RT Book, Section
A1 Kazazian, Haig H.
A1 Tuddenham, Edward G. D.
A1 Antonarakis, Stylianos E.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181455233
T1 Hemophilia A: Deficiency of Coagulation Factor VIII
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=1181455233
RD 2024/04/24
AB Hemophilia  A  (MIM  206700;  classic  hemophilia)  is  an  X-linked  bleeding  disorder  characterized  by  a  deficiency  in  the  activity  of  factor  VIII,  a  key  component  of  the  coagulation  cascade.  Approximately  1  in  5000  to  10,000  males  are  affected  in  all  populations.Affected  individuals  suffer  joint  and  muscle  hemorrhage,  easy  bruising,  and  prolonged  bleeding  from  wounds.  Because  platelet  function  is  not  affected,  blood  loss  from  minor  cuts  and  abrasions  is  not  excessive.  Of  hemophilia  A  patients,  50  to  60  percent  have  severe  hemophilia  with  factor  VIII  activity  <1  percent,  while  the  remainder  have  mild  to  moderate  disease  with  factor  VIII  levels  of  1  to  20  percent.  Nearly  all  patients  with  severe  disease  have  no  factor  VIII  protein  in  their  plasma  (cross-reacting  material  negative  or  [CRM−]),  but  a  small  proportion  of  these  patients  (about  5  percent)  have  inactive  factor  VIII  protein  circulating  in  their  plasma  (CRM+).Factor  VIII  functions  as  a  cofactor  in  the  activation  of  factor  X  to  factor  Xa  in  a  reaction  catalyzed  by  factor  IXa  on  a  phospholipid  surface.  Factor  VIII  is  activated  following  specific  proteolytic  cleavages  by  thrombin  and  factor  Xa,  which  results  in  an  effective  amplification  of  the  signal  through  this  step  of  the  cascade.  Factor  VIII  is  inactivated  by  limited  proteolysis  by  factor  Xa  or  by  activated  protein  C  (APC).Hemophilia  A  arises  from  a  variety  of  mutations  within  the  factor  VIII  gene,  which  is  located  near  the  telomere  of  the  long  arm  of  the  X  chromosome.  The  gene  comprises  26  exons  and  spans  186  kb.  The  cDNA  sequence  reveals  that  factor  VIII  is  synthesized  as  a  large  precursor  molecule  (2332  amino  acids).  The  amino  acid  sequence  of  the  protein  has  considerable  sequence  similarity  to  that  of  ceruloplasmin  and  coagulation  factor  V.Approximately  43  percent  of  patients  with  severe  disease  and  approximately  25  percent  of  all  patients  have  an  inversion  at  the  tip  of  the  X  chromosome  that  disrupts  the  factor  VIII  gene.  This  mutation  almost  always  has  its  origin  in  male  meiosis.  Of  the  remaining  75  percent  of  patients,  approximately  95  percent  have  one  of  a  large  variety  of  point  mutations.  Although  the  functional  consequences  of  some  of  the  400-odd  point  mutations  producing  the  disease  are  known  (for  example,  some  alter  a  thrombin  cleavage  site,  a  factor  IX  binding  site,  or  a  von  Willebrand  factor  binding  site),  the  structure-function  relationships  of  most  mutations  remain  unknown.Combined  deficiency  of  factors  V  and  VIII  is  an  uncommon  autosomal  recessive  disease  with  factor  levels  in  the  5  to  30  percent  range  and  symptoms  similar  to  mild  factor  VIII  deficiency.  Recently,  mutations  in  the  ERGIC-53  gene  were  shown  to  cause  this  combined  deficiency.  The  ERGIC-53  gene  encodes  a  protein  that  likely  transports  proteins  from  the  endoplasmic  reticulum  to  the  Golgi  compartment.  Deficiency  of  this  protein  in  combined  factor  V  and  factor  VIII  deficiency  suggests  that  it  may  act  uniquely  to  facilitate  the  intracellular  transport  and  secretion  of  these  two  coagulation  factors.Treatment  of  hemophilia  A  is  accomplished  by  infusions  of  factor  VIII,  usually  prepared  by  recombinant  DNA  technology,  or  sometimes  prepared  as  concentrates  from  human  plasma.  The  in  ...