Brains Review

Hematology: Anemia
 General Principles
• A sign, not a disease
• Acquired or hereditary abnormality (RBCs/
precursors); or non- hematologic
• A dynamic process
• Elderly are more prone to anemia, but is
not a cause of anemia
• Diagnosis of iron deficiency anemia
mandates further work-up
 Definition
• Decrease circulating RBC mass
(decrease in any: Hct, Hgb, RBC)

• Decrease O2- carrying capacity of the

blood
Main consequence:
Tissue Hypoxia
 Mild Severe chronic
• Asymptomatic • Dizziness
• Exertional dyspnea • Headache
• Fatigue
• Syncope
• Lightheadedness/
fainting • Tinnitus or vertigo
• Palpitation • Irritability
• Pica • Difficulty sleeping or
• Syncope (post concentrating
exercise)
• Bounding pulse anemia
 Common signs:
• Pallor
• Tachycardia
• Ejection systolic (flow) murmur
• Mild peripheral edema
• Venous hums & wide pulse pressure
• Angina pectoris (elderly)
• Abnormal menstruation
• Decrease in libido & impotence
 Cardiovascular Adaptations
• Rapid:
• Sudden marked
contraction of IV vol
• Postural hypotension
• Fall in cardiac output
• Shunting of blood- skin to
central organs
• Sweating
• Restlessness
• Thirst and air hunger
• Slow:
• Adaptations for O2
mantainance
• Increase of plasma
volume
• Right shift- O2-hgb
dissociation curve
 History:
• Age
• Duration & time of onset
• Previous anemia / intake of hematinics
• Other subjacent illness (gallbladder, liver, renal, endocrine dse/
surgery)
• Associated symptoms related w/ one specific etiology (change in
bowel habits, rheumatic)
• Family / Social history
• Occupation
• Hemotransfusion
• Blood loss
• Drug / Toxin exposure
• Diet
 Physical findings:
• Skin: Jaundice; Petechiae; Leg ulcers
• Urine: dark urine
• Spleen: enlargement
• Neurologic symptoms: loss of vibration
sensibility, paresthesia, ataxia
• HEENT: Tongue atrophy
• Lymphadenopathy
• Evidence of blood in feces or vomit
• Signs of primary dse leading to secondary
anemia
 Basic Laboratory Exams
• CBC (Retic, Platelet, Diff ct)
• RBC Indices (MCH, MCV, MCHC)
• PBS (Color/Inclusions/Aniso- Poikilo-
cytosis)
• Serum ferritin
• Serum iron
• TIBC
• BMA
 Others:
• Stool Guaiac, Creatinine,
• B1 (increase)
• Haptoglobin (decrease)
• Urine hemosiderin (present)
• Hemoglobin-emia/uria (present)
• Serum LDH (increase)
• Stool/urine urobilinogen (increase)
• Methgb (increase)
 PATHOPHYSIOLOGIC
CLASSIFICATION OF ANEMIA
1. Impaired production
2. Increased destruction (Hemolytic)
3. Blood loss
 IMPAIRED PRODUCTION
(1) STEM CELL PROLIFERATION/
DIFFERENTIATION
• APLASTIC ANEMIA
• PURE RED CELL APLASIA
• ENDOCRINE DEF (PITUITARY,
THYROID, ADRENAL, TESTIS)
 IMPAIRED PRODUCTION
(2) RBC-BLAST PROLIF / DIFF
• MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
– VIT. B12 DEFICIENCY
– FOLIC ACID DEFICIENCY
• HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS)
– HEME: IDA; SIDEROBLASTIC ANEMIA
– GLOBIN: THALASSEMIAS
• MULTIPLE MECHANISMS
– ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
– RDA
– MYELOPHTHISIC ANEMIA (BM INFILTRATION)
– REFRACTORY ANEMIA W/ CELLULAR BM
– PROTEIN MALNUTRITION
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
 INCREASED DESTRUCTION
(2) EXTRINSIC
• ANTIBODY: • MECHANICAL:
• AIHA (IgG) • PROSTHETIC HEART
• COLD REACTING (IgM) VALVE
• DRUG INDUCED • MAHA
• BURNS

• INFECTION: • OTHERS:
• BACTEREMIA • HYPERSPLEENISM
• PARASITEMIA • OXIDIZING AGENTS
– MALARIA • VENOM (SNAKE,
– BARTONELLOSIS INSECT)
 BLOOD LOSS
• ACUTE • CHRONIC
 Classification of anemia
• Reduced production • Increased destruction
– Def of hematinics – Hemolytic anemia
• IDA • Intrinsic causes
• Folate & B12 def – Membrane defects
– Enzymopathies
– Dyserythropoiesis
– Hemoglobinopathy
• ACD
• Extrinsic causes
• MDS
– Immune reactions
• Sideroblastic a – Microangiopathic
– Marrow infiltration – Parasitic
– Failure of production – Hypersplenism
• Aplastic anemia • Bleeding
• Pure red cell aplasia
MORPHOLOGIC
CLASSIFICATION
 MICROCYTIC HYPOCHROMIC
(MCV < 80)
• IDA
• ACD (25%)
• THALASSEMIA
• SIDEROBLASTIC A
 MACROCYTIC (MCV > 100)
• MEGALOBLASTIC • NORMOBLASTIC BM

