ANEMIA

- a clinical condition which refers to the decreased in Hb/Hct or the RED BLOOD CELL
mass as a whole leading to decreased oxygen tension in the body.
According to McPherson (2011), ANEMIA is considered to be present if the hemoglobin (Hb)
concentration or the hematocrit (Hct) is below the lower limit of the 95% reference interval for
the individuals age, sex, and geographic location (altitude). This means that 2.5% of normal
individuals will be classified as anemic. Conversely, an individual whose Hb falls within the
reference intervals for age and sex yet significantly below his or her own reference values should
be considered anemic.
Since no one is certain of the true or general value of Hemoglobin and Hematocrit, we consider
the standardization of normal values depending on the average results/values of the patients in
terms of age, sex and geographic location.

- cannot be considered as a disease itself but only as a condition that is caused by an

underlying disorder.
- Anemia may be absolute, when red blood cell mass is decreased, or relative, when associated
with a higher plasma volume.
The manifestation of anemia may vary depending on the patients different modifying factors:
Cardiac Output, Respiratory Rate, Oxygen affinity of Hemoglobin, etc. This means that a
patient who is not severely ill may have a hemoglobin value of as low as 6g/dL without having
evident discomforts or other signs and symptoms as long as the patient is at rest. Consequently,
an average anemic person, who doesnt have severe condition, may have a hematocrit of 20 %
and only experience slight dyspnea. When compared to a geriatric patient when left untreated
might lead to death if presented with a hematocrit of 20%.

DIAGNOSIS is usually made through three general factors:

a. BLOOD PICTURE LAB FINDINGS
b. BONE MARROW ASPIRATE/BIOPSY FINDINGS
c. Specific tests depending on the underlying disease
ANEMIA is a complex condition and it is categorized in many different ways, below is an
example of a general classification of ANEMIA.

MORPHOLOGIC CLASSIFICATION OF ANEMIA:

1. MACROCYTIC
A. DISEASES OF THE LIVER
B. VITAMIN B12 DEFICIENCY/FOLIC ACID DEFICIENCY
- PERNICIOUS ANEMIA
-DIETARY
-SPRUE
-ABNORMAL INTRINSIC FACTOR
-FOLLOWING GASTRECTOMY
-TAPEWORM INFECTION
2. NORMOCYTIC
- APLASTIC ANEMIA
- LEUKEMIA
- HODGKIN DISEASE
- MULTIPLE MYELOMA
-LEUKOERYTHROBLASTOSIS
- METASTATIC CANCER
- ANEMIA ASSOC. WITH RENAL AND
ENDOCRINE DISORDERS
- HEMOLYTIC ANEMIA

- PNH
- SICKLE CELL ANEMIA
- HDN
- ANEMIA OF CHRONIC RENAL
INSUFFICIENCY

3. MICROCYTIC
- IRON DEFICIENCY ANEMIA
- THALASSEMIA
- SIDEROBLASTIC ANEMIAS
- CHRONIC BLOOD LOSS

ETIOLOGIC CLASSIFICATION OF ANEMIA

I. ABSOLUTE ANEMIA (decreased red cell volume)
A. DECREASED/IMPAIRED RED CELL PRODUCTION
A.1. ACQUIRED
A.1.1. PLURIPOTENT STEM CELL FAILURE
EXAMPLES:
APLASTIC ANEMIA
> RADIATION INDUCED
> DRUGS AND CHEMICALS (CHLORAMPHENICOL MOST COMMON, BENZENE, ETC.)
> VIRUSES (HEPATITIS VIRUS, EBV)
> IDIOPATHIC
ANEMIA OF LEUKEMIA AND OF MYELODYSPLASTIC SYNDROMES
ANEMIA ASSOCIATED WITH MARROW INFILTRATION
POSTCHEMOTHERAPY
A.1.2. ERYTHROID PROGENITOR CELL FAILURE
EXAMPLES:

