ERYTHROCYTIC DISORDERS

X. Introduction to Erythrocyte Abnormalities

Quantitative changes in erythrocytes

A. Absolute vs. Relative

Classification of Anemia

Relative anemia fluid shift (extravascular to

intravascular; expanding plasma volume and diluting
RCM)
ie. Pregnancy, hyperproteinemia
Relative erythrocytosis decrease in plasma volume
(mami); dehydration

Not true hematologic disorders

B. Laboratory Definition of Red Cell Abnormalities

Anemia decreased Hemoglobin level ; decreased

oxygen-carrying capacity of the blood
Polycythemia or erythrocytosis hematocrit levels
above reference range (hypervolemia, hyperviscosity)

C. Disorders Characterized by Decreased Red Cell

Concentration

Presence of underlying disease process

o Hypoproliferative
o Maturation disorders
o Hemolytic disorders
o Blood loss

Decreased or ineffective bone marrow erythrocyte production

Increased red cell destruction or blood loss

Physiologic Response to Anemia

Chemical and Physical Response

o Shift to the right (moving on oxygen; readily
release oxygen to the tissues)
o Increased 2,3-DPG
o Selective redistribution of blood flow
(prioritizes internal organs rather than skin)
Hematologic Response
o Increased erythropoietic marrow stimulation
o Shift reticulocytes
o Increased [RPI] indicates whether or not
BM is responding adequately to anemia

Etiologic pathophysiologic mechanisms ; caused by

multiple factors
Morphological red cell indices, direct examination
of morphology
o Anemia can be classified according to rbc
size and hb content
o Normocytic, normochromic
o Microcytic, hypochromic
o Microcytic, normochromic
o Macrocytic, normochromic
o RDW can be used in conjunction with the
MCV to make classification more accurate
o RDW useful in the differential diagnosis of
microcytic anemias
Physiologic ability of the BM to respond to anemia
with increased erythropoiesis; assessing ret count and
RPI
o RPI = > 3 effective erythropoiesis

Hemolytic anemias; anemias

secondary to blood loss
o RPI = < 2 ineffective erythropoiesis

Hypoproliferative anemias;
anemias resulting from maturation
disorders
Ineffective Erythropoiesis
o Hypoproliferative anemias N/N
o Maturation disorders

Two groups (MCV):

Macrocytic
megaloblastic from
nonmegaloblastic

Microcytic -
Effective Erythropoiesis
o N/N

D. Disorders Characterized by Increased Red Cell

Concentration
Pathophysiology

Relative erythrocytosis decreased plasma volume

Absolute erythrocytosis- primary, secondary
o Primary: true increase in RCM
(myeloproliferative disorder

Ie. polycythemia vera)

Unregulated cell production
o

Clinical Manifestations:

Pallor (dermal vasoconstriction and blood

redistribution)

o
o

Secondary:
o Appropriate increased EPO to
alleviate hypoxia
o Inappropriate increased EPO
result of LOCALIZED renal hypoxia
or tumor generation that mimics
EPO
Hypervolemia, vasodilation -> decreases
blood flow (hyperviscosity) and thrombosis
Vessel dilation (bloodshot eyes)

Classification of Erythrocytosis

Relative Erythrocytosis
o Dehydration
o Anxiety and stress (stress syndrome,
spurious erythrocytosis, or Gaisbocks
syndrome)
o Smoking tobacco polycythemia
Absolute Erythrocytosis
o Primary:

Clonal, pluripotent stem cell

disorder

EPO decreased in PV
o Secondary:

Appropriate:

Chronic mountain sickness

(Monges disease) ->
individuals who fail to
adapt living at high
altitudes

Inappropriate

XI. Anemia of BM Failure and System Disorders

Anemia can be a result of absolute failure of the BM to

replace destroyed RBCs or those that are prematurely
destroyed (hemolysis) -> defect of the BM itself:
Aplastic anemia and Pure Red Cell Aplasia
Failure of hematopoietic stem cell growth resulting in
hypoplastic marrow and pancytopenia

