TY  - CHAP
M1  - Book, Section
TI  - Antithrombin Deficiency
A1  - Tollefsen, Douglas M.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.208
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Antithrombin  is  a  58-kDa  glycoprotein  that  is  present  in  human  plasma  at  a  concentration  of  ~2.6  μM.  It  inhibits  several  activated  coagulation  factors,  including  thrombin,  factor  IXa,  and  factor  Xa.  Inhibition  occurs  by  formation  of  a  stable  1:1  complex  between  antithrombin  and  the  protease.Heparin  and  heparan  sulfate  increase  the  rate  of  the  antithrombin-protease  reaction  at  least  1000  times  by  a  catalytic  mechanism  that  requires  binding  of  the  glycosaminoglycan  chain  to  antithrombin.  The  binding  site  for  antithrombin  is  a  specific  pentasaccharide  sequence  that  contains  an  unusual  3-O-sulfated  glucosamine  residue.  This  structure  occurs  in  ~30  percent  of  heparin  molecules  isolated  from  mast  cells  and  in  1  to  10  percent  of  heparan  sulfate  molecules  synthesized  by  vascular  endothelial  cells.  Current  evidence  suggests  that  heparan  sulfate  proteoglycans  anchored  in  the  vessel  wall  interact  with  circulating  antithrombin  to  inhibit  thrombus  formation.Antithrombin  deficiency  (MIM  107300)  is  present  in  ~2  percent  of  patients  with  venous  thromboembolic  disease,  in  whom  it  is  generally  inherited  as  an  autosomal  dominant  trait.  The  prevalence  of  symptomatic  antithrombin  deficiency  is  estimated  to  range  from  1  per  2000  to  1  per  5000  in  the  general  population.  Affected  heterozygous  individuals  have  ~50  percent  of  the  normal  plasma  antithrombin  activity.  Deficiency  results  from  mutations  that  affect  the  biosynthesis  or  stability  of  antithrombin  and  hence  lower  the  amount  of  antithrombin  antigen  detectable  in  plasma,  or  from  mutations  that  affect  the  protease  and/or  heparin-binding  sites  and  are  associated  with  essentially  normal  levels  of  antithrombin  antigen.  Mutations  confined  to  the  heparin  binding  site  appear  to  be  more  common  than  the  other  types  of  mutations  and  are  usually  asymptomatic  unless  present  in  a  homozygous  state.Clinical  manifestations  of  antithrombin  deficiency  include  deep  vein  thrombosis  and  pulmonary  embolism.  Thrombosis  may  occur  spontaneously  or  in  association  with  pregnancy,  trauma,  or  surgery.  Arterial  thrombosis  is  rare.  Many  patients  experience  recurrent  thromboembolic  disease  beginning  in  early  adulthood.  It  has  been  estimated  that  by  30  years  of  age  ~60  percent  of  patients  with  antithrombin  deficiency  will  have  had  at  least  one  thrombotic  episode.  Acute  episodes  are  generally  treated  with  a  5-  to  7-day  infusion  of  heparin  followed  by  oral  anticoagulant  therapy  for  an  indefinite  period  of  time.  Prophylactic  therapy  of  asymptomatic  patients  remains  controversial.Heparin  cofactor  II,  which  is  homologous  to  antithrombin,  inhibits  thrombin  in  the  presence  of  heparin  or  dermatan  sulfate  but  does  not  inhibit  other  coagulation  proteases.  The  concentration  of  heparin  cofactor  II  in  plasma  is  normal  (~1.2  μM)  in  patients  with  inherited  antithrombin  deficiency.  Several  patients  with  thrombosis  and  inherited  deficiency  of  heparin  cofactor  II  have  been  reported  (MIM  142360),  but  a  causal  relationship  between  these  phenomena  has  not  been  established.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.208
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181455807
ER  -