Normocytic Anemia
David Lee, MD, FRCPC
Normocytic anemia
• a heterogenous group of anemias• normocytosis implies normal DNA
metabolism and hemoglobin synthesis
• no common pathophysiology
Approach to anemia
anemia
check MCV
MCV < 80microcytic
anemia
MCV 80 - 100normocytic
anemia
MCV > 100macrocytic
anemia
Approach to normocytic anemia
Is there increased red cell production?
check reticulocyte count
normocytic anemia
increased
Is there evidence of hemolysis?
hemolytic anemia
yes
Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease
normal or decreased
recent bleed
no
If not, then consider a primary marrow problem (MDS, MM, infiltration…)
bone marrow investigation
Approach to normocytic anemia
Is there increased red cell production?
check reticulocyte count
normocytic anemia
increased
Is there evidence of hemolysis?
hemolytic anemia
yes
Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease
normal or decreased
recent bleed
no
If not, then consider a primary marrow problem (MDS, MM, infiltration…)
bone marrow investigation
Anemia of chronic disease
• Anemia due to cytokines IL-1, TNF-, TGF- associated with chronic inflammation– rheumatoid arthritis– systemic lupus erythematosis– inflammatory bowel disease– chronic infections: osteomyelitis, TB
Anemia of chronic disease
• Mechanisms– defective iron utilization
• iron is present, but cannot be utilized by erythroid precursors
– impaired response to erythropoietin– ?blunted increase in erythropoietin in
response to anemia
Anemia of chronic disease
• usually normocytic, but 25% are microcytic
• usually mild to moderate anemia • anemia of chronic disease is a
diagnosis of exclusion• bone marrow often needed to rule
out other causes of anemia
Iron studies in IDA and ACD
Test IDA ACD
serum iron
low low
TIBC high normal or low
transf. sat.
low low
serum ferritin
low normal or increased
marrow iron
absent normal or increased
Anemia of chronic disease
• Treatment– treat the underlying cause– erythropoietin can be effective, but is
expensive
Anemia of chronic renal failure
• Mechanism:– mainly due to reduced production of
erythropoietin by diseased kidneys– also iron or folate deficiency, chronic
inflammation, shortened red cell survival
• Treatment– erythropoietin thrice weekly– dialysis
Anemia of endocrine failure
• Uncommon cause of anemia, but correctable– hypothyroidism– hypogonadism– pan-hypopituitarism
Approach to normocytic anemia
Is there increased red cell production?
check reticulocyte count
normocytic anemia
increased
Is there evidence of hemolysis?
hemolytic anemia
yes
Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease
normal or decreased
recent bleed
no
If not, then consider a primary marrow problem (MDS, MM, infiltration…)
bone marrow investigation
Pure red cell aplasia
Pure red cell aplasia
• Very rare cause of normocytic anemia
• immune-mediated destruction of red cell precursors in the marrow
• reticulocyte count is low• treatment: immune suppression
Approach to normocytic anemia
Is there increased red cell production?
check reticulocyte count
normocytic anemia
increased
Is there evidence of hemolysis?
hemolytic anemia
yes
Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease
normal or decreased
recent bleed
no
If not, then consider a primary marrow problem (MDS, MM, infiltration…)
bone marrow investigation
Hemolytic anemia
• Anemia due to increased rate of RBC destruction
• anemia occurs when rate of destruction exceeds production
Normal red cell turnover• normal RBC survival of ~ 120 days• macrophages of the reticuloendothelial
(RE) system removes RBC’s– unclear what marks a red cell for removal– spleen is major site of RBC clearance
• RE system is extravascular– 90% of normal RBC destruction occurs
without release of hemoglobin into circulation.
