ERYTHROCYTE (RBC) DISORDERS  Easy fatigability due to muscle hypoxia

Chamberlain I. Agtuca, Jr, MD  Cardiovascular: dizziness, SOB, worsening of IHD and HF

 Loss of concentration due to brain hypoxia
Anemias
 Hemoglobin (Hb) concentration or the hematocrit (Hct) is below the
lower limit of the 95% reference interval for the individual’s age, sex, and
geographic location (altitude)
 Anemia is not a disease, it is rather a manifestation of different diseases.

LABORATORY DIAGNOSIS OF ANEMIA

 Once anemia is discovered, the basic examination of the blood should
include the following:
o Hb, Hct, RBC count, RBC indices
o Blood film examination (PBS)
o Leukocyte count
o Platelet count
o Reticulocyte count
Normal Red Blood Cell  Evaluation of anemia should be guided by the morphologic findings and
 Under normal conditions, the circulating RBC has an average lifespan of the reticulocyte count
approximately 120 days  Morphologic characteristics providing etiologic clues:
 Non-nucleated, non-dividing cell o Red blood cell size (normocytic, microcytic, macrocytic)
 >90% of the protein content is oxygen-carrying molecule: hemoglobin o Degree of hemoglobinization (normochromic, hypochronic,
 Responsibility: deliver oxygen to the tissues of the body polychromatic)
 Primary consequence of anemia: Tissue hypoxia o Shape (poikilocytes, sickle cells, irregularly contracted forms,
spherocytes)
 Findings suggestive of hemolysis are poikilocytes (abnormally shaped
RBCs), sickle cells, irregularly contracted forms (including red cell
fragments or schistocytes), and spherocytes.

Etiology of Anemia
 Decreased production of RBC/hemoglobin (hypoproliferative
anemia)
 Increased destruction of RBC (hemolysis)
 Blood loss
 Sequestration

Effects of Anemia
Physiological: due to tissue hypoxia
 Increased 2,3 DPG in RBC (helps to deliver more O2 to tissues)
Most useful red cell indices
 Increased cardiac output (HR and stroke volume)
 Redistribution of blood flow to vital organs

Clinical:
 Pallor of the skin and mucous membranes

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 Megaloblastic Marrow

If the marrow is megaloblastic: the anemia is

d/t folate (B9) or cobalamin (B12) deficiency

Once the type of deficiency is defined, the

cause must be determined.

Nonmegaloblastic Marrow:
 Mean cell volume (MCV): the average volume of a red cell
 Conditions that can be associated with macrocytosis should be
expressed in femtoliters (fL)
 Mean cell hemoglobin (MCH): the average content (mass) of investigated:
hemoglobin per red cell, expressed in picograms (pg) o liver disease
 Mean cell hemoglobin concentration (MCHC): the average o hemolytic anemias
concentration of hemoglobin in a given volume of packed red cells, o hypothyroidism
expressed in grams per decilter (g/dL) o excessive alcohol intake
 Red cell distribution width (RDW): the coefficient of variation of o hypoplastic anemias
red cell volume
o refractory anemias with hyperplastic bone marrow (MDS)
Normal Values for Red Blood Cell Measurements (INDICES) Microcytic and Hypochromic Anemias
 (Decreased MCV and MCH)
o MCV has assumed the leading role in the detection of microcytic
hypochromic anemias.
o These anemias reflect a quantitative defect in Hb synthesis.
 Major causes of microcytic anemia:
o Iron deficiency anemias – are due to increased requirement or
blood loss not balanced by intake.
o ACD is associated with infection, neoplasia, or collagen disease.
LABORATORY DIAGNOSIS OF ANEMIA ̶ may be normochromic and normocytic, but in longstanding
disease is often hypochromic and microcytic
o Thalassemia – is a genetically determined impairment in the rate of
globin synthesis
o Sideroblastic anemia – that group of refractory anemias with
Interpretation of BMA for Macrocytic Anemia erythroid hyperplasia of the marrow in which a defect in Hb
synthesis creates a population of hypochromic microcytic cells
Macrocytic Anemia (Increased MCV) ̶ blood film is dimorphic, macrocytes may prevail
̶ MCV = normal or high, particularly in acquired forms of
sideroblastic anemia.
Normochromic (determined by PBS and MCHC)  Because iron deficiency is the most common anemia, first step:
determine whether the body lacks iron.
 When blood loss cannot be documented, serum ferritin, serum iron and
First step: ascertain whether the anemia is megaloblastic
iron-binding capacity, or bone marrow study for iron should be
performed.
Clues: combination of oval macrocytes (especially egg  Hypochromic anemias (or erythrocytoses) with basophilic stippling, Nº or
macrocytes) and hypersegmented neutrophils d serum iron = thalassemias
 next exams: Hb electrophoresis; determination of Hb A2 and Hb F;
BMA should be performed to confirm the presence of
Family studies
megaloblastosis

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Normocytic and Normochromic Anemias (Normal MCV)
 A useful approach is evaluation of the erythrokinetics
 Reticulocyte production index (RPI) and examination of the bone marrow
will suffice

Intravascular versus Extravascular Hemolysis

BLOOD LOSS ANEMIA

Acute Posthemorrhagic Anemia
 Blood lost externally or internally into a tissue space or body cavity
 Earliest hematologic change: transient fall in platelet count, which may
Rise to elevated levels within an hour
 Next development: moderate neutrophilic leukocytosis with a shift to
the left
 A maximum leukocyte count of 10–35 × 109/L may occur in 2–5 hours
 Hb and Hct do not fall immediately; may not reveal the full extent of red
cell loss until 2 or 3 days after the hemorrhage
 At first is normochromic and normocytic, with a normal MCV and MCHC,
and only minimal anisopoikilocytosis
 Reticulocytes begin to reach the circulation in 3–5 days, reaching a
maximum by 10 days or so
 Transient macrocytosis (increased MCV), increased polychromasia, and
normoblasts may appear in the blood
 It takes about 2–4 days after blood loss for the WBC count to return to
normal, and about 2 weeks for the morphologic changes to disappear

Chronic Posthemorrhagic Anemia

 Significant anemia does not usually develop until after storage iron is
depleted  IDA
 At first normochromic and normocytic, and gradually the newly formed
red cells become microcytic, then hypochromic
 WBC count is normal or slightly decreased, owing to neutropenia
 Platelets are commonly increased  later in severe iron deficiency:
decreased
 Cause of blood loss must be identified: a hidden malignancy (GI tract)
may be the cause of the anemia

