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Lecture 4, fall 2014 pdf

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Download Lecture 4, fall 2014 pdf


  • Lecture  4   Disorders  of  Primary  Hemostasis:   Quan7ta7ve  Platelet  Disorders   1  
  • Disorders  of  Primary  Hemostasis   •  Abnormali7es  that  result  in  bleeding  due  to  defects  in  forma7on  of  the  primary   hemosta7c  (platelet)  plug   •  Defect  in  the  ability  of  platelets  to  adhere  to  the  vascular  endothelium   –  Platelet  aggrega7on  is  normal     •  Defects  in  primary  hemostasis  are  classified  as     –  Qualita7ve  defects     –  Quan7ta7ve  defects   •  Present  as   –  Acquired  defects   •  Bleeding  episodes  usually  do  NOT  present  un7l  adulthood   –  Congenital  defects   •  Bleeding  episodes  present  during  early  childhood     •  Purpura—refers  to  petechiae  and  ecchymoses   •  Easy  bruisability—too  many  petechiae  and  ecchymoses—less  than  “usual”  trauma   •  Excess  bleeding—Involves  both  platelets  and  coagula7on  abnormali7es   2
  • Clinical  Manifesta7ons   •  Petechiae   –  Small  red  to  purple  spots  in  the  skin,  [3  mm]   –  Caused  by  blood  escaping  through  the   endothelium  and  into  intact  subcutaneous  7ssue —come  from  vessels  larger  than  a  capillaries   –  Red  to  purple  ini7ally  à  turn  yellowish  green  as   they  heal   –  Found  in  defects  involving    blood  vessels,  platelet,   and  coagula7on  proteins   •  Hematoma   –  Blood  leaks  from  a  vessel  and  collects  in  the  intact   skin   –  Blue  or  purple  and  slightly  raised   –  Can  occur  in  organs  and  7ssues   –  May  be  in  the  form  of  a  clot     3
  • Quan7ta7ve  Platelet  Disorders   •  Thrombocytopenia   –  Clinical  symptoms  typically  not  seen  un7l  
  • Mechanisms  of  Thrombocytopenia   1.  Decreased  Produc7on     A.  Megakaryocy7c  hypoplasia     B.  Replacement  of  normal   marrow   Ø  Tumor  cells   (Myelophthisic  picture)   Ø  Fibrosis     C.  Ineffec7ve  thrombopoiesis   2.  Abnormal  Platelet  Distribu7on     A. Dilu7onal  thrombo-­‐ cytopenia   B.  Increased  splenic   sequestra7on   3.  Increased  Destruc7on   A.  Immune   B.  Nonimmune   5  
  • Mechanism  of  Destruc7on   •  Immunologic  causes   –  Alloan7bodies   –  Autoan7bodies   –  Drug-­‐induced  an7bodies   –  Isoan7bodies   •  Non-­‐immunologic  causes   –  DIC   –  TTP   –  HUS   –  Microangiopathy   –  Vasculi7s   6   1.  Result  in  hemorrhagic  diathesis   2.  Presence  of  schistocytes   Immune-­‐mediated  causes  occur  more  frequently  
  • Immune-­‐Mediated  Destruc7on   •  Group  of  thrombocytopenias  in  which  an  immune-­‐mediated  mechanism  causes  increased  destruc7on  of   platelets   •  Two  types  immune-­‐mediated  destrucCon   1.  Primary  (Idiopathic)     –  Defects  that  are  intrinsic  to  the  platelet       2.  Secondary   –  Defect  that  is  extrinsic  to  the  platelet   Ø  Due  to  an  underlying  disease     7
  • Immune  Mediated  Destruc7on   •  Caused  by  anCbodies  –  analogous  to  immune-­‐ mediated  destruc7on  of  RBC’s   •  Platelets  become  sensi7zed  with  an7body   •  Mononuclear  phagocytes  destroy  these  an7body-­‐ coated  platelets  in  the  spleen     •  Monocytes  (macrophages)  have  Fc    receptors  that  they   use  to  recognize  à  platelets  that  are  coated  with   an7body     –  Leads  to  decreased  survival  7me  in  circula7on  (2-­‐3   days)   •  An7bodies  abach  to  platelets  by  their  Fab  regions  to   either   1.  GPIIb/IIIa   2.  GPIb/IX   3.  Nonspecifically  to  immune  complexes  via  FcγRIIA     •  Monocytes  recognize  platelets  coated  with  IgG,  IgM,   IgA,  and  complement   8  
