The Cell Based Model of
Coagulation
A pharmacological perspective
Topics
 Physiology


Cascade Model
Cell Based Model
 Pharmacology




Anti-platelet Drugs
Anti-factor Drugs
Anti-cross linking Drugs
Anti-fibrinolytic drugs
Part One
Physiology
Hemostasis
 Vasoconstriction
 Platelet



plug formation
Activation
Adherence
Aggregation
 Stabilization


of platelet plug
Coagulation cascade
Fibrin
Cascade Model
XII
XIIa
TF
XI
VII
XIa
IX
IXa
VIIIa
X
VIIa
TF
Xa
Va
II
Fibrinogen
X
IIa
Fibrin
Intrinsic
XII
XIIa
Extrinsic
TF
XI
VII
XIa
IX
IXa
VIIIa
X
Common
VIIa
TF
Xa
Va
II
Fibrinogen
X
IIa
Fibrin
Tests
XII
PT
XIIa
TF
XI
VII
XIa
IX
IXa
VIIIa
VIIa
TF
aPTT
X
Xa
Va
X
TT
II
Fibrinogen
IIa
Fibrin
Problems
XII
XIIa
TF
XI
VII
XIa
IX
IXa
VIIIa
X
VIIa
TF
Xa
Va
II
Fibrinogen
X
IIa
Fibrin
Cell Based Theory
 Platelets
and IIa are central
 Sequence



Initiation
Amplification
Propagation
XII
XIIa
TF
XI
VII
XIa
IX
IXa
VIIIa
X
VIIa
TF
Xa
Va
II
Fibrinogen
X
IIa
Fibrin
VIIa
TF
Xa
IIa
XIa
XIa
IXa
VIIIa
IXa
VIIIa
VIIa
TF
Xa
Va
IIa
Fibrinogen
Fibrin
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Initiation
Va
IIa
IIa
IIa
Plt
Plt
Amplification
Xa
IXa
VIIIa
Plt
Fg
Xa
Va
IIa
Propagation
Fb
Subendothelial collagen
Plt
Fb
Fb
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Platelet activation
 Triggered






by
Sub-endothelial collagen
IIa
ADP
TXA2
5HT
Epinephrine
Platelet activation
 Results



in;
Greatly increased surface area
Dense granules release Ca2+, 5HT, TXA2,
ADP
Alpha granules release factor V, fibrin, VWF
Platelet activation
 Platelet
phospholipid bilayer is actively
controlled
 Resting internal surface is procoagulant
 Bilayer everts during activation, exposing
procoagulant surface
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Propagation
Fb
Subendothelial collagen
Plt
Fb
Fb
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Part Two
Pharmacology
Part Two - Pharmacology
 Topics

Anti-platelet Drugs

Anti-factor Drugs

Anti-cross linking Drugs

Anti-fibrinolytic Drugs
Aspirin
 Salicylate
that irreversibly acetylates COX
enzymes
 Prevents
thromboxane generation
 Thromboxane
is a potent stimulator of
platelet activation and aggregation
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Clopidogrel
 Irreversibly
inactivate platelet ADP
receptors
 Thus
preventing activation
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Heparin
 Sulfated
glycosaminoglycan naturally
bound to endothelial cells
 Negatively
charged + highly bound in
plasma
 Cleared
by reticuloendothelial system
Heparin
 Binds
to AT III, and increases its activity
1000 fold
 Heparin-ATIII
binds to IIa, IXa, Xa, XIa and
inactivates them
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
AD
P
TXA2
IIa
Plt
Plt
vWF
IIa
Plt
IXa
VIIIa
XIa
IXa
Fg
Xa
Va
Va
Plt
Plt
Xa
Plt
VIIIa
IIa
5HT
Fg
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Heparin
 Binds
to Anti Thrombin III, and increases
its activity 1000 fold
 Heparin-ATIII
binds to IIa, IXa, Xa, XIa and
inactivates them
 Requires
AT III for its actions
Heparin
Problems;
 Thrombocytopenia
 HITTS



IgG mediated
4-14 days to develop
Thrombosis
LMWH
 Derived
from heparin by chemical
depolymerization
 Xa:IIa
activity 4:1
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
LMWH
Advantages over heparin;
 Markedly reduced protein binding
 Lower
incidence of HITTS
 Renal
clearance
 More
effective thromboprophylaxis
Fondaparinux
 Synthetic
 Does
anticoagulant
not cause HITTS
 Inhibits
Xa
 Renally
excreted
Warfarin
 Coumarin
derivative with high oral
bioavailability
 Interferes
with vitamin K regeneration
Vitamin K dependent factors
 Factors
II, VIII, IX & X
 Carboxylation
allows interaction with
platelet membrane
 Interaction
requires Ca2+
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Warfarin
 High
protein binding
 Hepatic
clearance via inducable enzymes
Warfarin

Levels increased by;







Protease inhibitors
Macrolide antibiotics
Chloramphenicol
Azole antifungals
Bergamottin (constituent of
grapefruit juice)
Verapamil
Amiodarone











Ciprofloxacin
Cyclosporin
Diltiazem
Ergotamine
Metronidazole
Norfloxacin
SSRIs
Fluoxetine/norfluoxetine
Fluvoxamine
Cimetidine
Buprenorphine
Lepirudin
 Recombinant
 Directly
hirudin
binds to thrombin
 Monitored
by aPTT
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Lepirudin
 Renally
 No
excreted
effective antidote
 Half-life
2 hours
Abciximab
 Monoclonal
 High
antibody
affinity for platelet IIa/IIIb receptor for
fibrin
 Plasma
half life 20 minutes
 Has activity for 2 days
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Tranexamic Acid
 Competitive
inhibitor of the activation of
plasminogen
 Renally
excreted, half-life 2 hours
 Provides
survival benefit in trauma
patients with hemodynamic instability
Tissue factor bearing cell
VIIa
TF
Xa
Xa
Va
IIa
IIa
IIa
ADP
IIa
Plt
Plt
TXA2
Fg
Plt
IXa
VIIIa
XIa
IXa
Plt
Xa
Fg
Xa
Va
Va
Plt
IIa
5HT
Plt
VIIIa
IIa
vWF
IXa
VIIIa
IIa
Plt
IIa
Plt
Fb
Fb
Fb
Subendothelial collagen
Plt
vWF
Plt
Fb
Fb
Plt
vWF
Questions?