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Approach  To  The  Evalua4on  And    Management  Of  Anemia  

Usha  Perepu,  MD  Assistant  Professor  

Hematology/Oncology    9/29/15  

Objec4ves  

•  Defini4on  of  anemia  •  Review  the  causes  of  anemia  •  Laboratory  evalua4on  of  anemia    •  Management    

What  is  Anemia?  

•  Reduc4on  below  normal  in  the  mass  of  red  blood  cells  in  the  circula4on  

 •  Hemoglobin  concentra4on,  hematocrit,  RBC  count  

 •  Men:  HGB  <  13  g/dL,  HCT  40%  •  Women:  HGB  <  12.0  g/dL,  HCT  35%  

Anemia  and  Volume  Status  •  Hb  and  HCT  are  CONCENTRATIONS  •  Therefore  dependent  upon  plasma  volume    •  Acute  bleeds  not  reflected  for  24-­‐36  hrs  

–  Due  to  volume  deficit  being  slowly  repaired  via  movement  of  fluid  from  extravascular  to  intravascular  space  

 •  Anemic  pa4ents  who  are  dehydrated  will  not  appear  anemic    •  Pregnant  women  expand  RBCs  25%  but  plasma  volume  

increases  50%,  producing  “physiologic  anemia”  

Anemia:  Special  Cases  

•  Erythrocytosis  –  People  who  live  at  high  al4tude  have  greater  RBC  volume  

–  Smokers  have  increased  HCT  –  impairs  the  ability  of  the  RBCs  to  deliver  O2  

 •  African-­‐American  Hbs  are  0.5  to  1.0g/dL  lower  than  

Caucasians    •  Athletes  (increased  plasma  volume,  Fe  deficiency,  

hemolysis,  polycythemia,  use  of  performance  enhancing  agents)  

Anemia  and  the  Elderly  

•  Mul4ple  studies  show  that  the  elderly  do  not  have  a  “lower  normal  range”  

 •  Anemia,  while  common  in  the  elderly,  is  s4ll  abnormal  

 •  Hb  <  13  in  males  and  <  12  in  females  associated  with  an  increased  rela4ve  risk  of  mortality  (1.6  and  2.3  respec4vely)  

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Blood  2004;104:2263-­‐2268  

•  Data from the Third National Health and Nutrition Examination Survey (1988-1994)

•  Prevalence of anemia rises rapidly after age 50, prevalence 20% over age 85

•  11% of men, 10.2% of women over 65 are anemic

•  1/3 due to nutritional deficiency, 1/3 to chronic inflammation or renal disease, 1/3 unexplained

•  Most cases mild; only 2.8% of women and 1.6% of men had Hb < 11 g

Ø  Unexplained mild “anemia” in elderly people may simply be an effect of aging in some cases

Anemia:  History  

•  Is  the  pa4ent  bleeding?  –  NSAIDs,  ASA  –  Menstrual  history,  if  applicable  (include  older  women)  –  Prior  intes4nal  surgery?  –  Hx  of  hemorrhoids,  hematochezia,  or  melena?    

•  Past  medical  history  of  anemia?    Family  history?    •  Alcohol,  nutri4onal  ques4ons    •  Liver,  renal  diseases  •  Ethnicity  •  Environmental/work  toxins  (ie  lead)  

Symptoms  of  Anemia  

•  Decreased  O2  delivery    •  Hypovolemia  if  acute  loss    •  Exer4onal  dyspnea,  fa4gue,  palpita4ons,  lightheadedness    •  Severe:  heart  failure,  angina    •  “Pica”–  craving  for  clay  or  paper  products  •  Pagophagia–  craving  for  ice  

Signs  of  Anemia  

•  Tachycardia,  tachypnea,  orthostasis  •  Pallor  •  Jaundice  •  Murmur  •  Koilonychia  or  “Spoon  nails”  •  Splenomegaly,  lymphadenopathy  •  Petechiae,  ecchymoses  •  Atrophy  of  tongue  papillae  •  Heme  +  stool  

Red  blood  cell  matura4on   Kine4cs  Of  Erythropoiesis  

Hypoprolifera4ve  (marrow  not  working  well)  Hyperprolifera4ve  (marrow  working)  

Calcula4ng  the  re4culocyte  index  will  usually  tell  you  which  category  your  pa4ent  is  in  

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Re4culocytes  

•  Nucleated  RBCs  –  form  in  marrow  where  they  mature  for  3  days  and  then  spend  1  day  in  circula4on  (before  maturing  to  RBC)  

•  Given  avg  life  span  of  RBC  of  100  days,  1%  of  RBCs  are  destroyed  each  day  

•  Re4cs  form  1%  of  circula4ng  RBCs  qd  

Re4culocyte  response  

•  Assess  adequacy  of  bone  marrow  response  to  anemia    •  Must  adjust  for  the  degree  of  anemia,  use  Re4culocyte  

Index    •  RI  =  (measured  re4c  %)  x  (Hct/45)  x  (1/Correc4on  Factor)  

