TY  - CHAP
M1  - Book, Section
TI  - Pulmonary Hypertension and Heart Disease in Patients With Sickle Cell Disease
A1  - Gladwin, Mark T.
A1  - Ataga, Kenneth I.
A1  - Machado, Roberto
A2  - Gladwin, Mark T.
A2  - Kato, Gregory J.
A2  - Novelli, Enrico M.
PY  - 2021
T2  - Sickle Cell Disease
AB  - Sickle  cell  disease  (SCD)  is  an  autosomal  recessive  disease  caused  by  a  single  point  mutation  in  the  gene  encoding  the  β-globin  chain  of  hemoglobin.1  The  most  common  form  of  SCD  is  caused  by  the  inheritance  of  homozygous  mutant  hemoglobin  S  (HbSS;  occurring  in  up  to  75%  of  patients),  whereas  approximately  25%  of  patients  have  compound  heterozygosity  of  hemoglobin  S  with  another  β-globin  chain  variant  (ie,  hemoglobin  C,  D-Punjab,  O-Arab,  and  E).1-4  The  mutant  sickle  cell  hemoglobin  polymerizes  within  the  erythrocyte  during  deoxygenation,  altering  erythrocyte  rheology  and  causing  microvascular  obstruction  and  hemolytic  anemia.1-4  As  described  in  early  chapters  on  mechanisms  of  disease  and  summarized  in  Figure  14-1,  the  pathogenesis  is  determined  upstream  by  the  extent  of  hemoglobin  S  polymerization,  which  leads  to  the  following  2  major  downstream  pathologic  events:  microvascular  occlusion  (vaso-occlusion)  with  ischemia-reperfusion  tissue  injury  and  infarction,5,6  and  hemolytic  anemia,  which  releases  cell  free  hemoglobin  and  other  erythrocytic  products,  such  as  adenosine  diphosphate  (ADP)  and  arginase  1,  from  the  red  blood  cells,  reducing  nitric  oxide  (NO)  signaling  and  generating  reactive  oxygen  species.7-11  These  pathobiologic  processes  may  act  in  concert  to  activate  inflammatory  pathways  involving  selectin-mediated  adhesion  and  inflammasome-mediated  sterile  inflammation.4  For  example,  oxidation  of  hemoglobin  leads  to  heme  release  and  downstream  activation  of  P-selectin–dependent  platelet-neutrophil  interactions  and  toll-like  receptor  4  (TLR4)-dependent  and  -independent  sterile  inflammation  signaling  pathways.12-15  Cycles  of  ischemia-reperfusion  tissue  injury  and  infarction  likely  also  release  damage-associated  molecular  proteins  (DAMPs),  such  as  mitochondrial  DNA,  that  can  also  activate  toll-like  receptor  and  NLRP  (Nucleotide-binding  oligomerization  domain,  Leucine  rich  Repeat  and  Pyrin  domain  containing),  also  abbreviated  as  NALP  (NACHT,  LRR,  and  PYD  domains–containing  protein)  inflammasome-dependent  sterile  inflammation.  Furthermore,  steady-state  intravascular  hemolysis  releases  erythrocyte  DAMPs  (eDAMPs)  that  may  activate  the  innate  immune  system,  priming  it  for  a  second  hit,  such  as  infection  or  trauma,  that  activates  severe  inflammation  and  vaso-occlusive  events.4,16  During  acute  episodes  of  pain  crisis,  the  intensity  of  both  vaso-occlusion  and  hemolytic  anemia  may  increase  dramatically,  leading  to  severe  acute  organ  injury  and  severe  pain,  sometimes  culminating  in  acute  lung  injury  (called  the  acute  chest  syndrome),  cor  pulmonale,  multiorgan  dysfunction  and  failure,  and  death.2,4  See  Figure  14-1  for  an  overview  of  the  major  pathophysiologic  mechanisms  that  drive  SCD.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - hemonc.mhmedical.com/content.aspx?aid=1179344168
ER  -