Blood Clotting Cascade

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Blood Clotting Cascade
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Intrinsic (Kininogen Kallikrein) Extrinsic
XII XIIa
Trauma XI XIa
IX IXa VIIa VII
VIIIat TF Ca
X
Xa X
Vat (Vit. K) Prothrombin
Thrombin
Fibrinogen Fibrin

XIIIat

Clot
Blood Clotting Cascade
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Fibrinogen Soluble monomer unit
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Fibrinogen
Fibrin II
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46 nm
23 nm
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GLN
LYS
Factor XIII Transglutaminase
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Fibrin Stabilizing Factor (XIII) is a
transglutaminase - forms GLN-LYS, covalent
cross-links.
HARD CLOT
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Prothrombin Sequence
Binds membrane
His Asp Ser
Disulfide bond 336-482
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N
Activation Peptide 1 44-198
Activation Peptide 2 199-327
C
Prothrombin
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Modified Glu residues anchor Prothrombin to
platelets (Ca2) While Kringle domains bind
damaged tissue
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Control of Clotting
Antithrombin III (inhibits soluble thrombin,
XII, XI, IX, X)
Heparin - released by damaged mast cells
(enhances Antithrombin III)
Protein C - activated by thrombin
(destroys factor VIII V)
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Heparin sulfated polysaccharide
binds to AntiThrombin III and helps it bind
thrombin
etc.
OSO3-
hyaluronic acid
OH
OH
NH
COO-
O
SO3-
OSO3-
etc.
glucosamine
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Heparin
a natural polysaccharide released by mast cells
an anticoagulent in human blood
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Blood Clot
time after trauma
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Reversal of Clotting
TPA (72K)
Plasminogen (bound) ? Plasmin
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Plasmin
TPA
Fibrin binding Growth Factor Domain
Thrombin
Kringle binds tissue
Serine Protease
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Medical Reasons to prevent Clotting (heparin)
Angioplasty (restenosis rethrombosis 6-8)
Deep-Vein Thrombosis
Unstable Angina
Medical Reasons to dissolve Clots (cloned TPA)
Myocardial infarction (MI) or stroke
Hemophilia Factor VIII
1. X linked - 1 in 10,000 males 2. 50 severe lt
1 F8 activity 3. 10 moderate 2-5 F8 4. 40
mild 5-30 F8
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NSAIDs
Membrane Lipids arachadonic acid prostaglandi
ns (Cox-2) platelet activating factor (Cox-1) leu
kotrienes
Glucose Acetyl CoA cholesterol cortisone
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Aspirin
Vioxx