Hemolytic Anemias
 Cytoskeletal disorders
 Enzyme disorders
 Structurally abnormal hemoglobin variants (hemoglobinopathies)
 Thalassemia
 Paroxysmal Nocturnal Hemoglobinuria
 Immune hemolytic disorders

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CYTOSKELETAL DISORDERS Hereditary Stomatocytosis (HSt)
 Red cells have an elongated, mouthlike, central pallor, in association
with abnormal sodium/potassium permeability
Hereditary
 HSt syndromes have a marked tendency towards thrombosis following
Hereditary elliptocytosis (HE)/ Hereditary
spherocytosis (HS) Hereditary stomatocytosis splenectomy
ovalocytosis  Two main types:
o Hydrocytotic (overhydrated) type – severe, red cells take on extra
wate
Hereditary Spherocytosis ̶ hydrocytosis syndromes are characterized by stomatocytosis,
 Inherited defect of RBC cytoskeleton-membrane tethering proteins macrocytosis, moderate to severe hemolysis, low MCHC
 Mostly commonly involves ankyrin, spectrin, or band ̶ affected red cells have decreased production of membrane
 Membrane blebs are formed and lost over time protein stomatin
 Spherocytes are less able to manuever through splenic sinusoids and are o Xerocytotic type – less severe, red cells lose water
consumed by splenic macrophages  anemia ̶ normocytic red cells characterized as spiculated dessicocytes,
accompanied by mild stomatocytosis and target cells
Clinical findings:
 Splenomegaly ENZYME DISORDERS
 Jaundice with conjugated bilirubin
 Increased risk of bilirubin gallstones (extravascular hemolysis)
Glucose-6-
Pyrimidine 5’
Laboratory findings: phosphate Pyruvate kinase
nucleotidase
dehydrogenase (PK) deficiency
 Most characteristic CBC abnormality: increased MCHC (G6PD) deficiency
deficiency
 PBS shows spherocytes, lacking in central pallor
 Elevated reticulocyte count
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
 LD and bilirubin are elevated
 X-linked recessive disorder resulting in reduced half-life of G6PD
 Osmotic fragility or autohemolysis test may be used for screening
 RBCs are normally exposed to oxidative stress, in particular H2O2
Osmotic fragility test  Glutathione (an antioxidant) neutralizes H2O2, but becomes oxidized in
the process
 Performed by incubating red cells in incrementally hypotonic NaCl
solutions and measuring the degree of hemolysis  NADPH, a by product of G6PD, needed to regenerate reduced
glutathione
 Spherocytic cells hemolyze more readily in hypotonic saline
  G6PD   NADPH   reduced glutathione  oxidative injury by
 Test merely serves to identify the presence of spherocytes from any
H2O2  intravascular hemolysis
cause
 RBC G6PD is exceptionally fragile and short-lived
Autohemolysis test  hypersensitive to sources of oxidative stress: medications (methylene
 Performed by incubating the red cells at 37ºC for 48 hours and blue, sulf-containing drugs, nitrofurantoin, primaquine), fava beans,
measuring hemolysis infection
 HS cells autohemolyze more readily  Presents with hemoglobinuria and back pain hours after exposure to
oxidative stress
 may be corrected by incubating with excess glucose as energy source
 After oxidant exposure: PBS shows poikilocytosis, Heinz bodies, bite
Differential Diagnosis of Spherocytes in peripheral blood film cells, blister cells
 Hereditary Spherocytosis  Oxidative stress precipitates Hb as Heinz bodies
 Immune-mediated Hemolysis  Heinz bodies are removed from the RBCs by splenic macrophages  bite
o Perform Coombs test: cells
 HS is negative for DAT
 Immune-mediated Hemolysis is positive for DAT

Hereditary Elliptocytosis (HE)/ Hereditary Ovalocytosis

 HE is diagnosed when >25% of circulating red cells are elliptocytes
 Three types:
o Common HE type
 Variant: Hereditary pyropoikilocytosis – RBC sensitive to heat
o Spherocytic type
o Stomatocytic type / Southeast Asian Ovalocytosis (SAO)

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 THALASSEMIAS
Heinz preparation is used to screen for disease  usually results from underproduction of normal globin proteins, often
through mutations in regulatory genes.
Enzyme studies confirm deficiency (performed weeks after  The two conditions may overlap since some conditions which cause
hemolytic episode resolves)
abnormalities in globin proteins (hemoglobinopathy) also affect their
production (thalassemia)
 Fluorescent spot test is performed by incubating RBCs with NADP and
G6P and measuring the production of NADPH Hemoglobin A (most common Hgb in adults)
 Note: G6PD is abundant in younger RBCs, older cells are selectively  a tetramer composed of 2 α and 2 β chains
destroyed during acute hemolytic episodes  α genes are located on chromosome 16
o The surviving RBCs have a normal G6PD activity  β genes are located on chromosome 11p15.5
o Testing may yield false negative (normal) results  there is 1 copy of the β gene on each chromosome 11
o Repeat testing in >3 months should confirm the diagnosis  total of 2 productive genes in normal cells
• In adult life, the capacity to produce β chain substitutes (δ and γ) is
Pyruvate Kinase (PK) Deficiency preserved
 Inherited as an autosomal recessive trait  diminished production of β can be partially be compensated by
 PK catalyzes the rate-limiting step in the Embden-Meyerhof pathway increased production of HbA2 and HbF
(main source of RBC ATP) • There are 2 copies of α genes on each chromosome 16 = total of 4 α
 ATP depletion causes impaired ion pumps, RBC dehydrogenase  chain-producing gene loci in each normal cell
hemolysis • Even at birth, the capacity to produce α chain substitute is lost
 Echinocytes (dessicocytes) are classical PBS findings which appear in  no transcriptional way to compensate for α chain defect
large numbers after splenectomy • Refer to the production of a structurally abnormal globin chain
 Autohemolysis test is positive • Structurally abnormal hemoglobins are results of genetic alterations in
o Unlike HS, autohemolysis does not correct with addition of glucose, the coding sequence of α and β genes
it does normalize with addition of ATP  anomalies in posttranslational modification of normal hemoglobin
 A fluorescent spot test may be used for screening
o RBCs are incubated with NADH (which fluoresces under UV light at Hemoglobin Chains Role
340 nm) to check for conversion to NAD HbA α2β2 Major adult hemoglobin (alpha/beta)
 Quantitative PK assay is used for confirmation
o Measures the rate of decrease of absorbance at 340 nm HbA2 α2δ2 Minor adult hemoglobin (alpha/delta)