BM • RETICULOCYTOSIS
• LIVER DSE/ OBSTRUCTIVE
JAUNDICE
• FOLIC ACID DEF • POSTSPLEENECTOMY
• VIT B12 DEF • HYPOTHYROIDISM
• APLASTIC A
• THIAMINE DEF • MYELOPROLIFERATIVE DSE
• ALCOHOL ABUSE
• DRUGS
 NORMOCYTIC
• RPI > 3 INTRINSIC • RPI < 3
HEMOLYSIS:
HEMOLYSIS • BLOOD LOSS < 5- 7 DAYS
• ENZYMOPATHIES • CHRONIC DSE A (75%)
• MILD IDA
• HEMOGLOBINOPATHY
• SIDEROBLASTIC A
• MEMBRANE DEFECTS • REFRACTORY A
• RDA
• RPI > 3 EXTRINSIC
• MYELOPHTHISIC A
HEMOLYSIS:
HEMOLYSIS
• ENDOCRINE DYSFXN A
• AIHA • HYPO- / A- PLASTIC A
• MAHA • HEPATIC DISEASE A
• BLOOD LOSS > 1 WEEK
MICROCYTIC & NORMOCYTIC
• RPI < 3
• IDA • BLOOD LOSS < 5- 7
• ACD (25%) DAYS
• • ACD (75%)
THALASSEMIA
• • MILD IDA
SIDEROBLASTIC A
• SIDEROBLASTIC A
• REFRACTORY A
• RDA
• MYELOPHTHISIC A
• ENDOCRINE DYSFXN A
• HYPO- / A- PLASTIC A
• HEPATIC DSE A
 Erythrocytes
• Structurally the
simplest cell in the
body
• Basic function: Create
& maintain an
environment for
physical integrity &
functionality of Hgb
Erythropoiesis
(Kinetics)
 Substances necessary for RBC
production:
• Metals (iron, cobalt, • Regulatory
manganese) substances:
• Vitamins (B12, B6, C,
E, folate, riboflavin, • Erythropoietin
pantothenic, thiamine) • Thyroid hormones
• Amino acids • Androgens
 IMPAIRED PRODUCTION (1)
STEM CELL PROLIFERATION/
DIFFERENTIATION
• APLASTIC ANEMIA
• PURE RED CELL APLASIA
• ENDOCRINE DEF (PITUITARY,
THYROID, ADRENAL, TESTIS)
 Aplastic Anemia
• BM Aplasia (Lack of Cells)
• Failure of Multipotent
Stem Cell
– T cell Mediated
Suppression or
– Genetic Damage
• BM: Markedly
Hypocellular
• PBS: Pancytopenia;
Normochromic Normocytic
RBCs
 Aplastic Anemia
• Largely empty
marrow spaces
• Fat cells, fibrous
stroma, scattered or
clustered foci of
lymphocytes / plasma
cells
 Aplastic A: Causes
• Idiopathic (70 % or >) w/ Poor Prognosis esp if < 40 y/o

• Inherited:

• Fanconi anemia (rare, AR; defects in DNA repair;

multiple congenital anomalies)
• Familial aplastic anemia
• Dyskeratosis congenita
• Shwachman Diamond Syndrome
• Dubowitz syndrome
 Causes Of Aplastic Anemia
• Acquired:
• Drugs
– 6 –mecaptopurine
– Methotrexate
– Cyclophosphamide
– Chloremphenicol
• Chemicals: insecticides
• Toxin (benzene, CCl4)
• Whole body Irradiation
• Infection: *Viral hepatitis; HIV; IM; CMV
• MDS
 PATHOGENESIS CAUSES

DAMAGE TO STEM CELL

DEPRESSION OR CESSATION OF ACTIVITY OF

REPEATED
ALL BLOOD PRODUCING ELEMENT
INFECTION;
FREQUENT
SICK DAY

LEUKOPENIA
BLEEDING THROMBOCYTOPENIA
TENDENCY AEB
ECCHYMOSIS,
DECREASE IN FORMATION OF RBC
PURPURA,
PETICHIAE,
BLEEDING FROM NOSE,
MOUTH, PALLOR OF SKIN & MUCOUS
VAGINA, RECTUM MEMBRANE, CYANOSIS
PANCYTOPENIA

