RED

 CELL  DISORDERS  
 
IRON  DEFICIENCY  ANEMIA  
•   Microcytic  
•   Characterized  by  low  retic  count  and  low  MCV  
•   Storage  iron  depleted  first  à  serum  iron  depleted  à  normocytic  anemia  à  microcytic,  hypochromic  
anemia  as  iron  is  depleted  further  
•   Clinical  presentation:  glossitis,  koilonychias,  web  high  in  the  esophagus,  dysphagia,  pica,  exercise  
intolerance    
•   Labs:  low  ferritin,  low  serum  iron,  high  TIBC,  low  TIBC  saturation,  high  FEP,  absent  marrow  iron  stores,  
absent  sideroblasts  
•   Treatment:  ferrous  sulfate  
o   Sometimes  poorly  tolerated  because  of  constipation  and  nausea  
 
 
ANEMIA  OF  CHRONIC  INFLAMMATION  
•   Microcytic  
•   Iron  stores  are  normal  or  increased  but  cannot  be  delivered  to  developing  erythroid  precursors  due  to  
hepcidin  inhibition  of  ferroportin  –  block  of  iron  utilization  
•   Labs:  low  serum  iron,  low  TIBC,  low  TIBC  saturation,  high  ferritin  
•   Treatment:  correction  of  underlying  disease  and/or  red  cell  transfusion  
o   Do  NOT  give  epo  or  iron  therapy  
 
 
ANEMIA  OF  CHRONIC  RENAL  INSUFFICIENCY  
•   Normocytic,  normochromic  anemia  
•   Patients  with  chronic  renal  failure  fail  to  produce  an  adequate  amount  of  epo  
•   Treatment:  epo  subcutaneously  or  darbepoietin  (longer  acting)  
o   Acts  at  CFU-­‐E  stage  –  takes  about  7  days  to  see  bump  in  retic  count  
o   Iron  stores  must  be  adequate  for  epo  therapy  to  work  
 
 
SIDEROBLASTIC  ANEMIA  
•   Microcytic  
•   Occurs  due  to  defective  protoporphyrin  synthesis  
•   Can  be  congenital  or  acquired:  
o   Congenital:  ALA  synthase  defect  
o   Acquired:  alcoholism,  lead  poisoning,  vitamin  B6  deficiency  
•   Labs:  high  ferritin,  low  TIBC,  high  serum  iron,  high  TIBC  saturation,  ringed  sideroblasts  in  marrow  
o   Iron  overloaded  state  
 
 
HEREDITARY  HEMOCHROMATOSIS    
•   Genetic  disorder  that  results  in  increased  dietary  elemental  iron  absorption  as  a  consequence  of  
suppressed  hepcidin  expression  
 o   Point  mutation  in  HFE  gene  –  C282Y,  H63D  
•   Excess  iron  deposits  in  hepatocytes,  the  heart,  pancreas,  pituitary,  skin,  and  joints  
•   Clinical  features  tend  to  show  up  20  years  later  in  women  than  men  due  to  partial  protection  by  
menstrual  iron  loss  
•   Diagnosis:  PCR  
•   Treatment:  phlebotomy  
o   Normal  life  expectancy  if  diagnosed  and  treated  before  onset  of  tissue  damage  
o   If  AST  is  elevated,  biopsy  for  cirrhosis  –  increased  risk  of  hepatocellular  carcinoma  
 
 
TRANSFUSIONAL  IRON  OVERLOAD  
•   Most  common  in  patients  with  chronic  underproduction  anemia  who  require  chronic  transfusion  –  
aplastic  anemia,  myelodysplasia,  beta  thalassemia  
•   Diagnosis:  liver  biopsy,  iron  quantitation,  liver  MRI  
•   Treatment:  deferoxamine,  deferasirox  (iron  chelators)  
o   Phlebotomy  is  not  an  option  because  these  patients  tend  to  be  anemic  
 
 
THALASSEMIA  
•   Genetic  defect  in  hemoglobin  synthesis    
•   Imbalance  in  globin  chains  leads  to  globin  precipitation  in  erythrocytes  and  accelerated  destruction  of  
the  microcytic,  hypochromic  cells  (hemolytic  anemia)  
•   Malaria  is  driving  force  in  hemoglobinopathies  
•   Alpha  thalassemia  
o   Predominantly  due  to  deletions  
§   1  gene:  asymptomatic  
§   2  genes:  mild  anemia,  microcytosis  –  cis  deletion  is  worse  
§   3  genes:  hemoglobin  H  disease  (beta4)  –  moderately  severe  anemia,  splenomegaly,  
hypochromic  microcytic  red  cells      
•   Chronic  transfusion  not  required    
§   4  genes:  hydrops  fetalis  
•   Hemoglobin  barts  (gamma4)  
•   Homozygous  alpha  thal  
o   Highest  prevalence  in  Black  and  SE  Asians  
o   Diagnosis:  hemoglobin  electrophoresis,  BCB  (Hemoglobin  H)  
o   Treatment:  transfusion,  iron  chelation  
•   Beta  thalassemia  
o   Predominantly  due  to  point  mutations  
§   Thal  major  (homozygous  beta0):  transfusion  dependence,  overproduction  of  red  cells  in  
marrow  space  (chipmunk  facies,  osteoporosis),  and  production  outside  marrow  in  liver  
and  spleen  (hepatosplenomegaly)  
§   Thal  minor  (trait):  no  transfusions  
§   Thal  intermedia  (homozygous  beta+)  
o   Reduced  or  absent  beta  globin  synthesis  results  in  free  alpha  globin  accumulation,  which  
precipitates  in  cells  and  leads  to  apoptosis  of  developing  erythroid  cells    
o   Labs:  no  elevated  retics,  circulating  nucleated  red  cells,  target  cells  
 o   Diagnosis:  low  MCV,  poikilocytosis,  increased  HbA2  or  HbF,  sequencing,  Hb  electrophoresis,  
PCR  
o   Treatment:  allogeneic  bone  marrow  transplant,  iron  chelation,  bisphosphonates,  transfusion,  
hydroxyurea  
§   Hydroxyurea  stimulates  gamma  chain  production,  which  contributes  to  the  formation  of  
HbF  (alpha2gamma2)  and  reduces  alpha  chain  excess  
 
 
SICKLE  CELL  ANEMIA  
•   HbS  results  from  substitution  of  valine  for  glutamic  acid  at  position  6  of  beta  chain  due  to  single  base  
pair  mutation  
•   Intracellular  polymerization  of  deoxyhemoglobin  S  due  to  the  hydrophobic  valine  results  in  abnormal  
red  cell  shape  and  accelerated  red  cell  destruction      
•   Genotypes:  
o   Homozygous  sickle  cell  disease  (SS):  two  betaS  chains  
o   Sickle  cell  HbC  disease  (SC)  
o   Sickle  cell  beta+  thalassemia  (S  beta+)  
o   Sickle  cell  beta0  thalassemia  (S  beta0):  one  betaS  chain,  no  normal  beta  chain  
•   Increased  blood  viscosity  impairs  blood  flow  and  O2  delivery,  adhesive  interactions,  dysregulation  of  
nitric  oxide  pathway  leads  to  vasoconstriction  and  vascular  occlusion  
•   Pain  is  the  hallmark  clinical  manifestation  
o   Pain  crises  can  be  precipitated  by  infections,  other  serious  illnesses,  menstruation,  dehydration,  
or  cold  weather  
•   By  age  3,  most  patients  have  functional  asplenia  due  to  recurrent  microinfarcts  
o   Prophylactic  penicillin  for  infections,  especially  by  encapsulated  organisms  
•   Acute  chest  syndrome  is  the  most  common  cause  of  death  in  adults  
o   Pain  accompanied  by  symptoms  of  respiratory  distress  –  can  evolve  from  mild  shortness  of  
breath  unaccompanied  by  radiographic  changes  to  ARDS  in  a  few  hours  
•   Additional  clinical  presentations:  recurrent  bone  infarcts,  priapism,  urine  concentrating  defect,  
proliferative  retinopathy,  strokes  
•   Hemolysis  is  associated  with  the  premature  destruction  of  sickled  red  cells,  which  have  an  average  
survival  of  20  days  compared  to  120  days  normally  
o   Parvovirus  B19  can  lead  to  aplastic  crisis  
•   Co-­‐existent  factors:  
o   Alpha  thal:  decreases  severity  of  hemolysis  
o   Hereditary  persistence  of  fetal  Hb  (HPFH):  decreases  vasooclusive  severity  by  interfering  with  
polymerization  of  HbS  
•   Diagnosis:  hemoglobin  electrophoresis  
•   Treatment:  penicillin  prophylaxis,  opioids  for  pain,  regular  red  cell  exchange  transfusions,  hydroxyurea,  
hematopoietic  stem  cell  transplant  (curative  but  limited)  
o   Red  cell  transfusions  are  not  effective  in  pain  crises  and  may  precipitate  them  by  increasing  
whole  blood  viscosity  –  resist  the  urge  to  do  this  despite  low  HCT  
 
 
 
 
HEMOGLOBIN  C  DISEASE  
•   Results  from  a  mutation  in  nucleotide  triplet  with  the  replacement  of  glutamic  acid  with  lysine  at  
position  6  of  beta  chain  –  results  in  hemoglobin  with  decreased  solubility  and  propensity  to  aggregate  
•   HbCC  red  cells  are  less  deformable  and  patients  get  hemolytic  anemia  
o   Get  trapped  in  the  spleen  –  mild  to  moderate  splenomegaly  
•   Labs:  elevated  MCHC,  frequent  target  cells,  increased  bilirubin  
•   Diagnosis:  Hb  electrophoresis  
o   HbC  migrates  with  HbA2  –  distinguish  by  acid  citrate  agar  gel  elecrophoresis  
•   Treatment:  none;  folic  acid  may  be  beneficial  and  transfusion  may  be  needed  in  setting  of  aplastic  
crisis  following  viral  infections  
 
 
UNSTABLE  HEMOGLOBINOPATHIS  
•   Result  in  congenital  Heinz  body  hemolytic  anemia  in  heterozygous  individuals    
•   Mechanisms  of  Hb  instability:  
o   Hb  Koln:  destabilizes  heme  pocket  
o   Distortion  of  helical  configuration  
o   Alteration  of  alpha2beta2  interface  (Hb  Tacoma)  
o   Introduction  of  interior  polar  amino  acids  (Hb  Bristol)  
•   Abnormal  hemoglobins  precipitate  either  spontaneously  or  under  oxidative  stress,  forming  hemoglobin  
inclusions  (Heinz  bodies)  which  impair  red  cell  deformability  and  result  in  enhanced  clearance  by  the  
reticuloendothelial  system  
•   Diagnosis:  Hb  electrophoresis,  crystal  violet  Heinz  body  staining,  Hb  precipitation  with  heat  or  alcohol  
•   Treatment:  folate  supplementation,  transfusion  support  when  indicated,  avoid  oxidant  agents  
 
