ANEMIA

TYPE
DEFINITION
PATHOGENESIS
CLINICAL MANIFESTATIONS
DIAGNOSIS
PERIPHERAL BLOOD
LAB FINDINGS
Type Definition Pathogenesis Clinical Diagnosis Peripheral Lab Findings
Manifestation Blood
Iron Deficiency
Alpha-
thalassemia

Reference Ranges for Red Blood Cells

Measurement Men Women
Hemoglobin (g/dL) 13.6-17.2 12-15
Hematocrit (%) 39-49 33-43
RBC Count (10^6/microL) 4.3-5.9 3.5-5.0
Reticulocyte count (%) 0.5-1.5
MCV (mean corpuscular volume) 82-96
Mean Corpuscular hemoglobin (pg) 27-33
Mean corpuscular hemoglobin 33-37
concentration (g/dL)
RBC distribution width (expressing 11.5-14.5
degree of anisocytosis)

Differential Diagnosis of Anemia

Past medical History
Patients age
Ethnic background
Females- mensturation
Jaundice
GI problems- blood in stool
Fatique, hx of anemia, previous transfusions
Medications
o Rx, OTC, vitamins and supplements, dietary restrictions
Family History
Physical Exam
 Pallor
o Conjunctiva
o Oral mucosa
o Nail beds
o Palmar creases
Orthostatic BP changes
o Intravascular volume shifts
Labs
Ways to Classify anemia
Etiology
o Blood loss (acute/chronic)
o Deficient erythropoiesis
o Excessive RBC destruction
Defects extrinsic to RBC
Defects intrinsic to RBC
Reticulocyte response
Lab value description
o Morphology of RBCs
o MCV
Microcytic
Iron deficiency
Anemia of chronic disease
Thalassemias
Sideroblastic anemia
Normocytic
Hemolytic (extrinsic)
o Alloimmune
 o Autoimmune
o Nonimmue
o Hypersplenism
o Infections
o Physical trauma
Hemolytic (intrinsic)
o Enzyme deficiencies (g6pd)
o Hemopglobinopathies (sickle cell)
o Membrane defects (spherocytosis)
Non Hemolytic
o Acute blood loss
o Anemia of chronic disease
o Aplastic anemia
o Chronic renal insufficiency
Macrocytic
Megalopblastic
o Drug related
o Folic acid deficiency
Nonmegaloblastic
o Alcoholism
o Hypothyroidism
o Liver disease
o Myelodysplastic syndromes
o Reticulocytosis
o Spherocytosis
ANEMIA ALGORITHM
1. Establishment of anemia based on history, exam, Hgb/Hct
2. Mean corpuscular volume
 3. <80- microcytic pathway
4. 80-100 normocytic pathway
5. >100fL macrocytic pathway
Anemias of Blood Loss
Depend on rate of hemorrhage and whether external or internal
Internal allows recapture of iorn
External can lead to iron deficiency and hamper return to normal
Acute Blood Loss
Clinical effects due to loss of intravascular volume- shock and death can occur
If survival- fluid shifts away from interstitium to restore blood volume so lowering of hematocrit by
hemodilution
Reduction in O2 carrying capacity causes kidneys to release epo
Release of new RBCs at day 5 heralded by increased reticulocytes to 10-15% of RBC count by day 7
Significant bleeding hypotension triggers adrenergic that causes release of granulocytes from marginated
pool= leukocytosis and thrombocytosis
Chronic Blood Loss
Anemia will occur only if rate of loss exceed the marrow regenerative capacity
Anemia will also occur when iron reserves are depleted