PURE RED CELL APLASIA (PARVOVIRUS B19 INFECTION, DRUGS, THYMOMA

ASSOCIATED, AUTOANTIBODIES, ETC.
ENDOCRINE DISORDERS
ACQUIRED SIDEROBLASTIC ANEMIA (DRUG INDUCED, COPPER DEFICIENCY)
A.1.3. FUNCTIONAL IMPAIRMENT OF ERYTHROID AND OTHER
PROGENITORS DUE TO NUTRITIONAL AND OTHER CAUSES
EXAMPLES:
MEGALOBLASTIC ANEMIA
>B12 DEFICIENCY
>FOLATE DEFICIENCY
>ACUTE MEGALOBLASTIC ANEMIA DUE TO NITROUS OXIDE (NO)
>DRUG-INDUCED MEGALOBLASTIC ANEMIA (METHOTREXATE, PHENYTOIN
TOXICITY, PEMETREXED, ETC.)
IRON DEFICIENCY ANEMIA
ANEMIA RESULTING FROM OTHER NUTRITIONAL DEFICIENCIES
ANEMIA OF CHRONIC DISEASE AND INFLAMMATION
ANEMIA OF RENAL FAILURE
ANEMIA OF CHEMICAL AGENTS (LEAD TOXICITY)
ACQUIRED THALASSEMIAS (SOME CLONAL HEMATOPOIETIC DISORDERS)
ERYHTROPOIETIN ANTIBODIES
A.2. HEREDITARY
A.2.1. PLURIPOTENT STEM CELL FAILURE
EXAMPLES:
FANCONI ANEMIA
SHWACHMAN SYNDROME
DYSKERATOSIS CONGENITA
A.2.2. ERYTHROID PROGENITOR CELL FAILURE
EXAMPLES:
DIAMOND-BLACKFAN SYNDROME
CONGENITAL DYSERYTHROPOIETIC SYNDROMES
A.2.3. FUNCTIONAL IMPAIRMENT OF ERYTHROID AND OTHER
PROGENITORS DUE TO NUTRITIONAL AND OTHER CAUSES
EXAMPLES:
MEGALOBLASTIC ANEMIA
>SELECTIVE MALABSORPTION OF VITAMIN B12 (Imerslund-Grsbeck DISEASE)
>CONGENITAL INTRINSIC FACTOR DEFICIENCY
>TRANSCOBALAMIN II DEFICIENCY
>INBORN ERRORS OF COBALAMIN METABOLISM (METHYLMALONIC ACIDURIA,
HOMOCYSTINURIA, ETC.)
>INBORN ERRORS OF FOLATE METABOLISM (CONGENITAL FOLATE
MALABSORPTION, DIHYDROFOLATE DEFICIENCY, METHYLTRANSFERASE
DEFICIENCY, ETC.)
INBORN PURINE AND PYRIMIDINE METABOLISM DEFECTS (LESCH-NYHAN
SYNDROME, HEREDITARY OROTIC ACIDURIA, ETC.)
DISORDERS OF IRON METABOLISM