 
VITAMIN  B12  DEFICIENCY  
•   Macrocytic  anemia  
•   Deficiency  impairs  DNA  synthesis  and  nuclear  maturation  in  hematopoietic  cells  –  nuclear  maturation  
lags  behind  that  of  the  cytoplasm,  which  results  in  megaloblastic  hematopoiesis  
o   Intramedullary  hemolysis  of  megaloblastic  erythroid  and  myeloid  cells  results  in  elevated  serum  
LDH  
§   Ineffective  erythropoiesis    
•   Stomach  and  terminal  ileum  required  for  absorption  
•   Subacute  combined  degeneration  of  the  spinal  cord  
o   Symmetric  paresthesias  in  extremities,  decreased  vibratory  sense  and  proprioception,  ataxia,  
personality  change,  dementia  
o   Can  be  irreversible    
•   Body  contains  3-­‐5  year  supply  of  B12  –  clinical  features  develop  gradually  
•   Causes  of  deficiency:  
o   Dietary:  strict  vegetarianism  
o   Deficiency  of  intrinsic  factor:  pernicious  anemia,  gastrectomy  
o   Ileal  malabsorption:  ileal  resection,  Crohn’s  disease,  diphylobothrium  latum,  bacterial  
overgrowth  in  diverticulae  or  blind  loops  of  bowel  
•   High  methylmalonic  acid  and  homocysteine  
•   Clinical  presentation:  glossitis,  neurologic  syndrome  
 •   Labs:  high  MCV,  oval  macs,  mild  leukopenia  with  hypersegmented  neutrophils,  mild  
thrombocytopenia,  intramedullary  hemolysis  and  high  serum  LDH  
 
 
PERNICIOUS  ANEMIA  
•   Atrophy  of  gastric  parietal  cells  result  in  failure  to  secrete  intrinsic  factor  and  HCl,  which  impairs  
vitamin  B12  absorption  
•   2/3  of  patients  have  antibodies  against  intrinsic  factor  
o   Much  more  specific  than  anti-­‐parietal  cell  antibodies    
•   Often  associated  with  other  autoimmune  diseases:  Grave’s  disease,  Hashimoto’s  thyroiditis  
•   Labs:  anti-­‐intrinsic  factor  antibodies  
•   Treatment:  IM  injections  or  oral  vitamin  B12  –  lifelong    
 
 
FOLATE  DEFICIENCY  
•   Macrocytic  anemia  
•   Deficiency  impairs  DNA  synthesis  and  nuclear  maturation  in  hematopoietic  cells  –  results  in  picture  
similar  to  vitamin  B12  deficiency  
•   Proximal  jejunum  required  for  absorption  
•   Body  contains  only  several  weeks’  store  of  folate  
•   Causes  of  deficiency:  
o   Dietary:  lack  of  vegetables,  common  in  alcoholics  
o   Impaired  absorption:  sprue,  anticonvulsants,  birth  control  pills  
o   Increased  requirement:  pregnancy,  hemolytic  anemia,  extensive  psoriasis    
•   High  homocysteine,  normal  methylmalonic  acid  
•   Clinical  presentation:  glossitis  
•   Labs:  high  MCV,  elevated  LDH,  low  serum  folate  
•   Treatment:  oral  folate  
 
 
APLASTIC  ANEMIA  
•   Pancytopenia  
•   Marrow  lacks  hematopoietic  precursor  cells  and  is  unable  to  generate  blood  cells  of  any  lineage  
•   Stem  cell  damage  is  often  immunologically  mediated  and  likely  involves  the  production  of  excess  IFN-­‐
gamma  and  TNF  by  activated  Th1  lymphocytes,  which  trigger  Fas-­‐receptor  expression  on  progenitors  
and  stem  cells,  leading  to  apoptosis  
•   Generally  idiopathic,  though  some  associations  have  been  made    
•   Clinical  presentation:  fatigue,  palpitations,  headaches,  recurrent  infection,  mucosal  bleeding,  petechiae  
•   Diagnosis:  markedly  hypocellular  marrow  biopsy  where  marrow  space  is  replaced  by  fat,  low  retic  
count  
•   Treatment:  marrow  transplant  from  HLA-­‐matched  sibling,  transplant  of  stem  cells  mobilized  into  
peripheral  blood,  immunosuppression  (ATG)  
o   Transplant  more  common  for  patients  <50  years  old;  ATG  more  common  for  older  patients  
o   With  ATG,  many  patients  relapse  or  require  continued  cyclosporine  to  maintain  adequate  blood  
counts  
 o   Do  NOT  transfuse  –  exposure  to  foreign  blood  leads  to  alloimmunization,  which  can  
compromise  future  transplant  
 
 
ANEMIA  OF  AIDS  
•   Causes:  
o   Common:  
§   Drugs:  antiretroviral  drugs,  antibiotics  
§   HIV  infection  of  stromal  cells,  which  impairs  ability  to  produce  hematopoietic  growth  
factors  
•   Hematopoietic  progenitors  themselves  are  not  infected,  with  the  exception  of  
megakaryocytes  
§   Inadequate  epo  production  
§   Inflammatory  block  in  iron  use  due  to  opportunistic  infections  
o   Uncommon:  
§   Lymphoma  in  marrow:  aggressive  non-­‐Hodgkin’s  lymphoma  
§   TTP  
§   Immunohemolytic    
§   Vitamin  B12  deficiency  and  parvovirus  B19  infection  
•   Incidence  of  anemia  correlates  with  decreased  CD4  count  
•   Treatment:  epo,  HAART  to  decrease  viral  load  
 
 
ANEMIA  OF  PREGNANCY  
•   Largely  hemodilution  as  increase  in  plasma  volume  exceeds  that  of  red  cell  mass,  especially  in  third  
trimester  
•   Requirements  for  iron  and  folate  go  way  up  –  most  women  will  develop  anemia  if  not  supplemented  
•   MCV  may  not  be  reliable  index  since  iron  deficiency  causes  microcytosis  and  folate  deficiency  causes  
macrocytosis  –  MCV  may  be  normal  
•   Labs:  dimorphic  population  of  red  cells  and  hypersegmentation  of  neutrophils  due  to  folate  deficiency  
 
 
HEMOLYTIC  ANEMIAS  
•   Increased  rate  of  red  cell  destruction  
o   Extravascular:  red  cells  destroyed  by  reticuloendothelial  cells  in  spleen  and  liver  
o   Intravascular:  red  cells  destroyed  within  the  bloodstream    
o   Intramedullary  destruction:  developing  precursors  destroyed  within  the  bone  marrow  before  
exiting  to  blood  (vitamin  B12,  folate  deficiency,  thalassemia)  
§   Not  generally  classified  as  hemolytic  anemia  
•   Physical  exam:  pallor,  jaundice  
o   Ongoing  active  hemolysis:  splenomegaly  
o   Chronic:  erythroid  hyperplasia  (chipmunk  facies),  extramedullary  erythropoiesis  
(hepatosplenomegaly)  
o   Rapid  intravascular  hemolysis:  hemoglobinemia,  hemoglobinuria,  hemosiderinuria  
•   Labs:  high  retic  count,  low  haptoglobin,  high  serum  bilirubin  (indirect),  high  serum  LDH  
o   MCV  may  be  high  due  to  elevated  retics,  which  are  larger  than  mature  RBCs  
INTRINSIC  HEMOLYTIC  ANEMIAS  
•   Usually  genetic  issue  and  red  cells  don’t  survive  
•   Disorders  of  RBC  metabolism:  defects  arise  due  to  enzyme  deficiencies  critical  to  glycolytic  pathway  or  
hexose  monophosphate  shunt  or  maintenance  of  reduced  state  of  heme  iron  
o   G6PD  deficiency:  
§   Most  common  metabolic  disorder  leading  to  hemolytic  anemia  
§   X-­‐linked  
§   African  Americans,  Greeks,  SE  Asians  
§   Most  patients  only  sustain  anemia  and  symptoms  after  exposure  to  certain  oxidant  
drugs  or  chemicals  
•   Fava  beans    
§   Splenectomy  not  effective  
§   Labs:  blister  cells    
§   Treatment:  avoid  oxidant  drugs  or  ingestion  of  chemicals    
o   Pyruvate  kinase  deficiency:  
§   Most  common  enzyme  deficiency  in  glycolytic  pathway  
§   Autosomal  recessive  
§   Affected  individuals  require  splenectomy  
•   RBC  membrane  disorders  
o   Paroxysmal  nocturnal  hemoglobinuria  
§   Most  common  cause  of  hemolytic  anemia  in  pediatric  populations  
§   Acquired  clonal  stem  cell  disorder  due  to  defect  in  synthesis  of  phosphatidyl-­‐inositol  
membrane  anchor  for  a  number  of  proteins  including  decay  accelerating  factor  (C3  
convertase  inhibitor)  
§   Increased  sensitivity  to  complement  leading  to  intravascular  hemolysis  –  classically  
worse  at  night  and  significant  iron  deficiency  through  urinary  loss  
•   Urine  may  be  dark  in  the  mornings  
§   Patients  also  suffer  from  episodic  abdominal  pain  attributed  to  venous  thrombosis  due  
to  a  defect  in  platelets  
•   Hepatic,  portal,  splenic,  mesenteric  veins  
§   Can  evolve  into  aplastic  anemia  or  acute  leukemia  
§   Diagnosis:  flow  cytometry  demonstrating  lack  of  proteins  bound  via  the  PI  membrane  
anchor  
§   Treatment:  allogeneic  bone  marrow  transplant  (curative),  eculizumab  (antibody  to  C5)  
•   Eculizumab  prevents  hemolysis  but  does  not  affect  thrombotic  risk  of  
development  of  bone  marrow  failure  
o   Hereditary  spherocytosis  
§   Caused  by  defects  in  red  cell  membrane  protein  ankyrin  –  leads  to  loss  of  spectrin  and  
membrane  surface  area  so  the  cell  assumes  the  shape  with  minimal  surface  area  to  
volume  ratio  
§   Autosomal  dominant  
§   Labs:  spherocytes  
§   Diagnosis:  increased  osmotic  fragility,  flow  cytometry,  morphology  
§   Treatment:  usually  mild  and  splenectomy  can  improve  or  eliminate  symptoms;  severe  
forms  can  result  in  transfusion  dependent  anemia  despite  splenectomy  
o   Hereditary  elliptocytosis  
 §   Caused  by  defects  in  red  cell  membrane  protein  spectrin  
§   Labs:  elliptocytes    
§   Diagnosis:  morphology    
§   Treatment:  same  as  above  
 
