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Dans l’apport d’oxygène aux tissus, quel facteur Dans l’apport d’oxygène aux tissus, quel facteur parmi les suivants ne dépend pas de façon parmi les suivants ne dépend pas de façon importante du système hématopoïétique :importante du système hématopoïétique :
1.1. La concentration sanguine en HbLa concentration sanguine en Hb
2.2. L’affinité de l’Hb pour l’oxygèneL’affinité de l’Hb pour l’oxygène
3.3. Le degré de saturation de l’Hb en oxygèneLe degré de saturation de l’Hb en oxygène
4.4. La viscosité sanguineLa viscosité sanguine
Question 1Question 1
Quel est le facteur dont le déficit a le moins Quel est le facteur dont le déficit a le moins d’impact sur la production de globules d’impact sur la production de globules rouges ?rouges ?
1.1. Acide foliniqueAcide folinique
2.2. FerFer
3.3. ErythropoïétineErythropoïétine
4.4. ErythroblastesErythroblastes
Question 2Question 2
Epo
GrowthGrowthfactorsfactors
SRESREFeFe
ERYTHROPOIESISERYTHROPOIESISRegulationRegulation
KidneyKidney Bone marrowBone marrow MacrophagesMacrophages
ERYTHROPOIESISERYTHROPOIESIS
BONE MARROW BLOOD
Stem cellsStem cells ProgenitorsProgenitors PrecursorsPrecursors Mature cellsMature cells
S P P p p
BFU-EBFU-E CFU-ECFU-E ErythroblastErythroblast ReticRetic RBCRBC
PermanentPermanent 4 days4 days4 days4 days 120 days120 days????
< 1< 1x 10x 1066
500500x 10x 1066
300300x 10x 1099
500500x 10x 1099
200200x 10x 1099
20,00020,000x 10x 1099
EPO RESPONSE TO ANEMIA
IRONIRONMETABOLISM METABOLISM
Iron cycleIron cycle
IRON KINETICSIRON KINETICSNormalNormal
PlasmaPlasmaMacrophagesMacrophages MarrowMarrow
Un malade anémique chronique (Hb=9 g/dL) Un malade anémique chronique (Hb=9 g/dL) présente les signes suivants : lequel n’est pas présente les signes suivants : lequel n’est pas du à l’anémie ?du à l’anémie ?
1.1. Pâleur conjonctivalePâleur conjonctivale
2.2. Souffle systoliqueSouffle systolique
3.3. Dyspnée d’effortDyspnée d’effort
4.4. Hypotension orthostatiqueHypotension orthostatique
Question 3Question 3
ANEMIAANEMIA SymptomsSymptoms
Central nervous system Cognitive function Mood
Cardiovascular system Tachycardia Weakness
Cardiorespiratory system Dyspnea following exertion Dyspnea Cardiac decompensation
Skin Reduced perfusion Pale Cold
Kidney function Reduced perfusion Fluid retention
Genitourinary tract Menstrual disturbances Loss of libido Impotence
Immune system Immune deficiency
Ludwig & Strasser, Semin.Oncol. 28(Suppl 8):7, 2001
• PallorPallor : : nailbeds, mucous membranes, palmar creases, conjunctivaenailbeds, mucous membranes, palmar creases, conjunctivae(also influenced by skin thickness, blood distribution, melanin(also influenced by skin thickness, blood distribution, melaninpigmentation)pigmentation)
• Hyperactive heartHyperactive heart : : systolic murmur, forceful apical impulses, systolic murmur, forceful apical impulses, hyperactive heart soundshyperactive heart sounds
• HypovolemiaHypovolemia : : postural hypotension, anxiety, air hunger, sweating, postural hypotension, anxiety, air hunger, sweating, confusion, tachycardia at restconfusion, tachycardia at rest (in case of blood loss)(in case of blood loss)
• Signs related to the specific cause of anemiaSigns related to the specific cause of anemia
ANEMIAANEMIASignsSigns
Une femme de 19 ans avec une Hb = 11.0 g/dL :Une femme de 19 ans avec une Hb = 11.0 g/dL :
quelle la cause la plus fréquente ?quelle la cause la plus fréquente ?
