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Anaemias I Iron deficiency anaemia, ACD
Dr. Judit Demeter Semmelweis Egyetem ÁOK.,
I.sz. Belgyógyászati Klinika
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History taking in patients with haematological
disease 1.
Non-specific symptoms fatigue, fevers, weight loss
Symptoms relating to anaemia reduced exercise capacity, angina, ankle oedema
Symptoms relating to neutropenia recurrent oral ulceration, skin infections, sepsis
Evidence of compromised immunity recurrent oropharyngeal infection
Details of haemostatic problems easy bruising, bleeding episodes, rashes
Anatomical symptoms abdominal discomfort (spleen), CNS symptoms (spinal compr)
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History taking in patients with haematological
disease 2.
Past medical history
Transfusion history
Drug history prescribed and non-prescribed medications
Alcohol, tobacco consumption
Occupation, hobbies
Travel (HIV infection, malaria)
Family history inherited haematological disorders
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Normal RBC és PLT values (adult)
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Normal peripheral blood smear, thin, homogenous
part
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Normal RBC morphology
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Red blood cell maturation
1.
2.
3.
4.
5.
6.
1. proerythroblast 4. oxyphil normoblast 2.
basophil normoblast 5. polychromatophil
RBC 3. polychromatophil normoblast 6. mature
RBC
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Anaemias Kinetic approach
Reduced RBC production deficiency anaemias
(hematinic deficiency) (iron, B12, folic
acid) bone marrow disorders ( aplastic anaemia,
isolated RBC-aplasia,
myelodsyplasia, neoplastic
infiltration) Increased RBC destruction
(hemolysis RBC lifespan lt 100 days) congenital
hemolitic anaemias (hereditary
shaerocytosis, sickle cell
disease, thalassaemia maior) acquired
hemolytic anaemias (Coombs positiv hemolytic
anaemia TTP-HUS) Blood loss
apparent bleeding - hematemesis, melaena,
metrorrhagia, epistaxis occult bleeding
- slowly bleeding ulcus or carcinoma.
Az anemiás beteg
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Examination of the anaemic patient

• searching for signs of bleeding (at present or
  earlier)
• Signs of increased RBC destruction (
  hemolysis?)
• Bone marrow suppression?
• Iron deficiency? Why?
• Folic acid or B12 deficiency?

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Examination of the anamic patient II
Medical history melaena? since what
time? drug intake? (NSAID-s) geographical
localisation? Physical examination
severity ? tachycardia, dyspnoe,
fever, hypotension
hepatosplenomegaly, lymphadenopathy? (pallor)
icterus? petechiae?
Infections?
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Anaemia in pregnancy

• Dilutional anaemia red cell mass ? by
  30
  plasma volume ? by 60
• The normal Hb concentration 10-11g/dl
• Iron deficiency is a common problem

Cause of ? Fe requirements Amount of additional Fe
? Red cell mass 500 mg
Fetal requirements 300 mg
Placental requirements 5 mg
Basal losses over pregnancy 250 mg (1.0-1.5 mg/d)
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Reticulocytes in the peripheral blood smear
brillantcresilblue staining
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Retikulocyte shift in anaemia
With increasing severity of the anaemia and
increasing erythropoetic stimulation, the
reticulocytes leave BM increasingly earlier .
Thus their maturation time in the periphery
increases from 1 to 3 days.
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Polychromatophilia in reticulocytosis
A retiukulociták nagyobbak és nincs centrális
halvány középük (nem bikonkávak)
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Iron homeostasis
The amount of iron passing from mucosal cells
into the body is determined by the rate of
erythropoiesis and the state of body iron stores.
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• Anaemia is typically the first clue to iron
  deficiency, but an isolated haemoglobin
  measurement has both low specificity and low
  sensitivity.
• - improve sensitivity by
• including measures of iron-deficient
  erythropoiesis such as
• - the transferrin iron saturation,
• - mean corpuscular haemoglobin concentration,
  - erythrocyte zinc protoporphyrin,
• - percentage of hypochromic erythrocytes or
• - reticulocyte haemoglobin concentration.
• However, these results changes in iron def.
  indistinguishable from ACD.
• The optimal dg
• serum ferritin as an index of iron stores and
• serum transferrin receptor as a index of tissue
  iron deficiency.

