<ul><li>Brad Lewis </li></ul><ul><li>San Francisco General Hospital </li></ul><ul><li>Blood alone moves the wheels of hist...
Goals of this Talk <ul><li>How to Approach the Anemic Patient </li></ul><ul><li>Anemias specific to HIV </li></ul><ul><ul>...
Anemia in HIV (EuroSIDA) Mocroft A, AIDS  1999; 13:943–50
An Approach to Anemia Anemia
Evaluating Hemolysis The Bucket with The Hole
Evaluating Hemolysis The Bucket with The Hole
Reticulocytes Retic #=1/mm Retic %= 20% Retic # = 1/mm Retic % = 30% Corr Retic = Retic x hgb/nl hgb RPI = corrected retic...
An Approach to Anemia Retic Hi Retic Low Anemia
An Approach to Anemia Retic Hi Retic Low Anemia MCV Hi MCV Nl MCV Lo
An Approach to Anemia Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo Intrinsic Extrinsic Splenic Mechan...
An Approach to Anemia Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo Intrinsic Hgb’opathy Enzymopathy M...
Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo Intrinsic Extrinsic AIHA cold warm Drug/Toxins Sepsis Bu...
Hemolysis Diagnosis <ul><li>Check the RETIC! </li></ul><ul><li>Confirmatory Testing </li></ul><ul><ul><li>LDH, Haptoglobin...
Specific  Diagnostic Tests-High Retic <ul><li>Smear </li></ul><ul><li>Coombs- Direct and Indirect </li></ul><ul><ul><li>Do...
What Else Could It Be? <ul><li>56 yo Hawaiian male  </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320,  Ind. Bili 2...
What Else Could It Be? <ul><li>56 yo Hawaiian male  </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320,  Ind. Bili 2...
What Else Could It Be? <ul><li>56 yo Hawaiian male  </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320,  Ind. Bili 2...
Microangiopathic Hemolysis <ul><li>DIC </li></ul><ul><li>TTP , HUS </li></ul><ul><li>Malignant Hypertension </li></ul><ul>...
 
Microangiopathic Hemolysis
MAHA-What Else Could It Be? <ul><li>MDS </li></ul><ul><ul><li>Malignant </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul>...
G6PD <ul><li>X-linked, race variable </li></ul><ul><li>Unable to Reduce Glutathione </li></ul><ul><ul><li>Susceptible to o...
G6PD Deficiency Average G6PD Act. Time in Circulation
“Italian” G6PD Deficiency Average G6PD Act. Time in Circulation Normal Nl mean Severe G6PD Def.
“African” G6PD Deficiency Average G6PD Act. Time in Circulation
“African” G6PD Deficiency Average G6PD Act. Time in Circulation G6PD in hemolysis
“ African” G6PD Deficiency hemolysing with oxidant stress Average G6PD Act. Time in Circulation Hemolyzed New Average G6PD...
Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo B12 Folate Toxic AZT,DDC Chemo Dilantin MDS Hepatic ETOH...
Diagnostic Tests- Low Retic  Macrocytic <ul><li>Repeat Retic </li></ul><ul><li>Smear (round vs. oval macrocytes, hypersegm...
B12 Hyperseg PMN
B12 Deficiency <ul><li>??Diagnostic level (<300) </li></ul><ul><ul><li>Role of Methylmalonic acid </li></ul></ul><ul><li>?...
An Approach to Anemia Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo Iron (Lead) Thalassemia Fragmentat...
Diagnostic Tests Low Retic  Microcytic <ul><li>Iron/TIBC vs. Ferritin </li></ul><ul><li>Hemoglobin Electropheresis </li></...
Evaluating Iron <ul><li>Ferritin </li></ul><ul><ul><li>Sensitive/specific  </li></ul></ul><ul><ul><ul><li>Except  increase...
Iron Metabolism Plasma Fe-Tf Hepcidin Hepcidin Hepcidin Iron Signal? Erythropoiesis Signal anemia, hypoxia RBC Bone Marrow...