The fate of intravascular hemoglobin
free Hb tetramers)
Hbdimers
haptoglobin
haptoglobin-hemoglobin
complex
kidneys liver
metHb
binds tohemopexin &albuminferriheme (Fe3+)globin
Extravascular vs Intravascular hemolysis
Extravascular IntravascularTest Hemolysis Hemolysis
LD
bilirubin
haptoglobin N to absent absent
hemoglobinuria absent present
free Hb in plasma absent present
urine hemosiderin absent present
Causes of intravascular hemolysis
– Mechanical• prosthetic heart valve, tight AS• march & bongo drummer’s hemoglobinuria
– Microangiopathic• DIC, TTP, HUS
– Immunological• acute hemolytic transfusion reaction, PNH
– Infection• malaria• Clostridium welchii sepsis
– Enzymopathy• severe G6PD deficiency
Is there hemolysis?• Look for 3 lines of evidence:
– 1. Damaged red cells on the blood film– spherocytes (immune hemolysis, HS)– red cell fragments (microangiopathic anemias)
– 2. Marrow response to hemolysis– polychromasia on blood film– reticulocytosis– erythroid hyperplasia in marrow
– 3. Biochemical evidence of RBC destruction
– increased unconjugated bilirubin– increased lactate dehydrogenase– decreased/absent haptoglobin
Approach to normocytic anemia
Is there increased red cell production?
check reticulocyte count
normocytic anemia
increased
Is there evidence of hemolysis?
hemolytic anemia
yes
Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease
normal or decreased
recent bleed
no
If not, then consider a primary marrow problem (MDS, MM, infiltration…)
bone marrow investigation
An approach to hemolytic anemia
Immune Non-immune
Congenital Acquired
Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)
• RBC enzymes(eg. G6PD deficiency)
• Hemoglobin
• Infections sepsis malaria
• Mechanical prosthetic heart valve microangiopathic HA
• Autoimmune
• Alloimmune
• Drug-induced
(other causes of immune hemolysis are rare)
Hemolytic anemia
An approach to hemolytic anemia
Immune Non-immune
Congenital Acquired
Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)
• RBC enzymes(eg. G6PD deficiency)
• Hemoglobin
• Infections sepsis malaria
• Mechanical prosthetic heart valve microangiopathic HA
• Autoimmune
• Alloimmune
• Drug-induced
(other causes of immune hemolysis are rare)
Hemolytic anemia
Immune hemolysis
• most frequent cause of hemolysis• due to IgG or complement on red
cells– tags the red cell for phagocytosis– spherocytes if incomplete
phagocytosis– lysis of RBC occurs if complement
cascade goes to completion
Autoimmune hemolysis
• Most common type of immune hemolysis
• primary (idiopathic)• secondary
– autoimmune hemolysis secondary to:• autoimmune condition (such as SLE)• infection• lymphoma or CLL
Diagnosis of immune hemolytic anemia
– 1. Direct Antiglobulin Test (DAT or direct Coomb’s test)
– detects IgG or complement on patient’s red cells– the vast majority of patients with active immune hemolysis will
have a positive DAT.
– 2. Indirect Antiglobulin Test (IAT, indirect Coomb’s test)
– detects antibody in patient’s serum against red cell antigens– A positive IAT does not necessarily mean hemolysis is occurring -
It may simply mean allo-immunization due to previous exposure to “foreign” red cell antigens (past pregnancy or transfusion).
– 3. Peripheral Blood Film: spherocytes
Treatment of autoimmune hemolysis
• treat the underlying cause, if there is one
• stop suspect drugs if possible• prednisone• transfuse RBC’s, if needed
An approach to hemolytic anemia
Immune Non-immune
Congenital Acquired
Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)
• RBC enzymes(eg. G6PD deficiency)
• Hemoglobin
• Infections sepsis malaria
• Mechanical prosthetic heart valve microangiopathic HA
• Autoimmune
• Alloimmune
• Drug-induced
(other causes of immune hemolysis are rare)
Hemolytic anemia
Hereditary spherocytosis
• most common inherited red cell membrane disorder
• 1/5000 in northern European populations
• autosomal dominant• caused by mutations in the genes
that encode RBC membrane cytoskeleton proteins.
loss of membrane = loss of SA = loss of deformability = increased splenic clearance
Normal
Hereditary spherocytosis
membrane
cytoskeleton
Hereditary spherocytosis
• Spherocytes are cleared by the spleen more rapidly– lack of deformability means they
cannot squeeze through the sieve-like slits of the spleen.
