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Anaemia
Oliver Rácz, 2015
Repetition of physiology and
biochemistry
• Red cell properties and function
– Number, synthesis, life span, degradation
• Haemoglobin structure and function
– Structure, oxygen affinity and its regulation,
variants, degradation
• Iron metabolism
– See trace element lecture
• Vitamin B12 and folic acid
Definition of anaemia
 Deficiency in the oxygen-carrying capacity of the
blood due to diminished erythrocyte mass (THEORY)
 Low red cell count, Hb, HT (PRACTICAL MEDICINE)
 May be due to:
 Erythrocyte loss (bleeding, haemolysis)
 Decreased erythrocyte production
 Bone marrow dysfunction
 Low erythropoietin/high hepcidin
 Iron deficiency
 Vitamin B12, folic acid deficiency
Indicators of anaemia
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MEASURED ON AUTOMATIC ANALYZERS
Haemoglobin, grams of Hb/liter of whole blood (or g/dL in USA)
Hematocrit, ratio between cell and plasma volume
RBC = millions/microliter (= mm3) of whole blood (or 1012/liter)
MCV = Mean corpuscular volume (of 1 RBC)
• > 100 femtoliter Macrocytes (1 fl = 10-15 liter)
• 80 – 100 femtoliter Normocytes
• < 80 femtoliter Microcytes
• MCH = Mean corpuscular Hb (norm is 20 pg/cell; pico = 10-12)
• RDW = Red blood cell distribution width
– (Standard deviation of red cell volume/mean cell volume) × 100
– Normal value is 11-15%
– If elevated, suggests large variability in sizes of RBCs
Normal and decreased values
• Hb (160)
• Women: <120
• Men: < 135
severe <100
• Ht (0,45)
• Women: < 0,36
• Men: < 0,41
severe < 0,30
Symptoms of Anaemia ?
• Decreased oxygenation
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Pallor
Exertional dyspnea
Dyspnea at rest
Fatigue
Decreased mental function
• Decreased circulating volume
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Fatigue
Muscle cramps
Postural dizziness
Syncope
• Disease/condition specific, e.g.
– Jaundice
– Other
FOR LONG TIME
MOSTLY
NOTHING,
HIDDEN BEHIND
THE BASIC
DISEASE
OR
COMPENSATED
NO CYANOSIS
Special considerations
• Acute Bleeding
• Drop in Hb & Ht may not be shown until some time after acute
blood loss (even though patient may be hypotensive)
• WHY???
• Later reticulocytosis
• Pregnancy
• In third trimester, RBC and plasma volume are expanded but
there is a bigger expansion of plasma volume than of red cell
mass.
• Lab values show reductions in Hb, Ht, and RBC count, often to
pathological levels, but according to RBC mass this is a
haemodilution and not anaemia.
• BUT! Real anaemia is also frequent in gravidity
• Volume Depletion
• Patient’s who are severely volume depleted may have
physiological Ht results and do not show anaemic values until
rehydrated !!!
RBC Life Cycle
• In the bone marrow, erythropoietin enhances the
growth of differentiation of burst forming unitserythroid (BFU-E) and colony forming units-erythroid
(CFU-E) into reticulocytes.
• Reticulocytes spend ≈ 3 days maturing in the marrow,
and ≈ 1 day maturing in the peripheral blood
(reticulocyte count ≈ 0,5% of RBCs).
• After blood loss or haemolysis increased % of
reticulocytes if bone marrow is OK
• Mature RBCs circulate in the peripheral blood for 120
days. Under steady state conditions, the rate of RBC
production equals the rate of RBC loss. (Around
1/120 ≈ 0,8 % of cells/day. Iron recycling!)
Erythrocyte loss - bleeding
• Acute/Haemodynamically significant (not a
haematological problem in general practice)
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Injury (shock!)
Gastrointestinal (ulcus, oesophagus, polyps…)
Retroperitoneal
Hemophilia and other coagulation disorders
• Chronic
• kidney, abnormal menstrual cycle, ulcer disease in the past
• If not treated it can transform to iron deficiency anaemia
Haemolysis
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Osmotic – only in test tube (distilled water)
Mechanical – artificial heart valves (past)
Streptococcus haemolyticus ?
