RT Book, Section
A1 Kato, Gregory J.
A1 Gladwin, Mark T.
A2 Gladwin, Mark T.
A2 Kato, Gregory J.
A2 Novelli, Enrico M.
SR Print(0)
ID 1179338153
T1 Hemolysis and Endothelial Dysfunction
T2 Sickle Cell Disease
YR 2021
FD 2021
PB McGraw-Hill Education
PP New York, NY
SN 9781260458596
LK hemonc.mhmedical.com/content.aspx?aid=1179338153
RD 2024/04/18
AB Sickle  cell  anemia  (SCA)  is  characterized  by  severe  chronic  hemolysis  that  gives  rise  to  anemia.  There  are  many  pathophysiologic  responses  to  the  hemolysis  and  to  its  resulting  anemia.  Most  of  these  responses  are  adaptive  in  the  short  term,  but  some  of  these  can  have  maladaptive  consequences  in  the  long  term.  The  most  harmful  form  of  hemolysis  is  intravascular  hemolysis,  which  releases  the  contents  of  red  blood  cells  directly  into  plasma.  Cell-free  hemoglobin,  free  heme,  arginase,  and  methylated  arginines  reduce  nitric  oxide  (NO)  bioavailability  and  promote  oxidative  stress  and  inflammation.  Cell-free  hemoglobin  scavenges  NO  in  a  rapid,  nearly  diffusion-limited  dioxygenase  reaction.  Both  cell-free  hemoglobin  and  free  heme  promote  intense  oxidative  stress  and  serve  as  damage-associated  molecular  patterns  (DAMPs).  This  activates  the  innate  immune  system  to  produce  inflammatory  cytokines,  promoting  adhesion  molecule  expression  on  blood  cells  and  endothelial  cells.  Multilayered  adaptive  mechanisms  have  evolved  to  clear  hemoglobin  and  heme,  including  haptoglobin  and  hemopexin.  However,  the  severe  chronic  hemolysis  in  SCD  saturates  the  haptoglobin  system  and  depletes  both  haptoglobin  and  hemopexin.  Arginase  and  methylarginine  limit  the  activity  of  NO  synthase  to  increase  NO  production  to  compensate  for  the  destruction  of  NO.  The  physiologic  consequences  of  decreased  NO  bioavailability  include  chronic  vasoconstriction,  proliferative  arteriopathy,  and  increased  platelet  aggregation  and  clotting,  especially  in  the  pulmonary  vasculature.  Severe  anemia  results  in  high  erythropoietin  secretion,  with  increased  circulating  placenta  growth  factor  (PlGF)  and  endothelin-1,  a  potent  vasoconstrictor.  Severe  anemia  also  induces  red  cell  content  of  2,3-diphosphoglycerate  (2,3-DPG),  which  lowers  oxygen  affinity  and  basal  oxygen  saturation  and  promotes  HbS  polymerization.  Severe  hemolytic  anemia  increases  the  risk  of  gallstones,  systemic  and  pulmonary  hypertension,  leg  ulceration,  priapism,  nephropathy,  and  stroke.