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Todays Quranic verse

And hold fast, all together, by the rope which God


(stretches out for you), and be not divided among
yourselves; and remember with gratitude God's
favour on you; for ye were enemies and He joined
your hearts in love, so that by His Grace, ye
became brethren; and ye were on the brink of the
pit of Fire, and He saved you from it. Thus doth
God make His Signs clear to you: That ye may be
guided. [003:103]

Greatness is not in where we stand, but in what


direction we are moving. We must sail sometimes
with the wind and sometimes against it -- but sail
we must and not drift, nor lie at anchor

C.B.C

Haemoglobin - 152.5, 14 2.5 - g/dl

PCV - 0.47 0.07, 0.42 0.05 - l/l (%)


Haematocrit, effective RBC volume better

RBC count - 5.5 1, 4.8 1 x1012/l

MCHC - Hb/PCV - 30-36 - g/dl


Hb synthesis within RBC

MCH - Hb/RBC - 29.5 2.5 pg/l


Average Hb in RBC

MCV - PCV/RBC 85 8 fl

RDW (Red Cell Distribution Width )-13 1.5

RBC x 3 = HB x 3 = PCV

The Three Primary Measures


Measurement

Normal

Range

A. RBC count (RCC)


B. Hemoglobin

5 million
15 g%

4 to 5.7
12 to 17

C. Hematocrit (PCV)

45%

38 to 50

A x 3 = B x 3 = C - This is the rule of thumb


Check whether this holds good in a given result
If not -indicates micro or macrocytosis or hypochromia.

The Three Derived Indicies


Measurement

Normal

Range

A.

RCC

5 million

4 to 5.7

B.

Hemoglobin

15 g%

12 to 17

45 %

38 to 50

C. Hematocrit

MCV
MCH
MCHC (%)

C A x 10
B A x 10
B C x 100

=
=
=

90 fl
30 pg
33%

Red Cell Production (Erythropoiesis)


Kidney

Bone Marrow
Epo
mRNA
Epo

Multi-potent
stem cell
Erythroid
stem cell

Oxygen
sensor

3-4
days

Blood vessel

Peripheral blood
RBC survival
100-120 days

Steps in Erythropoisis
Early

Proerythroblast
(Pronormoblast)

Intermediate

Polychromatophilic
Normoblast
Basophilic
Normoblast

Late

Reticulocyte

Orthochromatophilic
Normoblast

Erythrocyte

Red Blood Cell Disorders


Anemias
Anemia of Blood Loss: (Acute vs. Chronic)
Anemia of Erythropoiesis
Hemolytic Anemia: (Congenital/Acquired)

Polycythemia

Anemias
An (without) -emia (blood):
Reduction below normal in hemoglobin or red blood
cell number (for age & sex).
Hemoglobin (g/dL)
Male
13-17
(152)

Female
12-15
(13.5 1.5)

Anemias
2,3 DPG

Anemia
HYPOXIA

REDISTRIBUTION

COMPENSATORY
MECHANISMS

C.O.

PATHOPHYSIOLOGY
OF ANEMAIS

PLASMA

Anemias

TIREDNESS
LASSITUDE
EASY
FATIGUABILITY

CNS

MUSCLE
WEAKNESS

GIS

CLINICAL FEATURES

CRS

PALLOR

GUS

Anemias
Classification

Etiological

Morphological

Anemias

ETIOLOGIC
Classification
I

II
IMPAIRED
RED CELL
FORMATION
(Erythropoiesis)
(Dyshaemopoietic)

BLOOD LOSS
(Haemorrhagic)

III
INCREASED
RED CELL
DESTRUCTION
(Haemolytic)

