血專HmostThromb by yurtgc548

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									General Review of Hemostasis
Fibrinolysis and Thrombosis

          高志平

        台北榮總
        血液腫瘤科
Von Willebrand Disease
   vWF:
     enhance production of FVIII
      protect FVIII
     binding platelet (GPIb/IX)
      and collagen in
      subendothelium
   vWD
       FVIII: low, prolonged aPTT
       BT: prolonged
       RIPA, ristocetin cofactor
       Mild bleeding tendency
                                     Blood, Hadin et al, eds,   2003
Hematology, Hoffman et al,
eds,2005
Laboratory Assays for vWD
 Diagnosis
   vWF Ag
   vWF activity: ristocetin cofactor
   FVIII activity (moderate and severe vWD)
   BT (moderate and severe vWD)
   aPTT: too insensitive
   Molecular diagnosis: type II, exon 28
 Classification
   RIPA
   vWF multimers
Management of vWD

 Reassurance
 Cryoprecipitate
 DDAVP
 FVIII
 vWF   product
Extrinsic pathway
Prothrombin time: adding tissue factor, Ca++
aPTT: activated partial thromboplastin time               Partial
thromboplastin: phospholipid, Ca++, lacking tissue factor
                                        Hemostasis and
TFPI: tissue factor pathway inhibitor   Thrombosis 2005
Coagulation
   Tissue factor initiate blood coagulation
     TF express in adventitial cells, vascular smooth
      muscle cells, epidermal cells, neuroglia
     TF express in monocytes and endothelium after
      activation
   Amplification of the initial stimulus
     FVIIa activate FIX
     FIIa (thrombin) can activate XI, V, VIII
   Feedback inhibition of the procoagulant system
     TFPI: tissue factor pathway inhibitor
     AT, PC, PS, EPCR
Thrombin can activate

 Fibrinogen
 FXI
 FV
 FVIII
 FXIII
 Protein C (after binding thrombomodulin)
 TAFI (thrombin-activatable fibrinolysis
  inhibitor)
Factors synthesized in endothelial
cells
 vWF
 Thrombomodulin
 EPCR (endothelial protein C receptor)
 Protein S
 TFPI
 tPA
 PAI-1
 PGI2 (prostacyclin), NO (EDRF), CD39, ET-1
Common Causes of Prolonged PT

 Deficiencies of FVII, X, V, II, fibrinogen
 Elevated FDP
 Heparin of high conc.
 Coumadin
 Lupus anticoagulant occasionally
 Inhibitors of clotting factors
Vitamin K-dependent coagulation
factors and anticoagulants

 Factors II, VII, IX, X
 Protein C, S
 Protein Z (anti-Xa


 (Not   AT, Not TFPI, Not TAFI)
Hematology, Hoffman et al, eds,2005
Superwarfarin


 Long-acting
 Need high dose vitamin K
 Potentially lethal
Common Causes of Prolonged aPTT

 Clotting factor deficiencies other than FVII
 Lupus anticoagulant
 Inhibitors of clotting factors
 Elevated FDP
 Heparin, coumadin
Interpretation of Mixed aPTT
 Definition of “correctable”:
  mixed aPTT – C : < 3-5”
 Inhibitior with time-dependence after
  incubation
Mixinf aPTT
 P: 60.5   C: 28.5   Mixed: 31.0   (o hr)
 P: 64.5   C: 32.5   Mixed: 34.0   (2 hr)

 P: 60.5   C: 28.5   Mixed: 56.0   (o hr)
 P: 64.5   C: 32.5   Mixed: 60.0   (2 hr)

 P: 60.5   C: 28.5   Mixed: 31.0   (o hr)
 P: 64.5   C: 32.5   Mixed: 63.0   (2 hr)
FVIII inhibitor

 P: 60.5 C: 28.5 Mixed: 34.0          (o hr)
 P: 64.5   C: 32.5 Mixed: 60.0        (2 hr)
 PNT : negative
 FVIII inhibitor assay: 5 Bethesda unit
 FVIII    5%
 FIX      90 %
 FVII     110 %
Lupus anticoagulant

 P: 60.5 C: 28.5 Mixed: 54.0       (o hr)
 P: 64.5   C: 32.5 Mixed: 60.0     (2 hr)
 PNT : +
 FVIII inhibitor assay: negative
 FVIII    90 %
 FIX      90 %
 FVII     110 %
Antiphospholipid syndrome
 Anticardiolipin antibodies
 Lupus anticoagulant
     Antigen specificity: majority 2-GPI, prothrombin
     Protein cofactor
     Syphilis: not dependent on protein cofactor
   Mechanisms of thrombosis
       Disruption of annexin A5 shield
       Interference protein C pathway
       Injury to endothelium
       …………. ?
Blood 1999;93:2153
Blood 1999;93:2153
Hematology Hoffman
et al, eds, 2005
Causes of bleeding in APS