1.1. Anémie inflammatoireAnémie inflammatoire
2.2. HémoglobinopathieHémoglobinopathie
3.3. Anémie ferripriveAnémie ferriprive
4.4. Valeur normale d’Hb pour l’ageValeur normale d’Hb pour l’age
Question 4Question 4
ETIOLOGY OF ANEMIA
• Red cell productionRed cell production-- Erythroid marrowErythroid marrow-- ErythropoietinErythropoietin-- IronIron
TISSUE OXYGEN SUPPLYTISSUE OXYGEN SUPPLYHb concentrationHb concentration
• Red cell lossRed cell loss -- HemolysisHemolysis-- Hemorrhage Hemorrhage
• Maturation defectsMaturation defects -- DNA (folate, B12, …) DNA (folate, B12, …) -- HbHb • Globin• Globin
• Heme• Heme-- Myelodysplasia Myelodysplasia
• Decreased number of erythroid precursorsDecreased number of erythroid precursors -- Marrow damage : Marrow damage : • Global : SAA, chemotherapy, …• Global : SAA, chemotherapy, …
• Pure red cell aplasia • Pure red cell aplasia -- Marrow replacement : myelofibrosis, tumor cellsMarrow replacement : myelofibrosis, tumor cells
• Decreased Epo productionDecreased Epo production -- Renal failureRenal failure-- Hypothyroidism, hypopituitarismHypothyroidism, hypopituitarism
• Decreased iron availabilityDecreased iron availability-- Absolute : IDAbsolute : ID-- Functional : inflammation Functional : inflammation
ANEMIAANEMIADefective red cell productionDefective red cell production
• Defect in DNA synthesisDefect in DNA synthesis -- B12 B12 -- FolateFolate
• Defect in Hb synthesisDefect in Hb synthesis -- Globin : hemoglobinopathiesGlobin : hemoglobinopathies-- Heme : sideroblastic anemia, leadHeme : sideroblastic anemia, lead
• Myelodysplasia (pre-leukemia)Myelodysplasia (pre-leukemia)
ANEMIAANEMIAMaturation defect (ineffective erythropoiesis)Maturation defect (ineffective erythropoiesis)
• Constitutional RBC abnormality :Constitutional RBC abnormality : -- Red cell membrane (spherocytosis …) Red cell membrane (spherocytosis …) -- Enzyme (G-6-PD …) Enzyme (G-6-PD …) -- PNH PNH
• Auto-immuneAuto-immune• External aggression :External aggression : osmotic shock, malaria, drug, toxin, osmotic shock, malaria, drug, toxin,
venom, incompatible transfusion venom, incompatible transfusion
• Fragmentation :Fragmentation : microangiopathy, DIC, valve microangiopathy, DIC, valve
• Hypersplenism :Hypersplenism : liver disease, lymphopathy, myelofibrosisliver disease, lymphopathy, myelofibrosis
ANEMIAANEMIAHemolysisHemolysis
Laquelle parmi ces anémies n’est pas macrocytaire ?Laquelle parmi ces anémies n’est pas macrocytaire ?
1.1. Anémie hemolytiqueAnémie hemolytique
2.2. MyélodysplasieMyélodysplasie
3.3. Anémie aplastiqueAnémie aplastique
4.4. Anémie de BiermerAnémie de Biermer
Question 5Question 5
• Microcytic :Microcytic : serum ironserum iron -- Low :Low : ID or inflammation ID or inflammation-- High :High : maturation defect (globin, heme) maturation defect (globin, heme)
• Normocytic :Normocytic : reticulocytesreticulocytes-- N/low :N/low : acute hemorrhage or decreased erythropoiesis acute hemorrhage or decreased erythropoiesis -- High :High : subacute hemorrhage or hemolysissubacute hemorrhage or hemolysis
• Macrocytic :Macrocytic : reticulocytesreticulocytes -- N/low :N/low : maturation defect (DNA, MDS) maturation defect (DNA, MDS) -- High :High : hemolysishemolysis
ANEMIAANEMIADifferential diagnosisDifferential diagnosis
• Serum ironSerum iron -- Low :Low : iron deficiency iron deficiency
ferritinferritin• Low :• Low : absoluteabsolute iron deficiency iron deficiency• Normal/elevated :• Normal/elevated : functionalfunctional iron deficiency iron deficiency
CRP :CRP : inflammation ? inflammation ?-- High :High : maturation defect (globin or heme) maturation defect (globin or heme)
Hb electrophoresis :Hb electrophoresis : thalassemia ? thalassemia ? marrow examination :marrow examination : sideroblastic anemia ? sideroblastic anemia ?