Hemolytic Anemias
RBC destruction- less than 120 day lifespan
Elevated erythropoietin with increased erythropoiesis
Increased hemoglobin catabolites- bilirubin
Excess bilirubin is unconjugated- levels of hyperbilirubinemia depend on liver functional capacity and rate of
hemolysis
Normal livers rarely have severe jaundice
 Extravascular Hemolysis
o In macrophages of spleen
o RBC membrane injury, reduced deformability, opsonization
o Features: anemia, splenomegaly, jaundice, modest reductions in haptoglobin
Intravascular hemolysis
o Damage to RBCs outside of spleen
o Mechanical injury (ie mechanical cardiac valves)
o Complement fixation (mismatched blood transfusion)
o Intracellular parasites (malaria)
o Extracellular toxin (clostridial enzymes)
o Anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice, marked reduction in haptoglobin
o Free hemoglobin oxidized to methhemoglobin and both free and meth are excreted in urine (brown
urine) or reabsorbed by renal proximal tubules
o Iron released from hemoglobin can accumulate in tubular cells- renal hemosiderosis
Hereditary Spherocytosis
Cytoskeletal or membrane protein defects that render RBCs spheroidal and less deformable
Vulnerable to splenic sequestration and destruction
Autosomal dominant in 75%
Pathogenesis
o Insufficiency of proteins: Spectrin, Ankyrin, Band 3, band 4.2
o Reduced density of membrane skeletal components so reduced stability of lipid bilayer and loss of
membrane fragments as RBC age
o Compound heterozygosity for 2 defective alleles is more severe phenotype
o Reduction in surface area causes RBC to assume a sphere rather than a biconcave disc
o Sphere leads to diminished deformability and propensity for beingtrapped and destroyed by splenic
macrophages
Morphology
 o Small and dark- lack central pallor
o Reticulocytosis
o Marrow erythroid hyperplasia
o Splenic congestion is seen with prominent erythrophagocytosis in cords of billroth
Clinical Features
o Anemia
o Splenomegaly
o Jaundice
o Generally stable due to increase erythropoiesis
o Parvovirus can induce aplastic crisis d/t suppression of erythropoiesis
o Increase in splenic RBC destruction (mono) can trigger hemolytic crisis
o Chronic hyperbilirubinemia- gallstone development
Diagnosis
o RBC Fragility assay
o RBC autohemolysis assay
o Direct antiglobulin (coombs) test
o Suspect in pt with unexplained hemolysis, splenomegaly
o Reticulocytosis 15-30%
Treatment
o Splenectomy but generally not needed

Glucose-6-Phosphate Dehydrogenase Deficiency

Hereditary metabolic defect
Enzyme in hexose monophosphate shunt that reduces NAPD to NADPH then NADPH reduces RBC glutathione
protecting RBCs against oxidative injury
Pathogenesis
 o Exposure to oxidative stress: inflammation, drugs, foods like fava beans
o Hemoglobin sulfhydryl cross-linking and protein denaturation
o 2-3 day lag period then intravascular lysis of severely damaged cells
o altered hemoglobin precipitates as Heinz bodies that cause direct hemolysis
o precipitated hemoglobin can attach to inner cell , reduce deformability and increase to splenic
macrophage destruction
o x-linked disorder only 2 variants lead to hemolysis African and Mediterranean
o in African American G6PD- abnormal proteins lead to loss of g6pd in older RBCs so self-limited
hemolytic episodes
o Mediterranean g6pd levels much lower so more severe hemolytic episodes
Diagnosis
o G6pd assay
o Consider in black males during acute hemolysis
o Heinz bodies
o Bite cells- macrophage removal of Heinz bodies from spleen but RBC is still around- looks like it has a
bite taken out of it
Treatment
o Avoidance of triggers- drugs that cause hemolysis
o Supportive care