  • Immune  Thrombocytopenia   Immune  Thrombocytopenic  Purpura—ITP   •  ITP  (autoimmune  thrombocytopenia)  –  autoimmune  disorder    characterized  by   •  (1)  Immune-­‐mediated  destrucCon  of  platelets   •  (2)  impaired  platelet  producCon   •  Autoan7bodies  –  mostly  IgG  –  directed  against  GPIIb/IIIa,  GPIb/IX,  GPV   •  One  of  the  most  common  disorders  causing  severe  isolated  thrombocytopenia   –  Most  cases  à  asymptoma7c   –  Low  platelet  counts  can  lead  to  a  bleeding  diathesis  and  purpura   –  There  is  no  specific  test  that  readily  confirms  the  diagnosis  of  ITP  à  therefore  it  is  a  diagnosis   of  exclusion     –  An7platelet  an7bodies  +  BM  examina7on  +  Clinical  presenta7on   •  Two  types  ITP   1.  Acute  ITP   2.  Chronic  ITP   •  50-­‐100  new  cases  per  million  per  year,  with  children  accoun7ng  for  half  of  that  amount   •  Clinical  features   Ø  Bruising,  Petechiae,  Epistaxis,  Gingival  bleeding     Ø  Thrombocytopenia  (platelet  count  is  below  30,000)   Ø  hbp://   9
  • Pathology  of  ITP   1.  A  trigger  for  platelet  destruc7on  is   the  produc7on  of  ITP   autoanCbodies   2.  An7bodies  to  the  platelet   glycoprotein  IIb/IIIa  complex  bind   to  platelets  and  leading  to   phagocytosis  by  re7culo-­‐ endothelial  macrophages  via  Fc   receptors   3.  The  platelet  proteins  are  degraded   and  displayed  on  the  macrophage   cell  surface  in  a  complex  with   CD154   •  CD154  =  CD40  LIGAND  à  it   binds  to  CD40  on  APCs   4.   Macrophages    à  s7mulate  T-­‐cell– mediated  an7body  produc7on  by   B  cells   5.  The  resul7ng  autoanCbodies   perpetuate  platelet  destrucCon    
  • Acute  ITP   •  E7ology   –  Post-­‐viral  infec7on  in  children  1-­‐7  years  of  age   –  Generally  lasts  
  • Chronic  ITP   •  E7ology   –  Unknown;  adults  20  -­‐  50  years  of  age   –  Insidious  onset  with  lack  of  a  previous  vial  infec7on   –  Female-­‐to-­‐male  ra7o  =  1.7:1   –  Median  age  38-­‐49   –  Spontaneous  remission  is  uncommon   –  Persistent  thrombocytopenia  las7ng  more  than  6-­‐12  months  to  years   –  An7platelet  an7bodies  found  in  58-­‐80%  of  pa7ents   •  Signs  and  Symptoms   –  Petechiae,  ecchymoses,  epistaxis,  menorrhagia,  gingival  bleeding,  hematuria,  absence  of   splenomegaly   –  Treat  if  platelet  count  drops  
  • Comparison  of  Acute  versus  Chronic  ITP   Feature   Acute  ITP   Chronic  ITP   Peak  age   Children  –  2-­‐4  years     Adults  –  20-­‐40  years   Platelet  count  (ini7al)  
  • Laboratory  Findings  in  ITP   Peripheral  blood   1.  Decreased  platelet  count  on  peripheral  blood  smear   2.  Megathrombocytes  (large  platelets)  on  peripheral  blood  smear     3.  Other  CBC  parameters  within  reference  range   Bone  marrow   1.  Megakaryocytes  are  normal  to  increased  in  the  bone  marrow   –  Autoan7bodies  may  interfere  with  platelet  produc7on  or  platelet  release   from  the  bone  marrow   –  Suppression  of  megakaryocyte  produc7on  by  autoan7bodies  may  be   associated  with  increased  apoptosis  in  adult  ITP  (ineffec7ve  thrombopoiesis)   2.  Thrombopoie7n  levels  are  normal  or  slightly  increased  in  some  ITP  pa7ents   resul7ng  in  normal  to  increased  megakaryocytes   14  
  • Lab  Findings  in  ITP   15   Normal  PB   ITP  PB  Bone  Marrow   Petechiae   Purpura  
  • Treatment  of  ITP   •  Treatment   –  When  PLTs  
  • Regula7on  of  Platelet  Produc7on   •  TPO  is  produced  in  the  liver   •  Inflamma7on  and  thrombocytopenia   enhance  TPO  produc7on   •  Platelets  have  high  affinity  TPO   receptors  and  remove  TPO  from  the   circula7on     •  Free  plasma  thrombopoie7n  binds  to   megakaryocytes  à  s.mula.on  of   megakaryocytopoiesis     The molecular mechansims that control hematopoesis. JCI. 2005.