>HEREDITARY ATRANSFERRINEMIA
>HYPOCHROMIC ANEMIA DUE TO DMT1 MUTATION
HEREDITARY SIDEROBLASTIC ANEMIA
THALASSEMIAS
B. INCREASED RED CELL DESTRUCTION
B.1. ACQUIRED
B.1.1. MECHANICAL
EXAMPLES:
MACROANGIOPATHIC (MARCH HEMOGLOBINURIA, ARTIFICIAL HEART VALVES, ETC.)
MICROANGIOPATHIC (DISSEMINATED INTRAVASCULAR COAGULATION, DIC;
THROMBOTIC THROMBOCYTOPENIC PURPURA, TTP; VASCULITIS, ETC.)
PARASITES AND MICROORGANISMS (MALARIA, BARTONELLOSIS, BABESIOSIS,
CLOSTRIDIUM WELCHII, ETC.)
B.1.2. ANTIBODY-MEDIATED
EXAMPLES:
WARM-TYPE AUTOIMMUNE HEMOLYTIC ANEMIA
CRYOPATHIC SYNDROMES (COLD AGGLUTININ DISEASE, PAROXYSMAL COLD
HEMOGLOBINURIA, CRYOGLOBULINEMIA)
TRANSFUSION REACTIONS (IMMEDIATE AND DELAYED)
B.1.3. HYPERSPLENISM
B.1.4. RED CELL MEMBRANE DISORDERS
EXAMPLES:
SPUR CELL HEMOLYSIS
ACQUIRED ACANTHOCYTOSIS AND ACQUIRED STOMATOCYTOSIS, ETC.
B.1.5. CHEMICAL INJURY AND COMPLEX CHEMICALS (ARSENIC, COPPER,
CHLORATE, SPIDER, SCORPION, AND SNAKE VENOMS, ETC.)
B.2. HEREDITARY
B.2.1. HEMOGLOBINOPATHIES
EXAMPLES:
SICKLE CELL ANEMIA
UNSTABLE HEMOGLOBINS
B.2.2. RED CELL MEMBRANE DISORDERS
EXAMPLES:

CYTOSKELETAL MEMBRANE DISORDERS (HEREDITARY SPHEROCYTOSIS, ELLIPTOCYTOSIS,

PYROPOIKILOCYTOSIS)
LIPID MEMBRANE DISORDERS (HEREDITARY ABETALIPOPROTEINEMIA, HEREDITARY
STOMATOCYTOSIS, ETC.)
MEMBRANE DISORDERS ASSOCIATED WITH ABNORMALITIES OF ERYTHROCYTE ANTIGENS
(MCLEOD SYNDROME, RH DEFICIENCY SYNDROMES, ETC.)

MEMBRANE DISORDERS ASSOCIATED WITH ABNORMAL TRANSPORT (HEREDITARY

XEROCYTOSIS)
B.2.3. RED CELL ENZYME DEFECTS (PYRUVATE KINASE, 5' NUCLEOTIDASE, GLUCOSE-6PHOSPHATE DEHYDROGENASE DEFICIENCIES, OTHER RED CELL MEMBRANE DISORDERS)
B.2.4. PORPHYRIAS (CONGENITAL ERYTHROPOIETIC AND HEPATOERYTHROPOIETIC
PORPHYRIAS, RARELY CONGENITAL ERYTHROPOIETIC PROTOPORPHYRIA)

C. BLOOD LOSS/ REDISTRIBUTION

C.1. ACUTE BLOOD LOSS
C.2. SPLENIC SEQUESTRATION CRISIS
II. RELATIVE (increased plasma volume)
A. MACROGLOBULINEMIA
B. PREGNANCY
C. ATHLETES
D. POSTFLIGHT ASTRONAUTS
SPECIFIC ANEMIAS
ANEMIA DUE TO IMPAIRED HEME SYNTHESIS
>IRON DEFICIENCY ANEMIA
>SIDEROBLASTIC ANEMIA
>PORPHYRIAS
>IRON OVERLOAD

IRON DEFICIENCY ANEMIA

Iron is one of the most abundant metals in the world, yet IDA continues to be one the
most prominent nutritional disorders worldwide. Many factors contribute to this situation
and they need to be understood to have a fuller appreciation of iron balance.
Iron balance is regulated by several conditions: (a) the amount of iron ingested, (b)
the amount of iron absorbed, (c) red blood cell formation using recycled and new iron,
(d) iron stores, and (e) iron loss through blood loss or other sources.
When iron loss exceeds iron intake for a time long enough to deplete the bodys iron
stores, insufficient iron is available for normal Hb production. When well developed, iron
deficiency is characterized by a hypochromic, microcytic anemia.
IRON METABOLISM

3 STAGES OF IRON DEFICIENCY ANEMIA

STAGE I: Continuum of iron depletion from the marrow (Prussian blue stain will show absence of
iron)
STAGE II: Iron deficient erythropoiesis
Slight microcytosis, Slight decreased haemoglobin, Decreased transferrin saturation
STAGE III: Finally, a frank case of IDA in the peripheral circulation

