Red Cell Disorders

Dr. Wangari Wambugu

Red cell disorders
 Anaemia
 Polycythaemia
Anaemia
 Definition:
 Reduction in the total number of
RBCs, Hb conc. in the circulation,
or circulating RBC mass.
 Hb conc. >2 SD below the mean
for age.
 WHO definition:
– Adult female < 12g/dl
– Adult male <13g/dl
 Polycythaemia
 An increase in the absolute red blood cell mass
in the body
 Causes:
1. Primary (polycythaemia vera)
- Myeloproliferative neoplasm
- Low serum EPO
2. Secondary polycythaemia: high serum EPO
- Very high altitude
- Obstructive sleep apnoea
- Certain types of tumour secreting EPO
- Heart or lung disease causing low oxygen levels
- Certain renal disorders-cysts, neoplasms, RAT, FSGN
 Age & Gender adjusted Hb & MCV values:

Age & Sex Hb mean (-2SD) (g/dl) MCV mean (-2SD) (fl)
Birth 16.5 (13.5) 108 (98)
1-3 days 18.5 (14.5) 108 (95)
2 weeks 16.6 (13.4) 105 (88)
1 month 13.9 (10.7) 101 (91)
2 months 11.2 (9.4) 95 (84)
6 months 12.6 (11.1) 76 (68)
6-24 months 12.0 (10.5) 78 (70)
2-6 yrs 12.5 (11.5) 81 (75)
6-12 yrs 13.5 (11.5) 86 (77)
12-18 yrs Male 14.5 (13) 88 (78)
12-18 yrs Female 14.0 (12) 90 (78)
Adult Male 15.5 (13.5) 90 (80)
Adult Female 14.0 (12) 90 (80)
Anaemia
 Results in impaired O₂ delivery to tissues.
 Clinical features dependent on degree of
anaemia (mild, moderate or severe)
– dyspnoea, palpitations, easy fatigability,
tachycardia, dizziness, headache & syncope.
 General mechanisms:
– increased Hb loss (usually bleeding)
– decreased Hb production
– increased RBC destruction (haemolysis)
Classification:

 Different approaches
 Facilitates selection of additional lab tests to
determine the underlying cause of the
anemia.
“Anaemia is a symptom, not a disease”
Classification:

a) Morphologic Classification:

 Integrates RBC indices and morphologic

characteristics.
– Microcytic (decreased MCV <76fl)
– Normocytic (normal MCV)
– Macrocytic (increased MCV >95fl)
Classification:
b) Classification by degree of BM response
or peripheral blood reticulocytosis:

i. Hypoproliferative – defective RBC

proliferation or maturation with little or
no increase in reticulocyte count.
ii. Normoproliferative – ↓RBC survival
with normal BM proliferative response.
iii. Hyperproliferative – increased BM
response = ↑peripheral blood
reticulocytes.
Classification:
c) Classification based on pathogenetic
mechanism:

i. Hereditary – caused by intrinsic

factors.
ii. Acquired – caused by extrinsic factors.
MICROCYTIC ANAEMIA
Microcytic Anaemia:

 ↓MCV (<76fl)
 Most due to deficient Hb synthesis
1. Disorders of Fe metabolism
– Iron deficiency
– Anaemia of chronic dis
2. Disorders of globin synthesis –
thalassemias, HbE & C syndromes,
unstable Hb disease.
3. Sideroblastic anaemias – hereditary or
acquired.
4. Lead poisoning
Causes of hypochromic anaemias
IRON DEFICIENCY ANAEMIA
Iron metabolism

 Most body iron is present in haemoglobin in

circulating red cells

 The macrophages of the reticuloendotelial

system store iron released from haemoglobin as
ferritin and haemosiderin
Iron metabolism

 They release iron to plasma, where it attaches

to transferrin which takes it to tissues with
transferrin receptors – especially the bone
marrow – where the iron is incorporated by
erythroid cells into haemoglobin

 There is a small loss of iron each day in urine,

faeces, skin and nails and in menstruating
females as blood (1-2 mg daily) is replaced by
iron absorbed from the diet.
Iron metabolism
Red cell cycle
RBC-The important players
 Iron
– key element in the production of
hemoglobin
– absorption is poor
 Transferrin
– iron transporter
 Ferritin
– iron binder, measure of iron stores,
*also acute phase reactant*
Iron absorption
 Increased by  Decreased by
– Haem iron – ↓d haem iron
– Animal foods – ↓d animal foods
– Ferrous iron salts – Ferric iron
– Acid pH e.g gastric – Alkalis e.g pancreatic
acid secretions
– LMW chelates e.g – Insoluble iron
vit c,sugars, amino complexes-phytates,
acids tannates in tea, bran
– Iron def – Iron overload
– Pregnancy – Inflammatory
– Hypoxia disorders(hepcidin)
 Sequence of events in iron deficiency