HbF α2γ2 Major late fetal Hb (alpha/gamma)

Pyrimidine 5’ Nucleotidase Deficiency
 Responsible for degradation of RNA that is present within reticulocyte Hb Gower1 ζ2ε2 Major early fetal Hb (sigma/epsilon)
 changes the tinctorial features of reticulocytes to resemble those of a
mature erythrocyte Hb Gower 2 α2ε2 Minor early fetal Hb (alpha/epsilon)
 Unmetabolized pyrimidine precipitate w/in the cell as basophilic
stippling  cause hemolysis
Variant Amino acid Alteration
HEMOGLOBINOPATHIES S 6 Glu  Val
 Genetic defect resulting in abnormal structure of one of the (4) globin
chains of hemoglobin C 6 Glu  Val
 Inherited as single-gene disorders; in most cases, as autosomal co-
CHarlem 6 and 73 Glu  Val and Asp  Asn
dominant traits
 Most common in populations from Africa, the Mediterranean basin and E 26 Glu  Lys
Southeast Asia.
 Imply structural abnormalities in the globin proteins themselves. D (D-Los Angeles, D-Punjab 121 Glu  Gln
 Many hemoglobin variants do not cause pathology or anemia, thus are
not classed as hemoglobinopathies OArab 121 Glu  Lys
 HEMOGLOBIN VARIANTS - part of the normal embryonic and fetal
development, but may also be pathologic mutant forms of hemoglobin
in a population

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Sickle Cell Anemia Laboratory findings
• Autosomal recessive mutation in β chain of hemoglobin • Sickle cells and target cells are seen in PBS in sickle cell disease but not in
• a single AA change replaces normal glutamic acid (hydorphilic) with valine sickle cell trait
(hydrophobic) • Metabisulfite screen causes cells with any amount of HbS to sickle;
• Gene is carried by 10% of individuals of Africal descent, d/t protective role positive in both disease and trait
vs falciparum malaria • Hb electrophoresis confirms the presence and amount of HbS
• Sickle cell disease arises when two abnormal β genes are present  – Disease – 90% HbS, 8% HbF, % HbA2 (no HbA)
results in >90% HbS in RBCs – Trait – 55% HbA, 43% HbS, 2% HbA2
• HbS polymerizes when deoxygenated  polymers aggregate to needle-
like structures  sickle cells
 Increased risk of sickling occurs with hypoxemia, dehydration, and
acidosis
 HbF protects against sickling
  HbF at birth is protective for the first few months of life Hemoglobin C (β6 glu  lys)
 Treatment with hydroxyurea increases levels of HbF a. Hemoglobin C disease (homozygous CC)
• Cells continuously sickle and de-sickle while passing thru the • Autosomal recessive mutation in β chain of hemoglobin
microcirculation • Normal glutamic acid is replaced by lysine
 complications related to RBC membrane damage • Less common than sickle cell disease
1. Extravascular hemolysis • Electrophoretic pattern: 90% HbC, 7% HbF, HbA2, 0% HbA
– RES removes RBCs with damaged membranes • Characterized by mild hemolytic anemia, splenomegaly,
 anemia, jaundice with unconjugated numerous target cells
hyperbilirubinemia, increased risk for bilirubin gallstones • Characteristic HbC crystals are seen in RBCs on PBS
2. Intravascular hemolysis b. Hemoglobin C trait (heterozygous AC)
– RBCs with damaged membranes dehydrate ● Electrophoretic pattern: 40-50% Hb within the C band
 hemolysis with decreased haptoglobin and target cells (contains both HbA2 and HbC)
on blood smears ● Generally asymptomatic
3. Massive erythroid hyperplasia ensues resulting in ● Scattered target cells in PBS
- expansion of hematopoiesis into the skull (“crewcut” Hemoglobin E (β26 glu  lys)
appearance on Xray) and facial bones (“chipmunk facies”) • Common in Southeast Asia
- Extramedullary hematopoiesis with hepatomegaly • Second most common abnormal hemoglobin worldwide
- Risk of aplastic crisis with parvovirus B19 infection of erythroid • CBC shows thalassemic indices
precursors • PBS shows numerous target cells
• Electrophoresis: abnormal band in the C band (with A2)
• By itself Hb E is benign; coexistence with thalassemia may be clinically
severe
Methemoglobin (Hi, hemiglobin)
• Hemoglobin in which iron is in the oxidized ferric (Fe+++) state instead of
ferrous (Fe++)
• Incapable of combining oxygen
• In normal circumstances: Hi is 15% of total Hb
• Hereditary methemoglobin – result from deficiency in the methemoglobin
reductase system or abnormal hemoglobins (HbM), e.g. cytochrome
Expansion of hematopoiesis into the skull (“crewcut” appearance on X-Ray) b5r deficiency
and facial bones (“chipmunk facies”). • Acquired methemoglobin – result from exposure to drugs or chemicals
that increase the formation of Hi (nitrites, quinones, phenacetin,
Sickle cell trait sulfonamides)
• the presence of one mutated and one normal β chain  <50% HbS in • Elevated Hi presents with cyanosis and poor tissue oxygenation
RBCs (HbA is slightly more efficiently produced than HbS) • Cyanosis results when Hi reaches 10% of total Hb or ~1.5 g.dL
• asymptomatic with no anemia • Blood is grossily chocolate brown
• RBCs <50% HbS do not sickle in vivo except in the renal medulla • Cooximeter is capable of measuring Hi directly
– xtreme hypoxia and hypertonicity of the medulla cause sickling  • Both pulse oximetry and ABG analyzers estimate O2 satn by
microinfarctions  microscopic hematuria  decreased emitting a red light (660 nm) absorbed mainly by reduced Hb and
ability to concentrate urine an infrared light (940 nm) absorbed by oxyhemoglobin
• Hi has a very high affinity for cyanide
• Tx is methemoglobinemia is methylene blue (reduces Hi to Hb)

