Approach to anemia to C1-2024.........pdf
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About This Presentation
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Slide Content
Yekatit-12 Hospital Medical College
Approach to anemia
Dr. Mekoya D Mengistu
(MD, Internist, Assistant professor of Internal Medicine)
2023/2024
Approach to anemia
Dr. Mekoya D Mengistu
(MD, Internist, Assistant professor of Internal Medicine)
2023/2024
Introduction: Hematopoietic Stem Cells
All the peripheral blood cell types and some cells in every tissue of the body are
derived from hematopoietic stem cells.
If the hematopoietic stem cell is damaged and can no longer function
+ Eg., due to a nuclear accident: A person would survive 2-4 wks in the absence
of extraordinary support measures.
Stem cells produce hundreds of billions of blood cells daily from a stem cell pool that is
estimated to be only in the tens of thousands.
All the peripheral blood cell types and some cells in every tissue of the body are
derived from hematopoietic stem cells.
If the hematopoietic stem cell is damaged and can no longer function
+ Eg., due to a nuclear accident: A person would survive 2-4 wks in the absence
of extraordinary support measures.
Stem cells produce hundreds of billions of blood cells daily from a stem cell pool that is
estimated to be only in the tens of thousands.
CARDINAL FUNCTIONS OF HEMATOPOIETIC STEM CELLS
« All stem cell types have two cardinal functions: self-renewal and differentiation
— Stem cells exist to generate, maintain, and repair tissues.
— The process of self-renewal assures that a stem cell population can be sustained over time.
+ Without self-renewal, the stem cell pool would become exhausted and
* tissue maintenance would not be possible.
— The process of differentiation leads to production of the effectors of tissue
function: mature cells.
Suero of Differentiation
Stem cell ra N
A = >
Differentiated cells
« All stem cell types have two cardinal functions: self-renewal and differentiation
— Stem cells exist to generate, maintain, and repair tissues.
— The process of self-renewal assures that a stem cell population can be sustained over time.
+ Without self-renewal, the stem cell pool would become exhausted and
* tissue maintenance would not be possible.
— The process of differentiation leads to production of the effectors of tissue
function: mature cells.
Suero of Differentiation
Stem cell ra N
A = >
Differentiated cells
‘Stem Cells: Progenitor Cells. Lineage Committed Mature Celts
Precursors
Actos,
common LEP EPA, Por
Lymphol SER POSS a la Tom
Progenitor vom _ wand)
m7 ¡Progenitor za nOTcHt, NOTCH. i
er a oe
rea
SO en
ice E
a [nat e =
e pc
Ar meno Fran
O ee fun 0808 e BB versan
(D Multipotent © ms tent Dendritic Cell
me ,
e
ac oar ‘Monocyte Monocyte
sor
ss
o
©
Fig. Hierarchy of hematopoietic differentiation
Precursors
Actos,
common LEP EPA, Por
Lymphol SER POSS a la Tom
Progenitor vom _ wand)
m7 ¡Progenitor za nOTcHt, NOTCH. i
er a oe
rea
SO en
ice E
a [nat e =
e pc
Ar meno Fran
O ee fun 0808 e BB versan
(D Multipotent © ms tent Dendritic Cell
me ,
e
ac oar ‘Monocyte Monocyte
sor
ss
o
©
Fig. Hierarchy of hematopoietic differentiation
The role of EPO in Erythropoiesis
* EPO is essential for the terminal maturation of erythroid cells.
— Its major effect is at the level of the CFU-E during adult erythropoiesis;
— Its recombinant preparations are also as effective as the natural hormone
+ HYPOXIA AND EPO EXPRESSION
— EPO is the physiologic regulator of red cell production
— produced in the kidney and fetal liver in response to hypoxia or exposure to cobalt chloride.
— Hypoxia-inducible factor and the response to hypoxia
+ Under hypoxic conditions, the hypoxia response element designated as hypoxia-inducible
factor 1-c (HIF-1-c) is increased
+ It regulates the expression of EPO genes to stimulate erythropoiesis
* EPO is essential for the terminal maturation of erythroid cells.
— Its major effect is at the level of the CFU-E during adult erythropoiesis;
— Its recombinant preparations are also as effective as the natural hormone
+ HYPOXIA AND EPO EXPRESSION
— EPO is the physiologic regulator of red cell production
— produced in the kidney and fetal liver in response to hypoxia or exposure to cobalt chloride.
— Hypoxia-inducible factor and the response to hypoxia
+ Under hypoxic conditions, the hypoxia response element designated as hypoxia-inducible
factor 1-c (HIF-1-c) is increased
+ It regulates the expression of EPO genes to stimulate erythropoiesis
Oxygen sensor model
While HIF-1-ß is ubiquitously expressed independent of 02 Hypoxia Normoxia
tension, HIF-1-a is only detectable under hypoxic conditions. oO oO EX
- line] Hydroxylation
Levels of the HIF-1a subunit increase exponentially as re
O, concentration declines. 0 y Fe
— This leads to transcription of EPO genes to increase EPO
production and then Erythropoiesis to respond to
hypoxia
Degradation via the Proteasome
Above a critical O2 concentration, HIF-1-alpha is
ubiquitinated and rapidly degraded in proteosomes.
— This O2 sensor in mammalian cells appears to be a
proline hydroxylase
CFU-E
While HIF-1-ß is ubiquitously expressed independent of 02 Hypoxia Normoxia
tension, HIF-1-a is only detectable under hypoxic conditions. oO oO EX
- line] Hydroxylation
Levels of the HIF-1a subunit increase exponentially as re
O, concentration declines. 0 y Fe
— This leads to transcription of EPO genes to increase EPO
production and then Erythropoiesis to respond to
hypoxia
Degradation via the Proteasome
Above a critical O2 concentration, HIF-1-alpha is
ubiquitinated and rapidly degraded in proteosomes.
— This O2 sensor in mammalian cells appears to be a
proline hydroxylase
CFU-E
RBC life cycles
Erythropoiesis in the adult takes place within the bone marrow
— under the influence of the stromal framework, cytokines, and the erythroid specific
growth factor, erythropoietin (EPO).
EPO is a true endocrine hormone produced in the kidney
RBC circulates for 110 to 120 days, after which it is removed from the circulation
— Removal by macrophages that detect senescent signals, primarily on the RBC membrane
Under steady state conditions, the rate of RBC production equals the rate of RBC loss
— The average adult produces 2 to 3M RBCs/sec, equating to about 200B RBCs every day.
Erythropoiesis in the adult takes place within the bone marrow
— under the influence of the stromal framework, cytokines, and the erythroid specific
growth factor, erythropoietin (EPO).
EPO is a true endocrine hormone produced in the kidney
RBC circulates for 110 to 120 days, after which it is removed from the circulation
— Removal by macrophages that detect senescent signals, primarily on the RBC membrane
Under steady state conditions, the rate of RBC production equals the rate of RBC loss
— The average adult produces 2 to 3M RBCs/sec, equating to about 200B RBCs every day.
Erythropoeisis: Sternum, pelvis, vertebrae, skull bones, long
| bones:- femure, Tibia (paed)
From stem cells (pleuripotent)
¥75% of marrow for WBC
¥ 25% of BM for Red cells
y Erythroid / Granulocyte Ratio 1:3
YE:G ratio increases in Anemia
y Large white areas are marrow fat
| bones:- femure, Tibia (paed)
From stem cells (pleuripotent)
¥75% of marrow for WBC
¥ 25% of BM for Red cells
y Erythroid / Granulocyte Ratio 1:3
YE:G ratio increases in Anemia
y Large white areas are marrow fat
Normal peripheral smear
Matures RBCs
v No nucleus,
v Biconcave discs -shaped
v Center 1/3 pallor
v Pink cytoplasm (Hb filled)
v Cell size 7- 8 um
oo v 110-120 days life span
o ono Ss
Normal peripheral blood smear
©
2-9 O = of oo.
oo On À
High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size and
shape. The diameter of the normal red cell should approximate
that of the nucleus of the small lymphocyte; central pallor (red
arrow) should equal one-third of its diameter.
Matures RBCs
v No nucleus,
v Biconcave discs -shaped
v Center 1/3 pallor
v Pink cytoplasm (Hb filled)
v Cell size 7- 8 um
oo v 110-120 days life span
o ono Ss
Normal peripheral blood smear
©
2-9 O = of oo.
oo On À
High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size and
shape. The diameter of the normal red cell should approximate
that of the nucleus of the small lymphocyte; central pallor (red
arrow) should equal one-third of its diameter.
Anemia
Is defined as a reduction in one or more of the major RBC measurements obtained as a part of
the CBC: Hb concentration, hematocrit, or RBC count
If anemia is defined as values which are more than two standard deviations (SD) below the
mean, then, by using these ranges, Table 21 Haemoglobin thresholds used to define anaemia
— Hb <13 g/dL or a HCT <40% in men AA — — 1
tien (050-499 ym) 10
— Hb <12 g/dL or HCT<36% in non pregnant women a Et us
— Hb<11g/dl ofr HCT< 33% in Pregnant women —e ne do
Man (215009) 120
Table 1
Anemia severity classification (hemoglobin values in grams per deciliter)
Anemia
Population Mild Moderate Severe
Pregnant women 10.0-10.9 7.033 <7.0
Nonpregnant women (>15 y of age) 11.0-11.9 3.0-10.9 <8.0
Men (>15 y of age) 11.0-12.9 8.0-10.9 <8.0
Data from WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of
severity. Vitamin and mineral nutrition information system. Geneva: World Health Organiza-
Is defined as a reduction in one or more of the major RBC measurements obtained as a part of
the CBC: Hb concentration, hematocrit, or RBC count
If anemia is defined as values which are more than two standard deviations (SD) below the
mean, then, by using these ranges, Table 21 Haemoglobin thresholds used to define anaemia
— Hb <13 g/dL or a HCT <40% in men AA — — 1
tien (050-499 ym) 10
— Hb <12 g/dL or HCT<36% in non pregnant women a Et us
— Hb<11g/dl ofr HCT< 33% in Pregnant women —e ne do
Man (215009) 120
Table 1
Anemia severity classification (hemoglobin values in grams per deciliter)
Anemia
Population Mild Moderate Severe
Pregnant women 10.0-10.9 7.033 <7.0
Nonpregnant women (>15 y of age) 11.0-11.9 3.0-10.9 <8.0
Men (>15 y of age) 11.0-12.9 8.0-10.9 <8.0
Data from WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of
severity. Vitamin and mineral nutrition information system. Geneva: World Health Organiza-
Clinical Consequences of Anemia
* The signs and symptoms induced by anemia are dependent upon
— the degree of anemia
— the rate at which it has evolved, as well as
— the oxygen demands of the patient
+ Symptoms are much less likely with anemia that evolves slowly,
— because there is time for multiple homeostatic forces to adjust to a reduced
oxygen carrying capacity of blood.
* The signs and symptoms induced by anemia are dependent upon
— the degree of anemia
— the rate at which it has evolved, as well as
— the oxygen demands of the patient
+ Symptoms are much less likely with anemia that evolves slowly,
— because there is time for multiple homeostatic forces to adjust to a reduced
oxygen carrying capacity of blood.