 
EXTRINSIC  HEMOLYTIC  ANEMIAS  
•   Mechanical  damage  to  red  cell  membrane  due  to  high  shear  stresses  or  mechanical  damage  –  results  in  
schistocytes,  helmet  cells,  and  cell  fragments  that  are  removed  by  the  spleen  
o   Examples  of  mechanical  damage:  
§   Artificial  or  damaged  heart  valves:  waring  blender  syndrome,  turbulent  flow  
§   “March”  hemoglobinuria:  trauma  from  stomping  of  the  feet  on  hard  surfaces  
§   Toxins  and  venoms  
§   Chemical  injury:  arsenic,  copper,  high  O2  tension  
§   Burn  victims:  direct  damage  to  RBC  membrane:  spherocytes,  schistocytes  
§   Malaria:  parasites  invade  red  cells  and  “knobs”  are  formed  on  membranes  
§   Babesiosis:  direct  membrane  damage,  especially  severe  in  patients  status  post  
splenectomy  
§   Severe  liver  disease:  spur  cell  anemia  characterized  by  acanthocytosis  due  to  
accumulation  of  unesterified  cholesterol  in  red  cell  membrane  and  hemolytic  anemia  
§   Splenomegaly:  hypersequestration  and  removal  of  red  cells  
•   Autoimmune  hemolytic  anemia  
o   Arises  by  destruction  of  red  cells  caused  by  antibody  binding  to  the  red  cell  surface  
o   Warm  reactive:  IgG,  extravascular  hemolysis,  direct  Coomb’s  test  
§   Fc  portion  of  the  antibody  is  recognized  by  the  reticuloendothelial  cells  of  the  spleen  or  
liver  and  the  complex  is  sequestered  and  destroyed  
§   Causes:  idiopathic,  drug-­‐induced,  chronic  lymphocytic  leukemia  or  lymphoma,  SLE  
§   Treatment:  steroids  (prednisone),  splenectomy  if  steroids  are  not  effective,  
immunosuppression,  rituximab  (antibody  to  CD20  on  B  cells)  
o   Cold  reactive:  IgM,  intravascular  hemolysis  
§   Cold  agglutinin  disease  commonly  occurs  in  the  extremities  –  painful  cyanosis  and  
numbness  of  the  hands,  feet,  ears,  and  nose  
§   Causes:  idiopathic,  mycoplasma  pneumonia  or  mono,  lymphoma  or  chronic  lymphocytic  
leukemia,  drug-­‐induced  
•   IgM  mediated  hemolysis  due  to  mono  and  mycoplasma  infection  will  abate  once  
the  infection  resolves;  other  causes  tend  to  be  chronic  and  poorly  responsive  to  
therapy  
§   Treatment:  avoid  cold  exposure,  evaluate  for  underlying  lymphoma  or  leukemia,  
chlorambucil  (alkylating  drug);  steroids  and  splenectomy  not  effective  
•   Microangiopathic  hemolytic  anemia  
o   DIC  
§   Vessels  partially  occluded  by  fibrin  deposition,  hemolysis,  consumption  of  platelets  and  
coag  factors  
§   Labs:  elevated  D-­‐dimer,  prolonged  PT,  PTT,  elevated  fibrinogen  
§   Treatment:  supportive  –  replenish  red  cells,  platelets,  FFP,  cryoprecipitate,  treat  
underlying  issue  
o   Thrombotic  thrombocytopenic  purpura  
 §   Deficiency  of  ADAMTS13  protease  that  cleaves  von  Willebrand  factor  multimers  
§   Clinical  presentation:  fever,  renal  dysfunction,  neurological  sequelae,  hemolytic  anemia,  
thrombocytopenia  
§   Labs:  high  retic  count,  high  LDH,  schistocytes  on  peripheral  smear  
§   Treatment:  plasma  exchange  
o   Hemolytic  uremic  syndrome  
§   Associated  with  toxigenic  E.  coli  and  certain  medications  
§   Hemolysis  and  renal  dysfunction  
§   Labs:  fragmented  cells  on  peripheral  smear  
o   Other  vascular  abnormalities  
§   Hemangiomas:  focal  preliferations  of  small  blood  vessels  that  cause  localized  
intravascular  coagulation  
§   Carcinomatosis:  metastatic  deposits  of  cancer  cells  lodge  in  blood  vessels  
§   Renal  vascular  disorders:  vessel  narrowing  (malignant  hypertension)  or  abnormal  
vasculature  (glomerulonephritis)  
§   Inflammation  of  small  vessels:  polyarteritis  nodosum,  SLE  
§   All  of  the  above  lead  to  shearing  of  red  cells  and  hemolysis  
o   HELLP  (hemolysis,  elevated  liver  enzymes,  low  platelet  count)  
§   Occurs  most  commonly  between  weeks  27-­‐36  gestation  
§   Characterized  by  presence  of  microangiopathic  hemolytic  anemia  accompanied  by  
profound  thrombocytopenia  in  the  setting  of  pre-­‐eclampsia    
 
 
 
BLEEDING  DISORDERS  DUE  TO  COAGULOPATHY  
 
HEMOPHILIA  
•   Factors  VIII  and  IX  are  part  of  the  intrinsic  pathway  
o   Hemophilia  A:  factor  VIII  deficiency  (more  common)  
o   Hemophilia  B:  factor  IX  deficiency  
•   X-­‐linked  recessive  
o   Up  to  50%  of  patients  have  no  family  history  and  reflect  de  novo  mutations  
•   Secondary  hemostasis  is  affected  –  deep  tissue  bleeding    
•   Severe  hemophilia  is  usually  diagnosed  in  infancy  or  early  childhood  
•   Clinical  presentation:  prolonged  bleeding,  easy  bruising,  hemarthrosis,  spontaneous  soft  tissue  
hemorrhage,  muscle  hematomas  
•   Labs:  isolated  prolonged  PTT,  need  specific  factor  assay  to  further  discern  
•   Treatment:  prompt  replacement  of  deficient  factor  during  acute  or  potential  bleeding  (plasma-­‐derived  
or  recombinant),  anti-­‐fibrinolytic  therapy  as  adjunctive  therapy  (tranexamic  acid  or  epsilon-­‐
aminocaproic  acid),  desmopressin  for  mild  hemophilia  A    
o   Patients  with  severe  hemophilia  benefit  from  prophylactic  factor  replacement  
o   Half-­‐life  of  factor  VIII  <  factor  IX  and  requires  more  frequent  dosing  
 
 
VON  WILLEBRAND  DISEASE  
•   Most  common  congenital  bleeding  disorder  
 •   vWF  is  synthesized  by  endothelial  cells  and  megakaryocytes  and  stored  in  alpha  granules  of  platelets  
and  in  endothelial  cells  
•   vWF  mediates  platelet  adhesion  to  the  vessel  wall  by  binding  platelet  membrane  and  stabilizes  
circulating  factor  VIII,  which  is  otherwise  rapidly  degraded  –  deficiency  affects  primary  and  secondary  
hemostasis  
•   Clinical  presentation:  
o   Type  I:  quantitative  deficiency  
§   Most  common  (80%  of  cases)  
§   Autosomal  dominant  
§   Mucocutaneous  bleeding    
o   Type  II:  qualitative  defect  
§   Autosomal  dominant  
§   Mucocutaneous  bleeding  
o   Type  III:  little  or  no  synthesis  of  vWF  
§   Rare,  autosomal  recessive  
§   Patients  have  very  low  factor  VIII  and  resemble  hemophilia  A  
•   Labs:  reduced  platelet  aggregation  to  ristocetin,  prolonged  or  normal  PTT  depending  on  factor  VIII  
levels,  prolonged  bleeding  time  
•   Treatment:  desmopressin,  plasma-­‐derived  vWF  concentrate  (increases  vWF  and  factor  VIII),  
cryoprecipitate  
o   Desmopressin  releases  stores  of  vWF  –  effect  is  often  mild  and  not  useful  in  vWD  types  where  
patients  do  not  make  any  vWF  
o   Risk  of  viral  transmission  restricts  use  of  cryoprecipitate  to  rare  cases  of  serious  bleeding  where  
no  vWF  concentrates  are  available  (often  low  resource  settings)  
 
 
VITAMIN  K  DEFICIENCY  
•   Usually  acquired  
•   Vitamin  K  normally  obtained  from  leafy  green  vegetables  and  via  synthesis  by  GI  bacterial  flora  
•   Vitamin  K  required  for  coag  factors  II,  VII,  IX,  X  and  anti-­‐coag  proteins  C  and  S  
•   Mucocutaneous  and  deep  tissue  bleeds  –  intrinsic,  extrinsic,  and  common  pathways  affected    
•   Causes:  fat  malabsorption,  chronically  ill,  newborn  infants,  Warfarin,  3rd  generation  cephalosporins  
•   Labs:  prolonged  PT  and  PTT,  normal  fibrinogen  and  platelets  
o   PT  is  the  most  sensitive  indicator  since  factor  VII  has  the  shortest  half  life  
•   Treatment:  FFP,  parenteral  vitamin  K  
o   FFP  used  in  severe  bleeding  that  requires  rapid  reversal  
o   Parenteral  vitamin  K  takes  24  hours  to  take  effect  
 
 
LIVER  DISEASE  
•   Functions  of  the  liver:    
o   Site  of  synthesis  of  all  coag  factors  (except  vWF  and  factor  VIII),  fibrinogen,  and  thrombopoietin  
o   Site  of  carboxylation  for  vitamin  K-­‐dependent  coag  factors  
§   Most  sensitive  to  liver  disease  
•   Liver  disease  can  be  associated  with  production  of  abnormal  fibrinogen  (dysfibrinogenemia)  and  
thrombocytopenia  
 •   Clinical  presentation:  can  exhibit  generalized  bleeding  tendency,  thrombosis  due  to  relatively  increased  
factor  VIII  and  vWF  in  the  absence  of  anti-­‐coag  factors  
•   Labs:  prolonged  PT,  PTT,  and  TT,  thrombocytopenia  
o   PT  is  usually  prolonged  first  
o   TT  prolonged  if  dysfibrinogenemia  is  present  
•   Treatment:  correct  any  underlying  anatomic  or  vascular  defect,  supportive  blood  component  therapy,  
modified  whole  blood  (significant  bleeding),  platelet  transfusion  (platelets  <50,000),  plasma  
transfusion  
 
 
DISSEMINATED  INTRAVASCULAR  COAGULATION  
•   Most  commonly  seen  in  severe  acutely  ill  patients  
•   Results  from  release  of  tissue  factor,  enzymes,  or  some  other  procoagulant  substance  from  damaged  
or  abnormal  tissue  that  ultimately  results  in  the  activation,  consumption,  and/or  degradation  of  coag  
factors,  coag  inhibitors,  and  platelets  –  can  exhibit  bleeding  or  thrombotic  complications  
•   Causes  of  DIC:    
o   Bacterial  sepsis:  particularly  gram  negative  organisms  
o   Severe  tissue  injury  
o   Hypotension  and/or  anoxia:  massive  trauma,  brain  injury  
o   Obstetrical  emergencies:  abruption  placenta,  retained  dead  fetus  
o   Vascular  disorders  that  involve  extensive  endothelial  disruption  
o   Malignancy:  more  chronic    
•   Labs:  thrombocytopenia,  hypofibrinogenemia,  prolongation  of  PT,  PTT,  and  TT,  elevated  D-­‐dimer,  
prolonged  bleeding  time  
•   Treatment:  treat  underlying  cause,  platelet  concentrates,  cryoprecipitate,  plasma  
o   Largely  supportive    
 
 
 
DISORDERS  OF  PLATELETS  AND  THROMBOSIS  
 
Platelet  bleeding  disorders  manifest  as  mucocutaneous  bleeding:  petechiae,  ecchymoses,  recurrent  epistaxis,  
GI  hemorrhage,  menorrhagia,  etc.    
 