ANEMIAANEMIAMicrocytic anemiaMicrocytic anemia
• ReticulocytesReticulocytes -- Normal/low :Normal/low :
• acute hemorrhage ?• acute hemorrhage ?• decreased erythropoiesis ?• decreased erythropoiesis ? marrow examinationmarrow examination
creatinine, CRP, thyroid hormonescreatinine, CRP, thyroid hormones -- High : High :
LDH/bilirubinLDH/bilirubin • Normal :• Normal : subacute hemorrhage subacute hemorrhage
• Increased :• Increased : hemolysis hemolysis
ANEMIAANEMIANormocytic anemiaNormocytic anemia
• ReticulocytesReticulocytes -- High :High : hemolysis hemolysis -- Normal/low :Normal/low : maturation defect (DNA, MDS) : maturation defect (DNA, MDS) :
B12/folateB12/folate• Decreased :• Decreased : megaloblastic anemia megaloblastic anemia • Normal :• Normal :
marrow examination : marrow examination : MDS ?MDS ? -GT : -GT : alcohol ?alcohol ? thyroid hormones : thyroid hormones : hypothyroidism ?hypothyroidism ?
ANEMIAANEMIAMacrocytic anemiaMacrocytic anemia
Laquelle parmi ces situations n’est pas cause Laquelle parmi ces situations n’est pas cause d’anémie ferriprive ?d’anémie ferriprive ?
1.1. ColectomieColectomie
2.2. GrossesseGrossesse
3.3. Maladie de Rendu-Osler (télengiectasies)Maladie de Rendu-Osler (télengiectasies)
4.4. HémodialyseHémodialyse
Question 6Question 6
• Increased iron losses Increased iron losses • Decreased iron intakeDecreased iron intake
-- Inadequate diet Inadequate diet -- Impaired absorption : Impaired absorption : achlorhydria, gastric surgery, duodenal disease, picaachlorhydria, gastric surgery, duodenal disease, pica
• Increased iron requirementsIncreased iron requirements-- Infancy (prematurity) Infancy (prematurity) -- PregnancyPregnancy-- Lactation Lactation
IRON DEFICIENCY ANEMIAIRON DEFICIENCY ANEMIAEtiologyEtiology
• Organic pathologyOrganic pathology-- Gastrointestinal Gastrointestinal -- Gynecologic (excessive menstrual flow)Gynecologic (excessive menstrual flow)-- Urinary (hematuria or hemoglobinuria)Urinary (hematuria or hemoglobinuria)-- Pulmonary (alveolar hemorrhage)Pulmonary (alveolar hemorrhage)-- Cutaneo-mucous (telangiectasia)Cutaneo-mucous (telangiectasia)
• Disorders of hemostasisDisorders of hemostasis• Runner’s anemia Runner’s anemia • Blood donation, blood tests, hemodialysisBlood donation, blood tests, hemodialysis• Self-induced bleedingSelf-induced bleeding
IRON DEFICIENCY ANEMIAIRON DEFICIENCY ANEMIAEtiology : increased iron lossesEtiology : increased iron losses
• Stage 1 : depletion of iron storesStage 1 : depletion of iron stores -- Serum ferritin : Serum ferritin : < 12 µg/L < 12 µg/L
• Stage 2 : iron-deficient erythropoiesisStage 2 : iron-deficient erythropoiesis -- Serum iron : Serum iron : < 60 µg%< 60 µg%-- Tf saturationTf saturation < 15 % < 15 % -- % hypochromic RBC % hypochromic RBC > 5 %> 5 %-- CHrCHr < 26 pg < 26 pg -- Soluble TfRSoluble TfR > 7 mg/L> 7 mg/L-- RBC protoporphyrinRBC protoporphyrin > 70 µg%> 70 µg%
• Stage 3 : iron-deficiency anemiaStage 3 : iron-deficiency anemia -- Hemoglobin : Hemoglobin : < 12 gr/dl (F) 13.5 gr/dl (M)< 12 gr/dl (F) 13.5 gr/dl (M)-- Hematocrit :Hematocrit : < 36 % (F) or 41 % (M)< 36 % (F) or 41 % (M)-- RBC :RBC : N then N then -- MCV :MCV : < 80 fl < 80 fl (microcytosis)(microcytosis)-- MCH :MCH : < 28 pg (hypochromia) < 28 pg (hypochromia)
IRON DEFICIENCY ANEMIAIRON DEFICIENCY ANEMIAStagesStages
Quelle est la cause la plus fréquente d’anémie chez Quelle est la cause la plus fréquente d’anémie chez un patient cancéreux ?un patient cancéreux ?