Causes of anemia
+ There are two general approaches to help identify the cause of anemia:
* Morphologic approach categorizing anemias via alterations in RBC size (ie, MCV) and the
Hemogram Values
reticulocyte response.
| MOV <78 FL MCV 78-100 FL MCV >100 fL
+ Kinetic approach, Based on the mechanism(s) responsible for anemia
— Anemia can be caused by one or more of three independent mechanisms:
* decreased RBC production,
* increased RBC destruction, and
* blood loss: Acute blood loss Vs Chronic blood loss(IDA)
+ There are two general approaches to help identify the cause of anemia:
* Morphologic approach categorizing anemias via alterations in RBC size (ie, MCV) and the
Hemogram Values
reticulocyte response.
| MOV <78 FL MCV 78-100 FL MCV >100 fL
+ Kinetic approach, Based on the mechanism(s) responsible for anemia
— Anemia can be caused by one or more of three independent mechanisms:
* decreased RBC production,
* increased RBC destruction, and
* blood loss: Acute blood loss Vs Chronic blood loss(IDA)
ALGORITHM OF THE PHYSIOLOGIC CLASSIFICATION OF ANEMIA
Reticulocyte Production Index (RPI) in adults
RPI = (Hct / 45) * Retic / Maturation
-0 for Het >=40%
.0 for Het 20 to 29.9%.
.5 for Hot <20%.
An RPI >2.5 shows a normal marrow response to anemia.
‘An RPI <2.5 is an inadequate response to anemia.
Prolongation of reticulocyte maturation time in
Blood loss
Intravascular
normochromic
hemolysis
Metabolic defect
Maturation disorder
Membrane
Hypoproliferative ]
abnormality
Marrow damage Cytoplasmic defects
+ Infiltration/fibrosis * Iron deficiency Hemoglobinopat
- Aplasia + Thalassemia SS >
Iron deficiency (early) + Sideroblastic Immune destruction
E anemia
+ Stimulation Fragmentation
+ Inflammation Nuclear defects hemolysis
+ Metabolic defect = Folate deficiency
+ Renal disease + Vitamin B,2 deficiency
= Drug toxicity
+ Refractorv anemia
Reticulocyte Production Index (RPI) in adults
RPI = (Hct / 45) * Retic / Maturation
-0 for Het >=40%
.0 for Het 20 to 29.9%.
.5 for Hot <20%.
An RPI >2.5 shows a normal marrow response to anemia.
‘An RPI <2.5 is an inadequate response to anemia.
Prolongation of reticulocyte maturation time in
Blood loss
Intravascular
normochromic
hemolysis
Metabolic defect
Maturation disorder
Membrane
Hypoproliferative ]
abnormality
Marrow damage Cytoplasmic defects
+ Infiltration/fibrosis * Iron deficiency Hemoglobinopat
- Aplasia + Thalassemia SS >
Iron deficiency (early) + Sideroblastic Immune destruction
E anemia
+ Stimulation Fragmentation
+ Inflammation Nuclear defects hemolysis
+ Metabolic defect = Folate deficiency
+ Renal disease + Vitamin B,2 deficiency
= Drug toxicity
+ Refractorv anemia
Hypoproliferative Anemia
* Is anemias associated with NCNC RBCs and low reticulocyte response (reticulocyte index <2-2.5) :-
V Early iron deficiency (before hypochromic microcytic red cells develop),
V Acute and chronic inflammation (including many malignancies),
Vv Renal disease,
Y” Hypometabolic states such as protein malnutrition and endocrine deficiencies,
y” Anemias from marrow damage.
+ Hypoproliferative anemias are the most common causes of anemia,
Y” In the clinic, IDA is the most common, followed by the anemia of inflammation.
+ The anemia of inflammation, similar to IDA, is related in part to abnormal iron metabolism
+ The anemias associated with renal disease, inflammation, cancer, and hypometabolic states are characterized
by a suboptimal erythropoietin response to the anemia.
* Is anemias associated with NCNC RBCs and low reticulocyte response (reticulocyte index <2-2.5) :-
V Early iron deficiency (before hypochromic microcytic red cells develop),
V Acute and chronic inflammation (including many malignancies),
Vv Renal disease,
Y” Hypometabolic states such as protein malnutrition and endocrine deficiencies,
y” Anemias from marrow damage.
+ Hypoproliferative anemias are the most common causes of anemia,
Y” In the clinic, IDA is the most common, followed by the anemia of inflammation.
+ The anemia of inflammation, similar to IDA, is related in part to abnormal iron metabolism
+ The anemias associated with renal disease, inflammation, cancer, and hypometabolic states are characterized
by a suboptimal erythropoietin response to the anemia.
The common causes for reduced (ineffective) RBC production:-
= Lack of nutrients, such as iron, B12, or folate. This can be due to:
Y” dietary deficiency,
y malabsorption (eg, pernicious anemia, sprue), or
Y” blood loss (iron deficiency).
= Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia, tumor infiltration)
= Bone marrow suppression (eg, drugs, chemotherapy, irradiation)
= Low levels of hormones stimulating RBC production: EPO , thyroid hormone and androgens.
= Lack of nutrients, such as iron, B12, or folate. This can be due to:
Y” dietary deficiency,
y malabsorption (eg, pernicious anemia, sprue), or
Y” blood loss (iron deficiency).
= Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia, tumor infiltration)
= Bone marrow suppression (eg, drugs, chemotherapy, irradiation)
= Low levels of hormones stimulating RBC production: EPO , thyroid hormone and androgens.
lron deficiency anemia(IDA)
+ IDA is the most common anemia worldwide,
+ is especially prevalent in women and children in regions
— where meat intake is low, food is not fortified with iron, and malaria, intestinal
infections, and parasitic worms are common
+ Women with frequent pregnancies, menorrhagia are particularly susceptible.
* Globally, 50% of anemia is attributable to IDA and accounts for approximately 841,000
deaths annually worldwide.
+ IDA is the most common anemia worldwide,
+ is especially prevalent in women and children in regions
— where meat intake is low, food is not fortified with iron, and malaria, intestinal
infections, and parasitic worms are common
+ Women with frequent pregnancies, menorrhagia are particularly susceptible.
* Globally, 50% of anemia is attributable to IDA and accounts for approximately 841,000
deaths annually worldwide.
LUS CAUSES OF IRON DEFICIENCY
Increased Demand for Iron
Rapid growth in infancy or adolescence
Pregnancy
Erythropoietin therapy
Increased Iron Loss
Chronic blood loss : UGIB/LGIB, Intestinal parasitosis(IP)
Menses
Acute blood loss
Blood donation
Phlebotomy as treatment for polycythemia vera
Decreased Iron Intake or Absorption
Inadequate diet
Malabsorption from disease (sprue, Crohn's disease)
Malabsorption from surgery (gastrectomy and some forms of bariatric surgery)
Acute or chronic inflammation (Involving duodenum)
Increased Demand for Iron
Rapid growth in infancy or adolescence
Pregnancy
Erythropoietin therapy
Increased Iron Loss
Chronic blood loss : UGIB/LGIB, Intestinal parasitosis(IP)
Menses
Acute blood loss
Blood donation
Phlebotomy as treatment for polycythemia vera
Decreased Iron Intake or Absorption
Inadequate diet
Malabsorption from disease (sprue, Crohn's disease)
Malabsorption from surgery (gastrectomy and some forms of bariatric surgery)
Acute or chronic inflammation (Involving duodenum)
+ The progression to iron deficiency can be divided into three stages:
“+ A. The first stage is negative iron balance,
— in which the demands for iron exceed the body's ability to absorb iron from the diet.
— This stage results from a number of physiologic mechanisms,
+ Eg. blood loss, Px, rapid growth spurts in adolescent, or inadequate dietary iron intake.
— Under these circumstances, iron deficit must be made up by mobilization of iron from RE storage sites.
— During this period, iron stores—reflected by the serum ferritin level or the appearance of stainable
iron on bone marrow aspirations—decrease.
— As long as iron stores are present and can be mobilized, the serum iron, TIBC, and red cell
protoporphyrin levels remain within normal limits.
— At this stage, red cell morphology and indices are normal.
“+ A. The first stage is negative iron balance,
— in which the demands for iron exceed the body's ability to absorb iron from the diet.
— This stage results from a number of physiologic mechanisms,
+ Eg. blood loss, Px, rapid growth spurts in adolescent, or inadequate dietary iron intake.
— Under these circumstances, iron deficit must be made up by mobilization of iron from RE storage sites.
— During this period, iron stores—reflected by the serum ferritin level or the appearance of stainable
iron on bone marrow aspirations—decrease.
— As long as iron stores are present and can be mobilized, the serum iron, TIBC, and red cell
protoporphyrin levels remain within normal limits.
— At this stage, red cell morphology and indices are normal.
“+ B. Iron-deficient erythropoiesis.
— As long as serum Fe is in normal range, Hb synthesis is unaffected despite declining stores.
— When iron stores become depleted, the serum iron begins to fall.
Gradually, the TIBC increases, as do red cell protoporphyrin levels.
— Once the transferrin saturation falls to 15-20%, Hb synthesis becomes impaired[mild anemia].
This is a period of iron-deficient erythropoiesis.
— Careful evaluation of blood smear reveals the first appearance of microcytic cells
if the lab technology is available, one finds hypochromic reticulocytes in circulation.
Gradually, the hemoglobin begins to fall, reflecting iron-deficiency anemia.
“C. iron-deficiency anemia
— When moderate anemia is present, the bone marrow remains hypoproliferative.
— With more severe anemia, hypochromia and microcytosis become more prominent,
+ target cells, poikilocytes, cigar- or pencil-shaped forms, and
+ the erythroid marrow becomes increasingly ineffective.
— As long as serum Fe is in normal range, Hb synthesis is unaffected despite declining stores.
— When iron stores become depleted, the serum iron begins to fall.
Gradually, the TIBC increases, as do red cell protoporphyrin levels.
— Once the transferrin saturation falls to 15-20%, Hb synthesis becomes impaired[mild anemia].
This is a period of iron-deficient erythropoiesis.
— Careful evaluation of blood smear reveals the first appearance of microcytic cells
if the lab technology is available, one finds hypochromic reticulocytes in circulation.
Gradually, the hemoglobin begins to fall, reflecting iron-deficiency anemia.
“C. iron-deficiency anemia
— When moderate anemia is present, the bone marrow remains hypoproliferative.
— With more severe anemia, hypochromia and microcytosis become more prominent,
+ target cells, poikilocytes, cigar- or pencil-shaped forms, and
+ the erythroid marrow becomes increasingly ineffective.
Three staged progression of iron deficiency
Negative Iron- Iron-
deficient deficiency
Normal balance erythropolesis anemia
Iron stores
Erythron iron
Marrow iron
gall cae 1-3+ o o
Serum ferritin
so-200
g/l)
TIBC (ug/al) 300-360 >400
Si (ug/L) 50-150 NL <=0
Saturation (%) 30-50 NL <10
Marrow
sideroblasts (9%) 2:00 ue te
RBC
protoporphyrin 30-50 NL >200
(Ma/aL)
RBC
mondes NE su ET
FIGURE 93-2 Laboratory studies in the evolution of iron deficiency.