IMMUNE  THROMBOCYTOPENIA  
•   Autoimmune  thrombocytopenic  purpura  (ITP)  
o   Most  common  cause  of  immune  thrombocytopenia  –  acute  in  90%  of  children;  chronic  in  90%  
of  adults  
o   Auto-­‐antibody  directed  against  glycoproteins  on  the  platelet  membrane    
o   Spleen  is  major  site  of  platelet  destruction  
o   Often  occurs  for  the  first  time  following  a  viral  illness;  subsequent  recurrences  typically  follow  
viral  infections  
o   Diagnosis:  number  of  megakaryocytes  in  marrow,  exclusion  of  other  causes  of  platelet  
destruction,  response  to  appropriate  therapy  
o   Treatment:  corticosteroids,  IVIG,  splenectomy,  immunosuppression  (uncommon),  TPO  
mimetics  if  unresponsive  to  first  line  therapy  
 §   Transfusion  is  not  effective  because  the  patient’s  antibodies  will  destroy  them  
§   IVIG  is  used  if  an  urgent  increase  in  platelets  is  needed  –  IgG  may  occupy  the  Fc  
receptors  on  macs  to  dampen  macrophage-­‐induced  clearance  of  antibody  coated  
platelets  
•   Other  diseases  associated  with  autoimmune  platelet  destruction:  HIV,  hepatitis  C,  thyroid  disease,  SLE,  
lymphoreticular  malignancies  –  treat  like  ITP  and  include  treatment  of  underlying  infection  or  
malignancy  
•   Drug-­‐induced  immune  thrombocytopenia  
o   Quinine  and  quinine  derivatives  
o   Drug-­‐antibody  complex  bound  to  the  platelet  surface  is  recognized  and  leads  to  platelet  
destruction  
o   Treatment:  removal  of  offending  agent  
•   Heparin-­‐induced  thrombocytopenia  
o   Heparin  can  combine  with  a  protein  released  from  platelet  alpha  granules  (platelet  factor  4)  to  
induce  production  of  an  antibody  that  causes  aggregation  and  immune-­‐mediated  destruction  of  
platelets  
o   Puts  patients  at  risk  for  thrombosis  rather  than  bleeding  
o   Treatment:  discontinue  heparin  and  anticoagulate  with  a  direct  thrombin  inhibitor  (bivalirudin,  
fondaparinux)  
 
 
NON-­‐IMMUNE  THROMBOCYTOPENIA  
•   Thrombotic  thrombocytopenic  purpura  (TTP)  
o   Caused  by  deficiency  of  ADAMTS13,  which  leads  to  accumulation  of  larger  vWF  multimers  
o   Platelets  adhere  to  these  large  forms  and  agglutinate  in  the  capillaries  –  thrombotic  
microangiopathy  
§   Red  cell  shearing,  possible  end  ischemic  damage  
§   Especially  affects  brain  and  kidneys  
o   Clinical  presentation  (pentad):  thrombocytopenia,  neurologic  abnormalities,  MAHA,  renal  
abnormalities,  fever  
o   Virtually  always  fatal  without  therapy  
o   Labs:  platelet  thrombi  in  microcirculation,  schistocytes,  decreased  platelets  
o   Treatment:  plasma  exchange  therapy  
§   Removes  vWF  multimers  and  antibodies  to  ADAMTS13  if  present  while  providing  
functional  ADAMTS13  enzyme  
•   Hemolytic  uremic  syndrome  
o   Associated  with  thrombotic  microangiopathy  
o   Most  commonly  affects  children  
o   Frequently  associated  with  shiga  toxin-­‐producing  bacterium  –  E.  coli  O157:H7  
o   Clinical  presentation:  renal  function  abnormalities,  MAHA,  thrombocytopenia  
o   Treatment:  resolves  spontaneously  as  the  infection  is  treated,  dialysis  may  be  required  before  
disease  remits,  discontinue  offending  agents  
•   DIC  
o   Thrombocytopenia  occurs  secondary  to  activation  and  consumption  of  coag  factors  with  
platelet  activation  and  consumption  
o   Labs:  decreased  fibrinogen  
 §   Distinguishes  DIC  from  TTP  and  HUS  
 
 
THROMBOCYTOPENIA  IN  PREGNANCY  
•   5-­‐10%  of  women  with  normal  pregnancy  develop  “gestational  thrombocytopenia”  that  is  not  immune  
mediated  
o   No  therapy  needed  and  no  increased  risk  of  neonatal  thrombocytopenia    
•   ITP  may  worsen  or  present  for  the  first  time  during  pregnancy  –  usually  uneventful  and  therapy  is  not  
required  
o   Babies  rarely  severely  affected  by  antibody  
 
 
THROMBOCYTOPENIA  DUE  TO  SEQUESTRATION  
•   Common  cause  of  hypersplenism  is  liver  disease  with  resulting  portal  hypertension  
•   Splenectomy  rarely  required  for  severe  hypersplenism  
 
 
AGGREGATION  DEFECTS  
•   Glanzmann  thrombasthenia  
o   Absence  of  functional  GPIIbIIIa  on  platelet  surface  –  inability  to  aggregate/crosslink  platelets  
with  fibrinogen  
 
 
ADHESION  DEFECTS  
•   Bernard-­‐Soulier  syndrome  
o   Abnormalities  of  GPIb  on  platelet  surface  leads  to  failure  of  platelets  to  adhere  to  
subendothelium  via  vWF  
o   Factor  VIII  and  vWF  levels  are  normal  
•   Von  Willebrand  disease  
o   vWF  deficiency  impairs  platelet  adhesion  and  results  in  decreased  factor  VIII  levels  
o   Abnormal  in-­‐vitro  platelet  aggregation  response  to  ristocetin  
 
 
ACQUIRED  DISORDERS  OF  PLATELET  FUNCTION  
•   Numerous  drugs  can  block  platelet  function  at  several  steps  
o   Aspirin:  irreversibly  acetylates  cyclooxygenase  for  the  life  of  the  platelet  and  blocks  synthesis  of  
thromboxane  A2    
o   Clopidogrel:  inhibitor  of  ADP-­‐induced  platelet  aggregation  
•   Activation  of  the  platelet  membrane  and  release  of  storage  pool  material  occurs  with  disturbed  
platelet-­‐vessel  interactions  
o   Platelets  are  fragile  and  easily  disrupted  
o   Cardio-­‐pulmonary  bypass,  valvular  heart  disease,  cavernous  hemangioma,  DIC,  thermal  injury,  
etc.  
o   Leads  to  circulation  of  “exhausted  platelets”  
•   Systemic  disorders:  uremia,  liver  disease,  myelodysplasia,  myeloproliferative  neoplasms  
 
VENOUS  THROMBOSIS  
•   Thrombi  that  form  in  areas  of  slow  flow  or  stasis  are  rich  in  RBCs  with  a  large  amount  of  interspersed  
fibrin  à  red  thrombi  
•   Often  occur  without  underlying  vessel  wall  damage  
•   Occur  most  commonly  in  the  veins  of  the  lower  extremities  –  can  cause  embolization  to  the  pulmonary  
arteries    
•   Important  to  assess  whether  venous  thrombosis  is  provoked  or  unprovoked  –  unprovoked  cases  are  
more  likely  to  recur    
•   Virchow’s  triad:  stasis,  endothelial  damage,  hypercoagulability  
o   Activated  platelets  and  coag  factors  may  contribute  to  the  development  of  thrombosis,  
especially  in  the  setting  of  vascular  stasis  
o   Abnormalities  of  the  vascular  endothelium  increase  risk  of  thrombus  formation  –  direct  injury,  
immune  complexes,  infection,  hemodynamic  stress,  enzymatic  damage,  prosthetic  devices,  
foreign  bodies,  etc.  
o   Inherited  and  acquired  abnormalities  of  the  normal  inhibitor  mechanisms  that  regulate  
coagulation  like  protein  C  and  ATIII  can  shift  the  balance  towards  thrombus  formation  
•   Pulmonary  embolism  
o   Accounts  for  5-­‐10%  of  all  hospital  deaths  
o   Most  tend  to  arise  from  DVT  
o   Life-­‐threatening  –  always  on  the  differential  for  someone  who  presents  with  new  acute  chest  
pain  and/or  shortness  of  breath  
o   Diagnosis:  helical  CT  scan/CT  angiogram,  V/Q  scan  
•   Clinical  presentation:  unilateral  limb  pain,  tenderness,  swelling,  warmth,  discoloration  
o   These  signs  may  be  subtle  of  absent  –  rely  on  clinical  suspicion  and  pre-­‐test  probability  
•   Diagnosis:  
o   Contrast  venogram:  historically  the  gold  standard,  but  now  rarely  done  since  it’s  invasive  and  
expensive  
o   D-­‐dimer:  sensitive  but  not  specific  –  if  negative,  rule  out  DVT  and  PE  
o   Compression  ultrasonography  and  Doppler  flow  studies  –  current  test  of  choice  
•   Treatment/prevention:  anticoagulants  (heparin,  fondaparinux,  warfarin,  rivaroxban,  apixaban,  
dabigatran),  early  ambulation,  external  leg  compression,  IVC  filter  
o   Objective  is  to  prevent  recurrent  clot  formation  while  the  body  breaks  down  the  current  one  
o   Fibrinolytic  therapy  is  added  if  patient  is  hemodynamically  unable  or  in  ventilatory  compromise  
o   Track  heparin  with  PTT;  warfarin  with  PT  
o   IV  heparin  requires  inpatient  hospitalization  while  LMW  heparin  can  be  administered  sub-­‐Q  as  
an  outpatient    
o   Factor  X  antagonists:  rivaroxban,  apixaban  
§   No  antidote  to  date  
o   Direct  thrombin  inhibitor:  dabigatran  
§   No  antidote  to  date  
o   Heparin  or  LMWH  must  be  overlapped  with  warfarin  therapy  because  if  warfarin  is  used  alone,  
protein  C  and  S  levels  will  decrease  before  the  corresponding  decrease  in  pro-­‐coag  proteins,  
causing  a  pro-­‐coagulant  effect  
§   Reversal  of  heparin:  protamine  sulfate  
§   Reversal  of  warfarin:  FFP  or  concentrate  of  plasma-­‐derived  clotting  proteins  
 