APLASTIC ANEMIA
 Aplastic A: Clinical Features
• Anemia: pallor, easy fatigability, weakness, loss of appetite
• Thrombocytopenia: petechiae, easy bruising, severe
nosebleeds, bleeding into GIT & renal tract
• Leukopenia: increased susceptibility to infections & oral
ulcer
• Hepatosplenomegaly & LAD do not occur; their presence
suggest underlying leukemia
• Hyperplastic gingivitis
• Special features
– Skin: Hyperpigmentation, café –au-lait spots, erythematous rash
– Head: Microcephaly, micro-ophthalmia
– Mouth: cleft lip, leukoplakia
– General: small stature
 Treatment: Aplastic Anemia
• Treatment of identifiable cause
• Supportive care
– Blood component therapy
– Treatment of infections
• Severe acquired AA:
– Stem cell transplantation
– Immunosuppression
• ALG or ATG + cyclosporine
• Moderate
– Androgens
ANTITHYMOCYTE GLOBULIN
• Immunosuppressant for post BMT or
undergo treatment for Aplastic Anemia
• Reduces activity of T lymphocytes
attacking BM stem cells.
• Prevents GVH Rxn via eliminating reactive
WBCs
 Precautions
• Allergic reaction to horses or rabbits
• Inc chance of getting other infections
• Fever, chills, shakes w/in few hours after
the 1st dose
• Side Effect: H20 retention
• Report: heart working harder, bloating or
swelling
 Cyclophosphamide
• Anti - cancer & immunosuppressant
• Drug of choice for BMT
• Side Effects: nausea, vomiting, hair loss; affects heart, lungs liver
• Severe bladder damage through acrolein production (colorless liquid
irritant used in chemical warfare as a tear gas)
• Another drug may be given before and after each dose of
cyclophosphamide to reduce its toxicity
• Inform MD of dysuria
• May lead to abnormal bleeding, inc risk of infection due to
pancytopenia & reduced fertility in men
• Drink lots of water while taking this drug to prevent bladder irritation
 CYCLOSPORINE
• Drug used w/ ATG / ALG for further
immunosuppression by inhibiting
T lymphocytes activity only
• Used for BMT vs GVHD
 Side Effects of Cyclosporine
• Confusion • When taking cyclosporine :
• Nervousness • Avoid eating excessive
• Unusual weakness/ tiredness amounts of foods high in
• DOB potassium
• Avoid grapefruit juice, may
• Shortness of breath
block breakdown of
• Tender, enlarged, or bleeding cyclosporine by liver
gums
• Nausea or vomiting
• Stomach pain (severe)
• Irregular heartbeat
• Convulsions
• Numbness
 IMPAIRED PRODUCTION (2)
RBC-BLAST PROLIF / DIFF
• MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
– VIT. B12 DEFICIENCY
– FOLIC ACID DEFICIENCY
• HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS)
– HEME: IDA; SIDEROBLASTIC ANEMIA
– GLOBIN: THALASSEMIAS
• MULTIPLE MECHANISMS
– ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
– RDA
– MYELOPHTHISIC ANEMIA (BM INFILTRATION)
– REFRACTORY ANEMIA W/ CELLULAR BM
– PROTEIN MALNUTRITION
 Myelophthisic Anemia
• BM Replacement Breast Cancer
BM failure: Replacing BM
• Mets Ca (MC)
• Destruction by non-
neoplastic process
(Fibrosis, Infection)
• PBS: Pancytopenia,
immature circulating
cells
 IMPAIRED PRODUCTION
(2) RBC-BLAST PROLIF / DIFF
• MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
– VIT. B12 DEFICIENCY
– FOLIC ACID DEFICIENCY
• HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS)
– HEME: IDA; SIDEROBLASTIC ANEMIA
– GLOBIN: THALASSEMIAS
• MULTIPLE MECHANISMS
– ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
– RDA
– MYELOPHTHISIC ANEMIA (BM INFILTRATION)
– REFRACTORY ANEMIA W/ CELLULAR BM
– PROTEIN MALNUTRITION
 Megaloblastic anemia
• disorder caused by impaired DNA
synthesis
• Cells primarily affected: blood cells, GI
epithelial cells
• slowed nuclear cell division with normal
progression of cytoplasmic maturation
megaloblastosis in bone marrow
 Causes of Megaloblastic
anemia
• Cobalamin deficiency
– Inadequate intake (vegans)
– Malabsorption
• Gastric achlorydia, partial gastrectomy, drugs that
block acid secretion
• Pernicious anemia, total gastrectomy
• Terminal ileal disease: sprue, enteritis, resection,
tumors
• Competition of cobalamin: fish tapeworm, “blind
loop” syndrome
 Causes of megaloblastic anemia
• Folic acid deficiency
– Inadequate intake: unbalanced diet (alcoholics,
teenagers, some infants)
– Increased requirements
• Pregnancy
• Infancy
• Malignancy
• Increased hematopoiesis (chronic hemolytic anemias)
• Chronic exfoliative skin disorders
• Hemodialysis
– Malabsorption
– Impaired metabolism
 Other causes of megaloblastic
anemia
• Drugs that impair DNA metabolism
– Purine antagonists: 6 mercaptopurine, azthioprine
– Pyrimidine antagonists: 5FU, cytosine arabinoside,
others
– Others: procarbazine, hydroxyurea, zidovudine
• Metabolic disorders (rare)
– Hereditary orotic aciduria
– Lesch Nyhan syndrome
• Megaloblastic anemia of unknown etiiology
– Refractory megaloblastic anemia
– DiGuglielmo’s syndrome
– Congenital dyserythropoietic anemia
 Megaloblastic A
• LAB DX:
– NEUTRO/ THROMBO- CYTOPENIA
– INC. SERUM Fe; DEC. TIBC
– INC. OF SERUM BILIRUBIN
– PBS: MACROOVALOCYTES; B. STIPPLINGS; HJ
BODIES; MACROPOLYCYTES (HYPERSEG. PMN)
– BM: DYSERYTHROPOIESIS- MEGALOBLASTS;
GIANT METAMYELOCYTES INEFFECTIVE
ERYTHROPOIESIS
VIT. B12 DEF. vs FOLIC A. DEF.
• DIET
– (VEGANS) DECREASE NORMAL
– (GENERAL) DECREASE DECREASE
• CELL TURNOVER
– DECREASE DECREASE
• GASTRIC SX
– DECREASE DECREASE
• PANCREATIC INSUFF.
– DECREASE NO EFFECT
VIT. B12 DEF. vs FOLIC A. DEF.
• PERNICIOUS A
+ -
– IF DEF (CHRONIC GASTRITIS)
– ANTI PARIETAL CELL Ab & ANTI IF Ab
• S/ S: SPASTIC ATAXIA
+ -
VIT. B12 DEF. vs FOLIC A. DEF.
• LAB DX:
• LDH
– INCREASE INCREASE
• PBS/B.M.
– MACRO- OVALOCYTES/ HYPERSEGMENTED PMN
(MACROPOLYCYTE)/ GIANT METAMYELOCYTE; LEUCO-
/THROMBO- CYTOPENIA
• URINARY
– MMA
• INCREASE NORMAL
– FIGLU
• NORMAL INCREASE
• GASTRIC ANALYSIS
– HISTAMINE FAST NONE
ACHLORYDRIA
 Macrocytic: RPI < 2
Megaloblastic Anemia…. PBS
• Macro-ovalocytic
• Polychromasia
• Hypersegmented neutrophil
• Other Labs:
• Homocysteine – Folate def.
• Methylmalonic acid – B12
def.
• IF Ab test: specific for PA
but only 50% sensitive
• Parietal cell Ab test:
sensitive (90%) but not
specific
• Schilling test
VIT. B12 DEF. vs FOLIC A. DEF.
• SCHILLING TEST
+ -
• Non radioactive B12 1st given to bind to all
available transcobalamin in the PB:
– Prevents any reabsorbed radioactive B12 from
binding to transcobalamin
– Forces it to be excreted into the urine
• Radioactive B12 given by mouth followed by 24h
urine to test for % radioactive B12 reabsorbed:
no radioactive B12 in 24h urine confirms BI2 def
VIT. B12 DEF. vs FOLIC A. DEF.
• SCHILLING TEST
+ -
• If corrected w/ addition of IF to oral
radioactive B12: patient has Pernicious a
• If corrected after antibiotic therapy: patient
has bacterial overgrowth
• If corrected w/ addition of pancreatic extract
followed by intake oral radioactive B12:
patient has chronic pancreatitis
 Clinical Manifestations:
• Anemia with slight icteresia
• GI manifestations – glossitis, smooth,
beefy red tongue, malabsorption
• Neurologic manifestations (Cobalamin) -
subacute combined degeneration of CNS
peripheral neuropathy – numbness,
weakness, ataxia, paresthesia,
disturbances of mentation
 Management:
• Treatment of underlying problem
• Replacement therapy: oral folic acid;
parenteral B12
Treatment of Megaloblastic anemia
• Treat the cause
• Cobalamin deficiency
– IM cyanocobalamin: 1000 mcg per week for 8
weeks then monthly
– Oral cobalamin: 2 mg crystalline B12 per day
• Folic acid: 1 mg/day po
 IMPAIRED PRODUCTION (2)
RBC-BLAST PROLIF / DIFF
• MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
– VIT. B12 DEFICIENCY
– FOLIC ACID DEFICIENCY
• HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS)
– HEME: IDA; SIDEROBLASTIC ANEMIA
– GLOBIN: THALASSEMIAS
• MULTIPLE MECHANISMS
– ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
– RDA
– MYELOPHTHISIC ANEMIA (BM INFILTRATION)
– REFRACTORY ANEMIA W/ CELLULAR BM
– PROTEIN MALNUTRITION
 Hemoglobin

