Coagulation and fibrinolysis
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Transcript of Coagulation and fibrinolysis
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Coagulation and fibrinolysis
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Hemostasis
• Blood must be fluid
• Must coagulate (clot) at appropriate time– Rapid– Localized– Reversible
Thrombosis…inappropriate coagulation
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3 Major systems involved
• Vessel wall– Endothelium
– ECM = BM (type 4 collagen + other proteins)
• Platelets• Coagulation cascade
– Coagulation factors (proteins)• Names and numbers
• Active and inactive forms (zymogens)
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Antithrombogenic Thrombogenic
Vessel injury
(Favors fluid blood) (Favors clotting)
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Antithrombotic Properties of the Endothelium
• Anti-platelet properties– Covers highly thrombogenic basement
membrane– Uninjured endothelium does not bind platelets– PGI2 (prostacyclin) and NO from uninjured
endothelium inhibit platelet binding– ADPase counters the platelet aggregating
effects of ADP
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Antithrombotic Properties of the Endothelium
Anticoagulant properties
*HEPARIN-LIKE MOLECULES: activate anti-thrombin III (inactivates active proteases)
*THROMBOMODULIN: changes specificity of thrombin (activates protein C , which
inactivates factors Va and VIIIa
*Endothelial cells produce tPA which activates fibrinolysis via plasminogen to plasmin
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Prothrombotic Properties of the Endothelium•Synthesis of von Willebrand factor
•Release of tissue factor
•Production of plasminogen activator inhibitors (PAI)
•Membrane phospholipids bind and facilitate activation of clotting factors via Ca bridges
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
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Coagulation Cascade
• Enzymatic cascade (amplification)• Several serine proteases
– Produced by liver (most)
– Require Vit K (several)
• 3 protein cofactors (not enzymes)• Requires Ca 2+
• Localized to site of injury • Reversible (via production of plasmin)
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Fibrinogen Fibrin
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Fibrinogen FibrinThrombin
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
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Hemophilia A
Deficiency of/nonfunctional VIII
Hemophilia BDeficiency of /nonfunctional IX
Why do they bleed?
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
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Thrombin (IIa)
Prothrombin (II)
Xa
VIIa
TF
IXa
Revised Coagulation Pathway (Tissue Factor Pathway)
IX
NB: production of IXaInteraction of intrinsic and extrinsic pathways
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Tissue Factor Pathway Inhibitor
• Kunitz-type protease inhibitor (kringles)• 34 and 41 kD forms in plasma (C-term truncation)• Directly inhibits Xa• Inhibits VIIa-TF complex in a [Xa]-dependent
manner• Bound to LDL, HDL and Lp (a)• ~10% present in platelets (endothelium also)
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Thrombin (IIa)
Prothrombin (II)
Xa
VIIa
TF
IXa
Tissue Factor Pathway Inhibitor
IX
TFITFPI
NB: Inhibition of Xa and VIIa
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Production of IXa
Production of small amounts of thrombin (IIa)
Tissue Factor Pathway
Net result:
NB: no/little fibrin formed!
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Thrombin (IIa)
VIII
VIIIa
V
Va
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Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
IXa
VIIIa
XIIIa
Soft clot
FibrinHard clot
VVIII
Tissue Factor Pathway NB: activation of IX by VIIa
IX
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Tissue Factor Pathway
• VIIa forms as usual via binding of VII to TF
• VIIa activates some XXa
• Xa converts a small amt of prothrombin to thrombin; this thrombin is used to produce small amts of VIIIa and Va
• As the conc of TF-VIIa-Xa-thrombin increases, Tissue Factor Pathway Inhibitor inactivates this complex stopping further production of thrombin.
• New: VIIa also activates IXIXa (Key to new scheme)
• IXa, with VIIIa (produced as above), produces Xa; this Xa with Va (produced as above) produces new thrombin; this thrombin produces more VIIIa and Va and now we get lots of thrombin and fibrin!
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Physiologic Inhibitors of coagulation
• Antithrombin III (serpin)• Activated Protein C + protein S
– Inactivates Va and VIIIa (via proteolysis)– NB: Factor V Leiden
• Thrombomodulin (EC glycoprotein)– Binds to thrombin– Decreases ability to produce fibrin– Increases ability to activate Protein C
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Role of vitamin K
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Role of vitamin K
Some clotting factors require a post-translational modification before they are active in clotting
These factors are II, VII, IX, X, proteins C and S
This PTM involves the addition of a COO- to certain Glu residues in the clotting factors
This PTM results in the formation of several -carboxy glutamates = Gla
This PTM requires vitamin K
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Role of vitamin K
• Vit K is altered in carboxylation Rx and must be regenerated before reuse
• Regeneration involves 2 reductases which convert vit K epoxide to vit K
• Vit K antagonists inhibit these reductases
• Vit K-dependent PTM provides sites on modified coag factors for Ca bridgeing
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Non-physiologic inhibitors of coagulation
• Vitamin K antagonists (in vivo only)
• Ca chelators (in vitro only)– EDTA– Citrate– Oxalate
* Heparin (in vivo and in vitro)
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Vitamin K antagonists
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Clot removal
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Fibrin Fibrin Split Products (FSP)Plasmin
Fibrinolysis
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Fibrin Fibrin Split Products (FSP)Plasmin
Plasminogen
tPA
Fibrinolysis
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Inhibitors of fibrinolysis
• Plasminogen activator inhibitors (PAIs)
2-antiplasmin (serpin)
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