Anemias

ETIOLOGIC
Classification
ACUTE

II
IMPAIRED
RED CELL
FORMATION
DEFICIENCY

NON
DEFICIENCY

CHRONIC

BLOOD
LOSS

III
HEMOLYTIC
ANEMIAS
RBC
ABNORMALITIES

RBC ENVIRONMENT
ABNORMALITIES

DEFICIENCY ANEMIAS
ANEMIAS DUE TO DEFICIENCY OF SUBSTANCES
ESSENTIAL FOR ERYTHROPOIESIS

IRON
DEFICIENCY
ANEMAIS

FOLIC ACID &


VITAMIN B12
DEFICIENCY
ANEMAIS

NON DEFICIENCY ANEMIAS


ANEMIAS

NOT DUE TO DEFICIENCY OF

SUBSTANCES
ESSENTIAL FOR ERYTHROPOIESIS

ACD

ANEMIA
OF
BONE MARROW
INFILTRATION

ANEMIA OF
CHRONIC
DISORDERS

(myelophthisic)
INFECTION COLLAGEN DISEASES,
RENAL FAILURE, LIVER FAILURE,
MALIGNANCY

APLASTIC
ANEMIA

LEUKEMIAS,LYMPHOMAS
MYELOMA,MYELOFIBROSI
S

OTHERS

OTHER
NON DEFICIENCY ANEMIAS

SIDEROBLASTIC
ANEMIAS

CONGENITAL
DYSERYTHROPOITC
ANEMIAS

Anemias

II
MICROCYTIC
HYPOCHROMIC

Iron Deficiency
Thalassemias

MORPHOLOGIC
Classification
I
NORMOCYTIC
NORMOCHROMIC

ACD

III
MACROCYTIC
ANEMIAS

Megaloblastic

Believe those who are seeking the


truth; doubt those who find it.

Iron Deficiency Anemia


A world-wide problem
3% of toddlers age 1-2 years
2-5% of women of child bearing age

Iron metabolism
Iron stores
Laboratory findings of iron deficiency
Causes of iron deficiency
Treatment

Body Iron Distribution and Storage


Utilization

Duodenum
(average, 1 - 2 mg
per day)

Dietary iron
Utilization

Plasma
transferrin
(3 mg)
Muscle
(myoglobin)
(300 mg)

Circulating
erythrocytes
(hemoglobin)
(1,800 mg)

Storage
iron

(Ferritin)

Liver
(1,000 mg)

(TIBC)

Sloughed mucosal cells


Desquamation/Menstruatio
Other blood
n
loss 1 - 2 mg per day)
(average,

Iron loss

Bone
marrow
(300 mg)

Reticuloendothelial
macrophages
(600 mg)

Major Iron Compartments


Metabolic
Hemoglobin
Myoglobin

1800-2500 mg
300-500 mg

Storage
Iron storage

0-1000 mg

Transit
Serum iron

Total

3 mg

3000-4000 mg

Causes of Iron Deficiency


Iron deficiency is a symptom, not a disease
Increased iron
requirements

Inadequate iron supply

Blood loss

Gastrointestinal tract
Genitourinary tract
Blood donation
Worm infestation

Pregnancy and lactation

Insufficient dietary iron (malnutrition)


Impaired iron absorption
Gastric surgery
Intestinal malabsorption
Celiac disease

IDA- Pathogenesis
Decreased Iron stores
Decreased Hb Synthesis
Delayed maturation of erythroblasts (cytoplasmic)
Decreased cytoplasm, more division (microcytes)
Decreased Hb content (hypochromia)

Anemia

Systemic Manifestations of Iron


Deficiency

Behavioral and neuropsychiatric


manifestations

Pica (pagophagia)

Angular stomatitis
Glossitis

Esophageal webs and strictures

Koilonychia

Development of Iron Deficiency


Iron status

Ferritin

BM iron

S. Fe/TIBC

Anemia

Depleted stores

Low

Absent

Normal

Absent

Compromised delivery

Low

Absent

Low/High

Absent

Iron deficiency anemia

Low

Absent

Low/High

Present

Hypochromic Microcytic RBC

Smear
Microcytic / Hypochromic RBCs,
Anisocytosis, Poikilocytosis

Microcytic Hypochromic Anemia


Mild (MCV > 70 fl)

Iron deficiency
Thalassemia
Lead toxicity
Sideroblastic anemia
Anemia of chronic disease

Severe (MCV < 70 fl)


Iron deficiency
Thalassemia

Macrocytic Anaemias
Defition:- Anaemias with MCV >95 fl
Classification:A. Megalo-blastic
B. Non-megalo-blastic