Measurements of marrow iron stores, serum ferritin, and total iron-Dinding
capacity (TIBC) are sensitive to early ironstore depletion. Iron-deficient
‘erythropoiesis is recognized from additional abnormalities in the serum iron
(SN, percent transferrin saturation, the pattern of marrow sideroblasts, and the
red blood cell (RBC) protoporphyrin level. Patients with iron-deficiency anemia
demonstrate all the same abnormalities plus hvpochromic microcvtic anemia.
Negative Iron- Iron-
deficient deficiency
Normal balance erythropolesis anemia
Iron stores
Erythron iron
Marrow iron
gall cae 1-3+ o o
Serum ferritin
so-200
g/l)
TIBC (ug/al) 300-360 >400
Si (ug/L) 50-150 NL <=0
Saturation (%) 30-50 NL <10
Marrow
sideroblasts (9%) 2:00 ue te
RBC
protoporphyrin 30-50 NL >200
(Ma/aL)
RBC
mondes NE su ET
FIGURE 93-2 Laboratory studies in the evolution of iron deficiency.
Measurements of marrow iron stores, serum ferritin, and total iron-Dinding
capacity (TIBC) are sensitive to early ironstore depletion. Iron-deficient
‘erythropoiesis is recognized from additional abnormalities in the serum iron
(SN, percent transferrin saturation, the pattern of marrow sideroblasts, and the
red blood cell (RBC) protoporphyrin level. Patients with iron-deficiency anemia
demonstrate all the same abnormalities plus hvpochromic microcvtic anemia.
Laboratory tests in iron deficiency of increasing severity
neal Tron Benciengy without Iron deficiency with mild | Severe iron denies cy with
anemia anemia severe anemia
‘Marrow reticuloendothelal ron 2+ to3+ None None None
Serum iron (Fe), meg/dL 60 to 150 60 to 150 <60 <a
Serum iron (Fe), microM/L 1070267 1070267 <10.7 TA
Total iron-binding capacity (transferrin, | 300 to 360 300 to 390 350 to 400 >410
IBC), meg/dL.
Total ion binding capacity, microW/L | 53.7 to 64.4 53710698 626to716 >734
Transferrin saturation (Fe/TIBC), 201050 2 «5 <10
percent
Hemoglobin, g/dL Normal Normal 9t012 6to7
Hemoglobin, g/L Normal Normal 90 to 120 600 70
Red cell morphology Normal Normal ‘Normal or slight hypochromia Hypochromia and microcytosis.
Plasma or serum ferritin, ng/mL or | 40 to 200 <40 <20 <10
microg/L
Plasma or serum fertin, picoM/L | 89.9 to.449 <89.9 <5 <25
Erythrocyte protoporphyrin, ng/mL | 30 to 70 30t070 >100 100 to 200
REC
Other tissue changes None None None Nail and epithelial changes
NOTE: Test results outined in bold type are the ones most likely to define the various stages of iron deficiency Thus, the presence or absence of iron stores (marrow reiculoendotheli iron} in a non-
anemic patient serves to distinguish normal subjects from those with iron deficiency without anemia, respectively.
neal Tron Benciengy without Iron deficiency with mild | Severe iron denies cy with
anemia anemia severe anemia
‘Marrow reticuloendothelal ron 2+ to3+ None None None
Serum iron (Fe), meg/dL 60 to 150 60 to 150 <60 <a
Serum iron (Fe), microM/L 1070267 1070267 <10.7 TA
Total iron-binding capacity (transferrin, | 300 to 360 300 to 390 350 to 400 >410
IBC), meg/dL.
Total ion binding capacity, microW/L | 53.7 to 64.4 53710698 626to716 >734
Transferrin saturation (Fe/TIBC), 201050 2 «5 <10
percent
Hemoglobin, g/dL Normal Normal 9t012 6to7
Hemoglobin, g/L Normal Normal 90 to 120 600 70
Red cell morphology Normal Normal ‘Normal or slight hypochromia Hypochromia and microcytosis.
Plasma or serum ferritin, ng/mL or | 40 to 200 <40 <20 <10
microg/L
Plasma or serum fertin, picoM/L | 89.9 to.449 <89.9 <5 <25
Erythrocyte protoporphyrin, ng/mL | 30 to 70 30t070 >100 100 to 200
REC
Other tissue changes None None None Nail and epithelial changes
NOTE: Test results outined in bold type are the ones most likely to define the various stages of iron deficiency Thus, the presence or absence of iron stores (marrow reiculoendotheli iron} in a non-
anemic patient serves to distinguish normal subjects from those with iron deficiency without anemia, respectively.
Clinical features of IDA
The onset of IDA is insidious and the progression of symptoms is gradual
The signs and symptoms of IDA are also not specific
The degree of fatigue may be disproportionate to the apparent severity of anemia
Vv This may be attributed to depletion of energy generation by the muscles
Rare but characteristic clinical features of IDA
Y Pica: is craving for unusual substances
+ Amylophagia-for starch, Geophagia- for clay, Phagophagia for ice
V Koilonychia: finger nails that are thin, brittle and friable, with distal
half in a concave or spoon shape
Y” Glossitis, Angular stomatitis
y” Plummer-Vinson (Peterson-Kelly) syndrome:
+ Combination of glossitis, sore or burning mouth, dysphasia and IDA
+ The dysphasia is due to mucosal web at the junction of hypopharnyx and esophagus.
+ This may later be complicated by the development of esophageal carcinoma
The onset of IDA is insidious and the progression of symptoms is gradual
The signs and symptoms of IDA are also not specific
The degree of fatigue may be disproportionate to the apparent severity of anemia
Vv This may be attributed to depletion of energy generation by the muscles
Rare but characteristic clinical features of IDA
Y Pica: is craving for unusual substances
+ Amylophagia-for starch, Geophagia- for clay, Phagophagia for ice
V Koilonychia: finger nails that are thin, brittle and friable, with distal
half in a concave or spoon shape
Y” Glossitis, Angular stomatitis
y” Plummer-Vinson (Peterson-Kelly) syndrome:
+ Combination of glossitis, sore or burning mouth, dysphasia and IDA
+ The dysphasia is due to mucosal web at the junction of hypopharnyx and esophagus.
+ This may later be complicated by the development of esophageal carcinoma
In severe, uncomplicated iron-deficiency anemia
+ the erythrocytes are hypochromic and microcytic;
+ the plasma iron concentration is diminished
+ the iron-binding capacity is increased
+ the serum ferritin concentration is low;
+ the marrow is depleted of stainable iron
Diagnosis of Microcytic Anemia
Tests Iron Inflammation | Thalassemia Sideroblastic
Deficiency ‘Anemia
Smear Micro/hypo [Normal Micro/hypo with targeting Variable
micro/hypo
sI <30 <50 Normal to high Normal to high
TIBC >360 <300 Normal Normal
Percent saturation |<10 10-20 30-80 30-80
Ferritin (g/L) <15 30-200 50-300 50-300
Hemoglobin pattern | Normal Normal Abnormal with Normal
on electrophoresis B thalassemia; can be
normal with « thalassemia
Abbreviations: SI, serum iron; TIBC, total iron-binding capacity.
23
+ the erythrocytes are hypochromic and microcytic;
+ the plasma iron concentration is diminished
+ the iron-binding capacity is increased
+ the serum ferritin concentration is low;
+ the marrow is depleted of stainable iron
Diagnosis of Microcytic Anemia
Tests Iron Inflammation | Thalassemia Sideroblastic
Deficiency ‘Anemia
Smear Micro/hypo [Normal Micro/hypo with targeting Variable
micro/hypo
sI <30 <50 Normal to high Normal to high
TIBC >360 <300 Normal Normal
Percent saturation |<10 10-20 30-80 30-80
Ferritin (g/L) <15 30-200 50-300 50-300
Hemoglobin pattern | Normal Normal Abnormal with Normal
on electrophoresis B thalassemia; can be
normal with « thalassemia
Abbreviations: SI, serum iron; TIBC, total iron-binding capacity.
23
Peripheral smear: Microcytic hypochromic
Normal peripheral blood smear
Microcytic hypochromic red cells in iron deficiency anemia pep
Oo 0002 20
Er E Os Seo 00905 Z
Po: 0
RER gr DO: e? e orem 8 5%
¿00 ‘82 A u 32 RE
Er N
« Anemia is considered "microcytic" when the MCV is less than 78-80 fL.
+ Microcytosis is usually accompanied by a decreased hemoglobin content within the RBC (low
mean corpuscular hemoglobin, MCH) on the blood smear
Normal peripheral blood smear
Microcytic hypochromic red cells in iron deficiency anemia pep
Oo 0002 20
Er E Os Seo 00905 Z
Po: 0
RER gr DO: e? e orem 8 5%
¿00 ‘82 A u 32 RE
Er N
« Anemia is considered "microcytic" when the MCV is less than 78-80 fL.
+ Microcytosis is usually accompanied by a decreased hemoglobin content within the RBC (low
mean corpuscular hemoglobin, MCH) on the blood smear
Microcytic hypochromic red cells in iron deficiency
ui = ern A
09,200 © © o E
o. 87 = LON D * A o ©,
-Co e oo 0-09, … OD & =R @¢
Ñ 2
As O, a QS O ne O,
Periph from a pi ith iron deficiency I :
mall red cells with just a scant rim of pink hemoglobin; occasional Aa 0 =~
cil" nt. Normal red cells are simil
in size t small lymphocyte (arrow); thus, many
microcytic mear.
pl tin this
Courtesy of Carola von Kapff, SH (ASCP). Sever iron deficiency anemia
ui = ern A
09,200 © © o E
o. 87 = LON D * A o ©,
-Co e oo 0-09, … OD & =R @¢
Ñ 2
As O, a QS O ne O,
Periph from a pi ith iron deficiency I :
mall red cells with just a scant rim of pink hemoglobin; occasional Aa 0 =~
cil" nt. Normal red cells are simil
in size t small lymphocyte (arrow); thus, many
microcytic mear.
pl tin this
Courtesy of Carola von Kapff, SH (ASCP). Sever iron deficiency anemia
OTHER HYPOPROLIFERATIVE ANEMIAS:
1. chronic inflammation,
2. renal disease,
3. endocrine and nutritional deficiencies (hypometabolic states),
— Patients who are starving, particularly for protein, and have hypothyroidism
+ have lower metabolic rates,
* may develop a mild to moderate hypoproliferative anemia.
+ Due to low EPO level : EPO release is sensitive to the need for O2, not just O2 levels
4. marrow damage DIAGNOSIS OF HYPOPROLIFERATIVE ANEMIAS
Tests Iron Deficiency Inflammation Renal Disease Hypometabolic States
Anemia Mild to severe Mild Mildto severe Mild
MCV (fl) 60-90 80-90 90 90
Morphology Normo-microcytic Normocytic Normocytic Normocytic
SI (ug/dl) <30 <50 Normal Normal
TIBC (ug/dL) >360 <300 Normal Normal
Saturation (%) <10 10-20 Normal Normal
Serum ferritin (ug/L) <15 30-200 115-150 Normal
Iron stores 0 2-44 1-44 Normal
1. chronic inflammation,
2. renal disease,
3. endocrine and nutritional deficiencies (hypometabolic states),
— Patients who are starving, particularly for protein, and have hypothyroidism
+ have lower metabolic rates,
* may develop a mild to moderate hypoproliferative anemia.