Heme = Fe++ Plus Porphyrin

+
Globin
 Hemoglobin
• Conjugated protein for transport of O2 &
CO2

&

• Buffer (O2 Dissociation Curve)

 Basic Structure of All Human
Hemoglobin
• Each Hgb molecule:
• 4 iron-containing,
tetrapyrrole heme
rings
• 4 polypeptide globin
chains
– 2 alpha chains
– 2 non-alpha chains
 Normal Hgb:
• Hgb A1
– 95 - 98% (adult)
– 15 - 40% at birth predominates at 6 – 12 mons
• Hgb A2
– 2 - 3% (adult)
– 0 - 1.8%- cord blood
– 5 - 6 mons- adult levels
• Hgb F
– < 2% (adult)
– 1 - 0.8% (3 y/o)
– 90 - 95% - fetal life
• Hgb Gower 1 & 2; Portland Hgb - Embryonic
Hgb derivatives (CHON (N) but Fe
& nature of organic grp changed)
• Oxyhgb
– O2 + reduced hgb (purple red) bright red
– Maintained by methemoglobin- cytochrom C reductase
– 575 nm
• Carboxyhgb
– CO + Hgb cherry pink
– Collect in citrate
– 200 X affinity vs O2
– Heavy smokers
– Test: ammonia + blood (25% COHgb); 540 nm
 Hgb derivatives (CHON (N) but Fe
& nature of organic grp changed)
• Methgb (0.5% normal in blood)
– Fe++ Fe+++ brown
– No O2 binding cyanotic
– Induced by oxidizing agents
– 525 nm
• Sulfhgb (0- 2.2% normal in blood)
– Sulfa drugs or trinitrotoluene + hgb
– Irreversible binding RES
• Myoglobins
• Porphyrins
Body Iron Distribution and Storage
Duodenum Dietary iron
(average, 1 - 2 mg
Utilization Utilization
per day)

Plasma
transferrin
(3 mg)
Bone
Muscle marrow
(myoglobin) Circulating (300 mg)
(300 mg) erythrocytes
Storage
iron (hemoglobin)
(1,800 mg)

Sloughed mucosal cells

Desquamation/Menstruation
Other blood loss
(average, 1 - 2 mg per day) Reticuloendothelial
Liver
(1,000 mg) macrophages
Iron loss (600 mg)
 Dietary sources of iron
Sources of iron
Heme iron: Meat,
fish, liver
Fe+2

Non-heme iron:
Vegetables
Fe+3
 Absorption of Iron

• Vit C, amino acids promote absorption

• Gastric acid helps in solubility
• Tea, veg. fiber decrease absorption
 Major Iron Compartments