Macrocytic Anemia
(with Low Reticulocyte Count)

Megaloblastic anemia
Vitamin B12 deficiency
Folate deficiency

Nonmegaloblastic macrocytic anemia

Liver disease
Hypothyroidism
Drug-induced (DNA synthesis block)
Myelodysplastic syndrome

Megaloblastic anemia
Vitamin B12/Folic acid deficiency
Second most common type of anemia.
Multi System disease All organs with increased cell division.
Macrocytic anemia, pancytopenia.
Nurological manifestations in Vitamin B12 deficiency
(demyelination of the posterior and lateral columns of the spinal cord peripheral nerves)

Assays for serum folate and vitamin B12 and determination of


RBC folate levels

Folate and Cobalamin Daily


Requirements
Diet

Source
Body stores
Daily requirement
Daily intake
Dietary deficiency

Vitamin B12
(Cobalamin)

Folate

Animal products
5 mg
2-5 g
10-20 g
Rare

Widespread
5 mg
50-200 g
400-800 g
Common

Cofactor Activities of Folate and


Cobalamin
Methionine
synthetase

Homocysteine

Methionine

CH3-Cobalamin

Cobalamin

THF

THF-CH3
MMA-CoA
mutase

Methylmalonic acid (MMA)


AdenosylCobalamin

Succinyl-CoA
Cobalamin

Metabolic Testing for the Diagnosis of


Vitamin B12 and Folate Deficiency
Vitamin B12
Deficiency

Folate Deficiency

Methylmalonic acid

Increased

Normal

Homocysteine

Increased

Increased

Vitamin B12 Deficiency


Mechanisms
Malnutrition
Intragastric events
Inadequate dissociation of cobalamin from food protein
Total or partial gastrectomy
Absent intrinsic factor secretion

Proximal small intestine


Impaired transfer of cobalamin from R protein to intrinsic factor
Usurpation of luminal cobalamin
Bacterial overgrowth
Diphylobothrium latum (fish tapeworm)

Distal small intestine


Disease of the terminal ileum

Enteric Processing and Absorption


of Cobalamin
Stomach

Food-Cbl
H + Peptic
digestion

Cbl + R-binder
R-Cbl

Duodenum

Pancreatic
enzymes R-Cbl
IF + Cb OH -

Cbl-TC complex

Cbl-IF

Distal ileum
Cbl-IF

IF receptor

Cbl + TC

Megaloblastic AnemiaPathogenesis
Decreased Vit B12 / Folate
Decreased DNA Synthesis
Delayed maturation of erythroblasts (Nucleus)
Increased cell size (macrocytes)
Normal Hb content (Normochromia)
Decreased RBC number & Decreased WBC number (pancytopenia)
Anemia & Pancytopenia.

Pernicious Anemia
Most common cause of vitamin B12 deficiency
Occurs in all ages and ethnic backgrounds
Autoimmune destruction of gastric mucosa chronic Atrophic gastritis IF
Associated with other autoimmune diseases
Screen for thyroid disease every 1-2 years

Pernicious anemia is a systemic disease


Gastrointestinal tract involvement
Neurologic involvement (sub-acute combined degeneration of spinal cord)

Anti-intrinsic factor antibodies (~60% positive)


Specific but not sensitive

Anti-parietal cell antibodies (~90% positive)


Sensitive but not specific

Schilling test

Procedure & Interpretation of Schilling test


Schilling test Procedure
Administer IM vitamin B12 to prevent incorporation of radioactive cobalamin
Provide PO radiolabeled cobalamin Intrinsic factor
Measure urinary excretion of radioactivity

Cobalamin

Cobalamin + IF

Interpretation

Normal

Normal

Dietary insufficiency

Abnormal

Normal

Intrinsic factor deficiency


(Gastrectomy, PA)

Abnormal

Abnormal

Small bowel abnormality


(terminal ileum disease)

Macrocytes & Macropoly & Megaloblast

Folate Deficiency

Minimum daily folate requirement is 50 g


Usual dietary folate 50-500 g
Absorption in small intestine
Causes of folate deficiency
Dietary (90%)
Alcohol abuse
Pregnancy
Malabsorption
Drug-induced

Treatment - oral folic acid supplementation

That man is richest whose pleasures


are cheapest.