+ Due to low EPO level : EPO release is sensitive to the need for O2, not just O2 levels
4. marrow damage DIAGNOSIS OF HYPOPROLIFERATIVE ANEMIAS
Tests Iron Deficiency Inflammation Renal Disease Hypometabolic States
Anemia Mild to severe Mild Mildto severe Mild
MCV (fl) 60-90 80-90 90 90
Morphology Normo-microcytic Normocytic Normocytic Normocytic
SI (ug/dl) <30 <50 Normal Normal
TIBC (ug/dL) >360 <300 Normal Normal
Saturation (%) <10 10-20 Normal Normal
Serum ferritin (ug/L) <15 30-200 115-150 Normal
Iron stores 0 2-44 1-44 Normal
Anemia of Chronic Disease (ACD)
ACD, also called the anemia of inflammation, or anemia of chronic inflammation
initially thought to be associated primarily with infectious, inflammatory, or neoplastic disease.
However, can be seen in a variety of conditions: CKD, severe trauma, DM, older adult, .....
The anemia is typically normochromic, normocytic, hypoproliferative, and mild-mod in degree.
It is the most important anemia in the differential diagnosis of IDA,
© because many of its features are due to inadequate iron delivery to the marrow, despite the
presence of normal or increased iron stores.
© This is reflected by a low serum iron, increased red cell protoporphyrin, a hypoproliferative BM, but
normal or high ferritin.
© The serum ferritin values are often the most distinguishing features from IDA
© TYPICALLY, FERRITIN INCREASE THREEFOLD OVER BASAL LEVELS IN THE FACE OF INFLAMMATION.
ACD, also called the anemia of inflammation, or anemia of chronic inflammation
initially thought to be associated primarily with infectious, inflammatory, or neoplastic disease.
However, can be seen in a variety of conditions: CKD, severe trauma, DM, older adult, .....
The anemia is typically normochromic, normocytic, hypoproliferative, and mild-mod in degree.
It is the most important anemia in the differential diagnosis of IDA,
© because many of its features are due to inadequate iron delivery to the marrow, despite the
presence of normal or increased iron stores.
© This is reflected by a low serum iron, increased red cell protoporphyrin, a hypoproliferative BM, but
normal or high ferritin.
© The serum ferritin values are often the most distinguishing features from IDA
© TYPICALLY, FERRITIN INCREASE THREEFOLD OVER BASAL LEVELS IN THE FACE OF INFLAMMATION.
PATHOGENESIS of ACD
* ACD primarily reflects reduced RBC production and mild shortening of RBC survival
+ A number of factors are thought to contribute to this hypoproliferative state :
“ Hepcidin-induced alterations in iron metabolism:
v It reduced Gl absorption of iron and trapping of iron in macrophages.
v This results in reduced plasma iron(hypoferremia)> Reduced Erythropiesis
* Inability to increase erythropoiesis in response to anemia.
v EPO levels are somewhat elevated in ACD, but virtually no increase in erythropoiesis,
v perhaps due to increased apoptotic death of red cell precursors within BM
* A relative decrease in EPO production.
Y” The inverse relationship between Hct and EPO seen in most anemia is not maintained in ACD.
v Eg. pts with ACD have lower EPO level than do pts with IDA and similar degree of anemia
« A minor component of ACD is due to decreased red cell survival.
+ Shortened red cell life may occur in acute inflammation due to increased macrophage activity
* ACD primarily reflects reduced RBC production and mild shortening of RBC survival
+ A number of factors are thought to contribute to this hypoproliferative state :
“ Hepcidin-induced alterations in iron metabolism:
v It reduced Gl absorption of iron and trapping of iron in macrophages.
v This results in reduced plasma iron(hypoferremia)> Reduced Erythropiesis
* Inability to increase erythropoiesis in response to anemia.
v EPO levels are somewhat elevated in ACD, but virtually no increase in erythropoiesis,
v perhaps due to increased apoptotic death of red cell precursors within BM
* A relative decrease in EPO production.
Y” The inverse relationship between Hct and EPO seen in most anemia is not maintained in ACD.
v Eg. pts with ACD have lower EPO level than do pts with IDA and similar degree of anemia
« A minor component of ACD is due to decreased red cell survival.
+ Shortened red cell life may occur in acute inflammation due to increased macrophage activity
Role of hepcidin in the pathophysiology of ACD
Hepatocyte de
Macrophage
o
> E © © 1.6, IL-1
€ Hepcidin Ferroportin
€ € Cc is an iron exporter
C Fe O # RBC
Enterocyte
__ Ferroportin
is an iron exportel
Erythroblast
in Bone Marrow
Hepatocyte de
Macrophage
o
> E © © 1.6, IL-1
€ Hepcidin Ferroportin
€ € Cc is an iron exporter
C Fe O # RBC
Enterocyte
__ Ferroportin
is an iron exportel
Erythroblast
in Bone Marrow
Making the diagnosis of ACD
There is no one test that will reliably make the diagnosis of ACD.
Rather, a "pattern" of abnormalities serves to make this diagnosis.
ACD is most likely when all of the following are present :
Y Low serum iron
Y” Normal to low serum transferrin (total iron binding capacity)
Y” Increased serum ferritin
Y” Elevated ESR (Normal: 0-20mm/h in female and 0-15 in male) or elevated CRP
The following are helpful in diagnosing ACD when the above test results are equivocal:
V Reduced reticulocyte response for the degree of anemia
V An elevated hepcidin level, although assays are not yet widely available.
There is no one test that will reliably make the diagnosis of ACD.
Rather, a "pattern" of abnormalities serves to make this diagnosis.
ACD is most likely when all of the following are present :
Y Low serum iron
Y” Normal to low serum transferrin (total iron binding capacity)
Y” Increased serum ferritin
Y” Elevated ESR (Normal: 0-20mm/h in female and 0-15 in male) or elevated CRP
The following are helpful in diagnosing ACD when the above test results are equivocal:
V Reduced reticulocyte response for the degree of anemia
V An elevated hepcidin level, although assays are not yet widely available.
Laboratory findings in iron deficiency anemia, thalassemia, and anemia of chronic disease /inflammation
Test Iron deficiency anemia Alpha or beta thalassemia Anemia of chronic
disease/inflammation
‘Complete Blood court
Hemoglobin Decreased Deercaces Decreased
Mean corpuscular volume (MCV) Decreased Decreases Normal to decreseeé
Red call distribution width (ROW) Increased Increased or normal Normal to increased
Red blood cel count Decreased Incressed or normal Decrease
Iron studies
Serum ion Dstreases Normal or increased Decreases
Total ron-bineing capacity (TBC): increased Normal em
transferrin
Transferin saturation Daszamec pe Decreased
= ec rer increased y
Enjtrocye protoporphyrin” Increased Normal or increased Increased
Soluble transferrin receptor" Increased Increased Normal
Reticulocyte hemoglobin equivalent (Ret:he or | Decreased Decreased Normal
cue}
reactive protein Normal Normal Increased
Refer to UpToDate topics on anemia for further details of the evaluation and interpretation. Refer to UpToDate topic on iron deficiency anemia for early changes associated with iron defi
(before anemia develops).
= Not used in the routine evaluation of anemia.
Test Iron deficiency anemia Alpha or beta thalassemia Anemia of chronic
disease/inflammation
‘Complete Blood court
Hemoglobin Decreased Deercaces Decreased
Mean corpuscular volume (MCV) Decreased Decreases Normal to decreseeé
Red call distribution width (ROW) Increased Increased or normal Normal to increased
Red blood cel count Decreased Incressed or normal Decrease
Iron studies
Serum ion Dstreases Normal or increased Decreases
Total ron-bineing capacity (TBC): increased Normal em
transferrin
Transferin saturation Daszamec pe Decreased
= ec rer increased y
Enjtrocye protoporphyrin” Increased Normal or increased Increased
Soluble transferrin receptor" Increased Increased Normal
Reticulocyte hemoglobin equivalent (Ret:he or | Decreased Decreased Normal
cue}
reactive protein Normal Normal Increased
Refer to UpToDate topics on anemia for further details of the evaluation and interpretation. Refer to UpToDate topic on iron deficiency anemia for early changes associated with iron defi
(before anemia develops).
= Not used in the routine evaluation of anemia.
Megaloblastic Anemia-MBA
Characterized by the presence of distinctive morphologic appearances of the red cells (Macroovalocytosis)
The marrow is usually hypercellular and the anemia is based on ineffective erythropoiesis.
The cause is usually a deficiency of either cobalamin (vitamin B12) or folate,
MBA can also occur because of :
— genetic or acquired abnormalities that affect the metabolism of Folate or B12 or
— defects in DNA synthesis not related to cobalamin or folate
Characterized by the presence of distinctive morphologic appearances of the red cells (Macroovalocytosis)
The marrow is usually hypercellular and the anemia is based on ineffective erythropoiesis.
The cause is usually a deficiency of either cobalamin (vitamin B12) or folate,
MBA can also occur because of :
— genetic or acquired abnormalities that affect the metabolism of Folate or B12 or
— defects in DNA synthesis not related to cobalamin or folate
DIETARY SOURCES AND REQUIREMENTS
Dietary sources of cobalamin are animal origins: meat, fish, and dairy products.
— Vegetables, fruits, and other foods of nonanimal origin are free from cobalamin
Proximal smal intestine
fal
— Daily cobalamin requirement is about 1-3 ug, absorption at distal ileum of GIT el
* because the body does not have the ability to degrade cobalamin, aio acids
+ Body stores are 2-3 mg, sufficient for 3-4 years if supplies are completely cut off. au
aim
— Risk for MBA: Poor dietary intake, strict vegitarian, malabsorption syndrome... pole
Folate aka vit-B9 is present in many plant and animal products, (id sal sie
— especially dark green leafy vegetables and liver | un
— Recommended daily folate intake: 65 ug in young infants Vs 400 ug in adults, | prea
+ with higher levels during Px and lactation (600 and 500yg, respectively) Con {| nate
— Absorbed primarily in the duodenum and also in the jejunum Water ||
— Total body folate stores: 0.5 to 20 mg. m Ve
Cam Bie ats
— If folate intake ceases, deficiency may develop within weeks to months amas Viami Bry
¡div i R A á : x Ver
* more rapidly if demands for folate are increased, as in chronic hemolytic anemia lag ectoyes
Dietary sources of cobalamin are animal origins: meat, fish, and dairy products.