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Sulfhemoglobin (SHb) β-Thalassemia
• Formed when Hb is oxidized in the presence of sulfur • Due to gene mutations (point mutation in promotor or splicing
• If further oxidized, SHb precipitates to form Heinz bodies sites)
• SHb cannot transport oxygen • mutations result in absent (β0) or diminished (β+) production of the
• Normally, SHb is <1% of total Hb β-globin chain:
• SHb cannot be reduced to Hb 1. Β-Thalassemia major (β0/β0)
• Cyanosis manifests at around 3-4% or 0.5 g/dL 2. β-Thalassemia minor (β/β+)
Carboxyhemoglobin (HbCO)
• CO binds tightly (with 200X the affinity of O2) to Hb forming HbCO  β-Thalassemia Major (β0/β0)
reducing the available binding sites for oxygen • Most severe form of disease
• CO has even greater avidity for fetal Hb  great risk for infants and • Presents with severe anemia a few months after birth
fetuses • High HbF at birth is temporarily protective
• CO is directly toxic to intracellular oxidative mechanisms and appears to • α tetramers aggregate and damage RBCs, resulting in ineffective
enhance production of NO  vasodilation erythropoiesis and extravascular hemolysis (removal of circulating
• Measured by cooximeter RBCs by the spleen)
• Venous blood is as good as arterial blood for • Massive erythroid hyperplasia ensues resulting in
determination • Expansion of hematopoiesis into the skull (crewcut
• Blood gas analyzers do not measure hemoglobin variants appearance on Xray) and facial bones (chipmunk facies)
and determine oxyhemoglobin by calculation  Extramedullary hematopoiesis with hepatosplenomegaly
• Pulse oximetry may give falsely reassuring O2 satn  Risk of aplastic crisis with parvovirus b19 infection of erythroid
• Oxygen gap (difference between pulse oximetry and cooximetry) reflects precursors
the level of HbCO  Chronic transfusions are often necessary; leads to risk for secondary
Additional lab testing for CO poisoning: hemochromatosis
• Measurement of lactate  Smear show microcytic, hypochromic RBCs with target cells and
• Calculation of anion gap nucleated RBCs
• Myocardial markers  Electrophoresis shows HbA2 and HbF with little or no HbA
• Cyanide levels
• CO is eliminated by slowly being replaced by O2 on Hb molecules β-Thalassemia Minor (β/β+)
• Half-life of CO depends on the O2 tension • Mildest form of disease
• Room air: ~ 6 hours • Usually asymptomatic with an increased RBC count
• 100% O2: 1 hr • Microcytic, hypochromic RBCs and target cells are seen in blood smears
Thalassemia • Hemoglobin electrophoresis shows slightly decreased HbA with
• Refers to a quantitative abnormality of structurally normal globin chain increased HbA2 (5%) and HbF (2%)
synthesis
 globin   hemoglobin  microcytic anemia Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Inherited mutation; carriers are protected against Plasmodium falciparum • Acquired defect in myeloid stem cells resulting in absent
malaria glycosylphosphatidylinositol (GPI)  renders cells susceptible to
• Divided into α- and β-thalassemia based on decreased production of alpha destruction by complement
or beta globin chains • Blood cells coexist with complement
α-Thalassemia • Decay accelerating factor (DAF) on the surface of blood cells protects
• Due to gene deletion: against complement-mediated damage by inhibiting C3 convertase
 One gene deleted – asymptomatic • DAF is secured to the cell membrane by GPI (an anchoring protein)
 Two genes deleted – mild anemia with  RBC count; cis deletion is • Absence of GPI leads to absence of DAF, rendering cells susceptible to
associated with an increased risk of severe thalassemia in offspring complement-mediated damage
 Cis deletion is when both deletions occur on the same • Intravascular hemolysis occurs episodically, often at night during sleep
chromosome • Mild respiratory acidosis develops with shallow breathing during sleep
 Trans deletion is one deletion occur on each chromosome and activates complement
 Three genes deleted • RBCs, WBCs, platelets are lyzed
– severe anemia • Intravasculacular hemolysis leads to hemoglobinemia and
– β chains form tetramers (HbH) that damage RBCs; HbH is seen on hemoglobinuria
electrophoresis • Screening tests: Ham test, Sucrose hemolysis test – low sensitivity
 Four genes deleted  Sucrose hemolysis test
– lethal in utero (hydrops fetalis) - performed by incubating the patient’s RBC in serum and isotonic
– γ chains form tetramers (Hb Barts) that damage RBCs; Hb Barts is sucrose (promotes complement binding)
seen on electrophoresis

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 - enhanced hemolysis in comparison with control RBCs is consistent Iron Deficiency Anemia
with PNH  Due to decreased levels of iron
 Acidified serum (Ham) test   iron   heme   Hb  microcytic anemia
- performed by incubating RBCs in heterologous and  Most common type of anemia
homologous serum that has been acidified (activating – Lack of iron is the most common nutritional deficiency in the world,
complement) affecting roughly 1/3 of world’s population
- hemolysis in both types of sera is consistent with PNH  Iron is consumed in heme (meat-derived) and non-heme (vegetable
 Confirmatory test is flow cytometry to detect lack of CD55 (DAF) on cells, derived) forms
A more sensitive diagnostic procedure  Absorption or iron occurs in the duodenum
 Main cause of death is thrombosis of the hepatic, portal, or cerebral – enterocytes have heme and non-heme (DMT1) transporters
veins – heme form is more readily absorbed
o Destroyed platelets release cytoplasmic contents into • Enterocytes transport iron across the cell membrane into the blood via
circulation, inducing thrombosis ferroportin
 Complications include IDA and AML which develops in 10% of • Transferrin transports iron in the blood and delivers it to liver and BM
patients macrophages for storage
• Stored intracellular iron is bound to ferritin, which prevents iron from
Immune Hemolytic Anemia (IHA) forming free radicals via the Fenton reaction
 Antibody-mediated (IgG or IgM) destruction of RBCs • Fe is stored in two forms: ferritin and hemosiderin
 IgG-mediated disease usually involves extravascular hemolysis • Ferritin
o IgG binds RBCs in the relatively warm temperature of the – Ferric Fe complexed to a protein called apoferritin
central body (warm agglutinin) – Hepatocytes are the main site of ferritin storage
o Associated with SLE (most common cause), CLL, certain – Minute quantities are present in plasma in equilibrium with the
drugs (PCN, Cephalosporins) intracellular ferritin
 IgM-mediated disease usually involves intravascular hemolysis – Hemosiderin
o IgM binds RBCs and fixes complement in the relatively – Aggregates or crystals of ferritin with the apoferritin partially removed
cold temperature of the extremities (cold agglutinins) – Macrophage-monocyte system is the main source of hemosiderin
o Associated with Mycoplasma pneumoniae and infectious Causes of IDA
mononucleosis Physiologic Causes:
 Coombs test is used to diagnose IHA • Increased need for iron in the body
 Direct Coombs test confirms the presence of antibody-coated RBCs • Infancy
– Anti-IgG is added to patient RBCs • Adolescence, menstruation
– Agglutination occurs if RBCs are already coated with • Pregnancy, lactation
antibody Pathologic Causes:
– Most important test foe IHA • In adult males and postmenopausal females, Fe defieciency is
 Indirect Coombs test confirms the presence of antibodies in patient usually related to chronic blood loss mainly from GIT
serum • Dietary deficiencies (rarely the only etiology)
– Anti-IgG and test RBCs are mixed with the patient serum – Cow’s milk (infant diet)
– Agglutination occurs if serum anitbodies are present – Poor dietary iron intake (elderly)
• Absorption imbalances
Anemias of Diminished Erthrocytosis – Post-gastrectomy
– malabsorption
• Hemorrhage
 Iron deficiency anemua – Obvious causes – menorrhagia
 Megaloblastic anemia – Occult – peptic ulcer disease, aspirin, GIT CA,
 Anemia of folate and B12 deficiency ankylostoma
 Anemia of chronic disease • Intravascular hemolysis, iron will be lost in the urine
 Aplastic anema Stages of Iron Deficiency
 Pure red cell aplasia • Storage iron is depleted -  ferritin;  TIBC
• Serum iron is depleted -  serum iron;  % saturation
• Normocytic anemia – BM makes fewer, but normal-sized, RBCs
• Microcytic, hypochromic anemia – BM makes smaller and fewer
RBCs