ARTERIAL  THROMBOSIS  
•   Thrombi  that  form  in  areas  of  high  slow  are  composed  mainly  of  platelet  aggregates  held  together  by  
strands  of  fibrin  à  white  thrombi  
•   Underlying  vessel  pathology  plays  a  major  role  in  pathogenesis  
•   May  occlude  a  vessel  causing  ischemia  or  infarction;  can  break  free  and  embolize  downstream  
•   Treatment:  agents  that  affect  platelet  function  (Aspirin),  fibrinolytics,  tPA  or  urokinase  
o   Increased  risk  of  bleeding  with  thrombolysis  vs.  anticoagulation  
 
 
HEREDITARY  THROMBOTIC  DISORDERS  
•   Clues  to  the  presence  of  a  thrombotic  disorder:  history  of  recurrent  thrombosis,  family  history  of  
thrombosis  or  sudden  death,  thrombosis  at  a  young  age  (<45),  thrombosis  in  locations  other  than  the  
deep  veins  of  the  legs  
•   Thrombophilias  are  uncommon  and  expensive  testing  is  not  warranted  if  it  does  not  change  treatment  
recommendations  
•   Activated  protein  C  resistance  
o   APC  acts  as  a  potent  anticoagulant  by  destroying  activated  factors  V  and  VIII  and  stimulating  
the  fibrinolytic  system  
o   Polymorphism  results  in  factor  V  that  is  resistant  to  the  action  of  protein  C  –  factor  V  Leiden    
o   5-­‐10x  increase  in  risk  of  first  thrombosis  
o   Especially  common  in  northern  Europeans  
•   Protein  C  and  S  deficiencies  
o   Autosomal  dominant    
o   Diagnosis:  assays  
o   Warfarin  will  cause  assays  to  be  abnormal  since  these  factors  are  vitamin  K-­‐dependent  
•   Prothrombin  mutation  
o   DNA  polymorphism  in  prothrombin  gene    
o   Mutation  associated  with  3-­‐5  fold  risk  of  first-­‐time  venous  thrombosis  
o   Elevated  prothrombin  levels  
•   Antithrombin  deficiency  
o   Antithrombin  inactivates  thrombin  and  coag  factors  XII,  XI,  X,  and  IX  by  irreversibly  binding  to  
the  active  serine  site  of  the  protease  
o   Normally  inactivation  is  slow  except  in  the  presence  of  heparin  
o   Autosomal  dominant    
o   Heterozygotes  display  intermediate  levels  of  antithrombin  activity  –  thrombotic  tendency  
o   Homozygous  state  is  probably  not  compatible  with  life    
 
 
 
ACQUIRED  THROMBOTIC  DISORDERS  
•   Antiphospholipid  antibodies  
o   Antibodies  directed  against  antigens  that  are  composed  of  negatively  charged  phospholipids  
§   Lupus  anticoagulant,  anticardiolipin  antibodies,  antibodies  responsible  for  false  positive  
VDRL  test  
•   Lupus  anticoagulant  is  only  an  anticoagulant  in  vitro;  in  vivo,  it  promotes  the  
formation  of  venous  and  arterial  thrombosis  
 o   Associated  with  increased  risk  of  arterial  and  venous  thromboembolism,  thrombocytopenia,  
and  spontaneous  abortion  
o   Treatment:  warfarin  to  prevent  venous  thrombosis;  warfarin  +  aspirin  to  prevent  arterial  
thrombosis  
•   Thrombosis  and  cancer  
o   One  of  the  most  commonly  acquired  causes  of  venous  and  arterial  thrombosis  
o   Occurs  due  to  the  release  of  procoagulant  substances  from  malignant  cells  
o   Indwelling  central  venous  catheters,  chemo,  and  direct  compression  of  vessels  by  a  tumor  also  
contribute  to  the  risk  of  thrombosis  
•   Pregnancy  and  OCP  
o   Increase  risk  of  all  thrombotic  vascular  events  –  stroke,  MI,  DVT,  and  PE  
o   Impairment  of  venous  flow  in  pelvis,  increased  levels  of  procoagulant  proteins  induced  by  
estrogen,  and  decreased  levels  of  endogenous  anticoagulants  such  as  antithrombin    
 
 
 
ADVERSE  EFFECTS  OF  TRANSFUSION  
 
In  all  adverse  reactions,  stop  the  transfusion,  keep  IV  line  open,  perform  clerical  check,  treat  symptomatically,  
and  notify  the  blood  bank  
 
IMMUNE-­‐MEDIATED  TRANSFUSION  REACTIONS  
•   Hemolytic  transfusion  reactions  
o   Major  mismatch:  patient  has  red  cell  alloantibodies  or  naturally  occurring  ABO  antibodies  that  
are  directed  toward  a  red  cell  antigen  
o   Minor  mismatch:  transfused  plasma  in  transfused  blood  products  contains  high-­‐titer  ABO  
antibodies  to  the  patient’s  red  cells  (less  common)  
o   Serious  complications  occur  in  cases  in  which  intravascular  hemolysis  mediated  by  IgM  
antibodies  is  predominant  –  usually  due  to  ABO  incompatibility  
§   Most  common  error  is  misidentification  of  the  donor  or  patient  
o   Clinical  presentation:  fever,  chills,  anxiety,  hypotension,  dyspnea,  bronchospasm,  chest  pain,  
back  pain,  burning  in  vein  used  for  administration  of  transfusion,  urticarial,  nausea,  vomiting  
o   Complications:  DIC,  acute  ischemic  renal  failure  
o   Delayed  transfusion  reactions  occur  in  patients  who  have  been  previously  sensitized  to  a  red  
cell  antigen  
§   Alloantibody  is  not  detectable  at  the  time  of  transfusion,  however  there  will  be  an  
unexplained  drop  in  HCT  3-­‐10  days  later  as  antibody  titer  climbs  
•   Indirect  Coombs  test  will  reveal  the  antibody  
o   Labs:  examine  patient’s  plasma  for  presence  of  free  hemoglobin  
§   Will  be  pink  if  significant  hemolytic  reaction  has  occurred  
o   Treatment:  maintain  urine  flow  by  diuretics,  IV  fluids,  monitor  renal  function  and  coag  status  
•   Febrile  non-­‐hemolytic  transfusion  reactions  
o   Usually  due  to  cytokines  in  the  blood  component  or  antibodies  to  WBCs  
§   Leukocyte  reduction  does  not  get  rid  of  all  WBCs  from  the  sample  –  remaining  WBCs  
may  die  in  storage  and  release  cytokines  into  the  unit  and  elicit  a  response  when  
transfused    
 o   Characterized  by  development  of  fever  and/or  chills  30  mins-­‐2  hours  after  the  start  of  
transfusion  
o   Labs:  examine  patient’s  plasma  for  pink  or  red  tinge  
o   Treatment:  aspirin  or  acetaminophen  (usually  self-­‐limiting),  corticosteroids  for  more  severe  
reactions  
§   Use  leukocyte-­‐depleted  blood  products  and/or  pre-­‐medications  before  future  
transfusions  
•   Allergic  transfusion  reactions  
o   Caused  by  patient  antibodies  to  donor  plasma  proteins  
o   Clinical  presentation:  localized  urticarial  (mild),  hypotension,  bronchospasm,  anaphylaxis  
o   Most  allergic  reactions  are  sporadic  and  do  not  predict  further  reactions  
o   Treatment:  pause  transfusion,  antihistamines  (mild  cases),  corticosteroids  or  epinephrine  
(severe  cases)  
§   Transfusion  does  not  need  to  be  discontinued  if  localized  urticarial  is  the  only  symptom  
that  also  disspates  with  treatment  
o   Prevention:  volume  reduction,  cell  washing  
•   Transfusion-­‐related  acute  lung  injury  (TRALI)  
o   Uncommon  but  sometimes  life  threatening  reaction  due  to  interaction  of  leukocyte  antibodies  
usually  transfused  in  the  blood  product  and  the  patient’s  leukocytes  
o   Leukoagglutination  in  pulmonary  microvasculature  and  subsequent  pulmonary  damage  
o   Clinical  presentation:  dyspnea,  fever,  bilateral  pulmonary  infiltrates,  and  hypoxia  within  30min-­‐
6  hours  of  transfusion  
§   Usually  resolves  over  48-­‐72  hours  –  O2  and  ventilator  support  may  be  necessary  until  
recovery  
o   Report  to  blood  bank  
o   Leading  cause  of  transfusion  related  death  
 
 
TRANSMISSION  OF  INFECTION  
•   One  of  the  most  common  concerns  patients  have  when  consenting  to  blood  products  –  risk  is  present  
but  very  low  
•   Hepatitis  
o   Most  important  of  the  diseases  transmissible  by  transfusion  
o   Incidence  has  decreased  dramatically  due  to  dual  screening  measures  –  PCR  and  antibody  
screening  
•   HIV  
o   Risk  is  very  small  
o   HIV+  blood  can  enter  the  blood  supply  if  it’s  drawn  from  donors  who  are  infectious  but  not  yet  
antibody  or  PCR  positive  
•   Cytomegalovirus  
o   Importance  of  post-­‐transfusion  CMV  infection  depends  on  the  immune  status  of  the  patient  
§   Immunocompetent:  mild  mono-­‐like  syndrome  
§   Severely  immunocompromised:  life  threatening  CMV  infection  
o   ~50%  of  blood  donors  in  the  NW  are  CMV  seropositive  
o   Transmission  can  be  prevented  by  providing  cellular  blood  products  from  CMV  seronegative  
donors  or  by  removing  leukocytes  from  all  cellular  blood  products  
OTHER  ADVERSE  EFFECTS  
•   Transfusion-­‐associated  graft  vs.  host  disease  
o   Fatal  disorder  that  may  occur  if  transfused  immunocompetent  lymphocytes  survive  and  engraft  
in  the  transfusion  recipient  
o   Most  likely  to  occur  if  patient  is  severely  immunocompromised  or  if  the  donor  and  recipient  are  
closely  HLA  matched  (blood  relatives)  
§   Classic  picture:  homozygous  HLA  parent  donating  to  heterozygous  child  
o   Prevented  with  gamma  or  x-­‐ray  irradiation  of  all  blood  products  
•   Alloimmunization  
o   RBCs  
§   ~2-­‐3%  of  transfusion  recipients  develop  red  cell  alloantibodies;  pregnancy  can  also  
cause  alloantibodies  
§   Once  an  alloantibody  is  formed,  all  transfusions  must  be  negative  for  the  antigen  –  
finding  antigen  negative  blood  takes  more  time,  which  can  affect  patient  care  
o   HLA    
§   Patients  may  become  immunized  to  foreign  HLA  antigens  by  leukocytes  that  are  
“passengers”  in  RBC  and  platelet  transfusions,  or  through  pregnancy  or  tissue/organ  
transplantation  
§   May  lead  to  rapid  destruction  of  transfused  platelets  since  HLA  is  on  platelets  –  immune  
platelet  transfusion  refractoriness  
§   Leukocyte  filtration  of  platelet  and  RBC  transfusions  may  prevent  alloimmunization  
 