Sickle Cell Disease

Normal RBCs contain HbA mostly (22), smaller amounts of HbA2 (22) and fetal hemoglobin HbF (22)
Sickle cell is hereditary hemoglobinopathy substitution of valine for glutamic acid at 6th position of globin
chain
Autosomal recessive disorder 8% to10% African Americans heterozygous for abnormal allele, 70,000
individual in US homozygous and have sickle cell disease
Pathogenesis
o Deoxygenation polymerizes HbS into long stif chains that sickle rBCs- causes chronic hemolysis,
microvascular occlusion, and tissue damage
o Rate of sickling
Interaction of HbS with other types of hemoglobin w/in RBCs
Heterozygotes HbS is 40% of hemoglobin with remainder being HbA so it interferes with
hbs polymerization
In heterozygotes- hbS occurs only with profound hypoxia
Newborns do not manifest disease because HbF interferes with sickling
For adult pt with hereditary persistence of HBF- sickle cell is less severe
o HBSC disease- so o
One parent gives them HbS, the other gives HbC
Variant of hemoglobin HbC (substituting lysine for glutamic acind in chain 6th) in pt with both S
cn C alleles HbSC have a tendency to lose salt and water and become dehydrated- so increase in
HbS concentration causing the hbs to polymerize so there is less sickling and fewer acute vaso-
occlusive events but more retinopathy, ischemic necrosis of bone, and priapism than those with
pure SS disease
Regular hemoglobin C disease just is a hemoglobinopathy and heterozygotes dont really develop
anemia, homozygotes have a mild hemolytic anemia
o Mean corpuscular hemoglobin concentration (MCHC)
Higher HbS concentrations increases probability of sickling so dehydration and stuff that increase
MCHC facilitate sickling
Disorder that reduce MCHC (thalassemia) lessen sickling severity
o Intracellular pH- reduced pH reduces hemoglobin oxygen affinity thereby increasing protion of
deoxygenated HbS and thus increasing probability of sickling
o Microvascular transit time- sickling is confined to tissue with sluggish blood flow- spleen, bone marrow,
or those involved by inflammation where transit rates are slow
 o Reoxygenation depolymerizes HbS but repeated sickling causes damage to RBC b/c HBS herniates thru
membrane and severe membrane derangements caus Ca2+ influx, protein cross-linking, and water
and potassium efflux
o Repeated sickling episodes RBCs become dehydrated, dense, rigid and then end stage cells retain
sickling shape
o Intravascular hemolysis
o Microvascular occlusion- with more tissue hypoxia and infarction- occlude small vessels b/c sickled cells
produce more adhesion molecules so local inflammation and platelet aggregation occurs
o VICIOUS CYCLE: stagnate rbcs in inflamed vascular beds causes sickling, obstruction, hypoxia, and then
more inflammation-
o Free hemoglobin from ruptured RBCs inactivates NO increasing vascular tone and enhancing platelet
aggregation
Clincial Manifestation
o Chronic hemolytic anemia= hyperbilirubinemia and gallstones due to the bilirubin excretion
o Chronic hypoxie causes impairement of growth and development
o Vaso-occlusive crises are painful ischemic necrosis episodes- bones, lungs, liver, brain, penis, spleen
o Acute chest syndrome- vaso-occlusive lung vascular flow and compromises pulmonary function leading
to systemic hypoxia
o Aplastic crisis- d/t parvo b/c of decreased erythropoiesis
o Sequestration crises- intact spleens massive entrapment of sickled RBCs rapid splenic enlargement,
hypovolemia and shock
o Splenic fibrosis impair complement pathway so predisposed to infections- encapsulated organisms-
step pneumo and h. influenzae
Diagnosis
o Severe anemia- Hgb is 3-8g/dL
o Smere is anisocytosis (cells are a bunch of different shapes) and poikosis
o Prenatal screening with PCR for those at risk of passing on sickle cell- can test amniotic fluid at 14-16
weeks
 o Newborn screening with high performance liquid chromatography
o Peripheral smear, HB solubiity testing, and Hb electrophoresis for individuals
o Splenomegaly in childhood but autosplenectomy d/t repeated episodes of vaso-occlusion caused
fibrosis and shrinkage
o Bonemarrow has normoblastic hyperplasia- if severe marrow can cause bone resorption and
extramedullary hematopoiesis
o Microvascular occlusions producing damage and infarction
o
Treatment
o Treat crisis triggers- broad spectrum antibiotics for infection
o Analgesics and iv hydration for vaso-occlusive pain crisis
o Transfusion
o Immunizations, folate supplementation and hydroxyurea (increase hbF but is teratogen and causes
neutropenia and thrombocytopenia)
Thalassemia Syndromes
Inherited disorders from mutations- reduce or globin chain synthesis
chains coded by gene on chromosome 11 (two copies)
chains encoded by two genes on 16 (4 copies)
diminished synthesis of one chain: low intracellular hemoglobin (hypochromia) and excess of other chain
effects