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Testing for iron-deficiency
Receiver operating characteristic (ROC) curves
showing the sensitivity and specificity of
various tests for the diagnosis of iron
deficiency ferritin, red cell protoporphyrin,
transferrin saturation, mean red cell volume
(MCV), and red cell volume distribution width
(RDW). Note that, at any given level of
sensitivity or specificity, serum ferritin
outperforms all the other tests shown
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Hypochromasia, anulocytes
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Causes of iron deficiency
Reproductive system menorrhagia
GI tract oesophagitis, oesophageal varices, hiatus hernia, peptic ulcer, IBD, haemorrhoids carcinoma stomach, colorectal
Malabsorption coeliac disease, atrophic gastritis, gastrectomy
Dietary vegans, elderly
Physiological growth spurts, pregnancy
Others PNH, frequent blood donation, hookworm
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Blood loss in gastrointestinal disease
ACUTE Immediately following acute haemorrhage - RBC indices usually normal
ACUTE ON CHRONIC RBC indices show low normal or marginally ?, film shows mixture of normochromic hypochromic RBCs (dimorphic)
CHRONIC RBC indices show established chronic Fe deficiency features ? MCV, MCH, platelets often ?
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Control of iron absorption
Pathways of iron absorption and excretion in an
intestinal mucosal cell. Normal iron absorption
is 1 mg/day with a total daily intake of 10 mg.
Iron absorption enhanced in iron deficiency,
and diminished in iron overload.
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Factors influencing the absorption of dietary
iron Absorption of heme iron Amount of heme
iron, especially in meat Content of calcium in
the meal Food preparation (time,
temperature) Absorption of nonheme iron Iron
status Amount of potentially available nonheme
iron Balance between positive and negative
factors Positive factors Ascorbic
acid Meat or fish Negative
factors Phytate (in bran, oats, rye fiber)
Polyphenols (in tea, some vegetables and
cereals) Dietary calcium Soy protein
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Role of specific proteins in iron metabolism

• Transferrin (Tf)
• Transferrin receptor (TfR)
• Ferritin
• Iron regulatory protein 1 and 2 (IRP1 and IRP2),
  the cellular iron sensing proteins
• Divalent metal transporter 1 (DMT1, Nramp2, DCT1,
  Solute carrier family 11, member 2 (Slc11a2)),
  the duodenal iron transporter
• Ferroportin (Ireg1, Slc11a2, Mtp1), the cellular
  iron exporter
• Hephaestin, which likely cooperates with
  ferroportin for exporting iron to transferrin.
• HFE, mutations responsible for the common form of
  hereditary hemochromatosis
• TFR2, mutations responsible for a rare form of
  hereditary hemochromatosis
• Hemojuvelin, a hepcidin regulator, mutations
  responsible for the common form of juvenile
  hemochromatosis
• Hepcidin, the key negative regulator of
• intestinal iron absorption
  macrophage iron release.
• Mutations cause a rare form of juvenile
  hemochromatosis.

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• Some truths about ferritin  the cellular
  storage protein for iron
• - a huge protein, consisting of light and heavy
  chains, which can store up to 4500 atoms of iron
  within its spherical cavity
• an acute phase reactant, and, along with
  transferrin and the transferrin receptor, is a
  member of the protein family that orchestrates
  cellular defense against oxidative stress and
  inflammation
• Much of the stored iron is accessible for
  metabolic needs. Ferritin within erythroid
  precursors may be of special importance in the
  donation of iron for heme synthesis,
• Ferritin measured clinically in plasma is usually
  apoferritin, a non-iron containing molecule.
• The plasma level generally reflects overall iron
  storage
• 1 ng of ferritin per mL ? 10 mg of total iron
  stores.
• A normal adult male plasma ferritin level of
• 50 to 100 ng/mL iron stores of appr. 500 to
  1000 mg
• A serum ferritin lt10 to 15 ng/mL is 99 percent
  specific for making a diagnosis of iron
  deficiency.
• An elevated serum ferritin ( in the absence of
  infection or inflammation) suggests the presence
  of an iron overload state.

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Distribution of body iron in men and women
70 kg man 60 kg woman
_________ ___________ Iron
stores - transferrin, ferritin, hemosiderin 1.4
g 0.3 g Hemoglobin 2.5 g 1.9
g Myoglobin 0.14 g 0.13 g Heme
enzymes 0.01 g 0.01g _______________________
________________________________________
TOTAL 4.05 g 2.34 g
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Laboratory tests in iron deficiency of increasing
severity
Normal Fe deficiency without anemia Fe deficiency with mild anemia Severe Fe deficiency with severe anemia
Marrow reticuloendo-thelial iron 2 to 3 None None None
Saturation (SIron/TIBC), percent 20-50 30 lt15 lt10
Hemoglobin, g/dL Normal Normal 9 to 12 6 to 7
Red cell morphology Normal Normal Slight hypochromia Hypochromia and mikrocyt
serum ferritin, ng/mL 20 to 200 lt20 lt15 lt10
Other tissue changes None None None Nail and epithelial changes
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KN born 1961 2007 Abdominal cramps, bloody
stool, colonoscopy M Crohn 2009 aug
prolapsus recti Status pallor no perimalleolar
anasarca no tachycardia, but systolic murmur
RDV stool Weber FBC Ht
0,18 Hb 54 g/l ret 35 MCV 65 fl (n
80-97) WBC norm CRP 0 Plt 582
G/l INR norm serumiron 3,0 TIBC
87,8 serum folic acid, serum B12
normal soluble transferrin
receptor 27,6 (norm 1,9- 4,4)
serumferritin 7 ng/ml (norm 10-120)