Hereditary spherocytosis• Clinical features:
– clinical severity varies– most have mild to moderate anemia– splenomegaly, cholelithiasis, jaundice may
occur
• Laboratory features– hemolytic anemia with spherocytes– osmotic fragility test– negative DAT
Hereditary spherocytosis
• Treatment– most patients do not need treatment– splenectomy– counsel patient and family about
inheritance
An approach to hemolytic anemia
Immune Non-immune
Congenital Acquired
Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)
• RBC enzymes(eg. G6PD deficiency)
• Hemoglobin
• Infections sepsis malaria
• Mechanical prosthetic heart valve microangiopathic HA
• Autoimmune
• Alloimmune
• Drug-induced
(other causes of immune hemolysis are rare)
Hemolytic anemia
G6PD deficiency
• Most common inherited red cell enzymopathy– up to 10% of those with African and
Mediterranean descent
• X-linked• hemolysis is due to increased
oxidative damage to red cells
G6PD deficiency
• clinical severity highly variable – Most experience little or no anemia
unless exposed to precipitating event or drug
– precipitants:• infections• sulfa, primaquine, dapsone• fava beans
G6PD deficiency
• Laboratory diagnosis– bite cells– Heinz bodies– measure G6PD level
• Treatment– supportive– avoid precipitants– counsel patient/family
Anemia cases1. A 45 year old woman presents to your office with a 2 week history of increasing fatigue and jaundice. Nohepatomegaly or splenomegaly on examination.
Hb 85 (120-150) g/LMCV 97.5 (80-96) fLRDW 19.8 (11.5-14.5)WBC 13.4 (4 - 10) x 109/LPlatelets 457 (150-450) x 109/L DAT positiveIAT positive
LD 301 (94-172) U/LT bili 53 (0-17) mol/Ldirect bili 2serum haptoglobin absentReticulocytes 357 (18-94) x 109/LPeripheral blood smear: some spherocytes
2. You are the ER doc in a remote town, 2 hours from a tertiary care hospital. At 2300h, a 57 year old man isbrought to the ER by his wife because of acute confusion and disorientation. She thought he had the “flu” forthe past 4 days because he has had a fever, headache, and was feeling unusually tired. He has been on nomedications and he had previously been well.
Hb 70 g/LMCV 98 fLWBC 14.8 x 109/Lplt 76 x 109/Lretics 267 x 109/Lblood smear RBC fragments
polychromasiathrombocytopenianeutrophilia with left shift
creatinine 97 mol/LPT normalPTT normal
2. You are the ER doc in a remote town, 2 hours from a tertiary care hospital. At 2300h, a 57 year old man is
3. A 30 year old woman with a 1 year history of rheumatoid arthritis, involving hands, wrists, On NSAIDS.
ESR 57 mm/hrHb 108 g/LMCV 80 fLRDW 18.5WBC 8.2 x 109/LPlt 317 x 109/LRetics 89 x 109/L
4. A previously healthy 67 year old man with recurrent pneumonia.
Hb 103MCV 98WBC 3.9Plt 153Retics 56Peripheral blood smear: rouleaux
What next?
urea creatinine normalLD 216Coombs negbili normal
serum protein electrophoresis: IgG kappa monoclonal protein with depression of IgA, IgM and polyclonalIgG.
Bone marrow investigation: excessive number of plasma cells
Skeletal survey: numerous lytic lesions in the axial skeleton and cranium.
Case 3. A 72 year old woman with a history of rheumatoid arthritis is found tohave a hemoglobin of 97 g/L (120-160) and an MCV of 79 fL (80-100). Thewhite blood cell and platelet counts are normal. Review of the peripheral bloodsmear does not show much abnormality. She takes ibuprofen twice a day forher joint symptoms.
1. What is the differential diagnosis for her microcytic anemia?
2. What other items on history and physical would be helpful?
3. What other investigations are indicated?
Case 3. A 72 year old woman with a history of rheumatoid arthritis is found to
This is case 3 from the iron lecture