— Vegetables, fruits, and other foods of nonanimal origin are free from cobalamin
Proximal smal intestine
fal
— Daily cobalamin requirement is about 1-3 ug, absorption at distal ileum of GIT el
* because the body does not have the ability to degrade cobalamin, aio acids
+ Body stores are 2-3 mg, sufficient for 3-4 years if supplies are completely cut off. au
aim
— Risk for MBA: Poor dietary intake, strict vegitarian, malabsorption syndrome... pole
Folate aka vit-B9 is present in many plant and animal products, (id sal sie
— especially dark green leafy vegetables and liver | un
— Recommended daily folate intake: 65 ug in young infants Vs 400 ug in adults, | prea
+ with higher levels during Px and lactation (600 and 500yg, respectively) Con {| nate
— Absorbed primarily in the duodenum and also in the jejunum Water ||
— Total body folate stores: 0.5 to 20 mg. m Ve
Cam Bie ats
— If folate intake ceases, deficiency may develop within weeks to months amas Viami Bry
¡div i R A á : x Ver
* more rapidly if demands for folate are increased, as in chronic hemolytic anemia lag ectoyes
CLINICAL FEATURES of MBA
+ Many symptomless patients are detected by the finding of raised MCV
+ The main clinical features in more severe cases are those of anemia.
— Anoroxia, wt loss, diarrhea or constipation
— Glossitis, angular cheilosis, mild fever in more severely anemic patients,
— Thrombocytopenia sometimes leads to bruising
— Leukopenia may predispose to infections, particularly pneumonia and UTI
+ Many symptomless patients are detected by the finding of raised MCV
+ The main clinical features in more severe cases are those of anemia.
— Anoroxia, wt loss, diarrhea or constipation
— Glossitis, angular cheilosis, mild fever in more severely anemic patients,
— Thrombocytopenia sometimes leads to bruising
— Leukopenia may predispose to infections, particularly pneumonia and UTI
Neurologic Manifestations
+ Vit- B12 ¡is used for myelination in Nervous System
« Its deficiency may cause
— bilateral peripheral neuropathy or
— Degeneration/demyelination of the cervical and thoracic posterior and lateral (pyramidal)
tracts of the spinal cord
Optic atrophy
cerebral symptoms: dementia, depression, psychotic symptoms,
There may also be anosmia and loss of taste.
+ Patients presents with
— paresthesias, muscle weakness, dementia, psychosis, or visual impairment
usually loss of proprioception and vibration with Romberg and Lhermitte signs.
— Gait may be ataxic with spasticity (hyperreflexia).
— ANS dysfunction can result in postural hypotension, impotence, and incontinence.
+ MRI may show the “spongy” degeneration of the cord.
+ Vit- B12 ¡is used for myelination in Nervous System
« Its deficiency may cause
— bilateral peripheral neuropathy or
— Degeneration/demyelination of the cervical and thoracic posterior and lateral (pyramidal)
tracts of the spinal cord
Optic atrophy
cerebral symptoms: dementia, depression, psychotic symptoms,
There may also be anosmia and loss of taste.
+ Patients presents with
— paresthesias, muscle weakness, dementia, psychosis, or visual impairment
usually loss of proprioception and vibration with Romberg and Lhermitte signs.
— Gait may be ataxic with spasticity (hyperreflexia).
— ANS dysfunction can result in postural hypotension, impotence, and incontinence.
+ MRI may show the “spongy” degeneration of the cord.
Peripheral morphology of MBA
+ PERIPHERAL BLOOD
« Oval macrocytes, usually with considerable anisocytosis and poikilocytosis, are the main
feature
Y” MCV is usually >100 fL unless mixed with other cause of microcytosis (e.g., IDA or thalassemia trait)
“ Neutrophil hypersegmentation
y Neutrophil hypersegmentation (NH) is defined as the presence of
— >5% of neutrophils with five lobed nuecli or
— the presence of one or more neutrophils with six or more lobes.
< Lekupenia and thrombocytopenia
+ The severity of all these changes parallels the degree of anemia.
+ Ina nonanemic patient:
“ The presence of few macrocytes and hypersegmented neutrophils in the peripheral blood may be the only
indication of the underlying disorder.
+ PERIPHERAL BLOOD
« Oval macrocytes, usually with considerable anisocytosis and poikilocytosis, are the main
feature
Y” MCV is usually >100 fL unless mixed with other cause of microcytosis (e.g., IDA or thalassemia trait)
“ Neutrophil hypersegmentation
y Neutrophil hypersegmentation (NH) is defined as the presence of
— >5% of neutrophils with five lobed nuecli or
— the presence of one or more neutrophils with six or more lobes.
< Lekupenia and thrombocytopenia
+ The severity of all these changes parallels the degree of anemia.
+ Ina nonanemic patient:
“ The presence of few macrocytes and hypersegmented neutrophils in the peripheral blood may be the only
indication of the underlying disorder.
Megaloblastic Anemia
Macroovalocytes in vitamin B12 deficiency Anisocytosis - Macrocytic Anemia
Macroovalocytes in vitamin B12 deficiency Anisocytosis - Macrocytic Anemia
Hypersegmented neutrophil
Hemolytic Anemia
* Defn: anemia due to shortened survival of circulating RBCs due to premature destruction.
+ There are numerous types of hemolytic anemia:
— Etiologic: inherited Vs acquired conditions:
= Clinical: acute Vs chronic processes,
— Severity: mild to potentially life-threatening severity.
— Anatomic site of Hemolysis: Intravascular Vs Extravascular
— Major defect for hemolysis: Intracorpuscular Vs Extracorpuscular
+ Intracorpuscular causes (intrinsic abnormalities of RBC Eg. Membrenopathies, Enzymopathty...) Vs
+ Extracorpuscular causes(in the circulation or RES)
+ The key finding that suggests hemolytic anemia is
— increased reticulocyte count that is not explained by recent bleeding or
recent correction of IDA or other nutrient deficiency.
+ Patients may also have evidence of RBC destruction including
— Increased LDH and bilirubin,
— decreased haptoglobin, and
— Spherocytes on the peripheral blood smear.
* Defn: anemia due to shortened survival of circulating RBCs due to premature destruction.
+ There are numerous types of hemolytic anemia:
— Etiologic: inherited Vs acquired conditions:
= Clinical: acute Vs chronic processes,
— Severity: mild to potentially life-threatening severity.
— Anatomic site of Hemolysis: Intravascular Vs Extravascular
— Major defect for hemolysis: Intracorpuscular Vs Extracorpuscular
+ Intracorpuscular causes (intrinsic abnormalities of RBC Eg. Membrenopathies, Enzymopathty...) Vs
+ Extracorpuscular causes(in the circulation or RES)
+ The key finding that suggests hemolytic anemia is
— increased reticulocyte count that is not explained by recent bleeding or
recent correction of IDA or other nutrient deficiency.
+ Patients may also have evidence of RBC destruction including
— Increased LDH and bilirubin,
— decreased haptoglobin, and
— Spherocytes on the peripheral blood smear.
General Clinical and Lab Features of HA
© The C/F is greatly influenced by whether the onset is abrupt or gradual.
“+ Autoimmune HA or with favism may be a medical emergency, whereas
«+ Mild hereditary spherocytosis or with cold agglutinin disease may be diagnosed after years.
v This is due to the of the body to adapt to anemia when it is slowly progressing
+ The differentiation of HAs from other anemias
+ the main sign of HA is jaundice; the patient may also have discoloration of the urine.
In many cases of HA, the spleen is enlarged
v because it is a preferential site of hemolysis, and in some cases liver may be enlarged as well.
«e In all severe congenital forms of HA, there also may be skeletal changes
Y” due to overactivity of the bone marrow (but never as severe as they are in thalassemia).
Table 106-2 Some Common Features of Hemolytic Disorders
General examination
Jaundice, pallor
Other physical findings
Spleen may be enlarged; bossing of skull in severe congenital cases
Hemoglobin level
From normal to severely reduced
MCV, MCH
Usually increased
Reticulocytes Increased
Bilirubin Increased (mostly unconjugated)
LOH Increased (up to 10x normal with intravascular hemolysis)
Haptoglobin
Reduced to absent (if hemolysis is part intravascular)
© The C/F is greatly influenced by whether the onset is abrupt or gradual.
“+ Autoimmune HA or with favism may be a medical emergency, whereas
«+ Mild hereditary spherocytosis or with cold agglutinin disease may be diagnosed after years.
v This is due to the of the body to adapt to anemia when it is slowly progressing
+ The differentiation of HAs from other anemias
+ the main sign of HA is jaundice; the patient may also have discoloration of the urine.
In many cases of HA, the spleen is enlarged
v because it is a preferential site of hemolysis, and in some cases liver may be enlarged as well.
«e In all severe congenital forms of HA, there also may be skeletal changes
Y” due to overactivity of the bone marrow (but never as severe as they are in thalassemia).
Table 106-2 Some Common Features of Hemolytic Disorders
General examination
Jaundice, pallor
Other physical findings
Spleen may be enlarged; bossing of skull in severe congenital cases
Hemoglobin level
From normal to severely reduced
MCV, MCH
Usually increased
Reticulocytes Increased
Bilirubin Increased (mostly unconjugated)
LOH Increased (up to 10x normal with intravascular hemolysis)
Haptoglobin
Reduced to absent (if hemolysis is part intravascular)
The lab features of HA are related to hemolysis and the erythropoietic response of BM.
Hemolysis produces increased unconjugated bilirubin; high urobilinogen in urine and stool
If hemolysis is mainly intravascular,
Y the telltale sign is hemoglobinuria (often associated with hemosiderinuria);
Y” in the serum there is increased hemoglobin and LDH with reduced haptoglobin
v In contrast, the bilirubin level may be normal or only mildly elevated.
The main sign of BM erythropoietic response is increased reticulocytes(RI>2.5-3%);
v The increased reticulocytes is associated with increased MCV in the blood count.
y On the blood smear, this is reflected in the presence of macrocytes; there is also polychromasia and
sometimes one sees nucleated red cells.
In most cases, a BM aspirate is not necessary in the diagnostic workup of HA;
v Ifitis done, it will show erythroid hyperplasia.
Hemolysis produces increased unconjugated bilirubin; high urobilinogen in urine and stool
If hemolysis is mainly intravascular,
Y the telltale sign is hemoglobinuria (often associated with hemosiderinuria);
Y” in the serum there is increased hemoglobin and LDH with reduced haptoglobin
v In contrast, the bilirubin level may be normal or only mildly elevated.
The main sign of BM erythropoietic response is increased reticulocytes(RI>2.5-3%);
v The increased reticulocytes is associated with increased MCV in the blood count.
y On the blood smear, this is reflected in the presence of macrocytes; there is also polychromasia and
sometimes one sees nucleated red cells.
In most cases, a BM aspirate is not necessary in the diagnostic workup of HA;
v Ifitis done, it will show erythroid hyperplasia.
Autoimmune Hemolytic Anemia (AIHA)
© AIHA is the most common form of acquired hemolytic anemia.
«+ Except for countries where malaria is endemic,
© Pathophysiology of AIHA
+ AIHA is caused by autoantibody against RBC antigen(a molecule on RBC surface)
The autoantibody binds to the red cells.
Once a red cell is coated by antibody, it will be destroyed.