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Iron Indices Causes of Megaloblastic Anemia
- BM biopsy is the gold standard test for iron stores I. Cobalamin( vit B12) deficiency
1. Serum ferritin A. Decreased ingestion: vegetarians.
- Single most important blood test for iron stores B. Impaired absorption: small intestinal disease
- Falsely elevated in inflammatory disease, liver disease (from C. Impaired utilization.
necrotic hepatocytes), neoplasm and hyperthyroidism II. Folate deficiency
2. Serum iron A. Decreased ingestion: prolonged parenteral feeding, alcoholism
- A measure of Fe present in blood B. Impaired absorption: small intestinal disease.
- Virtually all serum iron is bound to transferrin C. Impaired utilization: drug induced (eg sulfa drugs, methotrexate,
- Only a trace of serum iron is free or complexed to ferritin phenytoin)
3. Total iron binding capacity (TIBC) D. Increased requirement: pregnancy, hemolysis
- Measure of total amount of transferrin present in blood E. Increased loss: through urine.
- Normally, one third of the TIBC is saturated with Fe, the III. Drugs – metabolic inhibitors
remainder is unsaturated IV. Miscellaneous
4. Transferrin saturation A. Inborn errors
- Percentage of tranferrin molecules that are bound by iron B. Unexplained disorders
(normal 33%)
- Serum iron dvided by TIBC, expressed as a proportion or a Vitamin B12 Deficiency
percentage • Dietary vitamin B12 is complexed to animal-derived proteins
Diagnosis of IDA: Laboratory investigation – Salivary gland enzymes (amylase) liberate vitamin B12  bind to R-
1. Peripheral blood film binder  carried thru the stomach
• Hypochromic, microcytic RBC with  RDW – Pancreatic proteases in the duodenum detach vitamin B12 from R-
• Pencil forms binder
• Target cells (thin) – Vitamin B12 binds intrinsic factor IF (made by gastric parietal cells) in
• Platelet count may be elevated the small bowel  IF-Vitamin B12 complex is absorbed in
2. Serum iron studies the ileum
• Low serum iron, high TIBC, low Fe saturation • Vitamin B12 deficiency is less common than folate deficiency
• Serum ferritin <20 ug/l is diagnostic of IDA (IDA unlikely if • Takes years to develop due to large hepatic stores of Vitamin B12
ferritin >100 ug/l) • Pernicious anemia is the most common cause of vitamin B12 deficiency
• Increased free erythrocyte protoporphyrin (FEP) • Impaired uptake of Vit B12 because of lack of Intrinsic factor (IF
• Other causes of vitamin B12 deficiency include pancreatic insufficiency and
damage to the terminal ileum (Crohn’s disease or D. latum
parasitation)
• Dietary deficiency is rare except, in vegans

Folate Deficiency
Microcytic, hypochromic RBC with target cells • Dietary folate is obtained from green vegetables and some fruits
3. Hemoglobin electropheresis: decreased Hb A2 percentage • Absorbed in the jejunum
4. Bone marrow study (needed in difficult cases) • Folate deficiency develops within months, as body store are minimal
• Predominence of intermediated and late erythroblasts • Causes include poor diet (alcoholic, elderly), increased demand (pregnancy,
• Micronormoblastic maturation of erythroid precursors cancer, hemolytic anemia), folate antagonist (methotrexate, which
• Iron stain (prussian blue) shows decreased iron in inhibits dihydrofolate reductase)
macrophages Laboratory Investigations of Megaloblastic Anemias
• Decreased sideroblasts • CBC and Blood film:
– Macrocytosis (increased MCV), neutropenia,
Megaloblastic Anemias throbocytopenia, neutrophil hypersegmentation,
• Caused by various defects in DNA synthesis that lead to a common set of reticulocytopenia
hematologic abnormalities of bone marrow and peripheral blood cells. • BMA and biopsy:
• Megaloblastic – refers to a morphologic abnormality (mainly affecting the – Hypercellular, megaloblastic morphology, giant bands and
size and morphology) metamyelocytes
• Erythrocytic, granulocytic and megakaryocytic cell lines are all involved  • Indirect hyperbilirubinemia, elevated serum LDH
pancytopenia • Serum cobalamin: In cobalamin deficiency
(NV: 200-900 pg/ml)
• Serum folate: In folate deficiency
(NV: 2.5-20 ng/ml)

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 • Schilling test for diagnosing the cause of cobalamin malabsorption Aplastic Anemia
• Gastric biopsy for pernicious anemia (cobalamin deficiency) and/or • Damage of hematopoietic stem cells, resulting in pancytopenia
SI biopsy for malabsorption (anemia, thrombocytopenia, leukopenia) with low reticulocyte
• Anti-intrinsic factor Ab and Anti-parietal cell Ab in Pernicious count
anemia (cobalamin deficiency) ETIOLOGY:
• Elevated serum methylmalonic acid in cobalamin deficiency • Radiation
• Drugs
– Anticipated (chemotherapy)
– Idiosyncratic (chloramphenicol, phenylbutazone)
• Chemicals
– Benzene and other organic solvents
– DDT and insecticides

