii Fasoocclusi"e crises
2. Clinical findin!s in +b**
a. $actylitis
Painful swellin! of hands and feet in infants (usually 8= months old) is
due to bone infarcts.
b. &cute chest syndrome
ii Fasoocclusion of pulmonary capillaries
iii Chest pain# lun! infiltrates# hypo,emia
iiii 0ost common cause of death in adults
b. &septic necrosis of the femoral head
c. &utosplenectomy
ii *pleen is enlar!ed but dysfunctional by 2 years of a!e.
%uclear remnants (+owellPolly bodies) appear in RBCs
indicatin! loss of macropha!e function
iii *pleen is fibrosed and diminished in siEe in youn! adults.
d. (ncreased susceptibility to infections
ii $ue to dysfunctional spleen and impaired opsoniEation of encapsulated
bacteria
iii Children are at risk for Streptococcus pneumoniae sepsis.
0ost common cause of death in children
iiii (ncreased incidence of osteomyelitis due to Salmonella paratyphi
e. &plastic crisis
ii Reticulocytopenia
iii &ssociation with par"o"irus
f. *e'uestration crisis
ii Rapid splenic enlar!ement with entrapment of RBCs causin!
hypo"olemia
iii Reticulocytosis
!. (ncreased risk for calcium bilirubinate !allstones
$ue to increased con@u!ated bilirubin in bile from chronic hemolysis
ii Renal findin!s in +b&* (also in +b**)
a. *icklin! may occur in peritubular capillaries in the medulla.
$ue to the low O2 tension in the medulla
b. Presents with microhematuria due to infarctions
c. Renal papillary necrosis may occur.
Coss of concentration and dilution
ii Caboratory findin!s
a. *ickle cell screen
*odium metabisulfite reduces O2 tension# which induces sicklin!
b. +b electrophoresis
ii +b&* profile+b& 552 to 8H2# +b* .H2 to .52
iii +b** profile+b* =H2 to =52# +b? 52 to )H2# no +b&
h. Peripheral blood findin!s
ii %ormal peripheral blood in +b&*
iii (n +b**# there are sickle cells and tar!et cells.
i. Prenatal screenin!
&nalysis of fetal $%& to detect the point mutation
9lucose8phosphate dehydro!enase (98P$) deficiency
$ecrease in %&$P+ impairs neutrophils and monocyte killin! of bacteria by
the O2dependent myelopero,idase system which re'uires %&$P+ as a
cofactor for %&$P+ o,idase.
pa!e 22H
pa!e 22)
). Epidemiolo!y
a. Qlinked recessi"e disorder
b. *ubtypes of 98P$ deficiency
i. 0editerranean "ariant in 9reeks and (talians
ii. Black &merican "ariant
c. Protecti"e a!ainst Plasmodium falciparum malaria
2. Patho!enesis
a. (ntrinsic defect with predominantly intra"ascular hemolysis
0ild component of e,tra"ascular hemolysis
b. $ecreased synthesis of %&$P+ and !lutathione (9*+) in the pentose phosphate
pathway
i. 9*+ normally neutraliEes hydro!en pero,ide# an o,idant product in RBC
metabolism.
ii. (n 98P$ deficiency# pero,ide o,idiEes +b# which precipitates in the form
of +einE bodies.
+einE bodies dama!e the RBC membranes causin!
intra"ascular hemolysis.
+einE bodies remo"ed from RBC membranes by splenic
macropha!es produce bite cells.
b. +alflife of 98P$ in the 0editerranean "ariant is markedly reduced.
Produces a se"ere# chronic hemolytic anemia
b. +alflife of 98P$ in the black &merican "ariant is moderately reduced.
Episodic type of hemolytic anemia after e,posure to o,idant stresses.
c. O,idant stresses inducin! hemolysis
i. (nfection (most common)
ii. $ru!s
E,amplesprima'uine# chloro'uine# dapsone# sulfonamides
iii. ?a"a beans (mainly in 0editerranean "ariant)
-. Clinical findin!s
o *udden onset of back pain with hemo!lobinuria 2 to - days after an o,idant
stress
2. Caboratory findin!s
a. %ormocytic anemia
b. +einE bodies
i. (dentified with a supra"ital stain
ii. Best screen durin! acti"e hemolysis
c. RBC enEyme analysis
i. Confirmatory test after hemolysis has subsided
d. Peripheral blood findin!s
i. Bite cells (macropha!e remo"al of membrane)
Pyru"ate kinase (PO) deficiency
). Epidemiolo!y
a. &utosomal recessi"e disease
b. 0ost common enEyme deficiency in the Embden0eyerhof pathway
PO normally con"erts phosphoenolpyru"ate to pyru"ate leadin! to a net
!ain of 2 &/P.
2. Patho!enesis
a. (ntrinsic defect with e,tra"ascular hemolysis
b. Chronic lack of &/P causes membrane dama!e.