1.1. RadiothérapieRadiothérapie
2.2. Anémie inflammatoire (ACD)Anémie inflammatoire (ACD)
3.3. Anémie ferripriveAnémie ferriprive
4.4. Anémie par envahissement médullaireAnémie par envahissement médullaire
Question 7Question 7
• HemodilutionHemodilution• BleedingBleeding• HypersplenismHypersplenism• HemophagocytosisHemophagocytosis• Hemolysis (autoimmune, microangiopathic,...)Hemolysis (autoimmune, microangiopathic,...)• Nutritional deficiencies (global, iron, folate, B12)Nutritional deficiencies (global, iron, folate, B12)• Marrow damage Marrow damage
(metastases, necrosis, PRCA, myelodysplasia,...)(metastases, necrosis, PRCA, myelodysplasia,...)• Chemotherapy, radiotherapyChemotherapy, radiotherapy
ANEMIA OF CANCERANEMIA OF CANCER EtiologyEtiology
Epo
TNFTNF
SRESREFeFe
ACDACDPathogenesis : cytokinesPathogenesis : cytokines
IL-1IL-1
IFN-IFN- IFN-IFN-
IRON KINETICSIRON KINETICSFunctional iron deficiency : inflammationFunctional iron deficiency : inflammation
PlasmaPlasmaMacrophagesMacrophages MarrowMarrow
SHIFT RETICULOCYTOSIS
RBC INDICESRBC INDICESRBC analysis by flow cytometryRBC analysis by flow cytometry
0 28 41 50 g/dL0 28 41 50 g/dL Hgb Concentration (HC)Hgb Concentration (HC)
0 60 120 200 fL0 60 120 200 fL RBC Volume (V)RBC Volume (V)
0 100 pg0 100 pg Hgb Content (CH)Hgb Content (CH)
RB
C V
olu
me
(fL
)R
BC
Vo
lum
e (
fL)
Hgb Concentration (g/dL)Hgb Concentration (g/dL)
MicroMicro
HypoHypo HyperHyper
MacroMacro
120fL120fL
60fL60fL28g/dL28g/dL 41g/dL41g/dL
Adapted from Brugnara, 2001
• Normal < 5%Normal < 5%• Increased % hypochromic Increased % hypochromic
RBCs (>10-20 %) is an RBCs (>10-20 %) is an indicator of iron deficient indicator of iron deficient erythropoiesiserythropoiesis
• Good indicator of response Good indicator of response to IV iron treatment to IV iron treatment
RBC INDICESRBC INDICESHypochromic erythrocytesHypochromic erythrocytes
% Hypo24.4%
Adapted from Brugnara, 2001
RBC INDICESRBC INDICES RBC and retic parameters : rHuEpo therapyRBC and retic parameters : rHuEpo therapy
rHuEporHuEpo1200 U/kg1200 U/kg
over 10 daysover 10 days
C. Brugnara C. Brugnara et alet al. J Lab Clin Med 1994, 123:660. J Lab Clin Med 1994, 123:660 Adapted from Brugnara, 2001
SERUM ERYTHROPOIETINSERUM ERYTHROPOIETIN
Cazzola et al,Cazzola et al, Blood 89:4250, 1997Blood 89:4250, 1997
SERUM FERRITIN
Laquelle parmi ces pathologies n’est pas cause d’une Laquelle parmi ces pathologies n’est pas cause d’une élévation inappropriée de la ferritine sérique élévation inappropriée de la ferritine sérique (sans relation avec les réserves en fer) ?(sans relation avec les réserves en fer) ?