A. Anemia of BM Failure
Aplastic Anemia
o
peripheral blood pancytopenia; BM:
severely hypoplastic or aplastic
(thrombocytopenia, neutropenia)
o
no immature myeloid cells in the peripheral
blood
o Aplastic/hypoplastic marrow
hematopoietic cells replaced by fat
o Lack of splenomegaly
Diagnostic Criteria For Severe Aplastic Anemia
Bone Marrow
Cellularity
<25% of normal
Or 50% normal cellularity with
<30% hematopoietic cells
Plus two of the ff:
Peripheral Blood
Granulocytes
<0.5 x 10^9/L
Platelets
<20 x 10^9/L
Anemia with
<1% reticulocytes (corrected for
Hct)

Primary AA

Congenital Fanconi Anemia

Acquired Idiopathic (arising

spontaneously)
Secondary AA

Chloramphenicol (transient marrow

hyperplasia)

Vacuolated cells esp. in

erythroid series

Radiation

Ankylosing spondylitis

Damage stem cells or the

hematopoietic
microenvironment
o Laboratory Findings and Correlations with
Disease:

Normocytic, normochromic (slight

macrocytosis is observed)

Morphology of RBC is normal

Reticulocyte ct decreased
P

RPI significantly decreased

B

NO IMMATURE CELLS IN
PERIPHERAL BLOOD

BM aspirate and biopsy

Increased fat and

decreased hematopoietic
cells

Patchy areas of cellularity

Hematology tests:

HbF elevated;
distributed UNEVENLY
(Kleihauer-Betke
acid elution test)

Chemistry:

Serum iron elevated

Plasma iron clearance

Decreased
delayed (adequate iron
erythropoiesis
stores yet decreased iron
uptake)

Bone Marrow Transplantation

Fanconi Anemia (Congenital AA)
o Rare, inherited
o pancytopenia
o Microencephaly, short stature, malformation
of the thumbs, internal strabismus,
malformation of the kidney, genital
hypoplasia, mental retardation
o Laboratory Findings and Correlations with
Disease:

Peripheral blood abnormalities

generally do not manifest until 5-10
years after birth

Anisopoikilocytosis

Increased HbF
o Treatment:

Androgens
Maintain

Corticosteroids
reasonable Hb level

Diamond-Blackfan Anemia (Congenital PRC Aplasia)

o Diagnosis made in infancy or early childhood
o Lack of responsiveness of patients marrow
sample added to EPO (No reaction)
o Abnormal thumbs, retarded growth, bone
age retardation, failure of secondary sexual
maturation, DO NOT DEMONSTRATE
RENAL ABNORMALITIES

Laboratory Findings and Correlations with

Disease:

Expected increase in NRBCs not

found in peripheral blood

Normocytic, normochromic

EPO increased

o
o

T4, PRL, GH stimulate EPO

Result from dysfunction in the
conditioning role that pituitary
hormones exert on the secretion

Adrenal Abnormalities
o
o
o

Myelophthisic Anemia
o Carcinoma
o Hypoproliferative anmia (ACD)
o Marrow is replaced by abnormal cells

Hypo- Addisons disease

Hyper- Cushing disease
Reduction in plasma volume (mask
mild anemia)
Granulocytopenia, lymphocytosis

Hypogonadism
B. Anemia of Systemic Disorders

Anemia of Chronic Renal Disease

Anemia of several endocrine disorders
Anemia of Pregnancy

Anemia of Chronic Renal Disease

o Hypoproliferative; elevated BUN
concentration
o Failure of the renal excretory function ->
accumulation of waste products in plasma
o Failure of renal production and release of
EPO
o Decreased production of EPO
o Abnormal platelet function
o Normocytic, normochromic; normal indices
o Diseased kidneys -> plasma volume is
increased -> artifactually decreased
hematocrit (relative)
o Low serum iron (associated with renal
disease), normal TIBC
o Dialysis therapy