Treatment of Iron Deficiency <ul><li>Oral always preferred </li></ul><ul><ul><li>?low dose equally effective </li></ul></u...
Retic Hi Retic Low Anemia Destruction   Loss MCV Hi MCV Nl MCV Lo Early Anything Mild/Treated  Transfused  Chronic Disease...
 
Myelosuppressive Drugs in HIV <ul><li>ACV, Ganciclovir, Foscarnet, Cidofovir </li></ul><ul><li>Ampho </li></ul><ul><li>Sep...
Intrinsic Marrow Involvement <ul><li>Infections </li></ul><ul><ul><li>Fungal </li></ul></ul><ul><ul><li>AFB </li></ul></ul...
Parvovirus Infection <ul><li>Persistent/Relapsing anemia in immunocompromised </li></ul><ul><ul><li>Neutropenia in 35%, Th...
Bone Marrow Asp w/ Parvovirus Parvovirus
Hgb and Quality of Life Quality of Life (LASA) 7 9 11 13 Hgb Crawford. Cancer 2002;95:888, Soignet. Semin Hematol. 2000
Risks of PRBC Tx vs. EPO Erythropoietin  RBC Transfusion
 
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Lewis Brad Anemia H I V A I D S G R409

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Brad Lewis: Anemia and H I V A I D S

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  • Kaplan-Meier progression to death for patients in the EuroSIDA study, according to baseline hemoglobin level, in multivariate analysis [20]. Normal was defined as a hemoglobin level of 114 g/dL for men and 112 g/dL for women; mild anemia was defined as a hemoglobin level of 8–14 g/dL for men and 8–12 g/dL for women; and severe anemia was defined as a hemoglobin level of !8 g/dL for both men and women.
  • 30% + coombs w/o hemolysis
  • Note macrocytosis and hyperseg
  • 23 yo Thai, 13 weeks Pregnant Hgb 11, MCV 72 What Tests? Iron Studies first , may mask beta-Thal By decreasing Hgb A 2 If Hemoglobin Electropheresis is normal? If iron nl, then not beta-thal BUT alpha-thal carrier state has normal HPLC Evaluating Iron Ferritin Sensitive/specific Except increased in inflammation, liver disease, malignancy Fe/TIBC (Transferrin) and Saturation Decreased in inflammation, malignancy THEREFORE: Iron Trial Serum (soluble) Transferrin Receptor Mediates iron transfer into cell Increased in Fe-def, rapid cell production CHR-Retic Hemoglobin Concentration? Follow-up GI Eval 10 -15% with malignancy ?Only if ferritin &lt;100?
  • Anemia of chronic disease and iron deficiency anemia, the most common forms of anemia, are differentiated primarily by estimates of iron status. Standard measures of iron status, such as ferritin, total iron-binding capacity, and serum iron are directly affected by chronic disease. In contrast, soluble transferrin receptor (sTfR) is elevated in iron deficiency but is not appreciably affected by chronic disease. sTfR is elevated in subjects with hyperplastic erythropoiesis (eg, hemolytic anemia, beta-thalassemia, polycythemia, etc) and depressed in subjects with hypoplastic erythropoiesis (eg, chronic renal failure, aplastic anemia, or post-transplant anemia). Transferrin receptor (TfR) is the major mediator of iron uptake by cells. TfR is a transmembrane, disulfide-linked dimer of two identical subunits that binds and internalizes diferric transferrin, thereby delivering iron to the cell cytosol. When a cell needs iron, TfR expression is increased to facilitate iron uptake. Since the major use of iron is for hemoglobin synthesis, about 80% of total TfR is on erythroid progenitor cells. Soluble transferrin receptor arises from proteolysis of the intact protein on the cell surface, leading to monomers that can be measured in plasma and serum. Thus, the concentration of sTfR in plasma or serum is an indirect measure of total TfR. The serum level of sTfR reflects either the cellular need for iron or the rate of erythropoiesis. The concentration of sTfR in plasma or serum is elevated in iron deficiency. The concentration of sTfR in plasma or serum is correlated with erythron transferrin uptake, a ferrokinetic measure of erythropoietic activity. Postgraduate Medical Journal 2004;80:405-410 risk of colon CA with iron deficiency
  • Increased Hepcidin in inflammation blocks the marked iron movements Iron replacement at low doses: Am J Med Volume 118, Issue 10, Pages 1142-1147 (October 2005)
  • Iron replacement at low doses: Am J Med Volume 118, Issue 10, Pages 1142-1147 (October 2005)
  • Flunker G, Peters A, Wiersbitzky S, Modrow S, Seidel W. Persistent par- vovirus B19 infections in immnol (Berl). 1998;186:189–194.
