1. What is a Blood Clot?
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MEDC 604 Anti-coagulants

2. A) Physical Process B) Chemical Process
The Clotting Process
A) Physical Process B) Chemical Process
Wound
antithrombins
factor Xa
thrombin prothrombin
fibrinogen
fibrin
(monomers)
(polymer)
vitamin K-dependent
g-carboxylation of
Glu residues
coumarins
platelet activation
release thrombin release of
of ADP generation thromboxane A2
Further activation of platelets
Platelet aggregation
aspirin
ADP
receptor
antagonists
GP IIb-IIIa
CLOT
Taken from Desai UR (2004) Med. Res. Rev. 24,
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MEDC 604 Anti-coagulants

3. Physical Process of Clotting
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MEDC 604 Anti-coagulants

4. The Coagulation Cascade
XII XIIa XI
XIa IX
IXa X Xa II
IIa
VII
VIIa
V Va
VIII VIIIa F
Fm CLOT
XIII
HMWK TF
XIIIa
PL/Ca2+
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MEDC 604 Anti-coagulants

5. Interesting Features of the Coagulation Cascade
Catalysis and Specificity of Reactions Involved in the Cascade
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MEDC 604 Anti-coagulants

6. Interesting Features of the Coagulation Cascade
Polymerization
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MEDC 604 Anti-coagulants

7. Interesting Features of the Coagulation Cascade
Amplification
A E2 E1 C E3 D E4 F G
A B X Y E2
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MEDC 604 Anti-coagulants

8. Regulation of Coagulation
XII XIIa XI
XIa IX
IXa X Xa II
IIa
VII
VIIa
V Va
VIII VIIIa F
Fm CLOT
XIII
HMWK TF
XIIIa
PL/Ca2+ AT
Protein C
APC
TM:IIa
TFPI
Why Regulate Clotting?
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MEDC 604 Anti-coagulants

9. Inhibitors of Clotting (Anticoagulants)
Natural Anticoagulants
Antithrombin, Tissue Factor Pathway Inhibitor, Protein C
Natural Product-derived Anticoagulant Drugs
Heparin-based anticoagulants, e.g., heparin, low molecular weight heparin, fondaparinux, idraparinux
Coumarin-based anticoagulants, e.g., warfarin, acenocoumarin
Hirudin (derived from leeches), lepirudin, desirudin, bivalirudin
Tick anticoagulant peptide
Other Anticoagulants
Argatroban, melagatran, ximelagatran
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10. Inhibitors of Coagulation
Structure and sequence
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11. Pentasaccharide
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12. Clinically useful coumarins and 1,3-indanediones
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13. Direct Thrombin Inhibitors
HIRUDIN – Isolated from leech, hirudino medicinalis. A polypeptide consisting of 65 amino acid residues that binds thrombin in the active site as well as another site called exosite I
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MEDC 604 Anti-coagulants

14. All Anticoagulants have Significant Problems!!
Our Work …. designing molecules that are radically different from all known anticoagulants using a multidisciplinary approach involving computational chemistry, organic synthesis, enzyme assays, mechanistic biochemistry, and plasma, blood and animal studies …
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MEDC 604 Anti-coagulants