• Metabolic:
• Hgb 1800 - 2500 mg
• Myoglobin 300 - 500 mg

• Storage:
• Iron storage 0 - 1000 mg

• Transit:
• Serum iron 3 mg

• Total 3000 - 4000 mg

 Anemia due to deficiency of
hematinics- Iron deficiency
• MCC of anemia & is due to chronic blood
loss, deficient intake, increased demand
(pregnancy & lactation)
• Chronic blood loss - MCC of IDA in adults
(peptic ulcers, ca of the stomach & colon,
menorrhagia, UT lesions)
 Anemia due to deficiency of
hematinics- Iron deficiency
• Microcytic hypochromic anemia with a low
serum total iron, increased iron binding
capacity, and decreased serum ferritin
indicating reduced iron stores
Microcytic Anemia (IDA)
 IDA
• Low retic ct • DEC SERUM FERRITIN
• Most useful, cost effective
• DEC SERUM Fe test of Fe stores
• INC TIBC (high • > 100 ng/ml r/o IDA
Except in acute hepatitis
specificity- near 100% or liver necrosis but not
but poor sensitivity < chronic liver dse
(elevated- release of Fe
30%) stores)
• BM: • Falsely elevated in
disseminated TB &
ASYNCHRONOUS Hodgkin's dse
RBC-POIESIS
Iron Deficiency Anemia:
Iron Deficiency Anemia:
Status
 iron
transferrin
 Prussian Blue Stain
of Bone Marrow

Iron Present No Iron Present

Iron Deficiency Anemia - Diagnosis
• Low Hb, HCT, MCV, MCH, smear
• Retic count relatively low
• High RDW – Red cell Distribution Width
• Plt count high
• Low serum iron, high TIBC,
• Low serum ferritin
• Low transferrin saturation
• Transferrin saturation <15% excellent test
• FEP (free erythrocyte protoporphyin): high
• Stool for occult blood
 Low MCV and Low Retics
Differential diagnosis

• Iron deficiency
• Sideroblastic anemia
• Thalassemia trait
• Lead poisoning
• Anemia of chronic disease
 Treatment
• Severity and cause determine approach to
treament
– Elderly+/- cardiovasular instability: RBC
transfusions
– Younger individuals with compensated
anemia: iron replacement
 Oral Iron Therapy
• Optimal response occurs when about 200 mg
of elemental iron given per day
• Absorption more complete on empty stomach
• With or after a meal, absorption decreases
by 40 to 50%
• However gastric irritation is common, hence,
advise to take tablet immediately after a meal
may increase compliance
 Oral Iron Therapy
• Absorption enhanced by orange juice,
meat, poultry, fish
• Absorption inhibited by cereals, tea, milk
• Side Effects of Oral Iron: GIT: heartburn,
nausea, abdominal cramps, diarrhea
– Dose related
• Continue iron treatment 3 to 6 months
after anemia resolves
– Allows repletion of iron stores
 Oral Iron Preparations

Preparation Size Iron Usual Adult daily

Content dose
Ferrous sulfate

tablets (hydrated) 300 mg 60 mg 3 tablets

tablets (exsiccated) 200 mg 60 mg 3 tablets
syrup & elixirs 40 mg/ml 8 mg/ ml 25 ml
Ferrous gluconate 300 mg 37 mg 5 tablets

Ferrous fumarate 200 mg 67 mg 3 tablets

300 mg 100 mg 2 tablets
 Indications for Parenteral Iron
• Unable to tolerate iron compounds orally
• Poor compliance
• Persistent loss of blood or iron at a rate too rapid
for oral intake to compensate for the loss
• Disorder of GI tract e.g. ulcerative colitis
• Malabsorption of iron
• Inability of maintain iron balance during
treatment with hemodialysis
• Donating large amounts of blood for
autotransfusion
 Computing for the dose of parenteral
iron

= Body weight (kg) x 2.3 x (15 – patient’s

Hgb g/dL) + 500 or 1000 mg (for stores)
 ACD
Fe SEQUESTRATION IN BM HISTIOCYTES
Defect
w/ defective Fe utilization & shorten RBC survival
Storage Iron
IL-1
TNF 
BM Storage
 IFN Iron (Blue)

Erythroid Precursors
(dec responsiveness to EPO)
 ACD

IDA
Normal
 SIDEROBLASTIC ANEMIA
• ETIOLOGY / MECHANISM:
• HEREDITARY (X LINKED/ AR)
– HEPATOSPLENOMEGALY; THROMBOEMBOLISM
• ACQUIRED
– IDIOPATHIC
• NEUTROPENIA W/ PELGER HUET CELLS
• PRONE TO Fe OVERLOAD; TE
• 10% DEVELOP AML
– DRUG INDUCED
• ALCOHOL- FOLATE DEF. + MALNUtrition
• INH- VIT. B12 METABOLISM
• CHLORAMPHENICOL- MITOCHONDRIAL INHIBITION
• LEAD- HEME PATHWAY
– DISEASE ASSO (THYROID; CA; LYMPHOMA; MM; RA)
 SIDEROBLASTIC ANEMIA
• MECHANISM:
• REFRACTORY A. (RESISTANT TO TX)
• INEFFECTIVE ERYTHROPOIESIS
(ANEMIA W/ HYPERPLASTIC BM)
 Sideroblastic A – Lab Dx:
• PBS: Papenheimer
Bodies; Basophilic
stippling in Pb
poisoning; Dimorphic
(macrocytic +
intensely microcytic
RBCs) in patient w/
acquired sideroblastic
a; anisopoikilocytosis;
Target cells
 Sideroblastic A – Lab Dx:
• Serum Fe: Inc
• Stigmata of MDS
• BM: Ringed
sideroblasts on BM
Fe stain; inc
hemosiderin
 F e r r it in