  • In a review of 3 open-label community-based studies of &gt;7000 cancer patients, the effects of recombinant human erythropoietin (rHuEPO) on quality-of-life (QOL) outcomes and hemoglobin (Hgb) were summarized. Dosing was 3 times weekly in 2 studies (Glaspy et al and Demetri et al) and once weekly in the study by Gabrilove et al. In each study, the final Hgb significantly improved from baseline with mean increases of 1.8 g/dL, 2.0 g/dL, and 2.0 g/dL in the studies by Glaspy, Demetri, and Gabrilove, respectively (p&lt;0.001). QOL data collected in these open-label assessments were compiled by the Functional Assessment of Cancer Therapy (FACT) scale and the Linear Analogue Self-Assessment (LASA) test. Key parameters assessed included energy, activity, and overall QOL. As shown in this slide, very similar results, captured as percent change from baseline, were obtained by Demetri et al (1998) and Gabrilove et al (1999) who, between them, noted an approximate 30% increase in energy level, an approximate 28% increase in activity, and an approximate 20% increase in overall QOL. An earlier study reported by Glaspy (1997) with a smaller initial pool of patients (N=1498) reported slightly better improvements in energy (38%), activity (32%), and overall QOL (24%).
  • NEJM ICU pt study, 0.4 g difference at 29 days ICU Pts with trauma Decreased Mortality (4.8 vs 10.4%, 1400 pts) Increased Thrombosis
  • Lewis Brad Anemia H I V A I D S G R409

    1. 1. <ul><li>Brad Lewis </li></ul><ul><li>San Francisco General Hospital </li></ul><ul><li>Blood alone moves the wheels of history. </li></ul><ul><ul><li>Benito Mussolini </li></ul></ul><ul><li>Blood will tell, but often it tells too much. </li></ul><ul><ul><li>Don Marquis </li></ul></ul>Anemia in the Patient with HIV
    2. 2. Goals of this Talk <ul><li>How to Approach the Anemic Patient </li></ul><ul><li>Anemias specific to HIV </li></ul><ul><ul><li>Evaluating hemolysis </li></ul></ul><ul><ul><li>Iron Deficiency and CDA </li></ul></ul><ul><ul><li>G6PD </li></ul></ul><ul><ul><li>B12 Deficiency </li></ul></ul><ul><ul><li>Marrow Dysfunction </li></ul></ul>
    3. 3. Anemia in HIV (EuroSIDA) Mocroft A, AIDS 1999; 13:943–50
    4. 4. An Approach to Anemia Anemia
    5. 5. Evaluating Hemolysis The Bucket with The Hole
    6. 6. Evaluating Hemolysis The Bucket with The Hole
    7. 7. Reticulocytes Retic #=1/mm Retic %= 20% Retic # = 1/mm Retic % = 30% Corr Retic = Retic x hgb/nl hgb RPI = corrected retic. count/Maturation time (Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for 25%, and 2.5 for 15%.)