It is easy when we are in prosperity to


give advice to the afflicted.

Anemia of Chronic Disease


Associated conditions
Infection

Prevalence
20-95%

Viral, bacterial, TB, parasitic, fungal

Autoimmune disease

8-17%

RA, SLE, sarcoidosis, IBD, vasculitis

Cancer
Chronic solid organ rejection

Characteristics

WBC and platelet counts are normal


Anemia of variable severity (mild-severe)
Low erythropoietin level
Low reticulocyte count
Treat underlying condition

30-77%
8-70%

Anemia of Chronic Disease


Pathogenesis
Cytokines
(IL-1, TNF, IL-4, Interferon )

Disturbed iron metabolism


Diversion of iron from
circulation to the RE system

Decreased RBC
precursors

Inadequate Epo
response

Normch/normocy, Hypoch/microcy, serum iron, /N TIBC, /N S.Ferritin, Storage iron

Iron Transfer Between Cells and Tissues:


Impaired in Anemia of Chronic Disease

Blocked in
Anemia of chronic disease

Hentze, et.al, Cell 2004;117:285

Pure Red Cell Aplasia


Normocytic anemia with reticulocyte count < 0.5%
Absent erythroid precursors in marrow
Caused by parvovirus B19

Treatment with
IVIG

Clinical setting
Immunocompetent patients with chronic hemolysis
Immunodeficient patients with persistent viremia

Aplastic Anemia
Suppression of multipotent myeloid stem cells
Anemia, thrombocytopenia, neutropenia
Etiology: idiopathic (65%), irradiation, myelotoxic drugs,
chemicals, viruses (viral hepatitis)
Idiosyncratic reaction: chloramphenicol, sulfonamides
BM: hypocellular with fat replacement (>90%)
No splenomegaly, if + diagnosis, not AA
No reticulocytosis
Treatment: stop drug, BMT (< 40 y/o) for idiopathic,
immunosuppression for older patients, w/o donors

Aplastic anemia

HEMOLYTIC ANEMIA

Hemolytic Anemia with Extravascular


Hemolysis
Hereditary

Hemoglobinopathies (sickle cell anemia, thalassemia)


Enzymopathies (G6PD deficiency)
Membrane defects (hereditary spherocytosis)

Acquired

Immune mediated
Autoimmune hemolytic anemia

Nonimmune mediated
Spur cell hemolytic anemia

Paroxysmal Nocturnal Hemoglobinuria (PNH)


Extravascular (reticuloendothelial system)

Sickle Cell Anemia


Most prevalent hemoglobinopathy caused by mutations of the globin chain sickle Hb (HbS)
8% of American blacks (1:600)
30% of African blacks (protective effect of HbS vs. malaria)
Autosomal recessive
Single AA substitution in the globin chain (val for glu)
Normal adult: 96% HbA, 3% HbA2, 1% HbF
On deoxygenation: HbS polymerize (gelation/crystallization)
Change in physical state cause RBC distortion sickle/crescents
Reversible sickling irreversible sickling despite adequate O2
RBC hemolysis (anemia), capillary stasis (ischemia/thrombosis)

Pathophysiology of Sickle Cell Disease

Target cell

Sickle cells

Anisocytosis/poikilocytosis

Sickle Cell Trait


Protection against malaria
Genitourinary complications
Hyposthenuria
Painless hematuria
UTI during pregnancy

Vaso-occlusive complications

Sickle cell trait areas shown in


orange stripes

Splenic infarction with hypoxia


Sudden death during extreme exertion
Rhabdomyolysis

Sickle Cell Anemia: Clinical Presentations


Chronic hemolytic anemia
Susceptible to infection
S. pneumoniae
Salmonella osteomyelitis
Staphylococcal infections
Vaso-occlusion
Acute chest syndrome, strokes, acute pain crisis,
priapism, leg ulcers

Hemolytic Anemia: Sickle Cell Anemia

Diagnosis:
-Peripheral smear, Lab iron studies & Electrophoresis
Treatment:
Hydroxyurea
Increases HbF = retards sickling by inhibiting
polymer formation
RBC transfusions
RBC exchanges during acute crises

You can fool some of the people all of the time,


and all of the people some of the time, but you
can not fool all of the people all of the time.