Macrocytes and hypersegmented neutrophils DIAGNOSIS:

1. CBC: pancytopenia
Anemia of Chronic Disease • Normochromic, normocytic anemia
• Anemia associated with chronic inflammation (endocarditis, autoimmune • Neutrophilc count < 1.5 x 109/L
conditions), cancer • Platelet cound <20 x 109/L
• Most common anemia in hospitalized patients • Corrected reticulocyte count < 1 %
• Chronic disease results in production of acute phase reactants from the 2. BMA and biopsy
liver, including hepcidin • Aplasia or hypoplasia of BM cells with fat
– Hepcidin sequesters iron in storage by (1) limiting iron transfer replacement
form macrophages to erythroid precursors and (2)
suppressing EPO production
Pure Red Cell Aplasia
– Aims to prevent bacteria from accessing iron which is necessary
for their survival
Transitory Arrest of Erythropoiesis (Transient Aplastic Crises)
 available iron  heme  Hb  microcytic anemia
• May occur during the course of a hemolytic anemia
• RBC:
• RBC production occasionally cease during or following rather minor
– normocytic and normochromic (mild); 20-50% of patients,
infections in normal children or adults
microcytic and hypochromic
• Often appear to be due to parvovirus B19 infection  inhibits
– anisocytosis, poikilocytosis are slight
erythropoiesis by infecting mature CFU-Es
• reticulocyte count: not elevated
• Morphologic hallmark: Presence of scattered giant pronormoblasts in the
• WBC, platelets: not distinctively altered, except by the causative disease
BMA with marked reduction in the more mature erythroid
• BMA and biopsy:
precursors.
– normocellular or minimally hypocellular or hypercellular, and
• Transient with erythroid marrow recovery in 1 to 2 weeks after onset
the cell distribution is not greatly disturbed
– normoblasts may have frayed hypochromic cytoplasm, and the
Transient Erythroblastopenia of Childhood (TEC)
appearance of Hb in the cells may be delayed (as in iron
• occurs in previously healthy children, < 8 y (1 - 3 y)
deficiency anemia).
• history of a viral infection within the previous 3 months
– Sideroblasts are decreased, but storage of iron is normal or
• characterized by:
increased.
– moderate to severe normocytic anemia
– severe reticulocytopenia
DIAGNOSIS: – transient neutropenia (20%)
– increased platelet counts (60%)
 Serum iron concentration: Decreased
– macrocytosis observed during recovery
 TIBC: Decreased or Normal
• BM: normocellular, absence of erythroid precursors, except for a few
 % saturation: Decreased
 Free Erythrocyte Protoporphyrin (FEP), early forms; arrested granulocytic maturation
Serum Ferritin: Elevated • recovery within 1–2 months without therapy

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Congenital Red Cell Aplasia (Diamond-Blackfan Anemia; Congenital – if protoporphyrin is deficient, iron remains trapped in
Hypoplastic Anemia) mitochondria
• A rare, congenital red cell aplasia – Iron-laden mitochondria form a ring around the nucleus
• Usually becomes obvious during the first year of life but may occur of erythroid precursors  ring sideroblasts
as late as 6 years of age – “ring sideroblasts” - increased numbers of siderotic
• Severe anemia: macrocytic, reticulocyte level is low, WBC are Nº or granules surround the nucleus (five or more iron granules
slightly decreased, platelets are Nº or increased encircling at least one third of the circumference)
• BM: reduction in all developing erythroid cells, Nº granulocytic and • Congenital siderobastic anemia – congenital defect most
megakaryocytic cell lines commonly involves ALAS (rate-limiting enzyme)
• Half of cases have an autosomal dominant pattern of inheritance • Acquired sideroblastic anemia causes include
with variable penetrance – alcoholism (mitochondrial poisoning)
• Defect appears to be in the erythroid-committed progenitor cells. – lead poisoning (inhibits ALAD
• CFU-Es and BFU-Es are decreased in the marrow, and BFU-Es are – ferrocheletase, vitamine B6 deficiency (required cofactor
absent or decreased in the blood for ALAS; most commonly seen as a side effect of isoniazid
• A mutation in the RPS19 gene was detected (25%) tx for TB
• 75% of patients respond at least partially to corticosteroids • Hypochromic RBC, microcytic (hereditary forms) or macrocytic
• overall long-term survival is about 65% (acquired forms)
• RBC may be mixed with normochromic cells  dimorphic
TEC CONGENITAL RED CELL appearance
APLASIA • Serum Fe and ferritin are increased, TIBC is decreased, % saturation
Anemia Normocytic Marcocytic of the iron-binding protein is greatly elevated,
Hb F Elevated Normal • BM shows markedly increased storage iron, erythroid hyperplasia
Antigen I Absent Present
with evidence of defective hemoglobinization, and increased
ADA Decreased Increased
numbers of sideroblasts

Acquired Pure Red Cell Aplasia

Polycythemia
• Among middle-aged adults, rare
Definition (WHO):
• Characteristics: reticulocytopenia, BM devoid of all but the most primitive
• Polycythemia (erythrocytosis) is classically defined as an elevated
erythroid precursors,
Hct level above the normal range
• WBC, platelet production is normal
• Hgb >18.5 g/dL for men, >16.5 g/dL for women
• Associated with THYMOMA, noninvasive spindle cell type
• Hct >99th percentile of the method-specific range
• Also been associated with:
• lower values but with a documented unexplained Hgb increase of at
– drugs
least 2 g/dL
– collagen vascular disorders
 Absolute polycythemia - an increase in the total red cell mass in the
– viral infections such as HIV, lymphoproliferative disorders
body
of granular lymphocytes
 Relative polycythemia - the total red cell mass is normal, but the
– other disorders with immunologic aberrations
Hct is elevated because the plasma volume is decreased
• TREATMENT: Corticosteroids and immunosuppressive drugs

Sideroblastic Anemia
• Anemia due to defective protoporphyrin synthesis
 protoporphyrin   heme   Hb  microcytic anemia
• Protoporphyrin is synthesized via a series of reactions
– Aminolevulinic acid synthetase (ALAS) converts succinyl
CoA to aminolevunilic acid (ALA) using vitamin b6 as a
cofactor (rate-limiting step)
– Aminolevulinic acid dehydratase converts ALA to
porphobilinogen
– Additional reactions convert porphobilinogen to
protoporphyrin
– Ferrochelatase attaches protoporphyrin to iron to make
heme (final reaction; occurs in the mitochondria)
• Iron is transferred to erythroid precursors and enters the mitochondria to
form heme