+ destruction of RBCs will take place wherever macrophages are abundant, i.e., in spleen, liver, & BM
+ spleen is efficient in trapping antibody-coated RBCs: is the predominant site of RBC destruction.
Y most phagocytosis-mediated red cell destruction takes place in [spleen and liver]
V itis therefore called extravascular hemolysis.
«In severe cases even circulating monocytes can take part in this process,
© AIHA is the most common form of acquired hemolytic anemia.
«+ Except for countries where malaria is endemic,
© Pathophysiology of AIHA
+ AIHA is caused by autoantibody against RBC antigen(a molecule on RBC surface)
The autoantibody binds to the red cells.
Once a red cell is coated by antibody, it will be destroyed.
+ destruction of RBCs will take place wherever macrophages are abundant, i.e., in spleen, liver, & BM
+ spleen is efficient in trapping antibody-coated RBCs: is the predominant site of RBC destruction.
Y most phagocytosis-mediated red cell destruction takes place in [spleen and liver]
V itis therefore called extravascular hemolysis.
«In severe cases even circulating monocytes can take part in this process,
Mechanism of antibody-mediated immune destruction of red cells.
| rec Ai, —> compiomont —t Comploment activation —# Destroyed rad col
Immune hemolysis generally refers to RBC Ann re
destruction by antibodies and/or complement Reticuloendoihelal attack complox
proteins bound to the RBC surface. yay
Mononuclear
: : Ho di : . ohagocyte call &
It is characterized by a positive direct antiglobulin rc) y oles
test (DAT; also called direct Coombs test) and/or a
positive indirect antiglobulin test (also called
indirect Coombs test). er
Common causes of immune-mediated hemolysis
include AIHA, drug-induced hemolysis, and
hemolytic transfusion reactions.
Less-common causes of immune hemolysis include
paroxysmal cold hemoglobinuria and cold agglutinin
ñ Phacocytosis Fragmentation Cytotoxic
disease y Roco)”
NB: In some cases AIHA can be associated, on first presentation or
subsequently, with autoimmune thrombocytopenia [Evan’s syndrome]
| rec Ai, —> compiomont —t Comploment activation —# Destroyed rad col
Immune hemolysis generally refers to RBC Ann re
destruction by antibodies and/or complement Reticuloendoihelal attack complox
proteins bound to the RBC surface. yay
Mononuclear
: : Ho di : . ohagocyte call &
It is characterized by a positive direct antiglobulin rc) y oles
test (DAT; also called direct Coombs test) and/or a
positive indirect antiglobulin test (also called
indirect Coombs test). er
Common causes of immune-mediated hemolysis
include AIHA, drug-induced hemolysis, and
hemolytic transfusion reactions.
Less-common causes of immune hemolysis include
paroxysmal cold hemoglobinuria and cold agglutinin
ñ Phacocytosis Fragmentation Cytotoxic
disease y Roco)”
NB: In some cases AIHA can be associated, on first presentation or
subsequently, with autoimmune thrombocytopenia [Evan’s syndrome]
Lab features of HA
+ CBC(anemia), high LDH, high indirect bilirubin, Low haptoglobin, coomb’s test positive
High reticulocyte count or index
Blood smear: polychromatophilia, microspherocyts, fragmented RBCs
Peripheral blood smear in autoimmune hemolytic
anemia (AIHA)
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
This peripheral blood smear from a patient with AIHA due to a warm- platelets (arrows) and a normal lymphocyte (arrowhead) can also be
reactive immunoglobulin G (IgG) antibody demonstrates the presence of seen. The red cells are of relatively uniform size and shape. The
many dark red, small microspherocytes (red arrows) and larger diameter of the normal red cell should approximate that of the
spherocytes (black arrow) (x1000). Many large, irregular, blue-tinted nucleus of the small lymphocyte; central pallor (dashed arrow)
red cells are also present, representing reticulocytes (blue arrows). should equal one-third of its diameter.
+ CBC(anemia), high LDH, high indirect bilirubin, Low haptoglobin, coomb’s test positive
High reticulocyte count or index
Blood smear: polychromatophilia, microspherocyts, fragmented RBCs
Peripheral blood smear in autoimmune hemolytic
anemia (AIHA)
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
This peripheral blood smear from a patient with AIHA due to a warm- platelets (arrows) and a normal lymphocyte (arrowhead) can also be
reactive immunoglobulin G (IgG) antibody demonstrates the presence of seen. The red cells are of relatively uniform size and shape. The
many dark red, small microspherocytes (red arrows) and larger diameter of the normal red cell should approximate that of the
spherocytes (black arrow) (x1000). Many large, irregular, blue-tinted nucleus of the small lymphocyte; central pallor (dashed arrow)
red cells are also present, representing reticulocytes (blue arrows). should equal one-third of its diameter.
Peripheral smear in severe autoimmune hemolytic
anemia
Peripheral blood smear from a patient with Coombs-positive
autoimmune hemolytic anemia. The smear shows the presence of many
spherocytes (red arrows), one nucleated red blood cell (blue arrow),
and a number of larger polychromatophilic red cells (black arrows),
representing a reticulocytosis in response to the anemia.
anemia
Peripheral blood smear from a patient with Coombs-positive
autoimmune hemolytic anemia. The smear shows the presence of many
spherocytes (red arrows), one nucleated red blood cell (blue arrow),
and a number of larger polychromatophilic red cells (black arrows),
representing a reticulocytosis in response to the anemia.
Peripheral smear in microangiopathic hemolytic
anemia showing presence of schistocytes
DD
AS
1. MAHA
2. Prosthetic valves
3. Uremia (HUS)
4. Malignant HTN
Peripheral blood smear from a patient with a microangiopathic
hemolytic anemia with marked red cell fragmentation. The smear
shows multiple helmet cells (small black arrows), other fragmented
red cells (large black arrow); microspherocytes are also seen (blue
arrows). The platelet number is reduced; the large platelet in the
center (red arrow) suggests that the thrombocytopenia is due to
enhanced destruction.
anemia showing presence of schistocytes
DD
AS
1. MAHA
2. Prosthetic valves
3. Uremia (HUS)
4. Malignant HTN
Peripheral blood smear from a patient with a microangiopathic
hemolytic anemia with marked red cell fragmentation. The smear
shows multiple helmet cells (small black arrows), other fragmented
red cells (large black arrow); microspherocytes are also seen (blue
arrows). The platelet number is reduced; the large platelet in the
center (red arrow) suggests that the thrombocytopenia is due to
enhanced destruction.
Approach to the patient with anemia
Hx, P/E, and simple lab testing are all useful In evaluating the anemic patient.
Is the patient bleeding (now or in the past)?
Is there evidence for increased RBC destruction (hemolysis)?
Is the bone marrow suppressed?
Is the patient iron deficient? If so, why?
Does the patient has IP? PUD? LGIB?
Is the patient deficient in folic acid or vitamin B12? If so, why?
Hx, P/E, and simple lab testing are all useful In evaluating the anemic patient.
Is the patient bleeding (now or in the past)?
Is there evidence for increased RBC destruction (hemolysis)?
Is the bone marrow suppressed?
Is the patient iron deficient? If so, why?
Does the patient has IP? PUD? LGIB?
Is the patient deficient in folic acid or vitamin B12? If so, why?
History
+ Is the anemia of recent origin, subacute, or lifelong?
— Recent anemia is almost always an acquired disorder, while
— lifelong anemia, particularly if accompanied by a positive family history, is likely to be inherited (eg,
the hemoglobinopathies, hereditary spherocytosis).
* Is the anemia sever or not?
— Sever: Loss of consciousness, SOB, palpitation, hemodynamic compromize..
— Associated symptoms: Fever, jaundice, abdominal pain, abdominal swelling....?
+ Is there a Hx of medical condition which is known to result in anemia?
— Tarry stools in a patient with ulcer-type pain,
— Coffee ground vomiting in a CLD pt with abdominal swelling and Hx of jaundice
— rheumatoid arthritis, CKD?
+ Is the anemia of recent origin, subacute, or lifelong?
— Recent anemia is almost always an acquired disorder, while
— lifelong anemia, particularly if accompanied by a positive family history, is likely to be inherited (eg,
the hemoglobinopathies, hereditary spherocytosis).
* Is the anemia sever or not?
— Sever: Loss of consciousness, SOB, palpitation, hemodynamic compromize..
— Associated symptoms: Fever, jaundice, abdominal pain, abdominal swelling....?
+ Is there a Hx of medical condition which is known to result in anemia?
— Tarry stools in a patient with ulcer-type pain,
— Coffee ground vomiting in a CLD pt with abdominal swelling and Hx of jaundice
— rheumatoid arthritis, CKD?
The patient's ethnicity and country of origin may be helpful,
— thalassemias and other hemoglobinopathies are particularly common in patients from
the Mediterranean littoral, Middle East, sub-Saharan Africa, and South East Asia
— Residence or travel Hx: malaria endemic area?
The use of medications, both prescribed as well as over-the-counter,
A past Hx of blood transfusions, liver disease, herbal preparations, alcohol Hx
Menstrual history: Heavy, frequent menses
An assessment of nutritional status
— Is important in the elderly, alcoholics, Px and lactation, poor socioecomic groups.
— thalassemias and other hemoglobinopathies are particularly common in patients from
the Mediterranean littoral, Middle East, sub-Saharan Africa, and South East Asia
— Residence or travel Hx: malaria endemic area?
The use of medications, both prescribed as well as over-the-counter,
A past Hx of blood transfusions, liver disease, herbal preparations, alcohol Hx
Menstrual history: Heavy, frequent menses
An assessment of nutritional status
— Is important in the elderly, alcoholics, Px and lactation, poor socioecomic groups.
Physical examination
the presence or absence of tachycardia, dyspnea, fever, or postural hypotension should be noted
Pallor — pallor in the palms, nail beds, face, or conjunctivae
«+ The sensitivity & specificity to predict anemia varies from 19 to 70% and 70 to 100%, respectively
Jaundiced/icteric sclera
the presence or absence of lymphadenopathy,
hepatosplenomegaly,
Petichial rash, ecchymosis,
Bone tenderness, especially over the sternum
“+ Bone pain may signify expansion of marrow space due to:
v infiltrative disease, as CML, or acute leukemia
Y” lytic lesions as in multiple myeloma or
v metastatic cancer,
v TBinfiltrating to BM.
the presence or absence of tachycardia, dyspnea, fever, or postural hypotension should be noted
Pallor — pallor in the palms, nail beds, face, or conjunctivae
«+ The sensitivity & specificity to predict anemia varies from 19 to 70% and 70 to 100%, respectively
Jaundiced/icteric sclera
the presence or absence of lymphadenopathy,
hepatosplenomegaly,
Petichial rash, ecchymosis,
Bone tenderness, especially over the sternum
“+ Bone pain may signify expansion of marrow space due to:
v infiltrative disease, as CML, or acute leukemia
Y” lytic lesions as in multiple myeloma or
v metastatic cancer,
v TBinfiltrating to BM.
Laboratory evaluation
* Initial testing of the anemic patient should include CBC
— Hg and Hct- to grade the severity of anemia
— RBC distribution width (RDW), a measure of the degree of variation in RBC size.