Anemia of Pregnancy
o Iron deficiency Fe demand
o Increased plasma volume

XII. Anemia of Abnormal Nuclear Development

Cell maturation in BM is abnormal

Megaloblastic Anemias: vitamin b12 or folate
deficiency; usually acquired
Increased MCV (macrocytic, normochromic)
Congenital Dyserythropoietic Anemias: abnormalities
of BM erythroid precursors; inherited

A.) Vitamin B12 and Folate

B12

required for a single critical reaction during

normal DNA synthesis
o animal protein products; not found in
vegetables or fruit
o liver
Adenosylcobalamin
Methylcobalamin
B12 coenzyme forms
o

Anemia of Endocrine Disorders

o Hormones :
direct effect on marrow stem cells:
stimulatory effect on EPO
production
o normocytic, normochromic
o marrow: decreased erythroid production
o hypoproliferative disorders

Represents B12 in liver, most of B12 in RBCs and

kidneys
Represents B12 in plasma

Hypothyroidism
o
o
o
o

thyroid function -> need for oxygen

decreases
Decrease in plasma volume (mask mild
anemia)
Treatment: thyroxin
Hypothyroidism
Hypopituitarism
o

o
o

Deficiency of pituitary hormones

(normally control thyroid, gonads,
or adrenals)
Reduced metabolic demands
Decreased EPO production

o
o

Vitamin is released from foods through the

gastric juice (HCl) from parietal cells which
secrete Intrinsic Factor
Vitamin + IF complex absorbed in the ileum
through attachment on mucosal receptors ->
B12 is released and absorption takes place
In plasma = bound by carrier proteins (TC I,
II, III)
Transcobalamin II

most important

synthesized in the liver (B globulin)

transports B12 to liver, tissue and

some in BM
TC I and III

R (rapid) proteins or R binders

Migrate faster than IF in

electrophoresis
Do not assist in ileal B12 absorption

Megaloblastic Anemias
o Methylfolate trap hypothesis
o If B12 is deficient: homocysteine cannot be
converted to methionine; propionate
catabolism cannot take place
Increased urinary
excretion of
methylmalonic acid
(MMA)
o Folate is trapped (N5-methyl FH4) -> cannot
be converted to
FH4 ; formiminoglutamate (FIGlu) cannot
be converted to glutamate

o
o
o

TIBC reduced
LD-1
IF antibodies:

Blocking antibodies
Bind with IF; block VitB12
binding site
Immunologic test of choice
2 types of binding antibodies:

Type 1: antibody attaches

to an antigenic site on IF
(distant from actual
binding site)

Type 2: antibody binds

both to If and complexed
B12
Laboratory Tests:

Schilling Test: ability to secretes

viable IF and absorb orally
administered Co-labeled B12 in
ileum

Necessary for formation of N5 N10 methylene

FH4

o
o

Formiminoglutamate urinary excretion is

increased
Peripheral Blood Changes:

MCV 110 fL (110-130 fL; 160fL)

MCH 33-38 pg

MCHC normal

Pancytopenia -> ineffective

erythropoiesis (BM hypercellular)

Nuclear-cytoplasmic asynchrony

Hypersegmentation

Pernicious Anemia
o Acquired atrophy of stomach lining
o Achlorhydria
o Castles IF
o Autoantibodies
o Subacute combined degeneration; pins and
needles
o RBCs need B12 to absorb folate

Congenital Dyserythropoietic Anemias

o Rare, refractory anemia
o Erythroid hyperplasia
o Type 1

Neonatal jaundice

Splenomegaly

Thin, Feulgen + internuclear

chromatin bridges joining two
normoblasts
o Type 2

Hereditary erythroblast
multinuclearity with positive
acidified serum test (HEMPAS)

Abnormal rbc sensitivity to

acidified normal serum

Hepatosplenomegaly, jaundice

fetal i antigens
o Type 3

gigantoblasts