 
 
MYELODYSPLASTIC  SYNDROME  AND  MYELOPROLIFERATIVE  
NEOPLASMS  
 
MYELODYSPLASIA  
•   Clonal  hematopoietic  stem  cell  disorder  that  most  commonly  presents  in  people  in  their  60’s  or  70’s  
o   Uncommon  disease  with  slight  male  predominance    
•   Underproduction  of  mature  RBCs  and/or  WBCs  and/or  platelets  –  pancytopenia  and  macrocytosis  
•   Ineffective  hematopoiesis:  cellular  bone  marrow  but  cytopenias  in  peripheral  blood  
o   Precursors  are  present  but  do  not  develop  normally  into  mature  blood  cells  that  leave  the  
marrow  
o   Primitive  hematopoietic  progenitor  cells  continue  to  proliferate  but  there  is  excess  apoptosis  at  
the  later  stages  of  maturation  
•   Chromosomal  abnormalities:  5q  deletion,  7  deletion,  trisomy  8,  Y  deletion,  20q  deletion  
o   Confer  prognostic  significance    
o   5q  syndrome:  5q  region  contains  genes  encoding  several  growth  factors  –  deletion  results  in  
haploinsufficiency  
§   More  common  in  women  
§   Macrocytosis,  normal  platelets  
§   Good  prognosis  
§   Treatment:  lenalidomide    
•   Molecular  and  hematological  remission  
 •   Risks/exposures:  tobacco,  organic  solvents,  heavy  metals,  prior  chemo  or  radiation  for  cancer,  
inherited  bone  marrow  failure  disorders  (Fanconi  anemia,  Shwachman-­‐Diamond  syndrome,  severe  
congenital  neutropenia)  
•   Clinical  presentation:  fatigue,  recurrent  bacterial  infections,  mucosal  bleeding,  evolution  to  AML  
•   Diagnosis:  peripheral  smear,  bone  marrow  aspiration/biopsy  (essential),  cytogenetics,  absolute  
neutrophil  count  
•   Labs:  low  retic  count,  macrocytic  anemia,  pancytopenia  
o   Peripheral  smear:  oval  macrocytes,  hypolobulated  hypogranular  neutrophils  
o   Bone  marrow  aspirate/biopsy:  increased  cellularity  with  dysplastic  features,  
mononuclear/micro  megakaryocytes,  dys-­‐synchronous  maturation,  pseudo  Pelger-­‐Huet  cells    
•   Treatment:  cured  by  allogeneic  stem  cell  transplant,  supportive  care  as  needed  (transfusion  of  RBCs  
and/or  platelets),  iron  chelation,  hematopoietic  growth  factor  injections  (G-­‐CSF,  epo),  ATG  and  
cyclosporine  (directed  against  T  cells),  DNA  hypomethylating  agents  (azacitidine,  decitabine)  
o   High  dose  chemo  or  minimally  myeloablative  transplant  with  low  dose  total  body  irradiation  
followed  by  transplantation  of  peripheral  blood  stem  cell  sfrom  HLA-­‐matched  donor    
o   Risk  adapted  approach  to  therapy:  
§   Low  risk:  growth  factors,  lenalidomide,  or  hypomethylating  agents  
§   High  risk:  aggressive  therapy  with  hypomethylating  agents,  induction  chemotherapy,  
and  allogeneic  stem  cell  transplant    
 
 
MYELOPROLIFERATIVE  NEOPLASMS  
•   Each  of  the  myeloid  neoplasms  involves  overproduction  of  certain  types  of  cells  
•   Polycythemia  
o   Secondary  causes:  
§   Spurious  polycythemia:  due  to  decrease  in  plasma  volume  (dehydration,  diuretic  use,  
etc.)  
•   Red  cell  mass  is  normal  
•   Usually  mild,  HCT  <55%  
•   Middle-­‐aged,  obese,  hypertensive  men  
§   Tissue  hypoxia:  physiologic  response  to  decreased  tissue  oxygen  that  leads  to  increased  
epo  production  by  the  kidney  
•   Causes:  high  altitude,  right  to  left  shunt,  severe  COPD,  obstructive  sleep  apnea,  
chronic  carbon  monoxide  exposure,  smoking,  high  affinity  hemoglobin  
•   Elevated  serum  epo    
•   Treat  underlying  condition  to  correct  polycythemia  
§   Excessive  epo  production  
•   Renal  carcinoma  or  hepatocellular  carcinoma  cells  may  constitutively  produce  
epo,  not  regulated  by  normal  feedback  of  tissue  oxygenation  
•   Distortion  of  renal  anatomy  by  renal  cysts  or  hydronephrosis  may  increase  epo  
production  
•   Cerebellar  hemangiomas  and  uterine  fibroids  can  ectopically  produce  epo  
•   Elevated  serum  epo  levels  
o   Primary  cause:  polycythemia  vera  
§   Presents  most  commonly  in  people  60+  years  of  age  
 §   Stem  cell  disorder  where  a  multipotent  hematopoietic  stem  cell  proliferates  without  
control  by  usual  mechanisms  
§   Erythroid,  myeloid,  and  megakaryocytic  cells  are  overproduced  –  eventually,  all  
circulating  RBCs,  WBCs,  and  platelets  are  derived  from  the  neoplastic  cell  (clonal)  
§   V617F  mutation  results  in  a  hyperfunctional  Jak2  kinase  and  explains  the  increased  
growth  potential  and  hypersensitivity  to  epo  –  present  in  >95%  of  PV  patients  
§   Clinical  presentation:  headache,  dizziness,  pruritis,  erythromelalgia,  facial  plethora,  
hepatosplenomegaly  
§   Risks:  thrombosis,  bleeding,  transformation  to  AML,  bone  marrow  fibrosis  leading  to  
hepatosplenomegaly  (myeloid  metaplasia)  
§   Labs:  elevated  WBC  and  platelet  count,  low  serum  epo,  increased  red  cell  mass,  bone  
marrow  evaluation  not  required    
§   Treatment:  phlebotomy  as  needed  to  keep  HCT  <45%,  hydroxyurea,  ruxolitinib  (Jak2  
inhibitor),  IFNa,  low  dose  aspirin  
•   Consider  stem  cell  transplant  in  patients  heading  towards  AML  transformation  
•   Essential  thrombocythemia  
o   Primarily  characterized  by  an  elevated  platelet  count  –  other  counts  can  be  increased  as  well  
o   Occurs  primarily  in  the  elderly  but  survival  may  not  be  affected  if  managed  properly  
o   Risk:  thrombosis  
o   Treatment:  aspirin,  hydoxyurea,  anagrelide  (blocks  platelet  production)  
•   Primary  myelofibrosis  
o   Characterized  by  marrow  fibrosis  that  results  in  extramedullary  hematopoiesis  and  can  progress  
to  cytopenias  
o   Mean  age  of  presentation:  67  years  
o   Least  frequent  among  the  chronic  MPNs  but  has  the  highest  rate  of  progression  to  leukemia  
(~4%)  
o   Clinical  presentation:  hepatosplenomegaly  (extramedullary  hematopoiesis)  
o   Risks:  arterial  and  venous  thrombotic  events  
o   Diagnosis:  bone  marrow  examination  
§   Shows  abnormal  megakaryocytes  and  variable  presence  of  fibrosis  (reticulin  stain)  
o   Treatment:  bone  marrow  transplant  is  curative,  ruxolitinib  for  splenomegaly  and  severe  
symptoms  
 
 
 
LEUKEMIAS  
 
A  group  of  disorders  characterized  by  an  abnormal  clonal  proliferation  of  malignant  hematopoietic  cells  
circulating  in  large  numbers  in  the  bloodstream  –  cells  are  unable  to  differentiate  completely  or  function  
properly  
 
Acute:  neoplastic  clone  is  comprised  of  immature-­‐appearing,  large  hematopoietic  cells  (blasts)  
•   May  not  be  able  to  morphologically  determine  lineage  –  utilize  flow  cytometry    
•   Rapid  onset  
Chronic:  neoplastic  cells  differentiate  into  more  mature-­‐appearing  cells  –  can  be  hard  to  differentiate  from  
normal  
 •   Easier  to  determine  lineage  because  of  maturation  
•   Indolent  disease  
 