-Thalassemia
deficient synthesis of -globin
0 mutations stop chain synthesis- chain termination mutations that create stop codons
+ mutations- reduced globi synthesis- d/t weird RNA splicing
Pathogenesis
o With reduce -globin reduced HbA production, so under hemoglobinized RBC
 o Hypochromic and microcytic with reduced O2 carrying capacity
o Unbound chains form unstable aggregates that cause cell membrane damage- precursor destruction
in marrow and splenic sequestration of mature RBCs
o Membrane damage leads to extravascular hemolysis
o Severe anemia- compensatory expansion of epoietic marrow- encroaches on cortical marrow so
skeletal abnormalities in growing children
o Ineffective epoiesis= excessive absorption of dietary ion- iron overload
Clinical Syndromes
o Severity is based on genetic defect B0 or B+, as well as homozygous or heterozygous
o Thalassemia Major:
2 beta thalassemia alleles B+/B+, B+/B0, B0/B0
severe, transfusion dependent anemia
manifests 6-9 months after birth (switch from HBF to HbA
peripheral blood shows anisocytosis- many microcytic hypochromic RBCs, target cells, and
erythrocyte fragments
poorly hemoglobinized RBC precursors (normoblasts)
expansion of hematopoietic marrow with erosion of cortical bone
extramedullary hematopoiesis is common with splenomegaly
without transfusions- death at early age from profound anemia
in transfused patients- morbidity and fatality related to cardiac failure from iron overload and
hemochromatosis
o thalassemia minor
heterozygotes
usually asymptomatic
peripheral blood shows minor abnormalities: hypochromia, microcytosis, basophilic stiplling,
target cells
hemoglobin electrophoresis has increasesd HbA2 (22synthesis)
genetic counseling
 o thalassemia intermedia- patients generally heterozygotes- somewhere between major and minor

Thalassemia
inherited defect of reduce globin synthesis
gene deletion most common cause
HbH- chain tetramers have high O2 affinity and cause tissue hypoxia, prone to oxidation and precipitation of
intracellular protein aggregates that promote RBC sequestration by macrophages
Free chains form stable tetramers (HbBarts) that bind o2 with excessive avidity- tissue hypoxia
Silent carrier state
o Asymptomatic
o Single globin deletion-
thalassemia trait
o Either one chromosome has both globin genes or each chromosome has a deletion of 1 gene
o Looks like thalaseemia minor
Hemoglobin H disease:
o deletion of 3 hemoglobin genes
o suppression of alpha chains and formation of HbH tetramers- resembles beta thalassemia intermedia
Hydrops fetalis
o Deletion of all 4 alpha globin chains
o chain synthesis so early embryonic is ok
o As -globin ceases and fetal 22 are replaced by gamma globin tetramers (HbBarts) high o2 affinity
prevents o2 release in tissues- not compatible with life
o Intrauterine and lifelong transfusion requirement
Diagnosis
o Evaluation of rhemolytic anemia- severe Hb <6g/dL
o RBC may be elevated b/c cells are microcytic
 o Peripheral smear- nucleated erythroblasts, target cells, small pale RBCs, punctuate and diffuse
basophilia

Paroxysmal Nocturnal Hemoglobinuria

Immunohemolytic Anemia
Hemolytic Anemia resulting from Trauma to Red Cells

Anemias of Diminished Erythropoiesis

Megaloblastic Anemias
Iron Deficiency Anemia
Anemia of Chronic Disease
Aplastic Aneemia
Pure Red Cell Aplasia
Other forms of bone marrow failure