Results in dehydration of the RBC (echinocytes)
-. Clinical findin!s
a. +emolytic anemia with @aundice be!innin! at birth
b. (ncrease in 2#-BP9 synthesis pro,imal to enEyme block
Ri!ht shift of OBC causes increased release of O2# which offsets the
clinical effects of the anemia.
.. Caboratory findin!s
a. %ormocytic anemia
b. RBCs with thorny pro@ections (echinocytes)
c. RBC enEyme assay is the confirmatory test.
(mmune hemolytic anemias
Table 117! Classi"ication o" #mmune 8emolytic Anemias
Type o" #mmune
8emolytic Anemia E2amples
Autoimmune
;arm antibodies ((!9) Primary or idiopathic (no underlyin! cause)
*econdary (e.!.# *CE)
Cold antibodies ((!0) Primary or idiopathic
*econdary
Mycoplasma pneumoniae (anti( antibodies)
(nfectious mononucleosis (antii antibodies)
Dru'induced $ru! adsorption (e.!.# penicillin)M (!9 antibody directed a!ainst the dru!
attached to the RBC membrane
(mmunocomple, (e.!.# 'uinidine)M dru!(!0 immunocomple, deposits on the
RBC causin! intra"ascular hemolysis
&utoantibody induction (e.!.# Amethyldopa)M dru! alters Rh anti!ens on RBCs
causin! synthesis of autoantibodies a!ainst Rh anti!ens
Alloimmune +emolytic transfusion reaction
&BO hemolytic disease of newborn
Rh hemolytic disease of newborn
RBC# red blood cell: *CE# systemic lupus erythematosus.
pa!e 22)
pa!e 222
9roup of e,trinsic hemolytic anemias with e,tra"ascular or intra"ascular hemolysis.
). Classification
a. &utoimmune
i. 0ost common type of immune hemolytic anemia
ii. 0ore common in women than men
*CE is the most common cause of autoimmune hemolytic
anemia (&(+&).
iii. >H2 are warm type ((!9 antibodies) of &(+&
i". -H2 are cold type ((!0 antibodies) of &(+&
b. $ru!induced
c. &lloimmune
2. Patho!enesis
a. (!9mediated hemolysis
i. RBCs coated by (!9 are pha!ocytosed by splenic macropha!es
(e,tra"ascular hemolysis).
ii. *pherocytes are produced if a small portion of the membrane is
remo"ed.
b. Complementmediated hemolysis
i. RBCs coated by C-b alone are pha!ocytosed by li"er macropha!es
(e,tra"ascular hemolysis).
ii. RBCs coated by C5C= under!o intra"ascular hemolysis.
iii. RBCs coated by (!9 and C-b are pha!ocytosed by li"er and splenic
macropha!es (e.!.# *CE).
c. (!0mediated hemolysis
0ay be e,tra"ascular or intra"ascular dependin! on the de!ree of
complement acti"ation
ii Clinical findin!s
a. Paundice due to uncon@u!ated hyperbilirubinemia
Occurs in e,tra"ascular types of hemolysis
b. +epatosplenome!aly
$ue to work hyperplasia of splenic and li"er macropha!es
c. RaynaudNs phenomenon
0ay occur in cold types of &(+&
ii Caboratory findin!s
a. Positi"e direct antihuman !lobulin test ($&/: CoombsN test)
$&/ detects RBCs sensitiEed with (!9 and4or C-b.
b. Positi"e indirect antihuman !lobulin test (indirect CoombsN test)
$etects antibodies in the serum (e.!.# anti$ antibodies)
c. Gncon@u!ated hyperbilirubinemia in e,tra"ascular hemolysis is present.
d. +emo!lobinuria# decreased serum hapto!lobin in intra"ascular hemolysis
e. Peripheral blood findin!s
i. %ormocytic anemia
ii. *pherocytosis due to macropha!e remo"al of RBC membrane
0icro and macroan!iopathic hemolytic anemias (0+&)
Table 119! Causes o" Micro and Macroan'iopathic 8emolytic Anemia
Types E2amples
Microan'iopathic
Platelet thrombi +emolytic uremic syndrome
/hrombotic thrombocytopenic purpura
?ibrin thrombi $isseminated intra"ascular coa!ulation
+ECCP syndromeM +# hemolytic anemia: EC# ele"ated transaminases: CP# low platelets:
associated with preeclampsia
Macroan'iopathic &ortic stenosis (most common cause)
Prosthetic heart "al"es
). Causes
2. Patho!enesis
a. E,trinsic defect with intra"ascular hemolysis
b. 0icroan!iopathic
0icrocirculatory lesions cause RBC fra!mentation (schistocytes
c. 0acroan!iopathic
+emolytic process caused by "al"ular defects (e.!.# aortic stenosis)
-. Caboratory findin!s
a. %ormocytic anemia
Con!standin! hemo!lobinuria causes iron deficiency anemia.
b. $ecreased serum hapto!lobin# hemo!lobinuria
c. *chistocytes in the peripheral blood
0alaria
). Epidemiolo!y
o ?emale Anopheles mos'uito transmits Plasmodia to humans.