    8. 8. An Approach to Anemia Retic Hi Retic Low Anemia
    9. 9. An Approach to Anemia Retic Hi Retic Low Anemia MCV Hi MCV Nl MCV Lo
    10. 10. An Approach to Anemia Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo Intrinsic Extrinsic Splenic Mechanical Recovery Tissue On Floor Occult Iron (Lead) Thal Frags B12 Folate Liver ETOH Thyroid Toxic MDS Chronic Disease Renal Mixed Mild/Treated Early Transfused Endocrine Intrinsic BM Dilution
    11. 11. An Approach to Anemia Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo Intrinsic Hgb’opathy Enzymopathy Membrane HS PNH Extrinsic Splenic Mechanical Recovery Tissue On Floor Occult
    12. 12. Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo Intrinsic Extrinsic AIHA cold warm Drug/Toxins Sepsis Burns Splenic/Hepatic Mechanical MAHA Tissue On Floor Occult Recovery
    13. 13. Hemolysis Diagnosis <ul><li>Check the RETIC! </li></ul><ul><li>Confirmatory Testing </li></ul><ul><ul><li>LDH, Haptoglobin </li></ul></ul><ul><ul><ul><li>1% Population Ahaptoglobinemic </li></ul></ul></ul><ul><ul><li>Bilirubin </li></ul></ul><ul><li>Intravascular (massive) </li></ul><ul><ul><li>Plasma Hgb </li></ul></ul><ul><ul><li>Urine Hemosiderin (Hemoglobinuria) </li></ul></ul><ul><ul><ul><li>The Hgb A 1 C of the hematologist </li></ul></ul></ul>
    14. 14. Specific Diagnostic Tests-High Retic <ul><li>Smear </li></ul><ul><li>Coombs- Direct and Indirect </li></ul><ul><ul><li>Does NOT diagnose hemolysis </li></ul></ul><ul><li>G6PD ASSAY (and Retic count) </li></ul><ul><li>Hemoglobin Electropheresis??? </li></ul>
    15. 15. What Else Could It Be? <ul><li>56 yo Hawaiian male </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1 </li></ul><ul><ul><li>Fe studies nl, B12/Folate nl, Coombs 4+IgG </li></ul></ul><ul><ul><li>Well! </li></ul></ul>
    16. 16. What Else Could It Be? <ul><li>56 yo Hawaiian male </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1 </li></ul><ul><ul><li>Fe studies nl, B12/Folate nl, Coombs 4+IgG </li></ul></ul><ul><ul><li>Well! </li></ul></ul><ul><li>Given 12 mo prednisone without effect --- </li></ul>
    17. 17. What Else Could It Be? <ul><li>56 yo Hawaiian male </li></ul><ul><li>Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1 </li></ul><ul><ul><li>Fe studies nl, B12/Folate nl, Coombs 4+IgG </li></ul></ul><ul><ul><li>Well! </li></ul></ul><ul><li>Given 12 mo prednisone without effect --- </li></ul><ul><li>Retic #20 (0.5%) </li></ul><ul><li>BM with MDS, evolving AML </li></ul><ul><ul><li>PNH </li></ul></ul>
    18. 18. Microangiopathic Hemolysis <ul><li>DIC </li></ul><ul><li>TTP , HUS </li></ul><ul><li>Malignant Hypertension </li></ul><ul><li>Mechanical </li></ul><ul><ul><li>Vasculitis </li></ul></ul><ul><ul><li>Tumor </li></ul></ul><ul><ul><li>Cardiac Valve </li></ul></ul><ul><ul><li>SBE </li></ul></ul><ul><ul><li>TIPSS </li></ul></ul><ul><ul><li>AVM </li></ul></ul>
    19. 20. Microangiopathic Hemolysis
    20. 21. MAHA-What Else Could It Be? <ul><li>MDS </li></ul><ul><ul><li>Malignant </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><li>B12 </li></ul><ul><li>Iron Deficiency </li></ul>
    21. 22. G6PD <ul><li>X-linked, race variable </li></ul><ul><li>Unable to Reduce Glutathione </li></ul><ul><ul><li>Susceptible to oxidant damage </li></ul></ul><ul><li>Drugs </li></ul><ul><ul><li>Sulfa </li></ul></ul><ul><ul><li>Methylene Blue </li></ul></ul><ul><ul><li>Anti-Malarial </li></ul></ul><ul><ul><li>Nitrates </li></ul></ul><ul><li>Infections </li></ul><ul><li>DKA </li></ul><ul><li>Fava Beans </li></ul>
    22. 23. G6PD Deficiency Average G6PD Act. Time in Circulation
    23. 24. “Italian” G6PD Deficiency Average G6PD Act. Time in Circulation Normal Nl mean Severe G6PD Def.