1. Depletion of iron stores without reduced

serum iron
– Hb (N), MCV (N), iron absorption (),
transferin saturation (N), serum ferritin (),
marrow iron ()
2. Iron-deficient erythropoiesis iron stores
are exhausted, but the blood
haemoglobin level remains normal.
serum transferrin receptor conc 
• Hb (N), MCV (N), TIBC (), serum ferritin (),
transferin saturation (), marrow iron (absent)
Sequence of events in iron deficiency

3. Iron deficiency anaemia: blood HB

conc falls below the lower limit of
normal, RBCs become microcytic,
hypochromic
• Hb (), MCV (), TIBC (), serum ferritin (),
transferin saturation (), marrow iron (absent)
Causes of iron deficiency
 The end result of a long period of negative iron
balance
– decreased iron intake
• inadequate diet, impaired absorption, gastric surgery,
celiac disease, pica ingestion
– increased iron loss
• gastrointestinal bleeding (haemorrhoids, salicylate
ingestion, peptic ulcer, neoplasm, ulcerative colitis)
• excessive menstrual flow, blood donation, disorders of
hemostasis
– increased physiologic requirements for iron
• infancy, pregnancy, lactation
– cause unknown (idiopathic hypochromic anaemia)
Courtesy of Post-graduate text book of Haematology
 Clinical features
 Pallor of skin, lips, nail beds and conjunctival
mucosa
 Nails - flattened, fragile, brittle, koilonychia, spoon-
shaped
 Tongue and mouth
– glossitis, angular cheliosis, stomatitis
– dysphagia (Peterson-Kelly or Plummer-Vinson syndrome
(carcinoma in situ)
 Stomach
– atrophic gastritis, (reduction in gastric secretion,
malabsorbtion)

 The cause of these changes in iron deficiency is

uncertain, but may be related to the iron requirement
of many enzymes present in epithelial and other
cells
Laboratory findings (1)
 Blood tests
– erythrocytes
• haemoglobin level 
• the volume of packed red cells (VPRC) 
• RBC 
• MCV and MCH 
• Microcytic hypochromia
• anisocytosis
• poikilocytosis

– leukocytes
• normal

– Platelets
• usually thrombocytosis
Laboratory findings (2)

 Iron metabolism tests

– serum iron concentration 

– total iron-binding capacity 

– saturation of transferrin 
– serum ferritin levels 

– sideroblasts 

– transferrin receptors 
Normal

Microcytic hyprochromic RBCs

Normal bone marrow showing plentiful iron in Iron deficiency: bone marrow showing absence of
macrophages (Perls’ stain) with iron granules in stainable iron (Perls’ stain).
erythroblasts
(insets) Microcytic hypochromic RBCs
Management of iron deficiency
 Goals:
– Identification & treatment of underlying
cause
– Correction of deficiency
 Therapy:
– Oral therapy
– Parenteral therapy
Other disorders of heme synthesis
Causes of hypochromic anaemias
 Lead poisoning
 Sideroblastic anaemias
 Porphyria
Heme synthesis
Lead poisoning
 Affects heme synthesis
 Cells usu normochromic or slightly
hypochromic
 Red cell lifespan is shortened
 Slight increase in reticulocytes
 Sideroblastic anaemia

 A heterogenous group of disorders

characterized by:
– Variable red cell hypochromia
– Anaemia
– Ring sideroblasts in the bone
marrow(≥10%)
 Sideroblasts- ≥4 perinuclear granules
& covering ≥1/3 of the nuclear
circumference
 Sideroblastic anaemia

 These perinuclear granules consist of

iron laden mitochondria
 There is failure to utilize iron properly
during heme synthesis in the
mitochondria
 Iron accumulates in the mitochondria and
eventually adversely affect mitochondria
 Then premature erthroblast death,
eventually ineffective erythropoiesis
Sideroblastic anaemia
 Sideroblastic anaemia
 Classification:
– Congenital
• Primary x-linked
• Primary autosomal
• Pearson syndrome etc
– Acquired
• Primary idiopathic, refractory anaemia e.g in
myelodysplasia
 Sideroblastic anaemia
• Secondary acquired
– Drugs-isoniazid, chlorampenicol
– Toxins-alcohol, lead
– Cu def
– Zn excess
– Other diseases sometimes ass with
ringed sideroblasts
• Haemolytic anaemia
• Megaloblastic anaemia
• Myeloid malignancies
• Autoimmune disorders
 Porphyrias
 A rare group of metabolic disorders caused by
genetic or acquired deficiencies of enzymes in
the heme synthesis

 Affected individuals have an accumulation of

heme precursors (porphyrins) which are toxic in
high concentrations

 Attacks of the disease are triggered by certain

drugs, chemicals, foods & exposure to sunlight
Porphyrias
 Nervous & visceral symptoms are
related to accumulation of
porphyrin precursors(ALA, PBG)