Hereditary Spherocytosis
Abnormal RBC skeletal/membrane proteins (ie. Ankyrin)
RBCs with reduced membrane stability lose membrane
fragments, assume a sphere
Clinical: anemia, splenomegaly, jaundice
Lab: osmotic fragility
Upon exposure to hypotonic salt solution, spheroidal
shape limits volume of expansion.
RBCs shortened lifespan
Treatment: splenectomy to alleviate anemia, continue to
have spherocytes

Hereditary Spherocytosis

Glucose-6-Phosphate
Dehydrogenase Deficiency

G-6-PD essential for maintaining glutathione in active form

Detoxifies free radicals and peroxides

Sex-linked disorder
Effects > 200 million people
Hemolytic anemia occurs in the presence of stress (infection or
drugs- antimalarial, sulphonamide, nitrofurantoin etc)

African form - mild hemolysis


Mediterranean form - more severe

Peripheral smear shows Heinz bodies & bite cells


Unique sensitivity to fava beans

Autoimmune Hemolytic Anemia


Warm antibodies (IgG-mediated)
Primary
Secondary

Lymphoproliferative disease
Connective tissue disease
Infectious disease
Drug-induced (aldomet, PCN, Quinidine)

Cold antibody:
M. pneumoniae. Infectious mononucleosis

Laboratory testing
Normocytic/macrocytic anemia
+ DAT detects anti-RBC antibodies
Peripheral smear - spherocytosis

45%
40%

15%

Anti-Globulin (Coombs) Testing


Direct antiglobulin testing

+
Patients RBCs

Anti-C3d
Anti-IgG

Indirect antiglobulin testing

+
Patients serum RBCs

+
Anti-IgG

Hemolytic Anemia with Intravascular


Hemolysis

Mechanical damage (Microangiopathic hemolytic anemia)


Chemical damage (Burns)
Cardiac valve prostheses
Infection (Malaria or Babesiosis)
Transfusion reaction (ABO incompatibility)

Differential Diagnosis of Microangiopathic


Hemolytic Anemia

Thrombotic thrombocytopenic purpura (TTP)


Hemolytic uremic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
Vasculitis
Malignant hypertension
Metastatic neoplasm with vascular invasion
Preeclampsia/HELLP syndrome of pregnancy

Thalassemia

NORMAL INDIVIDUAL
4 -globin genes
on chromosomes No 16
( 2 on each chromosome)
2 from the father
& 2 from the mother

2 - globin genes
on chromosomes No 11
( 1 on each chromosome)
1 from the father
& 1 from the mother

Net result :-

Normal / globin chain ratio is 1/1

Normal Hemoglobin(s)

22

Hb%

2 2

A2

Adult

In ant

F
1

A2

1.6 - 3.2

A
97

7020 Negligible 3020

22

Gower 1

22

Portland

22

Gower II

22

22

A2

22

cluster - chromosome 11

Hg a d u
b lt

of

cluster - chromosome 16

De
ve
l
pe opm
rio en
d
t

Gl
o
co bin
mp ch
on ain
en
t
Hg
bn
am
e

Globin Chain Synthesis

Embryonic

Fetal

< 1%
1.5-3.5%

Adult
A

> 95%

Thalassemia
Decreased production of normal globin chains
thalassemia- deficiency of genes (mostly deletions)
thalassemia- deficiency of genes (mostly mutations)

Thalassemia
Heterozygote thalassemia

Italian, Sicilian, and Greek 10%


Southeast Asian populations 5%
African and American black populations 1.5%

thalassemia

Europe 4-12%
Middle East and western Asia - 12-55%
Southeast Asia 6-75%
Africa 11-50%
South America and the Caribbean - 7%

Imbalance of globin chain production


- vs. -thalassemia
Anemia due to both decreased production and increased
hemolysis in spleen
- thalassemia has decreased/absent Hgb A, increased Hgb
F, and increased Hgb A2
Treatment- hypertransfusion with chelation, splenectomy,
bone marrow transplantation