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Normal curve
Mikrocytosis
Cell-Dyn 3500
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Target RBCs, slight hypochromasia
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Target RBCs in thalassaemia minor
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Anisocytosis, microcytosis in irondeficiency
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Anulocytes, hypochromasia in iron-deficiency
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Anaemias morphological approach
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Change of RBC indices in the course of
successful iron treatment
1999.10.01
vvs
4.16
Hgb
72
Ht
25 MCV61
1999.10.01
vvs
4.16
Hgb
72
Ht
25 MCV61
1999.10.30
vvs
4.56
Hgb
107
Ht
34 MCV74
1999.10.30
vvs
4.56
Hgb
107
Ht
34 MCV74
1999.12.10
vvs
4.87
Hgb
125
Ht
39 MCV79
1999.12.10
vvs
4.87
Hgb
125
Ht
39 MCV79
2000.04.19
2000.04.19
vvs
vvs
4.83
4.83
Hgb
Hgb
138
138
Ht
Ht
41 MCV86
41 MCV86
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Causes of failure to respond to oral iron therapy
Coexisting disease interfering with marrow
response Infection Inflammatory disorder (eg,
rheumatoid arthritis) Concomitant malignancy
Coexisting folic acid and/or vitamin B12
deficiency Bone marrow suppression from another
cause Dg. incorrect, diff. diagnosis Thalassemia
Lead poisoning Anemia of chronic disease
(anemia of chronic inflammation) Copper
deficiency (zinc toxicity) Myelodysplastic
syndrome/refractory sideroblastic anemia Patient
not taking the medication Medication is being
taken but is not being absorbed contd
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Cont.
Medication is being taken but is not being
absorbed Enteric coated product coating is not
dissolving Malabsorption of iron (eg, sprue,
atrophic gastritis) Agents interfering with
absorption (eg, antacids, tetracycline, tea)
Continued blood loss -Cause treatable (eg,
bleeding peptic ulcer) -Cause not treatable
(eg, Osler Weber Rendu disease) or not by
oral iron (eg, renal failure responding to
Epo)
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CALCULATION OF PARENTERAL IRON DOSE
Body weight (kilograms) BW 68 kg Hemoglobin
concentration (g/dL) Hgb 5,5 g/dl Concentration
of elemental iron in the parenteral product
(mg/mL) C 12,5 mg/ml Assumptions Blood
volume is 65 mL per kilogram Hemoglobin
concentration to be corrected to 14.0 g/dL No
additional iron to be given for repletion of body
stores Intermediate calculations Blood volume
(dL) 65 (mL/kg) x body weight (kg) 100
(mL/dL) 65x68/10044,2 dl Hemoglobin deficit
(g/dL) 14.0 - patient hemoglobin conc. 8,5
g/dl Hemoglobin deficit (g) hemoglobin deficit
(g/dL) x blood volume (dL) 8,5x44,2375 g Iron
deficit (mg) hemoglobin deficit (g) x 3.3 (mg
Fe/g Hgb) 375x3.31237,5 mg Volume of
parenteral iron product required (mL) Iron
deficit (mg) C(mg/mL) 99 ml 20 ampulla Final
calculations Hemoglobin iron deficit (mg) BW x
(14 - Hgb) x (2.145) Volume of product required
(mL) BW x (14 - Hgb) x (2.145) C
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Anaemia of chronic diseases (ACD)
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Anemia of chronic disease - bone marrow iron
stain
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Anaemia in rheumatoid disease
Autoimmune phenomena warm antibody AIHA, DAT film show show reticulocytosis
Drug related problems Chronic blood loss, macrocytosis from antimetabolite immunosuppressives azathioprine, Mtx, oxidative haemolysis to dapsone, sulfasalazine (rare AIHA due to NSAID), unforeseeable marrow aplasia
2? to other organ problems hypersplenism, Feltys syndrom, renal failure in SLE
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Determination of soluble transferrin receptor
irondeficiency
ACD Anaemia of chronic disorders
Combined causes
Normal
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Myelodysplastic syndrom- refractory anaemia with
ring sideroblasts
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GUIDELINES FOR RED CELL TRANSFUSIONS IN ADULT
Need based on estimation of lost blood
volume
Ø Need based on hemoglobin concentration Hg
b lt7 g/dL RBC transfusion indicated. If the
patient is otherwise stable, the patient should
receive 2 units of packed RBC, following which
the patient's clinical status and circulating
HgB should be reassessed Hgb 7 to 10
g/dL Correct strategy is unclear Hgb gt10
g/dL RBC transfusion not indicated High
risk patients Patients gt65 and/or those with
cardiovascular or respiratory disease may
tolerate anemia poorly. Such patients may be
transfused when Hgb lt8 g/dL.
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reticulocyta?
Microcytás an.
Hemolizis
Microcytás an.E
Fe n/? TVK n/ ? ferritin ??
Lép nem tap
Vashiányos an.
Krónikus betegséget kíséro anaemia
Ólommérgezés