R educed N o rm a l In c r e a s e d

I r o n d e f ic ie n c y H B e le c t r o p h o r e s is A n e m ia o f C h r o n ic D is e a s e B o n e m a rro w
R in g e d s id e r o b la s ts

If HB electrophoresis is normal then do

alpha gene mapping
Further investigations to find the
cause are necessary

Hypochromia
Microcytic

Note: Anisocyosis: RDW

poikilocytes
Hemosiderosis
 Hemochromatosis
• Genetic dse
• Excess amounts of
iron
• Arthritis, cirrhosis,
DM, heart failure,
HCC
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
 Erythrocytes: Normal mature
RBC
• Biconcave disc
• Approximatly 8 um in
dia
• 2.5 um thick at the
periphery
• 1.0 um thick at center
• Contains 27- 34 pg
(10-12 g) of hgb (about
95% of dry wt of RBC)
 Breakdown of the RBC
• Toward the end of 120 day life span, 1%
of RBC’s per day
– Membrane becomes less flexible
– Concentration of cellular hemoglobin
increases
– Enzyme activity (esp glycolysis) diminishes
 Erthrocyte Destruction
• Extravascular Hemolysis (major- 90% via RES)
• Intravascular Hemolysis (minor- 5-10%)
Extravascular Hemolysis
Intravascular Hemolysis
Areas of RBC metabolism crucial
for RBC survival & function
RBC membrane
RBC metabolic pathways
Hemoglobin structure & function
RBC MEMBRANE: Hereditary
Membrane Dse.
Hereditary Spherocytosis
Hereditary Ovalocytosis /
Elliptocytosis
Hereditary Stomatocytosis
 RBC MEMBRANE:
3 Major Structural Proteins
• Semi-permeable bilayer of
lipids (including
cholesterol) & proteins

• Deformable to pass
through microvessels &
permeable to allow H2O &
electrolytes to exchange
(inc surface area)

Cytoskeletal Proteins: Maintain

• Major protein is spectrin
RBC Shape, Strength, Flexibility
Case
 HS
• AD- MC
• AR- More Severe
• MC in Northern • Vertical stabilization
European ancestry defect of phospholipid
• A spectrin def w/ bilayer spectrin -
principal defect in phospholipid bilayer
abnormality of separates
ankyrin • Portions PL bilayer
forms vesicles (lost) 
decreased surface
area spherocytosis
 Hereditary Spherocytosis
• Mutation of Ankyrin Gene
(Most Common Defect)

• Abnormal Ankyrin Protein

• Deficiency of Spectrin
Assembly
 Hereditary Spherocytosis
• Defects may be in:
• Actin - spectrin - band
3 complex
• Spectrin - 4.1
-glycophorin complex
• Connection between
bilayer & spectrin
 HS: S/S:
• Waxing / waning anemia, jaundice
(hemolysis accelerated by infection)
• Splenomegaly (hyperplasia secondary to
increased workload), pigmented gallstones
(hx cholecystectomy), ankle ulcers
• Family hx: (AD 1: 5000 people of
European descent)
 HS Lab Dx:
• PBS: Moderate Anemia;
Spherocytes;
Reticulocytes
(polychromatophilia)
• Inc retic ct, inc LDH, inc
B1, inc EOFT
• Normal MCH w/ an inc
MCHC
• BM - Erythroid
Hyperplasia
• Coomb’s Test - Negative
• Inc Autohemolysis Test
corrected by glucose
 Hereditary Spherocytosis
• Tx: folate replacement, splenectomy in
some circumstances
• Pearl: Parvovirus B19 infection in patients
w/ hemolytic anemias in general aplastic
crisis
 Management:
• Splenectormy – for moderate to severe
hemolysis
• Folic Acid supplementation
 Case
• 14 mon old African-
American child
presents w/ mild
anemia
• What are they
 Hereditary elliptocytosis &
Hereditary pyropoikilocytosis
• Defects in horizontal
junctions:
• Between a- & b-
spectrin dimers or
• Between spectrin,
actin & band 4.1
• RBC cytoskeleton
loose structural
strength & lateral
integrity
 Hereditary elliptocytosis
• Autosomal dominant
• Structural abnormality of spectrin or def of
RBC membrane protein 4.1
• W/o anemia & usually w/o splenomegaly &
only mild hemolysis; Most patients
asymptomatic
• EV hemolysis, thus splenectomy corrects
hemolysis, but not the RBC membrane
defect
 Hereditary elliptocytosis
• PBS: large #s of
elliptocytes &/or
ovalocytes
• # of elliptocytes does not
correlate w/ severity of
hemolysis
• EOFT is usually normal
• Reticulocytes mild inc
(<5%)
• Haptoglobin levels low
 Hereditary pyropoikilocytosis
• Rare AR
• Severe hemolysis, bizarre
poikilocytosis & RBC
fragmentation (hallmarks)
• Structural abnormality of
spectrin, RBCs fragment
when heated (45°C)
• Normal RBCs fragment at
49°C
Case
 Biochemical changes that can
cause shape change in RBC
• Accumulation of cholesterol causes
increased membrane
– Target cell
– Acanthocyte
• Decreased spectrin causes decreased
membrane
– Spherocyte
– Bite cell
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
 Paroxysmal Nocturnal
Hemoglobinuria
• Rare, acquired, • Complications:
chronic
• S/s: • Aplastic anemia
– Recurrent abdominal
• Leukemia
pain, vomiting,
headaches, eye pain, • Venous thrombosis
thrombophlebitis
– Breathlessness at
night
– Episodic Hgb in urine,
Hemosiderinuria
 PNH
• Mutation of Stem Cells - No Anchor
Protein (Chronic Hemolysis) + SERUM
C’ vs RBC, WBC, PLATELETS; INC C3
FIXATION; INC MAC; INC C’
PENETRATION OF LIPID MEMBRANe