–  CF:  Hct  >40  (1);  30-­‐40  (1.5);  20-­‐29  (2);  <20  (2.5)    –  Reflects  increased  circula4ng  4me  for  re4cs  as  Epo  pushes  them  

out  of  the  marrow  earlier  

•  RI  <  2.0  indicates  inadequate  marrow  response  

Causes  of  Anemia    

•  A  kine%c  approach,  addressing  the  mechanism(s)  responsible  for  the  fall  in  hemoglobin  concentra4on  

   •  A  morphologic  approach  categorizing  anemias  via  altera4ons  in  red  blood  cell  (RBC)  size  (i.e.,  mean  corpuscular  volume)  and  the  re4culocyte  response      

Decreased  RBC  produc4on  hypoprolifera4ve  anemia(  RI  low)  

•  Deficiency  of  iron,  B12,  folate    •  Marrow  is  dysfunc4onal  from  myelodysplasia,  tumor  infiltra4on,  aplas4c  anemia,  etc.  

 •  Bone  marrow  is  suppressed  by  chemotherapy  or  radia4on  

 •  Low  levels  of  erythropoie4n,  thyroid  hormone,  or  androgens  

Increased  RBC  destruc4on  hyperprolifera4ve  anemia  (RI  high)  

•  RBCs  live  about  100  days        •  Acquired:  autoimmune  hemoly4c  anemia,  TTP-­‐HUS,  DIC,  malaria  

 •  Inherited:  spherocytosis,  sickle  cell,  thalassemia  

   

Blood  loss  

•  Re4c  count  increase  generally  less  striking  than  in  hemolysis  

 1.  Obvious  vs  occult  2.  Iatrogenic:  daily  CBC,  surgical,  

hemodialysis,  excessive  blood  dona4on  3.  Menstrual  blood  loss  

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Morphologic  approach  to  anemia    Microcy%c  anemia  (  MCV  <  80  fL)  

Normocy%c  anemia  (  MCV  80-­‐100  fL)  

Macrocy%c  anemia  (MCV  >  100  fL)  

Iron  deficiency  anemia   Acute  blood  loss   Alcohol  abuse  

Thalassemic  disorders/  hemoglobinopathies    

Iron  deficiency  (early)   Folate,  B12  deficiency    

Anemia  of  inflamma4on/chronic  disease  

Anemia  of  inflamma4on/chronic  disease  

Hemoly4c  anemia  

Sideroblas4c  anemia  (  congenital,  lead,  alcohol,  drugs)  

Bone  marrow  suppression  (  aplas4c  anemia,  pure  red  cell  aplasia)  

Bone  marrow  disorders  such  as  MDS  

Copper  deficiency     Endocrine  dysfunc4on   Drugs  (chemotherapy  agents  )  

Combined  deficiency     Liver  disease    

Other  laboratory  parameters  •  RDW:            -­‐Red  blood  cell  distribu4on  width,  measures  the  degree  of  varia4on  of  the  red  cell  size              -­‐If  elevated,  suggests  large  variability  in  sizes  of  RBCs  

 •  MCH:  mean  corpuscular  Hb            -­‐Low  values  are  seen  in  iron  deficiency  and  thalassemia,  while  increased  values  occur  in  macrocytosis  of  any  cause    •  MCHC:  mean  corpuscular  Hb  conc            -­‐  low  values  occur  in  condi4ons  that  cause  low  MCV  and  MCH              -­‐  increased  values  occur  in  spherocytosis  and  hemoglobinopathies      •  Are  the  other  cell  lines  down?              -­‐  if  evidence  of  leukopenia:  consider  bone  marrow  suppression,  hypersplenism,  B12  deficiency                -­‐  platelet  count:  if  low  may  be  bone  marrow  suppression,  thrombo4c  microangiopathy  such  as  TTP/HUS              -­‐  high  platelet  count:  myeloprolifera4ve  neoplasm,  iron  deficiency      

 

Blood  smear  

•  RBC  size,  shape    •  Polychromasia  (young  re4cs)    •  RBC  inclusions  (nucleated  rbc,  Howell-­‐Jolly  bodies,  etc)    •  Rouleaux    •  Abnormal/immature  leukocytes    •  Platelet  number/morphology    

Normal Polychromasia

Normal rbc Microcytosis, hypochromia

Microangiopathic hemolytic anemia

Spur cell anemia (liver disease)

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Normal Macrocytic/megaloblastic

Iron  Deficiency  Anemia    

•  Iron  deficiency  affects  more  than  2  billion  people  worldwide  and  iron  deficiency  anemia  remains  the  top  cause  of  anemia  

 •  Blood  loss  or  decreased  absorp4on  

are  the  major  causes  of  iron  deficiency    

 •  In  determining  iron  status  it  is  

important  to  perform  iron  panel  and  ferri4n  

 •  Low  ferri4n  is  almost  always  due  to  

iron  deficiency  

 

Iron  deficiency  anemia-­‐treatment    

•  Oral  iron  is  inexpensive  and  effec4ve  when  taken  as  prescribed,  it  can  be  considered  front  line  therapy  