* alone it does not indicate why the RBC varies in size (anisocytosis) or shapes (poikilocytosis)
— RBCindices — Three RBC indices are usually measured by automated blood counters:
* mean corpuscular volume[MCV=HCT/RBC (normal: 78-83 - 97-100fL)]
* mean corpuscular hemoglobin[MCH=HGB/RBC, Normal: 28 to 32pg/red cell]
* mean corpuscular hemoglobin concentration[MCHC=HGB/HCT, Normal: 31 to 34 g/dL]
% Pancytopenia in a patient with anemia should lead to consideration of
— bone marrow suppression or replacement or infiltration
— hypersplenism, or
— deficiencies of cobalamin or folate
Hemolytic Anemia + Thrombocythopenia with normal WBC: Evan's syndrome
* Initial testing of the anemic patient should include CBC
— Hg and Hct- to grade the severity of anemia
— RBC distribution width (RDW), a measure of the degree of variation in RBC size.
* alone it does not indicate why the RBC varies in size (anisocytosis) or shapes (poikilocytosis)
— RBCindices — Three RBC indices are usually measured by automated blood counters:
* mean corpuscular volume[MCV=HCT/RBC (normal: 78-83 - 97-100fL)]
* mean corpuscular hemoglobin[MCH=HGB/RBC, Normal: 28 to 32pg/red cell]
* mean corpuscular hemoglobin concentration[MCHC=HGB/HCT, Normal: 31 to 34 g/dL]
% Pancytopenia in a patient with anemia should lead to consideration of
— bone marrow suppression or replacement or infiltration
— hypersplenism, or
— deficiencies of cobalamin or folate
Hemolytic Anemia + Thrombocythopenia with normal WBC: Evan's syndrome
Reticulocyte count
* The ret count, helps to distinguish among the different types of anemia:
< Anemia with a high ret count reflects high erythropoietic response to hemolysis or blood loss
y Eg. Hemolytic anemia or anemia of blood loss
Y Hemolysis or blood loss can be associated with a low reticulocyte count
— if there is concurrent disorder of impaired RBC production (eg, infection, prior chemo)
“+ A stable anemia with low ret count is strong evidence for reduced BM response to the anemia
Y A low ret% accompanied by pancytopenia is suggestive of Aplastic anemia, while
Y” Zero ret% with normal WBC and platelet suggests a Dx of pure Red cell aplasia.
Reticulocyte Production Index (RPI) in adults: RPI = (Hct / 45) * Retic%/ Maturation correction
Maturation = 1.0 for Hct >=40%.
Maturation = 1.5 for Het 30 to 39.9%.
Maturation = 2.0 for Hct 20 to 29.9%.
Maturation = 2.5 for Hct <20%.
* The ret count, helps to distinguish among the different types of anemia:
< Anemia with a high ret count reflects high erythropoietic response to hemolysis or blood loss
y Eg. Hemolytic anemia or anemia of blood loss
Y Hemolysis or blood loss can be associated with a low reticulocyte count
— if there is concurrent disorder of impaired RBC production (eg, infection, prior chemo)
“+ A stable anemia with low ret count is strong evidence for reduced BM response to the anemia
Y A low ret% accompanied by pancytopenia is suggestive of Aplastic anemia, while
Y” Zero ret% with normal WBC and platelet suggests a Dx of pure Red cell aplasia.
Reticulocyte Production Index (RPI) in adults: RPI = (Hct / 45) * Retic%/ Maturation correction
Maturation = 1.0 for Hct >=40%.
Maturation = 1.5 for Het 30 to 39.9%.
Maturation = 2.0 for Hct 20 to 29.9%.
Maturation = 2.5 for Hct <20%.
In megaloblastic anemia
In MBA due to cobalamin deficiency ( <74 pmol/L (100 ng/L)
— Values between 74 and 148 pmol/L (100 and 200 ng/L) are regarded as borderline
— Normal serum levels range from 118-148 pmol/L (160-200 ng/L)
— Serum Methylmalonate(MMA) and Homocysteine
* recommended for the early Dx of cobalamin deficiency,
+ even in the absence of hematologic abnormalities or subnormal serum cobalamin
+ Homocysteine is elevated in both vit B12 and folate deficiencies, whereas
+ MMA is only elevated in vitamin B12 deficiency
+ The folate level [red cell folate is low in all folate-deficient patients].
— Normal serum range is from 11 nmol/L (2 g/L) upto ~82 nmol/L (15 pg/L).
— Normal RBC folate: 880-3520 pmol/L (160-640 ug/L) of packed red cells: More sensitive and specific
— Serum folate rises in severe cobalamin deficiency
+ because of the block in conversion of MTHF to THF inside cells
+ Peripheral morphology
In MBA due to cobalamin deficiency ( <74 pmol/L (100 ng/L)
— Values between 74 and 148 pmol/L (100 and 200 ng/L) are regarded as borderline
— Normal serum levels range from 118-148 pmol/L (160-200 ng/L)
— Serum Methylmalonate(MMA) and Homocysteine
* recommended for the early Dx of cobalamin deficiency,
+ even in the absence of hematologic abnormalities or subnormal serum cobalamin
+ Homocysteine is elevated in both vit B12 and folate deficiencies, whereas
+ MMA is only elevated in vitamin B12 deficiency
+ The folate level [red cell folate is low in all folate-deficient patients].
— Normal serum range is from 11 nmol/L (2 g/L) upto ~82 nmol/L (15 pg/L).
— Normal RBC folate: 880-3520 pmol/L (160-640 ug/L) of packed red cells: More sensitive and specific
— Serum folate rises in severe cobalamin deficiency
+ because of the block in conversion of MTHF to THF inside cells
+ Peripheral morphology
Methylmalonic Acid
5,10-methylene TH4
r folate Y Methylmalonyl-CoA Succinyl-CoA
/ \
5
5 TH
Fy folate $ Adenosyl Cobalamin
2\ 1 ;
\ 4
« S-methyl TH4 dé Vitamin By, (Cobalamin)
vitamin 812
vitamin Be Re ne
betaine
Methylcobalamin
Homocysteine
vitamin Bg
choline
CYSTEINE
Vit-B12 (cobalamin) is a cofactor in conversion of
methylmalonyl coenzyme A (CoA) to succinyl CoA and of
homocysteine to methionine.
Elevated levels of the substrates methylmalonic acid and
homocysteine can be used to detect ‘functional’ B12
deficiency despite normal serum B12 concentrations
5,10-methylene TH4
r folate Y Methylmalonyl-CoA Succinyl-CoA
/ \
5
5 TH
Fy folate $ Adenosyl Cobalamin
2\ 1 ;
\ 4
« S-methyl TH4 dé Vitamin By, (Cobalamin)
vitamin 812
vitamin Be Re ne
betaine
Methylcobalamin
Homocysteine
vitamin Bg
choline
CYSTEINE
Vit-B12 (cobalamin) is a cofactor in conversion of
methylmalonyl coenzyme A (CoA) to succinyl CoA and of
homocysteine to methionine.
Elevated levels of the substrates methylmalonic acid and
homocysteine can be used to detect ‘functional’ B12
deficiency despite normal serum B12 concentrations
Laboratory features in IDA
In severe, uncomplicated iron-deficiency anemia
+ the erythrocytes are hypochromic and microcytic;
+ the plasma iron concentration is diminished
+ the iron-binding capacity is increased
+ the serum ferritin concentration is low;
+ the marrow is depleted of stainable iron
Diagnosis of Microcytic Anemia
Tests Iron Inflammation | Thalassemia Sideroblastic
Deficiency Anemia
‘Smear Micro/hypo [Normal Micro/hypo with targeting | Variable
micro/hypo
El <30 <50 Normal to high Normal to high
TIBC >360 <300 Normal Normal
Percent saturation |<10 10-20 30-80 30-80
Ferritin (49/L) <ı5 30-200 50-300 50-300
Hemoglobin pattern [Normal Normal Abnormal with Normal
on electrophoresis B thalassemia; can be
normal with & thalassemia
Abbreviations: SI, serum iron; TIBC, total iron-binding capacity.
In severe, uncomplicated iron-deficiency anemia
+ the erythrocytes are hypochromic and microcytic;
+ the plasma iron concentration is diminished
+ the iron-binding capacity is increased
+ the serum ferritin concentration is low;
+ the marrow is depleted of stainable iron
Diagnosis of Microcytic Anemia
Tests Iron Inflammation | Thalassemia Sideroblastic
Deficiency Anemia
‘Smear Micro/hypo [Normal Micro/hypo with targeting | Variable
micro/hypo
El <30 <50 Normal to high Normal to high
TIBC >360 <300 Normal Normal
Percent saturation |<10 10-20 30-80 30-80
Ferritin (49/L) <ı5 30-200 50-300 50-300
Hemoglobin pattern [Normal Normal Abnormal with Normal
on electrophoresis B thalassemia; can be
normal with & thalassemia
Abbreviations: SI, serum iron; TIBC, total iron-binding capacity.
Diagnostic approach in HA
Accurate Hx and P/E is the cornerstone of the patient's evaluation
Rapid onset of pallor and anemia
Jaundice with increased indirect bilirubin concentration
History of pigmented (bilirubin) gallstones
Splenomegaly
Presence of circulating spherocytic red cells (eg, AIHA, congenital spherocytosis)
Other informative red cell shape changes
Accurate Hx and P/E is the cornerstone of the patient's evaluation
Rapid onset of pallor and anemia
Jaundice with increased indirect bilirubin concentration
History of pigmented (bilirubin) gallstones
Splenomegaly
Presence of circulating spherocytic red cells (eg, AIHA, congenital spherocytosis)
Other informative red cell shape changes
Increased serum lactate dehydrogenase (LDH) concentration
— specifically the LD1 and LD2 isoenzymes LDH-1: heart and red blood cells.
LDH-2 heart and red blood cells.
LDH-3: lymph tissue, lungs, platelets, pancreas.
LDH-4: liver and skeletal muscle
LDH-5. liver and skeletal muscle.
Reduced or absent level of serum haptoglobin
— haptoglobin binds to Hb released during intravascular or extravascular hemolysis
A positive direct antiglobulin test (Coombs test) (sensitivity 90-95% in AIHA)
Increased reticulocyte count, indicating the BM's response to the anemia
— specifically the LD1 and LD2 isoenzymes LDH-1: heart and red blood cells.
LDH-2 heart and red blood cells.
LDH-3: lymph tissue, lungs, platelets, pancreas.
LDH-4: liver and skeletal muscle
LDH-5. liver and skeletal muscle.
Reduced or absent level of serum haptoglobin
— haptoglobin binds to Hb released during intravascular or extravascular hemolysis
A positive direct antiglobulin test (Coombs test) (sensitivity 90-95% in AIHA)
Increased reticulocyte count, indicating the BM's response to the anemia
Management of patients with Anemia
“+ General support care: ABC of life
VA: Airway patency
vB: Breathing
vC: Circulation: crystalloid, Transfusion
“+ General support care: ABC of life
VA: Airway patency
vB: Breathing
vC: Circulation: crystalloid, Transfusion
Management of IDA
* Red cell transfusion is reserved for individuals who have
— Symptoms of anemia,
— cardiovascular instability,
— continued and excessive blood loss, and
— Anemic patients who require immediate intervention.