1.1. HépatiteHépatite
2.2. HypothyroïdieHypothyroïdie
3.3. Insuffisance rénale sévèreInsuffisance rénale sévère
4.4. Aucune des 3Aucune des 3
Question 8Question 8
FERRITINFERRITINSerum ferritinSerum ferritin
• Reflection of iron stores (RES and hepatocytes):Reflection of iron stores (RES and hepatocytes): 1 µg/L = 120 µg/kg iron store1 µg/L = 120 µg/kg iron store
• Normal range varies with age and sexNormal range varies with age and sex• Low ferritin 100% specific for iron deficiency Low ferritin 100% specific for iron deficiency • Falsely elevated serum ferritinFalsely elevated serum ferritin
- - Inflammation : Inflammation : lower limit 40-120 µg/Llower limit 40-120 µg/L- - Renal failure : Renal failure : lower limit 40-100 µg/Llower limit 40-100 µg/L -- Liver damageLiver damage- - HyperthyroidismHyperthyroidism- - Some forms of cancerSome forms of cancer-- Hyperferritin-cataract syndromeHyperferritin-cataract syndrome-- Poorly controlled diabetes mellitus (ferritin glycosylation)Poorly controlled diabetes mellitus (ferritin glycosylation)
TRANSFERRIN SATURATION
La saturation de la transferrine est le plus La saturation de la transferrine est le plus influencée par ?influencée par ?
1.1. L’alimentationL’alimentation
2.2. L’activité érythropoïétique de la moelleL’activité érythropoïétique de la moelle
3.3. Le moment de la journéeLe moment de la journée
4.4. Le taux de transferrine sériqueLe taux de transferrine sérique
Question 9Question 9
IRON KINETICSIRON KINETICSAplasiaAplasia
PlasmaPlasmaMacrophagesMacrophages MarrowMarrow
IRON KINETICSIRON KINETICSFunctional iron deficiency : rHuEpo therapyFunctional iron deficiency : rHuEpo therapy
PlasmaPlasmaMacrophagesMacrophages MarrowMarrow
IRON KINETICSIRON KINETICSHemolysisHemolysis
PlasmaPlasmaMacrophagesMacrophages MarrowMarrow
SOLUBLE TRANSFERRIN RECEPTORSOLUBLE TRANSFERRIN RECEPTORErythropoiesisErythropoiesis
AA CRF Chemo0
2
4
6
8
10
(n=20) (n=61)(n=58)
Normal
sT
fR (
mg
/L)
AIHA HS Thal HbH PC0
10
20
30
40
50
60
70
(n=20) (n=11)(n=72)
Normal
(n=12)(n=8)
sT
fR (
mg
/L)
HyperplasticHyperplastic HypoplasticHypoplastic
7.07.0
Ferritin (µg/L)Ferritin (µg/L)
sTfR
(m
g/L
)sT
fR (
mg/
L)
SOLUBLE TRANSFERRIN RECEPTORSOLUBLE TRANSFERRIN RECEPTORIron deficiencyIron deficiency
IDEIDE FunctionalFunctionalIDID
NormalNormal
1212
StorageStoragedepletiondepletion
3.03.0
7.07.0
Ferritin (µg/L)Ferritin (µg/L)
sTfR
(m
g/L
)sT
fR (
mg/
L)
SOLUBLE TRANSFERRIN RECEPTORSOLUBLE TRANSFERRIN RECEPTORIron deficiencyIron deficiency
IDEIDE FunctionalFunctionalIDID
NormalNormal
1212
StorageStoragedepletiondepletion
50-10050-100
InflammationInflammation
3.03.0
ERYTHROID MARROW FUNCTIONERYTHROID MARROW FUNCTION
ErythroidErythroidmarrowmarrow
RESRES(macrophages)(macrophages)
SeFeSeFeTf saturTf satur
(marrow iron supply)(marrow iron supply)FerritinFerritin
(iron stores)(iron stores)
sTfRsTfRETUETU
(total erythropoiesis)(total erythropoiesis)
BFU-EBFU-ECFU-ECFU-E
(progenitors)(progenitors)
Retic indexRetic index(effective erythropoiesis)(effective erythropoiesis)
CHrCHrHypochromic RBCHypochromic RBC
FEPFEPsTfRsTfR
(functional iron deficiency)(functional iron deficiency)
Hb - Hct -RBCHb - Hct -RBC
EPOEPO