(FRANK ANEMIA) IRON DEFICIENCY ANEMIA

Decreased serum iron, Decreased serum ferritin, Increased TIBC, Decreased transferring
saturation

* After iron stores are depleted, the plasma iron concentration falls, saturation of
transferrin falls below 15%, and the percentage of sideroblasts decreases in the marrow.
As a result of lack of iron for heme synthesis, red cell protoporphyrin increases.
LABORATORY FEATURES
A. BLOOD
> Blood picture
Early IDA - normochromic normocytic erythrocytes (Hillman, 1996)

Late IDA - microcytosis, anisocytosis, poikilocytosis (including elliptical and elongated

cells), and varying degrees of hypochromia.
The plasma membranes of iron-deficient cells are abnormally stiff, and this abnormality
contributes to the development of poikilocytes, particularly elongated hypochromic
elliptocytes (pencil cells).
Anisocytosis may be identified by automated blood counters as increased red cell
distribution width (RDW). This finding, however, is not specific for iron deficiency anemia.
Reticulocytes are usually decreased in absolute numbers, except following iron therapy.
>RBC indices and other parameters
MCV decreased
RDW - increased
Hb and Hct low values
Osmotic fragility test (OFT) decreased
WBC count normal to slightly decreased
Granulocytopenia and a small number of hypersegmented neutrophils may be present.
Megaloblastic changes in severe iron deficiency may be related to decreased activity of
the enzyme ribonucleotide reductase, which contains an essential nonheme iron atom
(Beck, 1991). However, the detection of hypersegmented neutrophils should raise
suspicion for a mild folate deficiency, which may become more overt after iron therapy
(Dallman, 1993).

Platelets - increased, whether the lack of iron is due to blood loss or dietary deficiency
(but tend to be decreased in severe anemia)
B. BONE MARROW FEATURES
> Normoblastic hyperplasia occurs early but decreased in the later stages of IDA
> Iron Stains should be performed routinely (storage iron is absent unless there is iron
administration prior to bone marrow examination)
>percent sideroblasts are decreased in the bone marrow (<20%)
OTHER SPECIFIC LABORATORY PARAMETERS:
A. SERUM IRON
NV: 50 160 ug/dL
B. SERUM TOTAL IRON BINDING CAPACITY (TIBC)
NV: 250 400 ug/dL

C. % SATURATION TIBC
- THE RATIO OF SERUM IRON TO TIBC IS THE PERCENT SATURATION OF TIBC
NV: 20 55%
D. SERUM FERRITIN
NV: 12 300 ug/dL
E. ERYTHROCYTE PROTOPORPHYRIN

CLINICAL MANIFESTATIONS:
1. ANGULAR STOMATITIS/SORE MOUTH
THE PRESENCE OF THESE
SYMPTOMS W/
2. GLOSSITIS/ ATROPHY OF THE EPITHELIAL CELLS OF THE TONGUE
WITH IRON DEFICIENCY
AND DYSPHAGIA IS
ALSO
REFERED TO AS

SYNDROME
3.
4.
5.
6.
7.

PLUMMER-VINSON

CHRONIC GASTRITIS
PARESTHAESIAS
TINGLING/NUMBNESS
KOILONYCHIA
WEAKNESS/FATIGUE

TREATMENT:

IRON THERAPY OR ADMINISTRATION AND THE UNDERLYING CAUSE SHOULD BE IDENTIFIED AND
CORRECTED.