  • Thrombopoie7n-­‐Receptor  Agonists  for  Primary  Immune  Thrombocytopenia   NEJM.  2011   •  Eltrombopag   –  Oral  thrombopoie7n  (TPO)   receptor  agonist   –  Interacts  with  transmembrane   domain  of  human  TPO  receptor   –  Induces  megakaryocyte   prolifera7on  and  differen7a7on   from  bone  marrow  progenitor   cells   •  Romiplos7m   –  An  Fc-­‐pep7de  fusion  protein   (pep7body)   –  Increases  platelet  produc7on   through  binding  and  ac7va7on  of   the  thrombopoie7n  (TPO)   receptor  –  similar  mechanism  to   endogenous  TPO   18  
  • Other  Causes  of  Thrombocytopenia   •  ITP  in  Pregnancy   –  Gesta7onal  thrombocytopenia   –  Benign  condi7on   •  Platelet  count  returns  to  normal  within  12  weeks  post-­‐delivery   •  If  the  diagnosis  is  made  during  pregnancy  à  IVIG  and  steroid  therapy  may  be  used   •  An7body-­‐related  platelet  destruc7on  occurs  in  females  previously  immunized  –most   pa7ents  are  mul7parous   •  An7bodies  are  directed  against  platelet  an7gen  PLA-­‐1A  (HPA-­‐1a)   •  Post-­‐Transfusion  Purpura   –  Rare  form  of  alloimmune  thrombocytopenia  characterized  by  severe  thrombocytopenia  and   bleeding      à  following  TRANSFUSION  of  blood  or  blood  products   –  Caused  by  anCbody-­‐related  platelet  destrucCon  in  previously-­‐immunized  pa7ents   –  An7bodies  are  directed  against  platelet  an7gen  PLA-­‐1a  (HPA-­‐1a)  in  most  cases   –  Severe  thrombocytopenia  occurs  ~3-­‐12  days  following  transfusion   –  Diagnosis  of  PTP  made  by  detec;ng  an;bodies  against  platelet-­‐specific  an;gens  in  the   pa;ent’s  serum   19
  • Other  Causes  of  Thrombocytopenia   •  Neonatal  Alloimmune  Thrombocytopenia  (NAITP)   –  Caused  by  fetal-­‐maternal  incompa7bility  of  platelet  an7gens   –  Maternal  an7bodies  cross  the  placenta  causing  destruc7on  of  the  fetal   platelets   –  First  pregnancy  affects  50%  of  cases   –  Offending  an7body  is  an7-­‐HPA-­‐1a  and  is  an  IgG  alloan7body  (75%  of  cases)   •  These  are  also  directed  against  gpIIb/IIIa,  Ib/IX,  Ia/IIa,  and  CD109   •  In  whites  97.5%  of  the  an7bodies  are  against  gpIIb/IIIa   –  Affected  neonate  is  treated  by  transfusion  of  an7gen-­‐compa7ble  platelets  or   washed  maternal  platelets     •  Congenital  MegakaryocyCc  Hypoplasia   –  Decrease  in  bone  marrow  megakaryocytes   1.  Thrombocytopenia  with  Absent  Radii  (TAR)   2.  Wiskob-­‐Aldrich  Syndrome  (WAS)   3.  May-­‐Hegglin  Anomaly  (MHA)   20
  • Thrombocytopenia  Due  to  Impaired  Platelet  Produc7on   •  Thrombocytopenia  with  absent  radii   (TAR)   –  Characterized  by   A.  Neonatal  thrombocytopenia  and     B.  Hypoplasia  of  the  radial  bones  of   the  forearms  with  absent,  short,   or  malformed  ulnae   1.  Impaired  DNA  repair  that  results   from  a  fetal  injury  about  8  weeks   gesta7on   2.  Pa7ents  have  90%  incidence  of   leukemoid  reac7ons  with  WBC   counts  exceeding  100,000/  μL   3.  Platelet  counts  range  from   10,000-­‐30,000/μL     4.  A  failure  in  produc7on  of  humoral   or  cellular  s7mulators  of  mega-­‐ karyocytopoiesis   21
