RT Book, Section
A1 Gailani, David
A1 Renné, Thomas
A1 Emsley, Jonas
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181455672
T1 Factor XI and the Plasma Contact System
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181455672
RD 2024/04/24
AB Exposure  of  blood  or  plasma  to  negatively  charged  surfaces  results  in  activation  of  the  plasma  proteins  factor  XII  and  prekallikrein  (PK)  by  a  process  termed  contact  activation.  These  reactions  require  the  cofactor  high-molecular-weight-kininogen  (HK).  Contact  activation  triggers  fibrinolysis,  kinin  formation,  and  blood  coagulation  through  activation  of  factor  XI.The  cDNAs  for  human  factor  XI,  factor  XII,  PK,  and  HK  have  been  cloned,  and  the  amino  acid  sequences  and  domain  structures  of  the  proteins  have  been  determined.  Factor  XI,  factor  XII,  and  PK  are  zymogens  of  serine  proteases  containing  C-terminal  trypsin-like  catalytic  domains  and  N-terminal  domains  that  bind  other  macromolecules.  Factor  XI  is  a  homodimer  of  80-kDa  polypeptides  structurally  similar  to  PK.  Factor  XI  and  PK  circulate  as  noncovalent  complexes  with  HK.  HK  is  a  multifunctional  110-kDa  protein  with  domains  for  binding  to  cells,  factor  XI,  PK,  and  negatively  charged  surfaces,  and  two  domains  that  inhibit  cysteine  proteases.  HK  is  a  source  of  the  potent  vasodilatory  nanopeptide  bradykinin.Genes  for  factor  XI,  factor  XII,  PK,  and  HK  have  been  characterized  and  their  chromosomal  locations  determined.  Mutations  causing  hereditary  deficiency  states  have  been  identified  for  each  protein  except  PK.  The  genes,  cDNAs,  and  amino  acid  sequence  for  factor  XI  and  PK  are  very  similar,  which  suggests  that  they  are  the  products  of  a  duplication  event  involving  a  common  ancestral  gene.Deficiency  of  factor  XI  (mim  264900)  results  in  excessive  bleeding  following  trauma  or  surgery  indicating  that  this  protein  is  essential  for  normal  coagulation.  In  contrast,  deficiencies  of  factor  XII  (mim  234000),  PK  (mim  229000),  HK  (mim  228960)  are  not  associated  with  clinical  abnormalities.  These  observations  suggest  that  factor  XI  is  activated  in  vivo  by  processes  other  than  contact  activation.Factor  XI  deficiency  is  common  in  Ashkenazi  Jews,  in  whom  the  carrier  frequency  has  been  estimated  to  be  5  to  13  percent.  Two  distinct  point  mutations  account  for  the  majority  of  abnormal  alleles  in  this  group.  The  type  II  mutation  results  in  early  termination  of  the  protein,  while  the  type  III  mutation  causes  greatly  reduced  protein  secretion  from  the  liver.While  deficiencies  of  factor  XII,  PK,  or  HK  are  not  associated  with  an  abnormal  phenotype,  inappropriate  activation  of  these  proteins  may  contribute  to  pathologic  processes  in  several  clinical  conditions  such  as  sepsis,  inflammation,  and  hereditary  angioedema.