ABO or Rh incompatibility
Malaria, Babesiosis, and many others
Autoimmune, toxic
Inherited – Hb S and other Hbpathies,
thalassemia, membranopathies, enzymopathies
Some forms of haemolytic
anaemia
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Hereditary spherocytosis
Glucose-6-phosphate dehydrogenase
(G6PD) Deficiency
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Autoimmune Haemolytic Anaemia
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• Most common enzyme defect in
erythrocytes
• X-linked
• Brisk haemolysis when patients
exposed to oxidative stress from
drugs, infections or toxins.
•
Thrombotic Thrombocytopenic
Purpura (TTP)
• Thrombocytopenia and
microangiopathic haemolytic
Anaemia, fever, renal insufficiency,
neurologic symptoms
• Schistocytes on smear
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Haemolytic Uremic Syndrome
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Infections
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• Thrombocytopenia, Microangiopathic
haemolytic Anaemia, renal
insufficiency
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Warm-antibody mediated
• IgG antibody binds to erythrocyte
surface
• most common
• Diagnosed by POSITIVE Coomb’s
Test (detectgs IgG or complement on
the cell surgace)
• Can be caused drugs
• Treated with corticosteroids or
splenectomy if refractory
Cold agglutinin Disease
• IgM antibodies bind to erythrocyte
surface
• Does not respond to corticosteroids,
but usually mild.
Malaria
Babesiosis
Sepsis
Trauma
–
Includes some snake, insect bites
BABESIOSIS
Anaemia due to
Low erythropoietin
• Kidney Disease (including diabetic
nephropathy)
– Normocytic
– Low reticulocyte count
– Target Hb for patients on dialysis: 110 -120 g/L
• Administer erythropoietin
• Good iron stores should be maintained
– Peripheral smear in uraemic patients frequently
show echinocytes
Aplastic anaemia
(bone marrow dysfunction)
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Radiation
Toxic substances
Drug side effects
Leukaemias
Iron deficiency
• Iron Deficiency
– Can result from:
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Pregnancy/lactation
Normal growth
Blood loss
Intravascular haemolysis
Gastric bypass
Malabsorption
» Iron is absorbed in proximal small bowel; decreased abosrption in
celiac disease, inflammatory bowel disease
– May manifest as „pica“
• Tendency to eat ice, clay, starch, crunchy materials
– May have pallor, koilonychia of the nails, beeturia
– Peripheral smear shows microcytic, hypochromic red cells
with marked anisopoikilocytosis.
Koilonychia
Laboratory findings
• Serum Iron
• LOW
• Total Iron Binding Capacity (TIBC)
• HIGH
• Soluble transferrin receptors
• HIGH
• Serum Ferritin
• LOW
• Can be “falsely”normal in inflammatory states
Cobalamin deficiency
• Macrocytic Anaemia (megaloblastic, in the past “pernicious”
• Lab Values
– Cobalamin level < 200 pg/mL
– Elevated serum methylmalonic acid
– Elevated serum homocysteine
• Vit B12 binds to intrinsic factor in the small bowel in order to be
absorbed – the pernicious form was an autoimmune condition
blocking intrinsic factor
• Vit. B12 is needed for DNA synthesis
– The anaemia is only the tip of an “iceberg”
• Deficiency can result in cardiac and neuropsychiatric symptoms
– Spastic ataxia, psychosis, loss of vibratory sense, dementia
– Dilated cardiomyiopathy
• Smear shows macrocytosis and hypersegmentation of
polymorphonuclear cells, with possible basophilic stippling.
Folate deficiency
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– Macrocytic Anaemia and a lot of other consequences (spina bifida)
– Lab Values
– Low folate
– Increased serum homocystine
– NORMAL methylmalonic acid
– Often occurs with decreased oral intake, increased utilization, or
impaired absorption of folate
– Folate is normally absorbed in duodenum and proximal jejunum –
deficiency found in celiac disease, regional enteritis, amyloidosis
– Deficiency frequently in alcoholics, because enzyme required for
deglutamation of folate is inhibited by alcohol.