2. Patho!enesis
a. (ntraerythrocytic parasite causes intra"ascular hemolysis.
Correlates with fe"er spikes
b. E,trinsic defect with predominantly intra"ascular hemolysis
0inor component of e,tra"ascular hemolysis
2. Clinical findin!s
a. ?e"er and splenome!aly
b. Plasmodium vivax
ii 0ost common type
iii /ertian fe"er pattern (e"ery .7 hours)
b. Plasmodium falciparum
ii 0ost lethal type
iii Ruotidian fe"er pattern (daily spikes with no pattern)
c. Plasmodium malariae
ii &ssociation with nephrotic syndrome
iii Ruartan fe"er pattern (e"ery >2 hours)
2. Caboratory findin!s
o /hin and thick smears identify or!anisms in RBCs
*ummary table of normocytic anemias
Table 11:! Summary o" 0ormocytic Anemias
Anemia +atho'enesis Discussion
Reticulocytosis ; ,4
&cute blood loss Coss of whole blood (nitial +b and +ct normal
*i!ns of "olume depletion
Early iron deficiency $ecreased iron stores %ormocytic before microcytic
(ron studies abnormal
Early &C$ (ron trapped in macropha!es by
hepcidin
%ormocytic before microcytic
(ron studies abnormal
&plastic anemia *uppression or deficiency of
multipotent myeloid stem cells
Pancytopenia
+ypocellular marrow
Chronic renal failure $eficiency of EPO Presence of burr cells
Reticulocytosis ,4
+ereditary spherocytosis &$ disorder
$efect in ankyrin
E,tra"ascular hemolysis
(ncreased osmotic fra!ility
R, with splenectomy
+ereditary elliptocytosis &$ disorder
$efect in spectrin and band ..)
E,tra"ascular hemolysis
Elliptocytes D 252
Paro,ysmal nocturnal
hemo!lobinuria
Coss of anchor for $&? in myeloid
stem cell
Complement destruction of
hematopoietic cells
(ntra"ascular hemolysis
Pancytopenia
Positi"e su!ar water test (screen) and
acidified serum test (confirmatory test)
*ickle cell anemia &R disorder
Faline substitution for !lutamic acid K
!lobin chain
E,tra"ascular hemolysis
+b&*M +b& 558H2: +b* .H.52
+b**M +b* =H=52: +b? 5)H2: no
+b&
98P$ deficiency QR disorder
$eficiency 9*+ causes o,idant
dama!e to +b and RBC membrane
(ntra"ascular hemolysis
+einE body preparationM screen durin!
acti"e hemolysis
EnEyme assayM confirmatory test when
hemolysis subsides
Pyru"ate kinase deficiency &R disease
&/P synthesis
E,tra"ascular hemolysis
2#-BP9 ri!ht shifts OBC
$ehydrated RBCs with thorny
pro@ections (echinocytes)
&cute blood loss Coss of whole blood
Reticulocytosis 5> days
+b# +ct# RBC count
;arm &(+& (!9 with or without C-b
E,tra"ascular hemolysis
Positi"e direct CoombsN test
*CE most common cause
Cold &(+& (!0 with C-b
E,tra"ascular or intra"ascular
hemolysis
&ssociation with Mycoplasma
pneumoniae: EBF
$ru!induced immune
hemolytic anemia
$ru! haptenM penicillin E,tra"ascular
hemolysis
(mmunocomple,M 'uinidine
(ntra"ascular hemolysis
&utoantibodyM methyldopa
E,tra"ascular hemolysis
Positi"e direct CoombsN test
&lloimmune hemolytic
anemia
&ntibodies a!ainst forei!n RBC
anti!ens
E,tra"ascular hemolysis
+emolytic transfusion reaction
&BO and Rh +$%
Positi"e direct CoombsN test
0icro and macroan!iopathic
hemolytic anemia
0echanical destruction of RBCs with
formation of schistocytes
(ntra"ascular hemolysis
Calcific aortic stenosis most common
cause
Chronic hemo!lobinuria causes iron
deficiency
0alaria /ransmitted by female Anopheles
mos'uito
(ntra"ascular hemolysis
Rupture of RBCs corresponds with fe"er
&$# autosomal dominant: &R# autosomal recessi"e: BP9# bisphospho!lycerate: $&?# decay acceleratin! factor: EBF# Epstein
Barr "irus: EPO# erythropoietin: 98P$# !lucose8phasphate dehydro!enase: 9*+# !lutathione: +b# hema!labin: +b&*#
sickle cell trait: +b**# +ct# hematocrit: sickle cell disease: OBC# o,y!en bindin! cur"e: RBC# red blood cell: R,# treatment:
*CE# systemic lupus erythematosus: QR# Qlinked recessi"e.