 
ACUTE  MYELOID  LEUKEMIA  (AML)  
•   Most  common  acute  leukemia  in  adults  –  increasing  incidence  with  advancing  age  
•   Can  arise  from  a  pre-­‐existing  myelodysplastic  syndrome  or  myeloproliferative  disorder  
•   Acute  promyelocytic  leukemia  
o   Clinical  presentation:  markedly  decreased  platelets,  hemorrhage,  DIC  
o   Treatment:  ATRA  
§   Induces  maturation  and  differentiation  in  80%  of  APL  patients  
§   Remission  is  generally  not  durable  unless  additional  drugs  are  administered  
§   Cure  rates  are  significantly  improved  in  patients  receiving  ATRA  +  chemotherapy  or  
ATRA  +  arsenic  trioxide  (ATO)  in  excess  of  90%  
•   Clinical  presentation:  recent  onset  of  fatigue,  weakness,  fever,  infection,  and/or  bleeding  and  
petechiae  
o   Cytopenias  due  to  marrow  infiltration  
o   Acute  monocytic  leukemia:  skin  lesions,  gum  swelling  (leukemic  infiltration),  CNS  involvement  
o   Solid  tumors  are  chloromas  or  granulocytic/myeloid  sarcomas  
•   Some  patients  may  exhibit  greatly  elevated  WBC  counts,  which  can  cause  large  blasts  to  adhere  to  
vessel  walls  and  clog  small  vessels  –  leukostasis    
o   Impaired  circulation,  local  O2  consumption,  tissue  hypoxia  
o   Particularly  likely  to  occur  in  the  lung  and  CNS  –  may  lead  to  fatal  intracranial  hemorrhage  or  
respiratory  failure  
o   Blast  counts  >100,000/ul  is  oncologic  emergency  –  treat  with  leukophoresis  and  immediate  
chemotherapy  
•   Staging  either  by  FAB  (morphology)  or  WHO  (cytogenics  then  morphology)  classification  
•   Labs:  
o   Peripheral  blood  smear:  elevated  WBC  count,  leukemic  blasts  with  auer  rods,  rarely  aleukemic  
leukemia  where  blasts  are  absent  in  the  blood  and  only  present  in  bone  marrow  
o   Bone  marrow:  hypercellular  with  >20%  blasts  
§   Sufficient  for  diagnosis  
•   Treatment:    
o   Chemotherapy:  conventional  first  approach,  60-­‐80%  complete  remission  of  9-­‐15  month  
duration  
§   Induction:  antimetabolite  (cytosine  arabinoside)  +  anthracycline  (daunorubicin,  
idarubicin)  given  7+3  
•   Objective  is  to  destroy  the  leukemic  clone  and  restore  normal  hematopoiesis  
•   Bone  marrow  evaluation  performed  after  3-­‐4  weeks  to  determine  if  clone  
persists;  another  course  of  induction  is  administered  if  leukemia  is  still  present  
•   Supportive  therapy  is  crucial  during  2-­‐3  week  aplastic  period  
§   Consolidation:  2-­‐4  cycles  of  high  dose  cytosine  arabinoside  
•   Objective  is  to  eliminate  resistant  clones  and  diminish  the  risk  of  leukemic  
relapse  
•   Despite  high  rates  of  complete  remission  with  induction  therapy,  few  are  cured  
with  induction  alone  
 §   Maintenance:  lower  doses  of  chemo  (often  oral)  chronically  over  2-­‐5  years  on  
outpatient  basis  to  eradicate  remaining  leukemic  cells  
•   Increases  survival  in  ALL  
o   Stem  cell  transplant  
§   Long-­‐term  cure  rates  are  poor  in  adult  AML  with  chemotherapy  
§   Stem  cell  transplantation  has  been  used  to  try  and  improve  survival    
§   60%  cure  rate  with  HLA-­‐matched  allogeneic  stem  cell  transplant  in  first  remission  
•   Limited  to  patients  under  60  years  of  age  
§   40%  long-­‐term  remission  with  autologous  transplant  for  those  without  HLA-­‐matched  
donor  
•   Prognosis:  
o   Poor  prognostic  factors:  
§   Preceding  MDS  
§   Age  >60  years  
§   Cytogenetic  abnormalities  involving  chromosomes  5,  7,  11q23,  or  bcr-­‐abl  
§   Poor  performance  status  
§   Failure  to  achieve  complete  remission  with  1  cycle  of  induction  therapy  
§   Flt3  ITD  mutation  
o   Favorable  features:  
§   Young  age  
§   Chromosomal  abnormalities:  t(15;17),  t(8;21),  inversion  of  chromosome  16  
§   NPM1  mutation  
§   Double  mutations  for  CEPBalpha  
o   Cytogenetics  is  the  major  predictor  of  remission  and  survival  –  used  to  determine  which  
patients  should  receive  more  intensive  therapy  with  stem  cell  transplantation  
 
 
ACUTE  LYMPHOBLASTIC  LEUKEMIA  (ALL)  
•   Most  common  leukemia  of  childhood    
•   80%  pre-­‐B  cell,  10-­‐20%  pre-­‐T  cell  
•   Clinical  presentation:  bone  marrow  failure  (pallor,  fatigue,  bleeding,  infection),  lymphadenopathy,  
splenomegaly  
o   Precursor  T  cell  ALL:  large  mediastinal  mass,  shortness  of  breath,  obstruction  of  the  large  
vessels  (SVC  syndrome)  
o   Tissue  involvement:  lymph  nodes,  spleen,  liver,  CNS,  testes  
§   Remember  to  evaluate  CNS  and  testes  since  they  are  “sanctuary  sites”    
•   Labs:  
o   Peripheral  blood  smear:  elevated  WBC  count,  leukemic  blasts  
o   Bone  marrow:  >20%  blasts  
•   Staging  either  by  FAB  or  WHO  classification  –  cytogenetic  abnormalities  found  in  ~60%  of  cases  
•   Treatment:  
o   Chemotherapy:  mainstay  for  treatment  
§   Induction:  vincristine  +  prednisone  +  L-­‐asparaginase  in  combination  with  an  
anthracycline    
•   90%  achieve  remission  –  not  durable  without  consolidation  therapy  
 •   ~80%  of  children  are  cured;  adults  are  much  more  resistant  to  conventional  
therapy  
§   Consolidation:  very  complex  with  rotating  drug  regimens  of  moderately  intense  chemo  
§   Treatment  of  sanctuaries:  
•   CNS:  intrathecal  methotrexate,  cytosine  arabinoside,  or  both;  cranial  irradiation  
for  high  risk  children  and  adults  
•   Testes:  testicular  irradiation  
§   Maintenance:  lower  doses  of  methotrexate  and  6-­‐mercaptopurine  for  2-­‐3  years    
o   Stem  cell  transplant:  patients  in  second  remission  or  adult  patients  with  poor  prognostic  
features  in  first  remission  should  be  considered  
•   Poor  prognostic  factors:  
o   Age  less  than  1  year  or  greater  than  10  years  in  children  
o   Age  >35  in  adults  
o   Leukocyte  counts  >30,000/ul  in  pre-­‐B  cell;  >100,000/ul  in  pre-­‐T  cell  
o   Presence  of  Philadelphia  chromosome  t(9;22)  or  11q23  
o   Failure  to  achieve  remission  in  less  than  4  weeks    
 
 
CHRONIC  MYELOGENOUS  LEUKEMIA  
•   Myeloproliferative  disorder  
•   Malignant  cells  retain  their  capacity  to  differentiate  and  mature  in  initial  stages  
•   Responsible  for  about  20%  of  all  adult  leukemias  –  occurs  primarily  in  individuals  >40  years  old  
•   Clinical  presentation:  may  be  totally  asymptomatic,  fatigue,  weight  loss,  fevers,  sweats,  splenomegaly,  
early  satiety,  upper  abdominal  fullness,  priapism  due  to  leukostasis,  normal  size  lymph  nodes  
•   Labs:  
o   Peripheral  blood  smear:  leukocytosis,  mature  appearing  neutrophils  and  bands  predominate,  
myelocytes,  promyelocytes,  occasional  blasts,  basophilia,  elevated  platelets  
§   With  progression  of  disease,  more  immature  forms  appear  in  circulation  –  ultimately  
culminates  in  a  clinical  picture  identical  to  AML  with  >20%  blasts  in  blood  and  marrow  
o   Bone  marrow:  hypercellular  with  granulocytic  precursors  predominating,  mild  marrow  fibrosis  
•   Cytogenetics:  hallmark  is  Philadelphia  chromosome  t(9;22)  
o   Bcr-­‐abl  product  results  in  much  greater  tyrosine  kinase  activity  
o   Present  in  myeloid,  erythroid,  megakaryocytic,  and  sometimes  B  lymphocytic  cell  lines  
•   Differentiated  from  other  myeloproliferative  neoplasms  by  the  presence  of  the  Philadelphia  
chromosome;  low  LAP  score  differentiates  CML  from  a  leukemoid  reaction  
•   Phases  of  CML  progression:  
o   Chronic  phase:  stable  elevated  WBC  count  with  granulocytes  displaying  varying  degrees  of  
maturation  
§   Duration:  3  years  
§   WBC  count  responds  readily  to  therapy  
o   Accelerated  phase:  leukocytosis  increases  with  marked  left  shift  and  increased  basophilia  
§   Progressive  splenomegaly,  bone  pain,  fever,  night  sweats,  and  other  systemic  
complaints  
§   Duration:  weeks  to  months  
§   Response  to  therapy  is  suboptimal  
 o   Blast  crisis:  progressive  systemic  symptoms,  splenomegaly,  acquisition  of  new  chromosomal  
abnormalities,  >20%  blasts  in  marrow  and  blood  
§   Blasts  are  myeloid  in  2/3  of  cases;  lymphoid  in  1/3  of  cases  
§   Signals  the  terminal  stage  of  CML  since  acute  leukemia  is  refractory  to  treatment  
•   Treatment:  imatinib  targets  the  abl  tyrosine  kinase  and  can  result  in  high  rates  of  hematologic,  
cytogenic,  and  molecular  remission  
o   Chronic  phase:  imatinib,  allogeneic  stem  cell  transplant  for  patients  who  do  not  achieve  
molecular  remission  
§   90%  hematologic  remission  
o   Blast  crisis:  treat  similar  to  AML  or  ALL,  imatinib,  additional  chemotherapy,  allogeneic  stem  cell  
transplant  is  the  only  potential  cure  
§   Remission  is  less  durable  
§   Transplant  is  much  less  successful  
 
 
CHRONIC  LYMPHOCYTIC  LEUKEMIA  
•   Most  common  leukemia  in  the  US  
•   Clonal  proliferation  of  mature  small  B  lymphocytes  
•   Occurs  mainly  in  the  elderly  but  can  be  diagnosed  in  asymptomatic  stage  in  middle  age  individuals  by  
flow  cytometry  
•   Clinical  presentation:  persistently  swollen  lymph  nodes,  left  upper  quadrant  discomfort,  early  satiety  
(splenomegaly),  fatigue,  shortness  of  breath,  dizziness,  mucosal  bleeding  and  bruising,  frequent  
infections  
o   May  be  found  incidentally  in  early  stage  disease  
o   Symptoms  in  later  stages  due  to  bone  marrow  infiltration  and  splenomegaly  
o   Nodal  architecture  is  often  replaced  with  diffuse  pattern  of  well-­‐differentiated  small  
lymphocytes  
•   Labs  
o   Peripheral  blood  smear:  lymphocytosis,  mature  and  differentiated  malignant  clone,  smudge  
cells  
o   Bone  marrow:  hypercellular  with  extensive  infiltration  with  >30%  mature  lymphocytes,  
decreased  erythroid  and  myeloid  elements  
•   Chromosomal  abnormalities:  trisomy  12,  17p  deletion  (resistance  to  chemo),  13q  deletion  (good  
prognosis),  11q  deletion  (bulky  lymph  node  enlargement,  poor  survival)  
o   Low  CD38  and  low  Zap-­‐70  are  associated  with  more  favorable  prognosis  
•   Staging  by  Rai  classification  
•   Diagnosis:    
o   Demonstration  of  persistent,  mature,  monoclonal  lymphocytosis  in  patients  >50  years  
o   Clonal  expression  of  either  kappa  or  lambda  light  chains  +  CD5  antigen  (T  cell  marker)  on  
surface  of  malignant  CLL  B  cells  
•   Treatment:  CLL  is  not  curable  with  standard  therapy  
o   Indolent  disease  and  many  patients  are  asymptomatic,  so  therapy  does  not  need  to  be  
instituted  immediately  –  generally  observe  and  withhold  treatment  until  symptoms  arise  
§   Degree  of  lymphocytosis  is  not  an  indicator  for  treatment  since  small  cells  do  not  plug  
capillaries  or  cause  leukostasis  
o   Patients  with  complications  or  symptoms  should  be  treated    
 o   Chemotherapy:  fludarabine  +  cyclophosphamide  +  rituximab  (FCR)  is  a  regimen  of  choice  
§   90%  response  rates,  but  the  regimen  is  intense  and  difficult  to  tolerate  in  older  patients  
§   Bendamustine  +  rituximab  is  better  tolerated  
§   For  relapse  or  patients  with  17p  deletion,  alemtuzumab  (antibody  to  CD52)  has  good  
activity  
§   Prednisone  given  for  CLL-­‐associated  autoimmune  phenomena  
o   Stem  cell  transplant:  does  not  need  to  be  considered  unless  disease  is  resistant  to  fludarabine  
chemo  or  after  treatment  for  relapsed  disease  
§   Non-­‐myeloablative  allogeneic  mini  transplants  are  promising  
 