+ Indications for Parenteral iron therapy [(Iron injected=wt(kg)x2.3x(15-pt Hb)] + 0.5-1g
— Patients who are unable to tolerate oral iron,
— malabsorption,
— refractory to oral iron replacement
Oral iron replacement therapy
up to 200 mg of elemental iron per day can be given
oral iron preparations should be taken on an empty stomach
< The goal of therapy in IDA: repair the anemia, + stores at least 0.5-1 g of iron.
< The response to iron therapy varies, depending on EPO stimulus and rate of absorption
* Red cell transfusion is reserved for individuals who have
— Symptoms of anemia,
— cardiovascular instability,
— continued and excessive blood loss, and
— Anemic patients who require immediate intervention.
+ Indications for Parenteral iron therapy [(Iron injected=wt(kg)x2.3x(15-pt Hb)] + 0.5-1g
— Patients who are unable to tolerate oral iron,
— malabsorption,
— refractory to oral iron replacement
Oral iron replacement therapy
up to 200 mg of elemental iron per day can be given
oral iron preparations should be taken on an empty stomach
< The goal of therapy in IDA: repair the anemia, + stores at least 0.5-1 g of iron.
< The response to iron therapy varies, depending on EPO stimulus and rate of absorption
Tablet (Iron Content), mg| Elixir (Iron Content), mg in 5 mL
325 (65) 300 (60)
195 (39) 90 (18)
325 (107)
195 (64) 100 (33)
Ferrous gluconate |325 (39)
Polysaccharide iron| 150 (150)
Ferrous sulfate
Extended release
Ferrous fumarate
300 (35)
100 (100)
61
325 (65) 300 (60)
195 (39) 90 (18)
325 (107)
195 (64) 100 (33)
Ferrous gluconate |325 (39)
Polysaccharide iron| 150 (150)
Ferrous sulfate
Extended release
Ferrous fumarate
300 (35)
100 (100)
61
Expected response
Subjective improvement of well-being starts within 12-24hrs of treatment.
— If pagophagia (pica for ice) or restless leg syndrome is present, it often disappears almost as soon as
oral or iv iron therapy is begun
Reticulocytosis starts 3-4 days, peak 1 week followed by rise in Hb
— Patients with mild anemia may have little or no reticulocytosis.
— with moderate to severe anemia, a modest reticulocytosis, maximal in 7 to 10 days.
The hemoglobin concentration will rise slowly,
— usually beginning after 1-wek of treatment,
— rise about 2g/dL over the ensuing 3wks[criteria used to efficacy/response]
— The Hb deficit should be halved by approximately one month, and
— the hemoglobin level should return to normal by six to eight weeks.
— Continue the therapy to restore the iron store for 4-6months
Subjective improvement of well-being starts within 12-24hrs of treatment.
— If pagophagia (pica for ice) or restless leg syndrome is present, it often disappears almost as soon as
oral or iv iron therapy is begun
Reticulocytosis starts 3-4 days, peak 1 week followed by rise in Hb
— Patients with mild anemia may have little or no reticulocytosis.
— with moderate to severe anemia, a modest reticulocytosis, maximal in 7 to 10 days.
The hemoglobin concentration will rise slowly,
— usually beginning after 1-wek of treatment,
— rise about 2g/dL over the ensuing 3wks[criteria used to efficacy/response]
— The Hb deficit should be halved by approximately one month, and
— the hemoglobin level should return to normal by six to eight weeks.
— Continue the therapy to restore the iron store for 4-6months
Met of Autoimmune hemolytic anemia
+ AIHA can present as a medical emergency in some patients, especially those with underlying
cardiac disease.
“Immediate transfusion of packed RBCs may be needed.
© The aim of treatment is
«+ reducing the amount of antibody being produced
«+ reducing its efficiency in destruction of the red cells
«+ cessation of any possible offending drug (eg, penicillin)
«+ Identify and treat any underlying disease that might be present
+ AIHA can present as a medical emergency in some patients, especially those with underlying
cardiac disease.
“Immediate transfusion of packed RBCs may be needed.
© The aim of treatment is
«+ reducing the amount of antibody being produced
«+ reducing its efficiency in destruction of the red cells
«+ cessation of any possible offending drug (eg, penicillin)
«+ Identify and treat any underlying disease that might be present
Modality of treatment
«+ Identify and remove possible causes Eg. Drugs
“+ Patients with mild hemolysis require no treatment but observation
«+ Significant Warm autoimmune hemolysi:
= Glucocorticoids are frequently as the first therapy for warm AIHA
+ 1mg/kg per day of predenisolone
* When successful, a rising Hb is usually seen within one to three week.
= RITUXIMAB - monoclonal anti-CD20 antibody
+ Successful in warm AIHA, with or without glucocorticoids as 1st-line, or as 2" line therapy
= Splenectomy: second-line treatment for warm AIHA
" Splenectomy is nearly as efficient as corticosteroids in reducing hemolysis in patients with AIHA
= Immunosuppressive therapy: Azathioprine, cyclophosphamide
“ Cold autoimmune hemolysis -the hemolysis is usually mild
= The most useful single therapy is avoidance of cold
= Glucocorticoid, limited value
= splenectomy has limited value as liver is the predominant site for cold AIHA
«+ Identify and remove possible causes Eg. Drugs
“+ Patients with mild hemolysis require no treatment but observation
«+ Significant Warm autoimmune hemolysi:
= Glucocorticoids are frequently as the first therapy for warm AIHA
+ 1mg/kg per day of predenisolone
* When successful, a rising Hb is usually seen within one to three week.
= RITUXIMAB - monoclonal anti-CD20 antibody
+ Successful in warm AIHA, with or without glucocorticoids as 1st-line, or as 2" line therapy
= Splenectomy: second-line treatment for warm AIHA
" Splenectomy is nearly as efficient as corticosteroids in reducing hemolysis in patients with AIHA
= Immunosuppressive therapy: Azathioprine, cyclophosphamide
“ Cold autoimmune hemolysis -the hemolysis is usually mild
= The most useful single therapy is avoidance of cold
= Glucocorticoid, limited value
= splenectomy has limited value as liver is the predominant site for cold AIHA
Management of Megalobalstic anemia
“* Cobalamin deficiency:
Y” The typical adult dose: 1mg/wk IM until the deficiency is corrected and then once per month
= jin adults, oral dosing is equally effective, at a dose of Img orally once per day.
Y If symptomatic MBA, neurologic or neuropsychiatric symptoms or PX:
= img every other day for 2wks, then once monthly or until no further improvement is noted.
Y Bariatric surgery: 1 mg of oral vitamin B,, per day indefinitely
“ FOLATE DEFICIENCY
= Oral doses of 5-15 mg folic acid daily are satisfactory, for 4months
V Folate is absorbed from this large doses even with severe malabsorption.
V Long-term therapy is required when the underlying cause cannot be corrected
= Prophylaxis :
Y Px: 1- 5mg start preconception, through pregnancy,
y Supplemental folic acid reduces birth defects: 5 mg daily started preconception
“* Cobalamin deficiency:
Y” The typical adult dose: 1mg/wk IM until the deficiency is corrected and then once per month
= jin adults, oral dosing is equally effective, at a dose of Img orally once per day.
Y If symptomatic MBA, neurologic or neuropsychiatric symptoms or PX:
= img every other day for 2wks, then once monthly or until no further improvement is noted.
Y Bariatric surgery: 1 mg of oral vitamin B,, per day indefinitely
“ FOLATE DEFICIENCY
= Oral doses of 5-15 mg folic acid daily are satisfactory, for 4months
V Folate is absorbed from this large doses even with severe malabsorption.
V Long-term therapy is required when the underlying cause cannot be corrected
= Prophylaxis :
Y Px: 1- 5mg start preconception, through pregnancy,
y Supplemental folic acid reduces birth defects: 5 mg daily started preconception
Follow up
II E
Peripheral Morphology Megaloblastosis to Normoblastosis after 12hrs
Hypersegmented neutrophil begun to disappear from 10 to 14 days
Homocysteine or methylmalonic acid One week
level, or reticulocyte count (peak)
CBC 1. Reticulocytosis 3-4 days peak 1 week followed by rise in
hemoglobin starts at the 7-10‘ days & normalize 8' week
2. MCV starts to normalize after reticulocytosis
Neurologic Abnormalities 3 months to improve and resolved after 6-12 month
NB: Before large doses of folic acid are given, cobalamin deficiency must be excluded and, if
present, corrected; otherwise cobalaminneuropathy may develop despite a response of the anemia
of cobalamin deficiency to folate therapy.
II E
Peripheral Morphology Megaloblastosis to Normoblastosis after 12hrs
Hypersegmented neutrophil begun to disappear from 10 to 14 days
Homocysteine or methylmalonic acid One week
level, or reticulocyte count (peak)
CBC 1. Reticulocytosis 3-4 days peak 1 week followed by rise in
hemoglobin starts at the 7-10‘ days & normalize 8' week
2. MCV starts to normalize after reticulocytosis
Neurologic Abnormalities 3 months to improve and resolved after 6-12 month
NB: Before large doses of folic acid are given, cobalamin deficiency must be excluded and, if
present, corrected; otherwise cobalaminneuropathy may develop despite a response of the anemia
of cobalamin deficiency to folate therapy.
Management of ACD
The preferred initial therapy for ACD is correction of underlying disorder.
Other contributing factors should be treated, if present,
— Such as blood loss, iron deficiencies , folate and/or vitamin B12 deficiency
RBC transfusions or erythropoiesis-stimulating agent (ESA) are used for severe, symptomatic anemia.
— Itmay need blood transfusions or erythropoiesis-stimulating agent (eg, EPO, darbepoetin).
— Most patients with ACD have mild anemia that produces no symptoms,
Measurement of the plasma EPO may be helpful in patients with symptomatic ACD and/or who have not responded
to treatment of the underlying disorder
— Patients with Ca, RA, or AIDS who have EPO levels <500 mU/mL may respond to ESA
The preferred initial therapy for ACD is correction of underlying disorder.
Other contributing factors should be treated, if present,
— Such as blood loss, iron deficiencies , folate and/or vitamin B12 deficiency
RBC transfusions or erythropoiesis-stimulating agent (ESA) are used for severe, symptomatic anemia.
— Itmay need blood transfusions or erythropoiesis-stimulating agent (eg, EPO, darbepoetin).
— Most patients with ACD have mild anemia that produces no symptoms,
Measurement of the plasma EPO may be helpful in patients with symptomatic ACD and/or who have not responded
to treatment of the underlying disorder
— Patients with Ca, RA, or AIDS who have EPO levels <500 mU/mL may respond to ESA
References
Search Uptodate 21.6
{ AAFP
ritish Society for
Haematology
Listening - Learning - Leading
Search Uptodate 21.6
{ AAFP
ritish Society for
Haematology
Listening - Learning - Leading
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