    24. 25. “African” G6PD Deficiency Average G6PD Act. Time in Circulation
    25. 26. “African” G6PD Deficiency Average G6PD Act. Time in Circulation G6PD in hemolysis
    26. 27. “ African” G6PD Deficiency hemolysing with oxidant stress Average G6PD Act. Time in Circulation Hemolyzed New Average G6PD Activity Young Retics with more G6PD
    27. 28. Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo B12 Folate Toxic AZT,DDC Chemo Dilantin MDS Hepatic ETOH Thyroid Other Nuclear Maturation Lipid Bilayer
    28. 29. Diagnostic Tests- Low Retic Macrocytic <ul><li>Repeat Retic </li></ul><ul><li>Smear (round vs. oval macrocytes, hypersegmented PMN) </li></ul><ul><li>B12 and Folate (and Iron) </li></ul><ul><li>Hepatic </li></ul><ul><li>Toxic? </li></ul><ul><ul><li>AZT, DDC, Stavudine, Lamivudine </li></ul></ul><ul><ul><li>Chemo, ETOH </li></ul></ul><ul><li>Cold Agglutinin </li></ul><ul><li>To BM or not to BM </li></ul>
    29. 30. B12 Hyperseg PMN
    30. 31. B12 Deficiency <ul><li>??Diagnostic level (<300) </li></ul><ul><ul><li>Role of Methylmalonic acid </li></ul></ul><ul><li>??atrophic gastritis </li></ul><ul><li>Role of Schilling Test today </li></ul><ul><li>Anti-Intrinsic Factor Ab (specific and sensitive for Pernicious Anemia) </li></ul><ul><li>Diagnostic/therapeutic trial </li></ul><ul><li>??Multi-factorial etiology of B12 & Anemia </li></ul>
    31. 32. An Approach to Anemia Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo Iron (Lead) Thalassemia Fragmentation Sideroblastic Anemia acquired congenital
    32. 33. Diagnostic Tests Low Retic Microcytic <ul><li>Iron/TIBC vs. Ferritin </li></ul><ul><li>Hemoglobin Electropheresis </li></ul><ul><ul><li>Test Fe First </li></ul></ul><ul><ul><ul><li>May mask B-Thal </li></ul></ul></ul><ul><ul><li>GENETIC SCREENING OF FAMILY </li></ul></ul><ul><ul><li>The “Normal” Electropheresis </li></ul></ul><ul><ul><ul><li>Nl Fe, Nl HPLC = Alpha Thal! </li></ul></ul></ul><ul><li>Smear? </li></ul><ul><li>Value of MCV, RBC # and RDW </li></ul><ul><li>Lead? </li></ul>
    33. 34. Evaluating Iron <ul><li>Ferritin </li></ul><ul><ul><li>Sensitive/specific </li></ul></ul><ul><ul><ul><li>Except increased in inflammation, liver disease, malignancy </li></ul></ul></ul><ul><li>Fe/TIBC (Transferrin) and Saturation </li></ul><ul><ul><li>Decreased in inflammation, malignancy </li></ul></ul><ul><ul><li>< 10% Sat suggests Iron Deficiency </li></ul></ul><ul><li>THEREFORE: </li></ul><ul><ul><li>Iron Trial almost always safe </li></ul></ul><ul><ul><li>Serum (soluble) Transferrin Receptor </li></ul></ul><ul><ul><ul><li>Mediates iron transfer into cell </li></ul></ul></ul><ul><ul><ul><li>Increased in Fe-def, rapid cell production </li></ul></ul></ul><ul><ul><li>CHR-Retic Hemoglobin Concentration? </li></ul></ul><ul><li>Follow-up GI Eval </li></ul><ul><ul><li>10 -15% with malignancy </li></ul></ul><ul><ul><li>?Only if ferritin <100? </li></ul></ul>
