RT Book, Section
A1 Natrajan, Kavita
A1 Kutlar, Abdullah
A2 Kaushansky, Kenneth
A2 Lichtman, Marshall A.
A2 Prchal, Josef T.
A2 Levi, Marcel M.
A2 Press, Oliver W.
A2 Burns, Linda J.
A2 Caligiuri, Michael
SR Print(0)
ID 1121094129
T1 Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities
T2 Williams Hematology, 9e
YR 2015
FD 2015
PB McGraw-Hill Education
PP New York, NY
SN 9780071833004
LK hemonc.mhmedical.com/content.aspx?aid=1121094129
RD 2024/04/23
AB SUMMARYHemoglobinopathies  are  the  most  common  inherited  red  cell  disorders  worldwide.  Among  these  disorders,  sickle  cell  syndromes  and  thalassemias  constitute  a  major  public  health  problem.  A  glutamic  acid  to  valine  substitution  at  the  sixth  amino  acid  of  the  β-globin  chain  of  human  hemoglobin  (HbA)  results  in  formation  of  sickle  hemoglobin  (HbS).  Sickle  cell  disease  results  from  homozygosity  for  this  mutation,  or  from  a  compound  heterozygosity  for  sickle  hemoglobin  and  β-thalassemia  or  another  β-globin  variant  such  as  HbC,  HbD,  HbE,  or  HbOArab.  The  sickle  mutation  renders  the  hemoglobin  molecule  insoluble  upon  deoxygenation;  thus  red  blood  cells  containing  deoxy  HbS  polymer  are  rigid  and  have  impaired  rheologic  properties.  The  downstream  effects  of  the  sickling  process  include:  membrane  changes  leading  to  potassium  loss  and  cellular  dehydration,  interaction  of  sickle  hemoglobin  with  microvascular  endothelium,  neutrophils,  and  monocytes,  hemolysis,  nitric  oxide  depletion,  release  of  inflammatory  proteins  and  activation  of  coagulation.  These  processes  lead  to  a  hemolytic  anemia,  an  inflammatory  state,  painful  vasoocclusive  episodes,  and  damage  to  multiple  organ  systems  with  a  resultant  shortened  life  expectancy.  There  is  considerable  heterogeneity  in  the  severity  of  the  disease;  the  best  known  modifier  of  the  disease  is  an  elevated  level  of  fetal  hemoglobin  (HbF),  which  exerts  a  potent  antisickling  effect.  Concomitant  α-thalassemia  is  also  a  modifier,  which  leads  to  a  decrease  in  hemolysis.  There  is  an  interest  in  nonglobin  genetic  modifiers  of  sickle  cell  disease.  Over  the  past  3  decades,  advances  in  supportive  care  and  implementation  of  disease-modifying  therapies,  such  as  anti–γ  to  β-globin  switching  therapies,  which  result  in  increased  HbF  and  less  HbS  synthesis,  and  have  led  to  an  increase  in  life  expectancy.  Hydroxyurea  has  emerged  as  an  effective  disease-modifying  agent  that  has  been  approved  by  the  FDA  for  use  in  adults  with  sickle  cell  disease.  Although  its  main  mechanism  of  action  is  to  enhance  HbF  production,  other  effects  such  as  a  decrease  in  neutrophils,  platelets,  and  decreased  expression  of  adhesion  molecules  contribute  to  its  efficacy.  Novel  antiswitching  agents,  most  notably,  DNA  methyltransferase  1  inhibitors  (5′-azacytidine  and  decitabine)  and  histone  deacetylase  inhibitors  (butyrate  derivatives  and  others)  are  now  in  clinical  trials.  Evolving  therapies  include  antiadhesive  therapies  to  prevent  interaction  of  sickle  cells  with  microvascular  endothelium,  antiinflammatory  approaches,  and  modulation  of  hemoglobin–oxygen  affinity  to  prevent  sickling.  To  date,  the  only  curative  therapy  remains  allogeneic  hematopoietic  stem  cell  transplantation.Sickle  trait,  the  heterozygous  state  for  sickle  hemoglobin,  affects  approximately  8  percent  of  Americans  of  African  descent,  and  with  rare  exceptions  is  asymptomatic.  HbC  is  associated  with  target  cells  and  spherocytes  in  the  blood  film  and  splenomegaly.  HbD  disease  is  essentially  asymptomatic.  HbE  is  very  common  in  Southeast  Asia,  and  because  of  large  population  movements  from  this  area,  it  has  become  a  prevalent  hemoglobinopathy  in  other  regions  of  the  world.  HbE  is  a  thalassemic  variant  and  its  coinheritance  with  β0-thalassemia  mutations  can  result  in  severe  transfusion-dependent  thalassemia  major.  Unstable  hemoglobin  variants  appear  as  rare,  sporadic  cases  and  are  characterized  by  a  Heinz  body  hemolytic  anemia.  Variants  that  alter  the  oxygen  affinity  of  the  Hb  molecule  lead  to  erythrocytosis  (high  oxygen  affinity  variants)  or  anemia  (low  ...