1. Retics normal or increased
Anemia
CBC, retic count
Retics normal or increased
Hypoproliferative

2. Hypoproliferative Clues from morphology Marrow damage
> Infiltration; fibrosis
> Aplasia
> Myelodysplasia
> Drug or radiation injury
Iron deficiency
B12 deficiency
Folate deficiency
Stimulus
> Inflammation
> Endocrine defect
> Renal disease
Hypersplenism
Clues from morphology
microcytic, normocytic, or macrocytic
poikilocytosis
anisocytosis
nucleated red cells
target cells
Howell-Jolly bodies
hypersegmented polys

3. Retics normal or increased Hemorrhage and Hemolysis
Clues from morphology
Blood loss
Hemolysis
> Antibody-mediated
> Membrane defect
> Metabolic defect
> Red cell fragmentation
Hemoglobinopathy
microcytic, normocytic, or macrocytic
red cell fragmentation
red cell clumping
nucleated red cells
target cells

4. Foucade, Belaouni. Lab Hematol 1999; 5:153-8
IRF = immature reticulocyte fraction
= immature retics / total retics
HLR% = high light scatter retics
= Retics% x IRF
Foucade, Belaouni. Lab Hematol 1999; 5:153-8

5. Foucade, Belaouni. Lab Hematol 1999; 5:153-8
IRF and Anemia
Foucade, Belaouni. Lab Hematol 1999; 5:153-8

9. Direct anti-globulin test

16. Regulation of iron absorption
Gut lumen Fe
+++ Fe ++
Heme Fe
DMT1
Enterocyte
Ferritin Fe ++ Fe
+++
MTP1
Enterocyte
precursor
Plasma transferrin
Transferrin Receptor
HFE
Hepcidin

17. Iron stores
Erythron iron
Marrow iron stores
1 - 3+
0 - 1+
Ferritin
<20
<15
TIBC
>360
>380
>400
Serum iron
<50
<30
Red cells
normal
microcytic, hypochromic

19. Gastrointestinal absorption 1 mg/day
Functional iron
Blood, marrow, myoglobin
2 grams
Storage iron
Liver, RES
1 gram
Plasma transferrin
2 mg
Daily physiologic loss
1 mg

20. Serum iron after oral iron in patients with iron deficiency80 60
Serum iron 40 20 1 2 3 4
Hours
WH Crosby, Arch Int Med; circa 1970

21. Serum ferritin and total body iron
Kaltwasser, Gottschalk. Kidney Int. 1999; 55(suppl): S49 - S56

22. Serum transferrin receptor
Storage iron = 107 mg
Storage iron = 335 mg
Storage iron = 1,102 mg
Serial measurement of sTfr during phlebotomy in 3 individuals
Goodnough, Skikne, Brugnara. Blood, 2000; 96:

23. Cook, Flowers, Skikne. Blood 2003; 101: 3359 - 64
Ratio of serum transferrin receptor to ferritin as a measure of total body iron
Cook, Flowers, Skikne. Blood 2003; 101:

24. Erythropoietin response in iron deficiency
Spivak JL. Lancet 2000; 355:

25. Schreiber, Howalt, et at. NEJM 1996; 334: 619 - 23
Serum erthyropoietin levels in patients with inflammatory bowel disease
Controls = normal volunteers and patients with traumatic blood loss
Schreiber, Howalt, et at. NEJM 1996; 334:

26. IL-1 and anemia in patients with inflammatory bowel disease
Schreiber, Howalt, et at. NEJM 1996; 334:

27. Schreiber, Howalt, et at. NEJM 1996; 334: 619 - 23
Treatment with oral iron ± rEPO in patients with inflammatory bowel disease
Schreiber, Howalt, et at. NEJM 1996; 334:

28. Anemia of chronic disease
Inflammation
Tissue necrosis
Infection
Neoplasia
Congestive heart failure
Acute myocardial infarction

29. Anemia of chronic disease
Typical lab findings:
Serum iron < 50
TIBC < 150
Normochromic or hypochromic red cells
Normal ferritin
Normal serum transferrin receptor

30. Anemia of chronic disease
Mechanisms:
blunted erythropoietin response
diminished response of erythroid precursors to erythropoietin
decreased delivery of iron from RES, increased intracellular ferritin in macrophages
decreased gastrointestinal iron absorption

31. Anemia of chronic disease
Mediators:
IL-1
IL-6
g-interferon
TNF-a

32. Mozaffarian, Levy, et al. J Am Coll Cardiol 2003; 41(11): 1933 - 9
Mortality and initial hematocrit in PRAISE
Prospective randomized amlodipine survival evaluation
1130 patients
15 month follow-up
Results adjusted using multivariant Cox model for age, gender, diabetes, smoking, heart failure etiology, EF, NYHA class, systolic BP, WBC, creatinine, and 18 additional factors
Mozaffarian, Levy, et al. J Am Coll Cardiol 2003; 41(11):

33. Mortality and initial hematocrit in PRAISE
Mozaffarian, Levy, et al. J Am Coll Cardiol 2003; 41(11):

34. Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37: 1775 - 80
Prospective, randomized study of erythropoietin and i.v. iron in patients with CHF
Sq epo twice a week
i.v. iron sucrose weekly
32 patients
NYHA Class III or IV
LVEF < 40%
Hgb
Randomized
Continue standard therapy
Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37:

35. Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37: 1775 - 80
Prospective, randomized study of erythropoietin and i.v. iron in patients with CHF
epo and i.v. iron
observation
After 8 months:
NYHA class
LVEF
Days in hospital
Hgb
Ferritin
Creatinine
+ 48%
+ 5 %
- 79%
10.3 12.9
221  366
1.7  1.7
- 11%
- 5 %
+ 28%
10.9 10.8
264  283
1.4  1.8
Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37:

36. Anemia of chronic disease
In IBD study and in CHF study response to treatment was not predicted by:
serum erythropoietin
serum iron
ferritin

37. Effectiveness of treatment with erythropoietin
Goodnough, Skikne, Brugnara. Blood, 2000; 96:

38. Safety of intravenous iron
Sodium ferric gluconate in sucrose (Ferrlecit)
Available in Europe > 30 years
2.7 x 106 doses/year in Germany + Italy in 1995
Iron dextran (Imferon until 1992, InFed since 1992)
3 x 106 doses/year in US in 1996
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

39. Safety of intravenous iron
Reported severe adverse reactions ( ):
SFGS 3.3 severe allergic reactions/106 doses, no fatalities
ID 8.7 severe allergic reactions/106 doses, 31 fatalities
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

40. Safety of intravenous iron
Other theoretical risks:
iron overload
sepsis
accleration of athersclerosis
Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

41. Medicare warning :(
Recombinant human erythropoietin is approved only for treatment of anemia caused by renal failure or by cancer treatment and for certain hematologic malignancies.
Sodium ferric gluconate in sucrose is approved only for treatment of anemia in patients on hemodialysis and for patients who have had a severe reaction to iron dextran.