SIDEROBLASTIC ANEMIA
Sideroblastic anemias are a heterogeneous group of disorders that have as common features the
presence of large numbers of ringed sideroblasts in the marrow, ineffective erythropoiesis,
increased levels of tissue iron, and varying proportions of hypochromic erythrocytes in the blood.
They may be acquired or hereditary.
Sideroblasts are erythroblasts containing aggregates of nonheme iron appearing as one or more
Prussian blue-positive granules on light microscopy
In normal subjects, 30 to 50 percent of marrow erythroblasts contain such granules, which, when
viewed by electron microscopy, are seen to be neither within mitochondria nor associated with
other cytoplasmic organelles.64 In contrast to the normal cytoplasmic location of siderotic
granules, the pathologic sideroblasts in the sideroblastic anemias exhibit large amounts of iron
deposited as dust or plaque-like ferruginous micelles between the cristae of mitochondria.

As with ANEMIA resulting from INADEQUATE supplies of IRON for production of

HEMOBLOBIN, diseases that INTERFERE with the PRODUCTION of adequate amounts
of HEME also can produce anemia.

CLASSIFICATION OF SIDEROBLASTIC ANEMIA:

1. HEREDITARY
A. X CHROMOSOME LINKED
A.1. ALAS2 DEFICIENCY

A.2. Hereditary sideroblastic anemia with ataxia: Mitochondrial ATP binding cassette (ABC7)
mutations
B. AUTOSOMAL
B.1. Mitochondrial myopathy and sideroblastic anemia (PSU1 mutations)
C. MITOCHONDRIAL
C.1. Pearson marrow-pancreas syndrome
C.2. Subunit 1 of the mitochondrial cytochrome oxidase
2. ACQUIRED
A. PRIMARY SIDEROBLASTIC ANEMIA
B. SIDEROBLASTIC ANEMIA SECONDARY TO:
- ISONIAZID
- PYRAZINAMIDE
- CYCLOSERINE
- CHLORAMPHENICOL

- ETHANOL

- LEAD
- CHRONIC NEOPLASTIC AND
INFLAMMATORY DISEASE
- ZINC
- ETC.

The red cells may be mixed with normochromic cells, so that the appearance is
dimorphic. The serum iron concentration is increased, the TIBC is decreased, and the
percent saturation of the iron-binding protein is greatly elevated.
LAB DIAGNOSIS:
PBS: Papenheimer Bodies; Basophilic stippling in Pb
poisoning; Dimorphic (macrocytic + intensely microcytic
RBCs) in patient w/ acquired sideroblastic a;
anisopoikilocytosis; Target cells
Serum Fe: Inc
Stigmata of a myelodysplastic syndrome
BM: Ringed sideroblasts on BM Fe stain; inc hemosiderin

HEME PATHWAY

PORPHYRINS
PORPHYRINS metabolic intermediates in the
biosynthetic pathway that has HEME as its
principal product.
-

PORPHIN NUCLEUS/PORPHYRIN
NUCLEUS
o BASIC STRUCTURE COMMON TO ALL PORPHYRINS

Porphyrins are differentiated by the substituents found in the EIGHT peripheral positions. Only
few porphyrins are found in nature and only 3 are of clinical significance: UROPORPHYRINS,
COPROPORPHYRINS, and PROTOPORPHYRINS

WHAT IS PORPHYRIA?

Porphyria is a term that refers to a group of disordersthe porphyriasthat affect the nervous
system or skin, or both. Each type of porphyria is due to the deficiency of one of the enzymes
needed to make a substance in the body called heme
GENERAL TYPES OF PORPHYRIA
Type of Porphyria

Deficient Enzyme

Acute Porphyrias
ALAD porphyria

delta-aminolevulinic acid dehydratase

acute intermittent porphyria

porphobilinogen deaminase

hereditary coproporphyria

coproporphyrinogen oxidase

variegate porphyria

protoporphyrinogen oxidase

Cutaneous Porphyrias
congenital erythropoietic porphyria uroporphyrinogen III cosynthase
porphyria cutanea tarda

uroporphyrinogen decarboxylase (~50% def)

hepatoerythropoietic porphyria

uroporphyrinogen decarboxylase (~90% def)

hereditary coproporphyria

coproporphyrinogen oxidase

variegate porphyria

protoporphyrinogen oxidase

erythropoietic protoporphyria

Ferrochelatase