  • May-­‐Hegglin  Anomaly   •  Characterized  by  various  degrees  of  thrombocytopenia   •  May  be  associated  with   1.  Purpura  and  bleeding   2.  Giant  platelets  (20  μm  in  diameter)  containing  few  granules     3.  Large  (2-­‐5  µm  basophilic  cytoplasmic  inclusion  bodies  in  granulocytes  that  resemble   Döhle  bodies   •  Otherwise  normal  platelet  morphology  and  func7on   •  Muta7on  in  the  MYH9  gene  present  in  chromosomal  22   –  A  cytoskeletal  protein  in  platelets  that  may  be  responsible  for  the  abnormal  platelet   diameter   •  Most  pa7ents  have  no  bleeding  episodes  unless  thrombocytopenia  is  severe   22
  • Wiskob-­‐Aldrich  Syndrome   •  Wiskob-­‐Aldrich  syndrome  is  an  immune  deficiency  disorder  in  which  there  is  a   decreased  produc7on  of  IgM   •   WAS  is  characterized  by   1.  Thrombocytopenia  with  small  platelets  (microthrombocytes)   2.  Eczema   3.  Increased  risk  of  developing  an  autoimmune  disorder  or  cancer   4.  Associated  with  a  defec7ve  gene  on  the  X  chromosome   •  Females  tend  to  be  carriers  of  the  syndrome   •  Males  have  the  defec7ve  gene  and  develop  symptoms   •  X-­‐linked  mode  of  transmission   –  DefecCve  protein  called  WASp  (Wiskod-­‐Aldrich  syndrome  protein)  whose   expression  is  limited  to  cells  of  hematopoie7c  lineage   23
  • Thrombocytopenia  due  to  Ineffec7ve  Thrombopoiesis   •  Associated  with  normal  to  increased  marrow  cellularity  but  peripheral   blood  cytopenias   1.  Megaloblas7c  anemia  à  associated  with   a.  Vitamin  B12  or  folate  deficiency   b.  Thrombocytopenia  results  from  impaired  DNA  synthesis   c.  Lactate  dehydrogenase  (LD)  levels  are  elevated  due  to  intra-­‐ medullary  death  of  hematopoie7c  progenitors   2.  Myelodysplas7c  syndromes  may  simulate  vitamin  deficiency  and  do   not  respond  to  vitamin  replacement  therapy   3.  Alcohol  has  direct  toxic  effect  on  the  marrow  à  induces  folic  acid   and/or  vitamin  B12  deficiency     •  Thrombocytopenia  is  mild  with  normal  platelet  life  span     24
  • Drug-­‐Induced  Thrombocytopenia   •  Rela7vely  common—more  than  200  drugs  have  been  reported     •  hbp://   •  Symptoms  6-­‐7  days  azer  administra7on     •  Platelet  count  is  extremely  low  (
  • Hapten  Theory   •  Small  molecule  that  can   elicit  an  immune  response   ONLY  when  abached  to  a   large  carrier  protein   •  The  drug  (carrier  protein)   binds  covalently  to  platelets   à  [drug-­‐platelet  anCgenic   complex]    -­‐-­‐  the  drug  acts   as  a  hapten   hbp:// chap19/19-­‐05_Thrombocyto_1.jpg26  
  • Varia7ons  in  An7body  Binding  to  Platelets   •  A—Platelet  autoan7bodies  or  allo-­‐ an7bodies   –  Bind  to  epitopes  of  GPIIb/IIIa,  GPIb/ IX   •  B—Quinine/Quinidine-­‐dependent   an7bodies     –  Bind  to  a  complex  of  drug  and   glycoprotein   –  GPIIb/IIIa  or  GPIb/IX   •  C—Heparin-­‐dependent  an7bodies   –  Heparin  binds  to  PF4  and  the   heparin:PF4  complex  binds  to  IgG   an7heparin  an7bodies  via  the  Fab  of   the  an7body   –  The  Fc  por7on  of  the  an7body  binds   to  platelet  IgG  FCγIIa  receptors     27  