Father

/
Normal

Mother

-Thalassemia(s)

-/
--/
-/-

Silent carrier

- thal minor
(-thal trait)

--/-
--/--

HbH disease

Hb. Barts
Hydrops fetalis

Alpha Thalassemia: Clinical


Features
Absence of 1-2 alpha chains
Common
Asymptomatic
Does not require therapy

Absence of 3 alpha chains


(Hgb H disease)
Microcytic anemia (Hgb 7-10)
Splenomegaly

Absence of 4 alpha chains


Hydrops fetalis (non-viable)

X
XX

XX
XX

XX

X
X

Alpha Thalassemia: Laboratory Findings


Hemoglobin
Chains
Hgb (g/dl)

MCV (fl)

Analysis

Normal

Normal

Normal

/-

12-14

75-85

Normal

-/- or
--/

11-13

70-75

Normal with Hgb Barts (4);


Hgb H (4) - small

--/-

7-10

50-60

Normal with Hgb Barts (4);


Hgb H (4) - large

--/--

Not viable

- Thalassemia(s)

thalassemia
major
thalassemia
minor

Beta Thalassemia
Clinical
Syndrome

Genotype

Hgb (g/dl)

Hgb
Analysis

Minor (Trait)

/+ or /

Intermedia

+/+

7-10

Hgb A2, Hgb F

Major (Cooleys)

+/ or /

<7

Hgb A2, Hgb F

10-13

Hgb A2, Hgb F

Beta Thalassemia: Clinical


Manifestations
Skeletal
Osteoporosis due to bone marrow expansion (crew cut)
Pneumatization of the sinuses is delayed by expanded
hematopoiesis

Dilated cardiomyopathy secondary to severe anemia


Growth and development delayed
Hepatomegaly due to extramedullary hematopoiesis

Beta Thalassemia Major

Approach to Beta Thalassemia


thalassemia trait
Screening/counseling

thalassemia intermedia/major

Screening/counseling
RBC transfusion therapy (+ chelation therapy)
Agents to increase hemoglobin F (hydroxyurea)
Bone marrow transplantation

Smear
Microcytic / Hypochromic RBCs,
Anisocytosis, Poikilocytosis, target
cells

Thalassemia

New opinions often appear first as jokes and


fancies, then as blasphemies and treason, then
as questions open to discussion, and finally as
established truths.

Hemolytic Anemia
RBC destruction
erythropoiesis:
reticulocytosis
Iron accumulation:
hemosiderosis
Etiology:
Intravascular: heat,
clostridia toxin, trauma
complement fixation
Extravascular (RES)

Intravascular:
hemoglobinemia,
hemoglobinuria,
hemosiderinuria
haptoglobin

Extravascular
No hemoglobinemia or
hemoglobinuria
Normal haptoglobin
Microspherocytes

Differential diagnosis
of Anemia

Low Hb=Anemia
MCV

Low
microcytic

Normal
normocytic

High
macrocytic

Measure Ferritin
Low
Iron def anemia

Measure B12 + folate

Normal/high

Normal

Anemia of
chronic disease
Congenital Hb dis.

Low
Megaloblastic anemia

Reticulocyte count

Hemolytic anemia or
blood loss

high

low

Anemia of chronic disease


Renal failure
Marrow failure

Bone Marrow Cellularity

Normal

Hypercellular

Hypocellular

Causes of High Hct/polycythemia


Relative or spurious erythrocytosis
Hemoconcentration secondary to dehydration
(diarrhea, diaphoresis, diuretics, deprivation of water,
emesis, ethanol, etc.)

Absolute erythrocytosis (True ):


Secondary
Tissue hypoxia Smoking (Co), High altitude, Pulmonary disease,
Cardiac shunts, High oxygen-affinity Hb.
High EPO - Tumors eg. HCC.
Androgen therapy
Primary
Polycythemia vera

Always tell the truth. That way, you don't


have to remember what you said.

The weak can never forgive.


Forgiveness is the attribute of the
strong.

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