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Relative Polycythemia Renal Disorders
• Refers to an increase in Hct or red cell count as a result of decreased • mass impinging on the kidney  d pressure or local hypoxia
plasma volume within the kidney induces d renal production of EPO
• Total red cell mass is not increased • renal artery stenosis is also associated with polycythemia
• Occurs in acute dehydration (e.g., severe diarrhea, burns) and in patients • posttransplant erythrocytosis occurs in 10%–20% of renal
on diuretic therapy. transplant recipients
Spurious polycythemia (apparent polycythemia, Gaisböck’s syndrome) • angiotensin II has a role in regulating erythropoiesis as suggested by
• red cell mass is often high normal and the plasma volume is low normal therapeutic effects of ACE inhibitors
• almost all are men Familial Polycythemia
• high incidence of tobacco smoking • The most common familial polycythemia is d/t the presence of a
• obese high oxygen affinity hemoglobin, which is inherited as an
• hypertension autosomal dominant trait
• sleep apnea and diuretics may be contributory factors • Congenital polycythemia may be due to a defect in the hypoxia
• Serum EPO level is normal sensing mechanism
Absolute Polycythemia • Von Hippel–Lindau syndrome: an autosomal dominant disorder
- Appropriately Increased Erythropoietin Production Due to associated with mutations in the VHL gene
Hypoxia • Chuvash polycythemia: an autosomal recessive congenital
• Cellular response to hypoxia is controlled by hypoxia-inducible polycythemia, endemic in the Chuvash population of the Russian
factors (HIFs) federation
– a family of α-β heterodimeric transcription factors Polycythemia Vera
– regulate the transcription of EPO. • a panmyelosis
• Three HIF isoforms: • a condition in which excessive proliferation occurs in
– HIF1α – major isoform regulating EPO expression megakaryocytes, granulocytes, erythrocytes
– HIF2α • manifested by erythrocytosis, leukocytosis, and thrombocytosis of
– HIF3α varying degrees
• Normoxia: HIF1α is rapidly destroyed by the collaborative effect of • mutation in the JAK2 gene is a constant finding
O2, prolyl hydroxylase domain–containing enzymes, and the von Measurement of erythrocyte and plasma volume
Hippel–Lindau tumor suppressor protein (VHL) • diagnosis of absolute polycythemia depends on reliable
• Hypoxic conditions: degradation of HIF1α is slowed  increased measurements of erythrocyte and plasma volumes
transcription of its target genes, including EPO • erythrocyte and plasma volumes are measured with the use of
Arterial Oxygen Unsaturation radioactive isotopic tracers and the dilution principle
• Lack of O2 reaching the blood for whatever reason results in: • most commonly employed tracers: 51Cr in the form of sodium
– arterial unsaturation, chromate bound to erythrocytes for measurement of erythrocyte
– impaired O2 delivery to the tissues, volume
– increased production of EPO, • 125I or 131iodine is bound to albumin and can be used to measure
– erythroid hyperplasia in the marrow, and plasma volume
– resultant erythrocytosis. Erythrocyte Volume
• As a response to the hypoxia, the red cell 2,3-DPG and the p50 are • blood is collected from the patient, and the RBCs are labeled with 51Cr
increased. • chromated RBCs are washed in saline
• In case of CO poisoning, hypoxia is caused by two mechanisms: • an aliquot of the 51Cr RBCs diluted in saline is injected intravenously into
direct reduction of O2 saturation and interference with O2 release the patient
from Hb • after a period of equilibration (10–20 minutes), a sample of blood is
withdrawn from the opposite arm
Inappropriate Erythropoietin Production • in cases in which the equilibration time is likely to be prolonged
Neoplasms (splenomegaly, heart failure, or shock), another sample should be
• Neoplasms, benign or malignant, have been associated with withdrawn 60 minutes after injection
polycythemia. • radioactivity of each sample is recorded by a scintillation counter
• Renal neoplasms account for the majority. • erythrocyte volume (EV) is calculated using the following formula:
• In almost all cases, erythrocytosis has disappeared after resection of EV (mL) = I (cpm)/C (cpm/mL)
the tumor. where
• These neoplasms have been shown to express high levels of EPO I = total injected radioactivity (counts/minute)
mRNA. C = radioactivity in erythrocytes after mixing is complete
• These tumors include cerebellar hemangiomas, renal cell (counts/minute/mL of erythrocytes)
carcinomas, Wilms’ tumors, some hepatomas, uterine leimyomas,
pheochromocytoma, parathyroid adenomas, and meningiomas