  • Condi7ons  with  Mul7ple  Mechanism  of  Thrombocytopenia   28   Alcoholism   1.  In  alcoholic  pa7ents  without  cirrhosis  the   major  effect  is  ethanol.       a.   Ethanol  directly  suppresses  MGK   producCon.   b.   Causes  folate  deficiency.   2.  In  pa7ents  with  cirrhosis  the  major  effect  is   due  to  under  produc7on  of  coagula7on  factors   by  the  liver.   1.  Suppress  platelet  produc7on   2.  Ineffec7ve  platelet  produc7on   3.  Increased  destruc7on   4.  Splenomegaly   Lymphoprolifera7ve  Disease   1.  Impaired  produc7on   2.  Immune  destruc7on   3.  Splenomegaly   Cardiopulmonary  Bypass  Surgery     1.  Mechanical  destruc7on   2.  Increased  u7liza7on   3.  Dilu7onal  thrombocytopenia   •  10  or  more  units  of  blood   4.  Inadequate  neutraliza7on  of  heparin  
  • Thrombo7c  Microangiopathies  (TMA)   •  Group  of  disorders  characterized  by     –  Microangiopathic  hemoly7c  anemia     –  Thrombocytopenia   –  Microvascular  thrombosis   •  Subtypes  TMA   –  Thrombo7c  thrombocytopenic  purpura  (TTP)   –  Hemoly7c  uremic  syndrome  (HUS)   29   End  organ   damage  
  • Thrombo7c  Thrombocytopenic  Purpura     •  Congenital  –  Upshaw-­‐Shulman  syndrome     –  Characterized  by  repeated  episodes  of  thrombocytopenia  and  microangiopathic   hemoly7c  anemia  during  early  childhood   –  Moake  (1982)  described  unusually  large  vWF  mul7mers  in  the  plasma  of  pa7ents  with   TTP   •  Proposed  that  a  lack  of  a  “cleaving  protease”  was  responsible   •  Congenital  deficiency  of  ADAMTS-­‐13  –  disintegrin-­‐like  and  metalloprotease    with   thrombospondin  type  1  mo.f     30   Brass, L, 2001, Nature Med 7:1177-1178.
  • Thrombo7c  Thrombocytopenic  Purpura     •  Acquired    –  Idiopathic  TTP   –  Involves  an  autoimmune  mechanism  à  acquired  absence  of  ADAMTS13   ac7vity   –  Usually  associated  with  autoan7body  –  IgG  inhibitor  of  the  protease   –  Extremely  rare  in  pa7ents  without  a  thrombo7c  microangiopathy   •  With  the  possible  excep.on  of  sepsis   •  Secondary  TTP   –  Mechanisms  poorly  understood  –>  levels  of  ADAMTS13  ac7vity  generally  not   as  depressed  as  in  idiopathic   –  Comprises  ~40%  of  cases  of  TTP   –  Predisposing  factors     •  Cancer   •  BMT   •  Pregnancy   •  Medica7ons   •  HIV  infec7on   31  
  • vWF   •  Large  mul7meric  protein  –  ranges  from  600  kD  to  >  20  million  kD   –  Synthesized  by  endothelial  cells  and  megakaryocytes   •  Endothelial  cells  source  of  plasma  vWF   –  Released  from  the  endothelial  cells  as  mature  vWF  azer  cleavage  of  a  propep7de   –  vWF-­‐cleaving  protease  cleaves  the  ULvWF  into  inac7ve  monomers  to  prevent  interac7on  with   platelets   •  Func7on  of  vWF     1.  Supports  platelet  adhesion  and  ac7va7on  at  sites  of  vascular  injury:   a.  vWF  binds  extravascular  collagen   b.  Platelets  adhere  to  bound  vWF   2.  Supports  coagula7on  mechanism:   a.  vWF  protects  FVIII  in  circula7on   b.  vWF  co-­‐localizes  FVIII  at  sites  of  vascular  injury     32   Platelets   Coagula7on   Proteins   Endothelium   vWF  
  • Synthesis  of  vWF   •  Steps  in  synthesis  of  vWF     1.  First  synthesized  as  a  pro-­‐vWF  monomer   2. Dimeriza.on  occurs  in  ER   3.  Pro-­‐vWF  monomers  linked  together  at  the  carboxyl  terminal  end     4.  Dimeric  molecules  pass  to  the  Golgi  apparatus   5.  Dimers  mul.merize   6.  Propep7de  is  cleaved  off  à  mature  subunit   33   Blood  79:2507   Prog  Heamtol  9:233  