 Photosensitive skin lesions occur

when enzyme defects in haem
synthesis leads to accumulation of
formed porphyrins
Mitochondria PORPHYRIAS
GLYCINE + SuccinylCoA
ALA synthase
d-aminolevulinic acid(ALA)
ALA-dehydratase
ALA dehydratase Deficiency porphyria
Porphobilinogen(PBG)
Acute intermittent
PBG deaminase porphyria
hydroxymethylbilane
Uroporphyrinogen III Congenital erythropoietic
cosynthase porphyria
uroporphyrinogen III
Uroporphyrinogen Prophyria
decarboxylase cutanea tarda
coprophyrinogene III
Coproporphyrinogen Herediatary
oxidase coproporphyria
Protoporphyrinogene IX
Protoporphyrinogen Variegate
protoporphyrin IX oxidase porphyria

Ferrochelatase Erythropoietic
Heme protoporphyria
 Porphyrias

 May be classified on whether the effects are

predominantly in the liver or erythron
 Hepatic
– Acute intermittent porphyria
– Hereditary coporphryria
– Porphyria variegate
– Porphyria cutanea tarda
 Erythropoeitic
– Congenital erythropoietic porphyria
– Erythropoeitic protoporphyria
Iron overload
Definition
 Moderate or severe increase in
body iron stores that has or will
have negative effects on health
 Causes of iron overload
– Dysregulation of absorption
– Ineffective erythropoiesis
– Transfusion or iron therapy
 Classification:

1-Primary iron overload

A) Hereditary haemochromchromatosis
B) Aceruloplasminaemia
C) Congenital atransferrinaemia
D) Neonatal hemochromatosis
2-Secondary iron overload
A) Dietary iron overload
B) Parenteral iron overload
C) Iron loading anaemias
D) Long term haemodialysis
E)Chronic liver disease:
F) Porphyria cutanea tarda
G) Post-portacaval shunting
H)Dysmetabolic iron overload syndrome
3-Miscellaneous
African iron overload (Bantu siderosis)
Hereditary Haemochromatosis
 Abnormal accumulation of iron in
parenchymal organs leading to
organ toxicity
 Commonest cause of severe iron
overload
 Types 1, 2, 3 & 4
Hereditary Haemochromatosis
 Type 1
– Commonest
– mutation in HFE gene a/c for 90% of
cases
– Include:
• C282Y (major mutation):cysteine replaced
by tyrosine at psn 282 of aa chain
• H63D (minor mutation): histidine replaced
by aspartate at psn 63 of aa chain
• Abnormal HFE product formed
 Pathophysiology:
 The causative defect--the one permitting excessive
iron absorption--is most likely to be within the
intestinal lining. The sensor pathway inside the
enterocyte is disrupted due to the genetic errors.

 Abnormal HFE protein

 There is a deficiency of hepcidin which controls

amount of iron taken up by macrophages

 Persons affected with HH absorb 3 to 4 mg/day(normal

1-2) of iron. Thus the iron stores of the body increase.
which is toxic to tissue.
 Pathophysiology:
 As they increase the iron which is initially stored as
ferritin starts to get stored as a breakdown product of
ferritin called haemosiderin

 Haemosiderin unlike ferritin is an abnormal, insoluble

form of iron storage & does not circulated. Is
deposited in tissues & is unavailable when cells need it

 As ferrous iron accumulates in the parenchymal

tissues, the intracellular iron-binding sites are
overwhelmed. Labile iron can promote damage of
cellular organelles by radical formation which results
in lipid peroxidation, cellular injury, and fibrosis.
Effects on tissues
 Damage to organs
– Liver-chronic hepatitis, cirrhosis, HCC
– Heart-hypertrophy, cardiomyopathy
– Endocrine organs-DM, hypothyroidism
hypogonadism
– Musculo-skeletal tissues-
chodrocalcinosis
– Skin pigmentation-bronze coloured
patches in whites
– Immune system compromise
Damage to the liver:
Damage to the heart:
Damage to the endocrine system:
Effects on skin:
 Laboratory evaluation
 Iron studies
– Transferrin saturation levels
– Serum ferritin levels >200ng/ml in premenopausal
females or >300ng/ml in males or postmenopausal
females is considered elevated
 Genetic testing- HFE mutations ( C282Y, H63D)
 Hepatic iron studies
– Liver biopsy-usu indicated when serum ferritin is
›1000ng/ml
 Quantitative phlebotomy
Management
 Phlebotomy
 Chelation therapy esp pts with
heart dse, poor venous access
– Deferoxamine
– Deferasirox
– Deferipone
 Surgery-in pts with complications
e.g arthroplasty, liver
transplantation