anemia cbc, retic count hypoproliferative retics normal or increased

Anemia

CBC, retic count

Hypoproliferative Retics normal or increased

Hypoproliferative

Clues from morphology

microcytic, normocytic, or macrocytic

poikilocytosis

anisocytosis

nucleated red cells

target cells

Howell-Jolly bodies

hypersegmented polys

Marrow damage > Infiltration; fibrosis > Aplasia > Myelodysplasia > Drug or radiation injury

Iron deficiency

B12 deficiency

Folate deficiency

Stimulus > Inflammation > Endocrine defect > Renal disease

Hypersplenism

Retics normal or increased

Hemorrhage and Hemolysis

Blood loss

Hemolysis > Antibody-mediated > Membrane defect > Metabolic defect > Red cell fragmentation

Hemoglobinopathy

Clues from morphology

microcytic, normocytic, or macrocytic

red cell fragmentation

red cell clumping

nucleated red cells

target cells

IRF = immature reticulocyte fraction

= immature retics / total retics

HLR% = high light scatter retics

= Retics% x IRF

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

IRF and Anemia

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

Direct anti-globulin test

Gut lumen

Fe+++ Fe++ Heme Fe

Enterocyte DMT1

Ferritin Fe++

Fe+++

MTP1

Plasma transferrin

Enterocyteprecursor

Hepcidin

Transferrin Receptor

HFE

Regulation of iron absorption

•Marrow iron stores

•1 - 3+ •0 - 1+ •0 •0

•Ferritin •50 - 200 •<20 •<15 •0

•TIBC •300 - 360 •>360 •>380 •>400

•Serum iron

•50 - 150 •50 - 150

•<50 •<30

•Red cells •normal •normal •normal •microcytic, hypochromic

Iron stores

Erythron iron

Gastrointestinal absorption1 mg/day

Storage iron

Liver, RES

1 gram

Functional iron

Blood, marrow,

myoglobin2 grams

Plasma transferrin2 mg

Daily physiologic loss1 mg

Serum iron after oral iron in patients with iron deficiency

WH Crosby, Arch Int Med; circa 1970

20

40

60

80

1 2 3 4

Ser

um

iro

n

Hours

Kaltwasser, Gottschalk. Kidney Int. 1999; 55(suppl): S49 - S56

Serum ferritin and total body iron

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: 823 - 833

Ratio of serum transferrin receptor to ferritin as a measure of total body iron

Cook, Flowers, Skikne. Blood 2003; 101: 3359 - 64

Erythropoietin response in iron deficiency

Spivak JL. Lancet 2000; 355:1707 - 12

Schreiber, Howalt, et at. NEJM 1996; 334: 619 - 23

Controls = normal volunteers and patients with traumatic blood loss

Serum erthyropoietin levels in patients with inflammatory bowel disease

Schreiber, Howalt, et at. NEJM 1996; 334: 619 - 23

IL-1 and anemia in patients with inflammatory bowel disease

Schreiber, Howalt, et at. NEJM 1996; 334: 619 - 23

Treatment with oral iron ± rEPO in patients with inflammatory bowel disease

Anemia of chronic disease

Inflammation

Tissue necrosis

Infection

Neoplasia

Congestive heart failure

Acute myocardial infarction

Anemia of chronic disease

Typical lab findings:

Serum iron < 50

TIBC < 150

Normochromic or hypochromic red cells

Normal ferritin

Normal serum transferrin receptor

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

Anemia of chronic disease

Mediators:

IL-1

IL-6

-interferon

TNF-

Mortality and initial hematocrit in PRAISE

Mozaffarian, Levy, et al. J Am Coll Cardiol 2003; 41(11): 1933 - 9

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

Mortality and initial hematocrit in PRAISE

Mozaffarian, Levy, et al. J Am Coll Cardiol 2003; 41(11): 1933 - 9

Prospective, randomized study of erythropoietin and i.v. iron in patients with CHF

Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37: 1775 - 80

32 patients

NYHA Class III or IV

LVEF < 40%

Hgb 10 - 11.5

Random

ized

Sq epo twice a week

i.v. iron sucrose weekly

Continue standard therapy

Prospective, randomized study of erythropoietin and i.v. iron in patients with CHF

Silverberg DS, Wexler D, et al. J Am Coll Cardiol 2001; 37: 1775 - 80

NYHA class

LVEF

Days in hospital

Hgb

Ferritin

Creatinine

epo and i.v. iron

observation

+ 48%

+ 5 %

- 79%

10.312.9

221 366

1.7 1.7

- 11%

- 5 %

+ 28%

10.910.8

264 283

1.4 1.8

After 8 months:

Anemia of chronic disease

In IBD study and in CHF study response to treatment was not predicted by:

serum erythropoietin

serum iron

ferritin

Goodnough, Skikne, Brugnara. Blood, 2000; 96: 823 - 833

Effectiveness of treatment with erythropoietin

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

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

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

Reported severe adverse reactions (1976 - 1996):

SFGS 3.3 severe allergic reactions/106 doses, no fatalities

ID 8.7 severe allergic reactions/106 doses, 31 fatalities

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

Other theoretical risks:

iron overload

sepsis

accleration of athersclerosis

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.

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