  • Func7on  of  ADAMTS  13   •  ADAMTS-­‐13  abaches  to  binding  sites  on   the  endothelial  cell  surfaces   –  ADAMTS-­‐13  abaches  to  endothelial   surface  via  à  a  thrombospondin-­‐1-­‐ like  domain  –  RGD  (arginine/glycine/aspartate)       •  Cleaves  ULvWF  as  they  are  secreted  by   the  s7mulated  endothelial  cells   •  Smaller  vWF  forms  that  circulate  azer   cleavage  do  not  induce  the  adhesion  and   aggrega7on  of  platelets  during  normal   blood  flow    
  • Func7on  of  ADAMTS  13   35   •  Absent  or  severely  reduced  ac7vity  of   ADAMTS-­‐13  prevents  cleavage  of  ULvWF     as  they  are  secreted  by  endothelial  cells     •  The  uncleaved  mul.mers  induce  adhesion   and  aggrega7on  of  platelets  in  flowing   blood   •  Due  to:   –  Congenital  or  acquired  deficiency  of   ADAMTS-­‐13     •  Note:   –  Interference  with  the  aWachment  of   ADAMTS-­‐13  to  endothelial  cells  in   vivo  à  may  also  cause  TTP  in   pa.ents  with  normal  ADAMTS-­‐13   ac.vity  in  plasma  
  • Pathology  of  TTP   •  Classic  pentad  of  features   1.  Microangiopathic  hemoly7c   anemia     2.  Thrombocytopenia   3.  Neurologic  symptoms   4.  Kidney  failure   5.  Fever   •  Affects  kidneys,  heart,  and  brain  with   small  arteriolar  thrombi   •  TTP  overlaps  with  hemoly7c  uremic   syndrome  (HUS)  that  may  be   precipitated  by  verotoxins  from  such   organisms  as  E.  coli  (type  O157:H7)   à  endothelial  injury     hbp://   Glomerulus   BV  with  onion-­‐skinning   (thromboCc  microangiopathy)  Curr  Opin  Nephrol  Hypertens  19  (3):  242-­‐7  
  • Hemoly7c  Uremic  Syndrome—HUS     •  Thrombo7c  microangiopathy  that  mainly  affects  children   •  Characterized  by  a  Tetrad  of  clinical  findings   1.  Hemoly.c  anemia  with  RBC  fragmenta.on   2.  Acute  renal  failure   3.  Thrombocytopenia   4.  Variable  CNS  involvement   •  Associated  with   a.  Upper  respiratory  infec.on   b.  Urinary  tract  infec.on   c.  Viral  disease  such  as  varicella  or  measles     •  Generally  encompasses  several  diverse  disorders   –  Typical  form   1.  Associated  with  diarrhea  caused  by  verotoxin-­‐producing  E.  coli   –  ~95%  of  all  cases  in  children   2.  Most  none-­‐sporadic  cases  in  adults     –  Atypical  form   •  Exhibit  autosomal  dominant  or  recessive  inheritance   •  Associated  with  deficiencies  in  proteins  that  regulate  the  alterna7ve  pathway  of  complement  ac7va7on       •  Adult-­‐onset  HUS   –  Primary—no  iden7fiable  cause   –  Secondary—associated  with   •  Bacterial  infec7ons—classic  HUS   •  ConnecCve  Cssue  diseases—SLE,  Marfan  syndrome,  Ehlers-­‐Danlos  syndrome     •  Cancer  à  stomach,  colon,  breast     37
  • Diagnosis   •     Diarrhea  (ozen  bloody)   •       Hematological   •  Microangiopathic  haemoly7c  anemia     •  Thrombocytopenia           Fragmented  red  cells   Absence  of  platelets   ACUTE  KIDNEY  INJURY  
  • Mechanism  of  Ac7on  in  Typical  HUS   •  Subdivided  into  2  groups   1.  Bloody  diarrheal  prodrome  (+)   2.  Bloody  diarrheal  prodrome  (-­‐)   Ø  Diarrhea-­‐related  (classic)—(D+)HUS   1.  E.  coli  O157:H7   •  Found  in  GI  tract  of  cable   •  Majority  of  human  infec7ons  traced  to  inges7on  of  incompletely   cooked  beef  contaminated  with  the  organism   •  Associated  with  verocytotoxin  (shiga-­‐like  toxin  I  and  II)  produced   during  E.  coli  infec7on   2.  S.  dysenteriae  serotype  I   •  Produces  Shiga  toxin     Ø  Non-­‐diarrhea-­‐associated—(D—)-­‐HUS   –  Reported  in  both  children  and  adults   –  Sporadic  disease  NOT  preceded  by  diarrhea   –  Endemic  HUS   39 80 -­‐9 0%  ca se s   10%  cases  
