General Review of Hemostasis Fibrinolysis and Thrombosis

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General Review of Hemostasis Fibrinolysis and
Thrombosis

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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
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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

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Management of vWD

• Reassurance
• Cryoprecipitate
• DDAVP
• FVIII
• vWF product

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Extrinsic pathway
Prothrombin time adding tissue factor, Ca
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aPTT activated partial thromboplastin time
Partial thromboplastin
phospholipid, Ca, lacking tissue factor
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Hemostasis and Thrombosis 2005

• TFPI tissue factor pathway inhibitor

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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

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Thrombin can activate

• Fibrinogen
• FXI
• FV
• FVIII
• FXIII
• Protein C (after binding thrombomodulin)
• TAFI (thrombin-activatable fibrinolysis inhibitor)

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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

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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

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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)

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Superwarfarin

• Long-acting
• Need high dose vitamin K
• Potentially lethal

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Common Causes of Prolonged aPTT

• Clotting factor deficiencies other than FVII
• Lupus anticoagulant
• Inhibitors of clotting factors
• Elevated FDP
• Heparin, coumadin

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Interpretation of Mixed aPTT

• Definition of correctable
• mixed aPTT C lt 3-5
• Inhibitior with time-dependence after incubation

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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)

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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

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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

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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
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Blood 1999932153
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Causes of bleeding in APS

• Hypoprothrombinemia
• Severe thrombocytopenia
• Acquired platelet dysfunction
• Acquired inhibitor to specific coagulation
  factor, e.g. anti-FVIII

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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

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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

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FVIII activities in serial dilutions

• 110 3.5
• 140 7.6(1.9 x 4)
• 180 17.6(2.2 x 8)
• 1160 48 (3.0 x 16)

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Therapy

• No therapy for laboratory abnormality with
  clinical disorder
• Anticoagulation for recurrent thrombosis
• Low dose ASA and heparin for gt 3X pregnancy
  losses
• Steroid for refractory cases

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TTP

• Thrombotic Thrombocytopenic Purpura
• Mealloprotease (ADAMTS 13) ? ultralarge
  multimers of vWF ? platelet thrombi

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TTP

• Pentad
• thrombocytopenia
• microangiopathic hemolytic
• anemia
• fever
• renal failure
• fluctuating neurological symptoms
• Management
• Plasma exchange
• Immunomodulation

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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)

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Serpins

• Serine protease inhibitor
• Antithrombin
• PAI-1, PAI-2
• PCI
• Heparin cofactor II
• ?2-antiplasmin

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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

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Diagnosis of DVT/PE

• D-dimer
• Venogram less used
• Doppler, compression ultrasonography
• Spiral CT scan
• Radionucleotide lung scan
• MRI

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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?

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Management of Coumarin Overdose

• Risk of bleeding vs risk of thrombosis
• INR lt 6 lower dose
• INR 6-10 vit K 1-2 mg, PO or SQ
• INR gt 10 vit K 2-4 mg, PO or SQ
• Serious bleeding vit K 5-10 mg IV
• FFP
• PCC

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Fibrinolysis

• Lysine binding sites in tPA and PLG (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

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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

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