C C Complement-
Induced Lysis
(Intravascular
C - Hgb in Urine)
 PNH: Pathophysiology
• Acquired Somatic mutation in PIG-A gene
• Dec GPI proteins esp DAF (DAF usually binds to
GPIs on RBC surface to breakdown C’
components from lysing cell (specifically C3
convertase) inc C’ activity
• Clonal cell disorder (affects all cell lines), w/
ongoing IV & EV hemolysis, classically at night
(due slight acidosis during sleep; C’ components
more active ↓ in pH (likewise exercise)
 PNH: Lab Dx
• PANCYTOPENIA
• DEC. NAP
• SUCROSE HEMOLYSIS T (SCREEN)
> 10%= PNH
5-10%= MEGA. A; AIHA
• ACIDIFIED SERUM TEST/ HAM’S
(CONFIRM) 10- 15% HEMOLYSIS
• Flow cytometry: CD 59 negative (a product
of the PIG-A gene)
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
RBC Metabolic Pathways

Essential for O2 transport &

maintaining physical
characteristics of RBC
 Red cell metabolic pathways
• Generates 90% of energy
• Glucose 2 ATP(energy)
• 90-95% of intracellular gl
ucose thru free-energy dif
fusion
• RBCs have no glycogen
• Glucose (Na-K ATPase p
ump & Ca-Mg ATPase pu
mp affected in PK Def
 Red cell metabolic pathways
• Metabolizes 5-10% of
glucose
• Protects RBC from
oxidative injury
• G6PD also produces
NADPH (keeps
glutathione reduced)
• Glutathione protects
via break down of
H2O2 H2O + O
 Case
• 5 y/o African-
American boy
recently presented w/
fever. Prescribed
Bactrim for presumed
otitis media. Brought
back in by mom due
to increased fatigue &
PBS showed 
 G6PD Pathophysiology
• Defect in HMP
• G6PD def dec
GSH oxidant
stresses oxidized
hgb (Heinz bodies)
RES phagocytose • Quali > Quanti defect
inclusion body bite decrease half-life later
cells hemolysis stages of RBCs life (> 20
days), functional levels of
enzyme decline
 G6PD Pathophysiology
X-linked common in African Americans & Mediteraneans

• African American:
American • Mediterranean:
Mediterranean
• Asso w/ intermittent • Asso w/ fava bean
hemolysis since older ingestion
RBCs have dec levels • More severe
of G6PD & usually hemolysis because all
occurs in response to RBCs have dec
oxidative states G6PD activity due to
(infections) dec synthesis &
stability
 G-6-PD def
• > 400 Variants
• > 200 M people (Mediterranean, West African,
Mid-East & SEA) w/ chronic hemolysis
• Blacks often have an episodic variant in w/c
oxidant cmpds (antimalarials, sulfonamides, or
infections)
• Women heterozygotes (half the normal
amount of RBC) show increased resistance to
P falciparum
 G6PD Deficiency
• Jaundice in 1st 24 hrs of
life (pathologic jaundice)
• Acute self-limited IV
Episodic hemolytic a
triggered by oxidant
stress (drugs, infection)
• More severe, chronic
form seen in men of
Mediterranean descent
(fava beans)
 G6PD Deficiency
• PBS: Bite cells &
blister cells
• Dx: PBS, G6PD level,
Heinz body prep
• G6PD levels may be
normal in acute
setting due to
selective removal of
older RBCs w/ lower
baseline G6PD levels
 G6PD Deficiency
• Tx: Get rid of offending oxidant stress
 G-6-PD def:
Stressors of G6PD System
• Antimalarials
• Sulfonamides
• Nitrofurans
• Phenacetin
• Dapsone
• Synthetic Vit K
• Naphthalene (moth balls)
• Fava beans
• Infection
• Diabetic ketoacidosis
 Red cell metabolic pathways
• Methemoglobin
reductase Pathway:
• Maintains iron in the
ferrous (Fe2) state
• In the absence of the
enzyme (methgb
reductase), methgb
accumulates & it
cannot carry O2
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
 Porphyria cutanea tarda
• Etiology:Uroporphyrin • Features:
ogen decarboxylase – Portal inflam w/
def cirrhosis
• S/S: Cutaneous – HCC (Anti HC Ab +)
photosensitivity – Inc hepatic Fe
– Inc urinary
• Lab tests:
uroporphyrin
– Inc urine uroporphyrin
– Inc aminotransferase
 Acute intermittent porphyria
• AD w/ incomplete penetrance (other family
members w/ the condition maybe asymptomatic)
• Attacks precipitated by drugs & alcohol (P450
enzyme inducers)
• Acute attack: urine turns dark on standing due to
high ALA & PBG levels. Levels remain
moderately raised between attacks
 Other Porphyria
• Variegate porphyria: • Hereditary
• AD coproporphyria:
• Features: • AR
– Cutaneous fragility & • Uroporphyrinogen
photosensitivity synthetase defect
• Acute neurological expressed in RBCs w/ inc
attacks common porphyrin levels in stool
• Acute neurological
attacks + cutaneous
manifestations
 INCREASED DESTRUCTION
(1) INTRINSIC
• HEREDITARY CELL MEMBRANE DEFECT
– SPHEROCYTOSIS
– ELLIPTOCYTOSIS
– STOMATOCYTOSIS
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
• ENZYMOPATHIES
– GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
– PYRUVATE KINASE DEFICIENCY
• HEMOGLOBINOPATHIES
– SICKLE CELL ANEMIA
– HEMOGLOBIN C DISEASE
– HEMOGLOBIN E
• PORPHYRIAS
 INCREASED DESTRUCTION
(2) EXTRINSIC
• ANTIBODY: • MECHANICAL:
• AIHA (IgG) • PROSTHETIC HEART
• COLD REACTING (IgM) VALVE
• DRUG INDUCED • MAHA
• BURNS