    34. 35. Iron Metabolism Plasma Fe-Tf Hepcidin Hepcidin Hepcidin Iron Signal? Erythropoiesis Signal anemia, hypoxia RBC Bone Marrow Duodenum Spleen Tomas Ganz ASH 2006 Inflammation IL-6 Dec. Hep Inc. Hep Hepcidin
    35. 36. Treatment of Iron Deficiency <ul><li>Oral always preferred </li></ul><ul><ul><li>?low dose equally effective </li></ul></ul><ul><ul><li>?role for Vitamin C </li></ul></ul><ul><li>When to use IV iron </li></ul><ul><ul><li>Recent decreased risk of anaphylaxis </li></ul></ul><ul><ul><li>Poor compliance </li></ul></ul><ul><ul><ul><li>Side-effects, etc </li></ul></ul></ul><ul><ul><li>Poor Absorption </li></ul></ul><ul><ul><ul><li>Jejeunal/duodenal disease </li></ul></ul></ul><ul><ul><ul><li>Sprue </li></ul></ul></ul><ul><ul><ul><li>“ Chronic Disease”? </li></ul></ul></ul><ul><ul><ul><li>Anemia of Malignancy </li></ul></ul></ul>
    36. 37. Retic Hi Retic Low Anemia Destruction Loss MCV Hi MCV Nl MCV Lo Early Anything Mild/Treated Transfused Chronic Disease Renal Mixed Endocrine Intrinsic BM Aplastic Myeloma True Lymphoma Drug Infection Anorexia Malignancy Parvovirus
    37. 39. Myelosuppressive Drugs in HIV <ul><li>ACV, Ganciclovir, Foscarnet, Cidofovir </li></ul><ul><li>Ampho </li></ul><ul><li>Septra/Dapsone/ IV Pentamidine </li></ul><ul><li>Pyrimethamine </li></ul><ul><li>AZT, Zalcitabine </li></ul><ul><li>Chemo </li></ul><ul><li>Interferon </li></ul>
    38. 40. Intrinsic Marrow Involvement <ul><li>Infections </li></ul><ul><ul><li>Fungal </li></ul></ul><ul><ul><li>AFB </li></ul></ul><ul><ul><ul><li>MAC and TB </li></ul></ul></ul><ul><ul><li>Parvovirus </li></ul></ul><ul><li>Malignancy </li></ul><ul><ul><li>DLCL </li></ul></ul><ul><ul><li>Hodgkins </li></ul></ul><ul><ul><li>Myeloma </li></ul></ul><ul><ul><li>Other (Castlemans, Hemophagocytosis, etc) </li></ul></ul><ul><li>Dysplasia </li></ul>
    39. 41. Parvovirus Infection <ul><li>Persistent/Relapsing anemia in immunocompromised </li></ul><ul><ul><li>Neutropenia in 35%, Thrombocytopenia 20% </li></ul></ul><ul><li>Treatable with IVIG (repeated courses??) </li></ul><ul><li>Diagnosis </li></ul><ul><ul><li>Serology + 30% </li></ul></ul><ul><ul><li>PCR usually + (may be false “persistent” +) </li></ul></ul><ul><ul><li>Bone Marrow Bx Diagnostic (Cyto + Immuno) </li></ul></ul>Arch Path Lab Med. 2007 Nov;131(11):1697-9 Morelli, P. Eur J Clin Mic Inf Dis 26:833, 2007
    40. 42. Bone Marrow Asp w/ Parvovirus Parvovirus
    41. 43. Hgb and Quality of Life Quality of Life (LASA) 7 9 11 13 Hgb Crawford. Cancer 2002;95:888, Soignet. Semin Hematol. 2000
    42. 44. Risks of PRBC Tx vs. EPO Erythropoietin RBC Transfusion
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