 Hypoprothrombinemia
 Severe thrombocytopenia
 Acquired platelet dysfunction
 Acquired inhibitor to specific
  coagulation factor, e.g. anti-FVIII
Lupus anticoagulant with low levels
of cogaulation factor activity
 P: 60.5 C: 28.5 Mixed: 56.0     (o hr)
 P: 64.5   C: 32.5 Mixed: 60.0   (2 hr)
 PNT: negative
 FVIII inhibitor : negative
 FVIII    10 %
 FIX      16 %
 FVII     50 %
Lupus anticoagulant with low level
of cogaulation factor activity
 P: 60.5 C: 28.5 Mixed: 56.0     (o hr)
 P: 64.5   C: 32.5 Mixed: 60.0   (2 hr)
 PNT: negative
 FVIII inhibitor : negative
 FVIII    4%
 FIX      60%
 FVII     80 %
         FVIII activities in serial dilutions
 1:10   3.5%
 1:40   7.6%(1.9% x 4)
 1:80  17.6%(2.2% x 8)
 1:160 48%% (3.0% x 16)
Therapy

 No therapy for laboratory abnormality
  with clinical disorder
 Anticoagulation for recurrent
  thrombosis
 Low dose ASA and heparin for > = 3X
  pregnancy losses
 Steroid for refractory cases
      Thrombosis
         and
Antithrombotic Therapy
Blood, Handin et al, eds, 2003
             TTP
   Thrombotic Thrombocytopenic
    Purpura

   Mealloprotease (ADAMTS 13)
     ultralarge multimers of vWF
     platelet thrombi
                          TTP
   Pentad:
      thrombocytopenia
      microangiopathic hemolytic
       anemia
      fever
      renal failure
      fluctuating neurological
       symptoms
   Management
      Plasma exchange
      Immunomodulation
NEJM 2002;347:596
Postgraduate Hematology 2005
Blood, Handin et al, eds, 2003
Serine protease

 Canonical   catalytic triad
   His 57, Asp 102, Ser 195 by chymotrypsin
   number
 FII,VII, IX, X, XI
  (NOT FV, FVIII, FXIII, fibrinogen, vWF)
 Protein C (NOT protein S, AT)
 Plaminogen, tPA (NOT PAI-I, TAFI)
Serpins

 Serine protease inhibitor
 Antithrombin
 PAI-1, PAI-2
 PCI
 Heparin cofactor II
 2-antiplasmin
FV Leiden and FV HongKong

 FV Leiden: Arg506Gln
  APC resistance:
  APC sensitivity ratio
 FV HongKong: Arg306Gla
  no increased risk of venous thrombosis
 FV Cambridge: Arg306Thr
Hemostasis and Thrombosis, 5th ed, 2006
Postgraduate Hematology 2005
 Diagnosis of DVT/PE

 D-dimer
 Venogram:  less used
 Doppler, compression ultrasonography
 Spiral CT scan
 Radionucleotide lung scan
 MRI
 Management of DVT

 Underlying etiologies (provoked or unprovoked)
 Screening for thrombophilia genetics
 Heparin/LMWH
 Coumadin
     Contraindication in pregnancy
     Delayed effect
     Variation in dosage
   Thrombolytic agents?
Hemostasis and Thrombosis, 5th ed, 2006
Postgraduate Hematology 2005
Hematology
Hoffman et al,
eds, 2005
Hematology Hoffman et al, eds, 2005
Postgraduate Hematology 2005
Management of Coumarin Overdose

 Risk of bleeding vs risk of thrombosis
 INR < 6                 lower dose
 INR 6-10                vit K 1-2 mg, PO or SQ
 INR > 10                vit K 2-4 mg, PO or SQ
 Serious bleeding        vit K 5-10 mg IV
                          FFP
                          PCC
 Williams Hematology 7th ed, 2006
Fibrinolysis

       binding sites in tPA and PLG
 Lysine
 (plasminogen)
   Cofactor activity of fibrin
 tPA vs uPA: need of fibrin
 uPAR
 Glu-PLG  Lys-PLG
 Antifibrinolytic agents: blocking LBS in PLG
 Antiplasmin synthesized in liver
Blood, Handin et al, eds, 2003
  TAFI

 Thrombin-activatable   fibrinolysis inhibitor
  Procarboxypeptidase B
 Removing the carboxy-terminal lysine
  residue of fibrin, which are the binding
  sites for PLG and tPA
 Reducing cofactor activity of fibrin in PLG
  activation
Blood, Handin et al, eds, 2003

								
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