  • Proposed  Mechanism  Platelet-­‐Fibrin  Forma7on  in  “Classic”  HUS   1.  Shiga  toxin  binds  to  Gb3  receptor  on  EC’s   –  Local  damage  to  colon  mucosa   2.  Shiga  toxin  enters  circula.on   –  Damages  EC’s  of  capillaries  in   glomeruli  –  may  impair  ADAMTS13  on   these  EC’s)   3.  Causes  release  of  ULvWF  à  platelet   ac7va7on  à  microthrombi  forma7on  à   renal  failure     4.  TF  released  à  ac7va7on  of  coagula7on   cascade  à  fibrin  forma7on   5.  Erythrocytes  damaged  as  trapped  in   thrombi  à  Schistocytes  +  intravascular   hemolysis  à  splenic  sequestra.on     6.  Shiga  toxin  damages  the  endothelial  cell   causing  the  release  of  ULvWF       40
  • UPSHAW-­‐SHULMAN  SYNDROME   •  Congenital  deficiency  of  ADAMTS-­‐13   1.  Protease  cleaves  vWF  mul7mers   2.  Presents  at  birth  with  hemoly7c  anemia  and  thrombocytopenia   3.   Renal  involvement  develops  later  in  life   •   Inhibitor  auto-­‐an7bodies  to  ADAMTS-­‐13  can  also  cause  similar  syndrome   Brass, L, 2001, Nature Med 7:1177-1178.
  • TTP  versus  HUS   TTP   HUS   •  Adults—20-­‐50   •  Children  
  • Disorders  of  the  Vascular  System   •  Structural  abnormality  or  damage  either  to  the  endothelial  lining  or  the   subendothelial  structures  à  variety  of  clinical  manifesta7ons   •  Disorders  classified   –  Inherited  disorders  caused  by   •  Abnormal  synthesis  of  subendothelial  connec7ve  7ssue  components   –  Acquired  disorders  caused  by  an  underlying  disease  of  condi7on   •  Decreases  the  suppor7ve  connec7ve  7ssue    in  the  blood  vessel  wall   •  Abnormal  proteins  in  the  vascular  7ssue   •  Infec7ons  or  allergic  condi7ons   •  Mechanical  stress     43  
  • Hereditary  Vascular  Disorders   •  Hereditary  Hemorrhagic  Telangiectasia  (HTT)   –  Gene7c  disorder  that  causes  abnormali7es  of  blood  vessels   –  Blood  vessels  that  lack  capillaries  between  an  artery  and  vein   –  Under  high  pressure  blood  flows  through  arteriovenous  malforma7ons     –  These  are  fragile  sites  that  are  easily  ruptured  and  result  in  bleeding   –  Can  occur  in  the  skin  or  any  organ       •  Ehlers-­‐Danlos  Syndromes  (Oslo-­‐Weber-­‐Rendu  Syndrome)   –  Heterogeneous  group  of  inherited  connecCve-­‐Cssue  disorders  characterized   1.  Joint  hypermobility   2.  Cutaneous  fragility   3.  Hyperextensibility   –  Associated  with  arterial  rupture  and  visceral  perforaCon,  with  possible  life-­‐threatening   consequences   44  
  • Marfan  Syndrome   •  Marfan  syndrome  is  an  autosomal  dominant   gene7c  disorder  of  the  connecCve  Cssue       •  1  in  5,000  people  in  the  United  States  have   the  disorder   •  Unusually  long  limbs,  great  stature,  or  long   toes  (or  fingers)  in  propor7on  to  the  person's   height     •  PredisposiCon  to  cardiovascular  disease   •  Muta7on  in  the  fibrillin-­‐1  gene  (FBN1)— chromosome  15   •  Fibrillin—major    building  block  of  microfibrils     –  Serves  as  substrate  for  elas7n  in  the   aorta  and  other  connecCve  Cssues   45