 
 
LYMPHOMAS  AND  MYELOMA  
 
Lymphomas  typically  present  with  enlargement  of  lymph  nodes,  spleen,  and/or  other  lymphoid  organs  –  cells  
can  also  be  found  in  transit  in  the  bloodstream,  marrow,  and  lymphatics  
 
5th  most  common  cause  of  cancer  death  in  the  US  
 
Diagnosis  is  made  by  excisional  biopsy  of  the  most  centrally  involved  lymph  node  
•   Needle  biopsies  are  not  sufficient  
 
 
HODGKIN  LYMPHOMA  
•   2  age  peaks:  early  20’s  and  early  50’s  
•   Characterized  by  presence  of  Reed-­‐Sternberg  cells  
•   Bulk  of  tumor  mass  in  composed  of  normal  lymphocytes,  plasma  cells,  and  eosinophils,  which  
outnumber  the  RS  cells  
•   Clinical  presentation:  cervical  adenopathy  (>2cm,  firm,  painless)  
o   Typically  originates  in  neck  or  mediastinal  lymph  nodes  
o   Spleen  is  often  the  first  intra-­‐abdominal  site  of  disease  
•   Diagnosis:  excisional  biopsy  
•   Staging  based  on  number  of  sites  with  disease,  location  in  relation  to  the  diaphragm,  presence  of  
extranodal  sites,  and  presence  of  B  symptoms  (constitutional)  
o   B  symptoms  associated  with  dissemination  and  poorer  prognosis  
o   Work-­‐up:  chest  x-­‐ray,  blood  counts,  bone  marrow  aspiration  and  biopsy,  CT  (chest,  abdominal,  
pelvic),  PET  scan  
•   Treatment:  treat  to  cure  not  just  palliative  
o   Stage  I-­‐II:  small  radiation  fields  +  2-­‐4  cycles  of  modified  chemo    
o   Stage  III-­‐IV:  chemotherapy  with  ABVD  or  MOPP  6-­‐8  cycles  monthly  
§   70-­‐90%  remission;  60-­‐70%  cure  
§   ABVD  is  preferred  since  MOPP  contains  more  toxic  agents  and  is  more  likely  to  cause  
permanent  sterility  and  induce  secondary  malignancies  
o   HL  is  a  highly  curable  disease  for  young  people  –  be  aware  of  long  term  effects  of  treatment  like  
secondary  cancers  or  cardiovascular  risks  
 
NON-­‐HODGKIN  LYMPHOMA  
•   Heterogeneous  group  of  tumors  with  85%  of  cases  derived  from  B  cells,  15%  from  T  cells  
•   Incidence  increases  with  age  
•   Most  indolent  lymphomas  relapse  after  therapy  regardless  of  which  regimen  is  used,  while  aggressive  
lymphomas  are  often  curable    
•   Aggressive:  patient  will  get  sick  from  the  disease  and  present  due  to  symptoms  
o   Diffuse  large  B  cell,  anaplastic  large  cell,  Burkitt’s,  lymphoblastic  
•   Indolent:  incidentally  diagnosed  
o   Follicular,  small  lymphocytic    
•   Some  of  these  diseases  can  have  a  leukemic  phase  
•   Diagnosis:  histologic  pattern  of  involved  lymph  nodes  
o   Diffuse  vs.  follicular  
o   Large  vs.  small  cells  
•   Treatment:    
o   Indolent  
§   Stage  I-­‐II:  radiotherapy    
•   Patients  are  unlikely  to  present  early  due  to  the  lack  of  symptoms  
•   40-­‐50%  cure  rate  
§   Stage  III-­‐IV:  none  if  no  symptoms,  CVP  +  rituximab  if  symptomatic  
•   CVP:  cyclophosphamide,  vincristine,  prednisone  
•   Incurable  –  limited  evidence  that  any  treatment  available  prolongs  life  except  
with  allogeneic  bone  marrow  trasnplant  
o   Aggressive    
§   Stage  I-­‐II:  3  cycles  of  CHOP  +/-­‐  rituximab  +  radiotherapy  
•   80-­‐85%  cure  
•   Radiotherapy  used  to  treat  localized  disease  
§   Stage  III-­‐IV:  CHOP  +/-­‐  rituximab  
•   40%  cure  
§   Relapse:  autologous  bone  marrow  transplant  cures  20-­‐50%    
 
 
MULTIPLE  MYELOMA  
•   Malignant  disorder  characterized  by  monoclonal  proliferation  of  a  clone  of  plasma  cells  
•   Peak  incidence  in  70’s  
•   Clinical  presentation:  bone  pain,  anemia,  thrombocytopenia,  fever,  plasmacytomas/cutaneous  
nodules  
o   Clonal  proliferation  in  marrow  results  in  suppression  of  normal  marrow  elements  
o   Myeloma  cells  secrete  lymphokines  which  activate  osteoclasts  and  result  in  massive  bone  
resorption  –  localized  lytic  activity  produces  “punched  out”  lesions  in  skull  or  long  bones  
•   Renal  failure  is  a  major  cause  of  morbidity  and  mortality  
o   Excretion  of  light  chains  in  urine  may  have  a  direct  toxic  effect  on  tubule  or  precipitate  and  
cause  obstruction  
o   Bone  resorption  leads  to  hypercalcemia,  which  is  nephrotoxic  
o   Monoclonal  immunoglobulin  can  be  deposited  as  amyloid  in  the  parenchyma  
o   Patients  excreting  lambda  chains  are  at  greater  risk  of  kidney  damage  than  those  secreting  
kappa  light  chains  
 •   Bone  fractures  occur  due  to  direct  lytic  activities  of  the  myeloma  cells  are  osteoclast  activation  –  leads  
to  hypercalcemia  causing  renal  toxicity,  nausea/vomiting,  dehydration,  constipation,  coma  
•   High  levels  of  M  protein  can  cause  hyperviscosity  syndrome,  interfere  with  platelet  function,  and  
increased  risk  of  infections    
o   Infections  are  the  most  common  cause  of  death  in  myeloma  patients  
•   Labs:  hypoproliferative  anemia,  rouleaux,  low  WBC  or  platelet  count,  >10%  plasma  cells  in  marrow  
(frequently  binucleate),  clumps  within  marrow,  skeletal  bone  survey,  SPEP,  24hr  urine  
•   Diagnosis:  SPEP  with  M  spike,  bone  marrow  aspiration  and  biopsy,  serum  or  urine  monoclonal  
gammopathy,  Bence  Jones  proteinuria  (light  chains),  lytic  bone  lesions,  presence  of  plasmacytomas  
o   SPEP:  IgG  >  IgA  >  IgD  >  IgM  
•   Treatment:    
o   Chemotherapy:  cure  not  achievable,  thalidomide  +  dexamethasone  for  frontline  palliative  
chemo  
o   Stem  cell  transplant:  common  approach  involves  sequential  autologous  transplants  in  tandem  
or  autologous  followed  by  non-­‐myeloablative  allogeneic  transplant  
§   Prolongs  survival  but  not  curative  
o   Radiation:  local  control  of  plasmacytomas  or  painful  bone  lesions  
o   Bisphosphonates:  diminish  bone  resorption  –  all  symptomatic  patients  receive  monthly  
treatment  
 
 
WALDENSTROM’S  MACROGLOBULINEMIA  
•   Disease  of  the  elderly  
•   Overproduction  of  IgM  –  hyperviscosity  syndrome  much  more  common  than  in  multiple  myeloma  
•   Clinical  presentation:  insidious  onset  of  fatigue,  weakness,  oro-­‐nasal  bleeding,  adenoopathy,  
splenomegaly,  hyperviscosity  syndrome  
o   Triad  of  hyperviscosity  syndrome:  bleeding  (epistaxis,  ecchymoses),  visual  changes  (blurred  
vision,  segmentation  of  retinal  arterioles),  neurologic  changes  (headache,  confusion,  dizziness)  
•   Labs:  marked  increase  in  serum  IgM  on  SPEP,  pancytopenia  
•   Diagnosis:  large  IgM  spike  on  SPEP  in  association  with  other  clinical  features  
•   Treatment:  incurable,  mean  survival  is  ~5  years  
o   Alkylating  agents  or  purine  analogs:  control  organomegaly,  paraprotein  production,  and  
improve  cytopenias  
o   Rituximab  
o   Plasmapheresis  for  hyperviscosity  syndrome  
 
 
AMYLOIDOSIS  
•   AL  amyloidosis  associated  with  plasma  cell  dyscrasias,  which  produce  large  amounts  of  light  chains  
(Bence-­‐Jones  proteins)  
•   Clinical  presentation:  fatigue,  weakness,  weight  loss,  dyspnea,  purpura  of  eyelids,  edema,  signs  of  CHF,  
nephrotic  syndrome,  orthostatic  hypotension,  peripheral  neuropathy,  renal  insufficiency  
•   Diagnosis:  large  M  spike  on  SPEP,  Congo  red  staining  of  tissue  sample  exhibits  apple  green  
birefringence,  bone  marrow  aspiration  and  biopsy  (determines  degree  of  plasma  cell  infiltration)  
o   Needle  aspiration  of  abdominal  fat  pad  is  easiest  to  perform  
•   Treatment:  generally  unsatisfactory  
 o   Alkylating  agents  +  melphalan  +  steroid  is  standard  regimen  
o   Median  survival:  ~2  years  
o   Stem  cell  transplant  
 
 
MONOCLONAL  GAMMOPATHY  OF  UNDETERMINED  SIGNIFICANCE  (MGUS)  
•   Clinical  situation  where  patient  is  found  to  have  a  small  monoclonal  spike  on  SPEP  but  no  other  
evidence  of  a  plasma  cell  disorder  –  not  harmful  on  its  own  
•   Patients  typically  present  with  unrelated  complaints  and  paraprotein  is  discovered  incidentally  
•   Some  patients  develop  overt  myeloma  while  others  have  no  problems  
o   ~24%  of  MGUS  patients  develop  MM,  amyloidosis,  or  other  hematologic  malignancy  10  years  
after  presentation  
•   Follow  MGUS  closely  but  do  not  treat  until  progression  is  documented  
o   Annual  SPEP