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Plasma Volume • Inherited as autosomal dominant, autosomal recessive, or X-linked
• ~20 mL of blood is withdrawn from a patient dominant
• after centrifugation, the plasma is removed and radioiodine-labeled • Porphyria cutanea tarda - may also be due to increased iron in the liver,
albumin is added Hepatitis C, alcohol, iron in the liver, HIV/AIDS.
• after mixing, the labeled plasma is injected intravenously into the • Underlying mechanism: Decrease in the amount of HEME produced and
patient build-up of precursor substances.
• at 10, 20, and 30 minutes following injection, 5 mL of blood is
removed Acute porphyrias
• radioactivity is counted in a well-type scintillation counter • Acute intermittent porphyria (AIP), Variegate porphyria (VP), ALA
• radioactivity at zero time (P0) is determined by plotting the three dehydratase deficiency porphyria (ALAD) and Hereditary
points on semilogarithmic graph paper and extrapolating to zero coproporphyria (HCP).
time • Diseases primarily affect the Nervous system, resulting in episodic crises
• a standard is prepared by diluting an aliquot of the radioiodine- known as Acute attacks.
labeled albumin with saline containing a small amount of detergent • Major symptoms: Abdominal pain, accompanied by vomiting,
• plasma volume (PV) is calculated using the following formula: hypertension, and tachycardia.
PV (mL) = S (cpm/mL) × D ×V (mL)/P0 (cpm/mL) • Most severe episodes: Motor neuropathy - leads to muscle weakness and
where quadriplegia and CNS symptoms like seizures and coma.
S = counting rate of standard (counts/minute/mL) • Short-lived psychiatric symptoms such as anxiety,
D = dilution of diluted standard solution confusion, hallucinations, overt psychosis.
V = volume of radioiodine-labeled albumin solution injected • Symptoms resolve once the acute attack passes.
P0 = counting rate of plasma sample corrected to zero time • Porphyria is not a cause of chronic psychiatric illness
(counts/minute/mL)
Interpretation Chronic porphyrias
• normal erythrocyte volume • Aka ‘CUTANEOUS PORPHYRIAS’: X-linked dominant protoporphyria
– men = 20–36 mL/kg (XLDPP), Congenital erythropoietic porphyria (CEP), Porphyria
– women = 19–31 mL/kg cutanea tarda (PCT), and Erythropoietic protoporphyria (EPP).
• plasma volume • Also manifesting as skin diseases - VP and HCP
– men = 25–43 mL/kgr • Excess porphyrins accumulate in the skin.
– women = 28–45 mL/kg • Porphyrins are photoactive molecules, when exposed to
• newborns and premature infants light results in promotion of electrons to higher energy
– EV and PV are higher than in adults levels. When returning to resting energy level, energy is
• patients with polycythemia released. This accounts for the fluorescence.
– EV exceed 36 mL/kg for men; 32 mL/kg for women • Two distinct patterns of skin disease:
1. Immediate photosensitivity (XLDPP & EPP): Follows a period of sun
exposure—typically about 30 min
– Severe pain, burning, and discomfort in exposed areas.
Typically, the effects are not visible, though occasionally
there may be some redness and swelling of the skin.
2. Vesiculo-erosive skin disease: Characteristic vesicles and open sores in
patients
– CEP, PCT, VP, and HCP: Noted only in sun-exposed areas
such as the face and back of the hands.
– Milder disease (VP and HCP): Increased skin fragility in
exposed areas with a tendency to form blisters and
erosions. Heal slowly, leaving small scars that may be
lighter/darker than normal skin.
• PCT : More severe skin disease with prominent lesions, darkening of
Porphyrias
exposed skin and hypertrichosis (abnormal hair growth).
• Diseases affecting the skin or nervous system.
• Most severe disease is seen in CEP and a rare variant of PCT known as
• Symptoms of an attack include: Abdominal pain, chest pain, vomiting,
Hepatoerythropoietic porphyria (HEP):
confusion, constipation, fever, hypertension, and tachycardia
– Symptoms: Severe shortening of digits, loss of skin
• Complications: Paralysis, hyponatremia, seizures
appendages such as hair and nails, and severe scarring of
• Attacks triggered by: Alcohol, smoking, fasting, stress, hormonal changes,
the skin with progressive disappearance of ears, lips, and
or certain medications.
nose.
• Skin manifestations: Blisters or itching with sunlight exposure

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 – Patients may also show deformed, discolored teeth or • Physiologically- Porphyrias are classified as Liver or Erythropoietic
gum and eye abnormalities. (marrow & RBCs) based on the sites of accumulation of
Triggers for PORPHYRIA: Heme precursors.
• Acute porphyria can be triggered by a number of drugs, most of • The principal problem is the accumulation of the HEME precursors
which by interacting with enzymes in the liver which are made with – Toxic to tissue in high concentrations.
heme. • The chemical properties of the intermediates determine the
• Such drugs include: location of accumulation, whether they induce photosensitivity and
– Sulfonamides including Sulfadiazine, Trimethoprim/ whether the intermediate is excreted in the urine/feces.
Sulfamethoxazole • 8 enzymes in the HEME biosynthetic pathway, four of which—the
– Sulfonylureas like Glibenclamide, Gliclazide, Glimepiride first 1 and the last 3—are in the Mitochondria, while the other 4 are
– Barbiturates including Phenobarbital in the Cytosol.
– Systemic antifungals including Fluconazole, Ketoconazole • Hepatic porphyrias: characterized by acute neurological
– Certain antibiotics, ergot derivatives, antiretroviral agents, attacks
Progestogens, some anticonvulsants, painkillers, chemo- • Erythropoietic porphyrias: present with light-sensitive
therapeutic agents, and antipsychotic agents. blisters and increased hair growth.
Diagnosis of PORPHYRIA:
• Porphyrin studies
– Biochemical analysis of blood, urine, and stool
– Urine estimation of Porphobilinogen (PBG) is the first
step if acute porphyria is suspected.
– Decreased production of heme leads to increased
production of precursors, PBG being one of the first
substances in the porphyrin synthesis pathway.
– In nearly all cases of acute porphyria syndromes, urinary
PBG is markedly elevated except for ALA dehydratase
deficiency or in patients with Hereditary tyrosinemia type
I.
• Urine screening tests may fail in initial stages of a severe, life-
threatening attack of Acute intermittent porphyria.
• All taken during acute attacks; otherwise a false (-) result may
occur.
– Protect from light and either refrigerated/preserved.
• Further diagnostic tests of affected organs may be required.

Pathogenesis of PORPHYRIA
• Porphyrins - Main precursors of HEME, the essential constituent of
Hemoglobin, Myoglobin, Catalase, Peroxidase & P450 liver
cytochromes.
• Deficiency (inherited or acquired) of the enzymes that transform
the various porphyrins, leading to abnormally high levels of one or
more of the precursor substances.
• Porphyrias are classified in two ways:
– by Symptoms
– by Pathophysiology.

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Erythropoietic PORPHYRIA
• Accumulation of porphyrins in RBCs are rare.
• The pain, burning, swelling, and itching that occur in these
porphyrias generally require avoidance of bright sunlight. Most
kinds of sunscreen are not effective.
• Chloroquine may be used to increase porphyrin secretion in some
cases.
• Blood transfusion is occasionally used to suppress innate heme
production.
• Congenital erythropoietic porphyria (CEP), aka Gunther’s Disease:
• Rare disease; may present from birth as severe
photosensitivity, brown teeth that fluoresce in UV light
due to Type 1 porphyrins, and later hypertrichosis.
• Hemolytic anemia usually develops.
• Pharmaceutical-grade Beta Carotene may be used as
treatment.
• BM transplant successful in curing CEP in a few cases.
• Afemelanotide : Europe Commission (Dec 2014) authorized its use
as treatment for prevention of phototoxicity in adult patients with
EPP.

• Porphyria was suggested as explanation for the origin of Vampire

and werewolf legends
• Based upon certain perceived similarities between the
condition and the folklore.
• Potential for stigmatizing people with porphyria.

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