  • Acquired  Disorders  of  the  Vascular  System   •  Acquired  disorders  caused  by  an  underlying  disease  of  condi7on   –  Decreases  the  supporCve  connecCve  Cssue    in  the  blood  vessel  wall   •  Senile  purpura   –  Ecchymoses  that  appear  with  unrecognized  or  minor  trauma  in  elderly  individuals   –  Extracellular  matrix  components  of  the  skin  degenerate  à  loss  of  suppor7ve  collagen   fibrils  à  capillaries  burst  with  minor  pressure   •  Cushing  syndrome  and  corCcosteroid  therapy   –  Excess  endogenous  glucocorCcosteroids  (Cushing  syndrome)  à  breakdown  in  collagen     –  Exogenous  (therapeu7c)  glucocorCcosteroids    à  breakdown  in  collagen   •  Scurvy   –  Deficiency  of  vitamin  C  which  is  needed  for  collagen  synthesis  à  abnormal  collagen   producd7on  à  vascular  fragility  and  bleeding   46  
  • Acquired  Disorders  of  the  Vascular  System   •  Abnormal  proteins  in  the  vascular  Cssue   –  Paraproteins   •  Monoclonal  immunoglobulins  produced  by  monoclonal  neoplas7c  plasma   cells   •  Paraproteins  bind  to  calcium  à  interference  with  coagula7on  and   deposi7on  of  light  chain  proteins  in  the  vascular  wall   –  Amyloidoisis   •  Deposits  of  amyloid  (misfolded  or  modified  protein)  form  in  the  skin,   perivascular  7ssue,  and  vessel  walls  à  leads  to  fragility  of  the  vessels  and   bruising   47  
  • Acquired  Disorders  of  the  Vascular  System   •  Henoch-­‐Schönlein  purpura   •  Small-­‐vessel  vasculiCs  characterized  by  IgA,  C3,  and  immune  complex  deposi7on  in   arterioles,  capillaries,  and  venules     •  HSP  affects  mostly  children  and  involves  the  skin  and  connec7ve  7ssues,  gastrointes7nal   tract,  joints,  and  scrotum  as  well  as  the  kidneys   •  Drugs   –  Drugs  from  almost  every  pharmacologic  class  have  been  implicated  in  causing  vasculi7s  in   sporadic  cases   48  
  • Acquired  Disorders  of  the  Vascular  System   •  Miscellaneous  causes   –  Mechanical  purpura   •  Increased  pressure  within  the  lumen  of  the  capillaries  azer  intense  exercise,  coughing   spasms   –  Purpura  fulminans     •  Associated  with  abnormali7es  of  certain  clong  factors  or  their  inhibitors   •  Thrombi    form  in  small  vessels  supplying  the  skin  and  subcutaneous  7ssue  à  necrosis     49  
  • Lab  Tests  in  Disorders  of  Primary  Hemostasis       Platelet   count   PT   APTT   Bleeding   Cme   Vascular  disorder   Normal   Normal   Normal   Normal  or   abnormal   Thrombocytopenia   Decreased   Normal   Normal   Abnormal   Platelet  Dysfunc7on   Usually   Normal   Normal   Normal   Normal  or   Abnormal   Most  vascular  diseases     1.  Are  not  associated  with  platelet  or  plasma  defects   2.  Most  common  symptom     •  Abnormal  bleeding  into  or  under  the  skin  due  to  increased  permeability  to   blood   3.  Laboratory  tests  are  used  to  exclude     •  Coagula7on  or  platelet  disorders   4.  Majority  of  pa7ents   •  Hemosta7c  tes7ng  is  en7rely  normal,  despite  a  history  or  physical   examina7on  that  suggests  substan7al  bleeding   50  
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