•  Oral  iron  therapy  may  take  upto  6  months  to  replete  stores  

•  Gastrointes4nal  side  effects  are  extremely  common  and  may  result  in  poor  adherence  to  therapy  

Iron  prepara4ons  for  Intravenous  use  

Formula%on     Dose  per  infusion  standard  

Maximum  per  single  infusion  

Iron  sucrose  (  venofer)   100-­‐400  mg   300  mg/  over  2  hrs  

Ferumoxytol  (Feraheme)   510  mg  over  1  min   510-­‐1020  mg  over  15-­‐60  min  

Ferric  carboxymaltose  (  Injectafer)    

750-­‐1000  mg  over  15-­‐30  min  

750-­‐1000  mg  over  15-­‐30  min  

Total  iron  deficit  =  Body  weight  [kg]  x  (Target  Hb  –  Actual  Hb)  [g/l]  x  2.4  +  Iron  stores  [mg]    500  mg  iron  for  iron  stores  is  recommended  if  the  body  weight  is  above  35  kg.  

Anemia  of  Renal  Insufficiency  

•  Unremarkable  peripheral  blood  smear    •  Inappropriately  normal  erythropoie4n  level    •  Anemia  usually  severe  and  symptoma4c  when  Cr  >  3.0    •  Mild  to  moderate  anemia  found  in  Cr  1.5-­‐3.0    •  Tx:  Epogen  or  similar,  Fe  (oral,  IV)  if  iron  stores  are  found  

to  be  low  

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Anemia  of  Chronic  Disease  

•  Thought  to  be  a  cytokine  mediated  process  which  inhibits  red  blood  cell  produc4on  or  interferes  with  ac4on  of  erythropoie4n  –  Therefore,  the  disease  needs  to  be  inflammatory    

•  Decreased  iron  u4liza4on/mobiliza4on    •  Seen  with  rheumatologic  diseases,  chronic  infec4ons,  malignancy    •  Indices:  Low  Fe,  Low  TIBC,  N/increased  Ferri4n    •  May  be  seen  in  conjunc4on  with  Fe-­‐deficiency  

Folate  and  B12  

•  Serum  folate  usually  sufficient,  but  if  folate  level  is  normal  but  folate  deficiency  is  suspected,  check  serum  homocysteine  (elevated  because  of  impaired  folate  dependent  conversion  of  homocysteine  to  methionine)  or  RBC-­‐folate  

 •  When  B12  is  slightly  low–  a  

more  sensi4ve  and  specific  test  is  serum  methylmalonic  acid  level,  will  be  increased  if  B12  is  truly  low  

 

Evalua4on  of  Hemolysis  

•  LDH:  increases    •  Indirect  bilirubin  increases  

(increased  Hb  catabolism)    •  Haptoglobin  decreases    •  Re4culocyte  count  increases    •  Urine  hemosiderin  test  =  present    

in  intravascular,  absent  in  extravascular  hemolysis!  

 •  Coombs  test:  

–   (+)  =  immune  –  (-­‐)  non  immune    

Hemoly4c  Anemia      

Immune    •  Autoimmune  hemoly4c  

anemia  -­‐  Warm  -­‐  Cold  •  Alloimmune  -­‐  Hemoly4c  disease  of  

newborn  -­‐  Incompa4ble  blood  

transfusion  •  Drug  Induced  

Non  immune  •  Microangiopathic  hemoly4c  

anemia  (  TTP,  HUS)  •  Trauma:  prosthe4c  valves,  

burns,  exercise  •  Infec4on:  malaria  •  RBC  membrane  defects  •  Enzyme  defects  •  Hemoglobinopathy    •  Paroxysmal  nocturnal  

hemoglobinuria    

Indica4ons  For  Bone  Marrow  Biopsy  

•  Re4c  index  not  appropriately  increased      •  No  evidence  of  iron/B-­‐12/folate  deficiency,  renal  failure,  

endocrinopathy,  inflamma4on  or  other  low  EPO  state    •  Poor  response  to  EPO,  iron  or  vitamin  replacement    •  WBC/diff/  Plt  abnormal,  monoclonal  gammopathy,  or  

other  peripheral  blood  evidence  of  marrow  disorder    ­  Would  you  treat  leukemia/MDS  or  other  neoplas4c  

disorder  if  you  found  it?      

Approach  to  Anemia  CBC

Reticulocyte count MCV

RI < 2% RI > 2%

Underproduction Increased destruction or loss

MCV < 80 Microcytic

MCV > 100 Macrocytic

MCV 81 – 99 Normocytic

MCV Further work up Based on history, Physical, other

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Anemia:  Summary  

•  ANEMIA  IS  NEVER  NORMAL  •  Determine  if  ACUTE  or  CHRONIC  •  Consider  the  e4ology  •  CALCULATE  the  RETIC  INDEX  •  Look  at  the  smear  •  Consider  the  e4ology  based  on  rbc  morphology  and  laboratory  studies  

•  Treat  appropriately