• INFECTION: • OTHERS:
• BACTEREMIA • HYPERSPLEENISM
• PARASITEMIA • OXIDIZING AGENTS
– MALARIA • VENOM (SNAKE,
– BARTONELLOSIS INSECT)
 HA: Others
• Antibody Mediated
(Spherocytes)

VS
• Mechanical Trauma
(Schistocytes)
– Heart Valves,
Microthrombin Fibrin
Strands in Vessels
(DIC, TTP, HUS)
Coombs’ (+) w/ Spherocytes
Immune & Autoimmune HA
 Immune Hemolytic Anemias
• Ab Mediated:
• RBC Destruction Caused By Ab to RBC
Surface Ag
• Phagocytosis in Spleen
• More Common w/ Aging
• 2 Types - Warm & Cold Autoimmune HA
 Immune Hemolytic Anemias
• Warm Ab Type (IgG, 37o C):
• IgG + RBC Surface Ags
• Primary: Idiopathic (60%)
• Secondary: Leukemia, Lymphoma, SLE,
Drugs
• Spherocytes - Spleen Removes
Membrane Protein from Ab Coated RBCs
• Positive Direct Coomb’s Test
 Immune Hemolytic Anemias
• Cold Ab Type (IgM, <30o C)
• Usually Not Clinically Significant
• Acute
– Mycoplasma pneumoniae
– Infectious Mononucleosis (Mild Transient
Anemia)
• Chronic
– Idiopathic, Lymphoma
 Coombs’ (+) w/ Spherocytes
Autoimmune hemolytic a
• Warm AIHA: • Cold AIHA:
• Abrupt onset • Insidious onset
• IgG • IgM, complement
• Anti-Rh, e, C, c, LW, U
• Anti-I, I, P (PCH)
• Jaundice
• Cold agglutinin titer
• Splenomegaly
• SLE, CLL, Lymphoma • Absent jaundice
• Drugs: methyl-dopa, • Mycoplasma
mefenamic acid, • Virus
cimetidine, cefazolin
 Coombs’ (+) w/ Spherocytes
Other immune hemolytic a
• Alloantibody hemolytic anemia:
• Transfusion reaction
• Feto-maternal incompatibility (Kleihauer-Betke test)

• Drug related Hemolytic anemia:

• Toxic immune complex (drug+Ab+C3)
– Quinine, Quinidine, Rifampin, INH, Sulfonamides,
Tetracyclin
• Hapten formation (anti-IgG)
– PCN, methicillin, ampicillin
 Management:
• Steroids
• Splenectomy
• Immunosuppresants
 HA: Others
• Antibody Mediated
(Spherocytes)

VS
• Mechanical Trauma
(Schistocytes)
– Heart Valves,
Microthrombin Fibrin
Strands in Vessels
(DIC, TTP, HUS)
 TTP- HUS
• TTP - HUS: • Idiopathic:37%
• Thrombocytopenia • Drug asso:13%
• MAHA • Autoimmune dse:13%
• Neurologic symptoms • Sepsis: 9%
& signs • Pregnancy:7%
• Renal failure • Bloody diarrhea: 6%
• Fever • Hematopoietic cell
transplantation: 4%
 DIC
• DIC:
• Depletion of clotting factor (TTP: normal)
• Thrombocytopenia
• Bleeding (64%)
• Renal dysfunction (25%)
• Hepatic dysfunction (19%)
• Respiratory dysfunction (16%)
• Shock (14%)
• Thromboemboli (7%)
• CNS involvement (2%)
• Sepsis, trauma, malignancy
TTP-HUS / DIC
 Acanthocytosis:
Intrinsic vs Extrinsic
• AR • ACQUIRED
• MECHANISM: • MECHANISM:
– ABETALIPOPROTEIN – TERMINAL
EMIA CIRRHOSIS
– MALABSORPTION; • LAB DX:
RETINAL & CNS C – INC RBC MEMBRANE
• LAB DX: CHOLE.
– DEC LCAT/ INC – DEC LCAT
SPHI:LECI
– DEC SERUM CHOLE.
 Malaria
• Infections
– Malaria - Organisms
Destroy RBCs
• Most Common Acquired HA
Worldwide
• Tropical Distribution w/
Variety of Species
• Parasites Destroy RBCs
• Cyclical Hemolysis Produces
Fever & Chills
• Splenomegaly - 
Mononuclear Cells
WAKAS!!!