低分子肝素英文

Fibrin-Bound Thrombin
F
H
Thrombin
AT
S
C
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Inactivation of Thrombin by Heparin-AT Complexes
Fibrin
F
H
Thrombin
S
C
Heparin
When thrombin binds to fibrin, it becomes resistant to inactivation by heparin.
• LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester
• LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio
Thrombin
S
C
F
H
Thrombin
S
C
AT HC II
Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II
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Antithrombin and Free Thrombin
AT is an effective antithrombin but HC II is a very weak antithrombin
F
H
Thrombin
S
C
HC II
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Interaction of Heparin Co-Factors with Thrombin
F
H
The Coagulation Cascade
• Central to the coagulation cascade is the generation of thrombin (factor IIa)
• thrombin is generated from prothrombin by the action of activated factor X (Xa)
XIIa VIIa
XIa
IXa
Heparin / LMWH
(AT-III dependent)
aPTT
Xa Thrombin (IIa)
Hirudin/Hirulog
(direct antithrombin)
PT Thrombin-Fibrin Clot
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Courtesy of VTI
MedSlides
• thrombin then acts on fibrinogen to generate fibrin clot
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Coagulation Cascade
Intrinsic Pathway (surface contact)
Extrinsic Pathway (tissue factor)
2
Heparin Inhibits Hemostasis
THROMBOSIS Collagen XIa
Tissue Factor IXa Platelet Clumping
Thrombus Formation Thrombus Growth
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HEMOSTASIS
Tissue Factor &
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Mechanism of Action
• Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin (AT or AT III)
• catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa.
Heparin binds to antithrombin and increases the rate of thrombin inactivation
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Effect of Antithrombin on Fibrin-Bound Thrombin
The rate at which AT inactivates fibrin-bound thrombin is reduced 50-fold
• prolongs aPTT
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Interaction of Heparin Co-Factors with Thrombin
F
H
Thrombin
AT
S
C
There are two heparincofactors, Antithrombin (AT) and Heparin Co-factor II (HC II).
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Mechanism of Action
• Summary
Activation of Platelets And Coagulation
Amplification
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Xa Thrombin (IIa)
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Low-molecular-weight heparin
• UH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans)
AT alone does not inactivate free-thrombin
Free Thrombin
F
H
Thrombin
S
C
AT
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Inactivation of Thrombin by Heparin-AT Complexes
F
H
Thrombin
S
C
Heparin AT
HEP Xa
Collagen
Fluid Thrombin HEP & HIR
Platelet Aggregation
Platelet-rich Hemostatic Plug
MedSlides
3
The Procoagulant State in Thrombolysis
Vascular Injury