– Deficiency often found in pregnant women, persons with
desquamating skin disorders, patients with sickle cell Anaemia
(and other conditions associated with rapid cell division and turnover)
– Smear shows macrocytosis with hypersegmented neutrophils
– BE CAREFUL WITH FOLATE OVERDOSE
Anaemia of „chronic disease“
• Usually normocytic, normochromic (but can
become hypochromic, microcytic over time)
• Occurs in people with inflammatory conditions
such as collage vascular disease, malignancy or
chronic infections
• Iron replacement is not necessary
• May benefit from erythropoietin supplementation.
• HEPCIDIN BLOCKS RESORBTION – IRON IS A
GROWTH FACTOR OF BACTERIA
The anaemia of chronic disease
the hepcidin story
• Hepcidin – a 25 aminoacid peptide from liver
discovered in 2001
• Ferroportin – a very specific transmembrane iron
export system
• Hepcidin injection: Serum Fe decrease by
blocking the Fe export from cells storing iron
• Hepcidin deficiency: High serum Fe – iron
overload.
• Inflammation – hepcidin elevated to block iron for
microbes
Normal peripheral „smear“
Echinocytes (“burr cells”)
Iron deficiency anaemia
MICROCYTIC
Megaloblasts and hypersegmented
neutrophil
Spherocytosis
TTP / HUS – microangiopathic
haemolysis with schistocytes
Malaria
Babesiosis
Sickle Cell Anaemia
Lab Analysis in Haemolytic Anaemia
• Increased indirect bilirubin
• Increased LDH
• Increased reticulocyte count
• Normal reticulocyte count is 0.5 to 1.5%
• > 3% is sign of increased reticulocyte production,
suggestive of haemolysis
• Reduced or absent haptoglobin
• < 25 mg /dL suggests haemolysis
• Haptoglobin binds to free haemoglobin released
after haemolysis
Evaluating the patient with Anaemia
• Any history of medical problems that could
cause Anaemia?
– Sickle cell Disease?
– Thalassemia?
– Renal Disease?
– Hereditary Spherocytosis?
Evaluating the Patient with Anaemia
• Are the other cell lines also low?
– If WBC and platelets are both low, consider APLASTIC
AnaemIA!
– Check medication list
» NSAIDS (phenylbutazone), Sulfonamides, Acyclovir,
Gancyclovir, chloramphenicol, anti-epileptics
(phenytoin, carbamazepine, valproic acid), nifedipine
» Check parvovirus B19 IgG, IgM
» Consider hepatitis viruses, HIV
– If Platelets are low consider TTP or HUS!
– Must check smear for schistocytes (for sign of
microangiopathic haemolytic Anaemia)
– If renal failure, E. Coli O157:H7 exposure → HUS
– If renal failure, neurologic changes, fever → TTP
Evaluating the Patient with Anaemia
• Is the patient bleeding?!
– Any bright red blood per rectum
(hematochezia) or black tarry stools
(melena)?
• Check stool guaiac, may consider sigmoidoscopy
or colonoscopy
– Any abdominal pain, or recent faemoral
vein/artery manipulation?
• Consider retroperitoneal hematoma
Evaluating the Patient with Anaemia
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If other cell lines are okay, what is the MCV and RDW?
– If MCV < 80, then it’s a microcytic Anaemia
• Check serum iron, ferritin, TIBC
– If iron-deficiency Anaemia, look for sources of chronic bleeding – heavy menstrual
bleeding, consider colonoscopy
• Consider lead poisoning, copper deficiency, thalassemias
– If MCV 80-100, then it’s a normocytic Anaemia
• Any inflammatory conditions that could result in Anaemia of chronic
disease?
• Consider checking indirect bili, LDH, haptoglobin, reticulocyte count
– If MCV > 100, then it’s a macrocytic Anaemia
• Check Vit. B 12, folate
• Consider liver disease, alcoholism, myelodysplastic syndrome
• Check medications: hydoxyurea, AZT, methotrexate
Evaluating the Patient with Anaemia
• Any jaundice, elevated bilirubin,
suspicious for haemolysis?
– Check for increased indirect bilirubin,
increased LDH, decreased haptoglobin,
increased reticulocyte count
– Any sign of infection? Malaria? Babesiosis?
– Is Coombs test positive?
– If yes, may be warm antibody haemolytic Anaemia;
Consider drug as cause