Cuagulation
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BLOOD COAGULATION: AT THE INTERFACE BETWEEN PHYSICAL AND CHEMICAL KINETICS
©2006 UpToDate®
e-mail this to a colleague
©2006 UpToDate® • www.uptodate.com • Contact Us
©2006 UpToDate®
e-mail this to a colleague
©2006 UpToDate® • www.uptodate.com • Contact Us
FUSTER et al, 2005
FUSTER et al., 2005
Local homeostasis maintained by continuous adjustments to changes
threshold Tissue PERTURBATION RESPONSE “COAGULATION” Hemostasis thrombophilia hemophilia Disseminated coagulation
REACTION RATE CHANGE
“INFLAMMATION” Immunity hypersensitivity autoimmunity Immunodeficiency
PLASMA COAGULATION/FIBRINOLYSIS
FLOW
PROCOAGULANT SURFACES
COAGULATION CONTROL INHIBITORS HEPARIN (Glycosaminoglycans) Warfarin (Vit.-K antagonist) Anti-platelets PROCOAGULANTS COAGULATION FACTORS BLOOD TRANSFUSIONS
STATINS ? Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A Reduce cholesterol levels and cardiovascular disease
but Under the best circumstances 2/3 cardiovascular events remain.
Bradikinin -tPA Plasminogen Fibrin Plasmin FIBRINOLYSIS Hereditary angioedema
Contact activator “autoactivation of fXII Pre to kallikrein H-kininogen to bradikinin B1 and B2 receptors Of endothelial cells PLA2->PG->cAMP Ca2+->eNOS->NO-> cGMP RELAXATION
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
A + B ↔ AB →PRODUCT (1nmol ~ 1014 molecules)
FLUX : convective → pressure gradient diffusive→ concentration gradients FLOW-DEPENDENT TRANSFER?
SURFACE DIFFUSION ON CELLS?
PROTOTYPE REACTION SCHEME
Kf
KA A+B
PRODUCTS
[AB] Kd
K eff = KA.Kf / Kd + Kf
K f >>
Kd
K eff = K A
MODULAR STRUCTURE OF COAGULATION ZYMOGENS
Growth factor-like domain
Gla Domain Gamma-carboxylated Glutamic acid residues
Serine proteinase Domain Aspartic acid Histidine SERINE
DIFFUSION-CONTROLLED REACTIONS IN BIOLOGICAL SYSTEMS Soluble enzyme kinetics Steady-state diffusion-controlled reaction (Smoluchowski) Influence of intermolecular forces (Kramers, Debye) Hydrodynamics effects (Friedman, Deutch) (osmotic stress techniques?) Convective flow (Levich, Delichatsios) Diffusion toward an array of reactive traps. Spherical Influence of chemical reaction on diffusion in the reactive system
Mean first passage times.
Glycosaminoglycans role in the local regulation of interstitial fluid volume
Local hydration = competitive affinity of macromolecules for water Glycosaminoglycans form hydrophilic gels that store “dehydration energy” In vivo manifested as a dehydrating potential. In vitro detected as swelling pressure CARTILAGE VASCULATURE
Polymer rubber elasticity
Polymerpolymer affinity H20 H+ Pressure
OSMOTIC FORCES
GALACTOSAMINOGLYCANS
Vsat
K1/2
AT + GAG
AT·GAG+fXa
AT·GAG-fXa
GAG
AT-fXa
Antithrombin surface
Water activity
1.4 Å under 4.0 Å
K ΔG/Π = ΔV
20 18 16 DS (0.5 atm) DS (standard)
14
DD (0.5 atm)
Factor Xa nM
DD (standard)
12
Heparan (0.5 atm) Heparan (standard)
10 8 6 4 2 0
0
5
10
15 20 25 30 TIME (seconds)
35
40
45
50
20.2 20
G ( kcal/mol)
19.8 19.6 19.4 19.2 19 18.8
0
.5
1
1.5
Osmotic Pressure (atm)
2
2.5
TABLE 1 (kcal/mol/atm)
(water mol/mol)
Probe radius, (Å) PEG: 300
4
-0.072 ± 0.011
165 ± 25
600
7
-0.221 ± 0.060
508 ± 138
1500
9
-0.336 ± 0.031
772 ± 71
3400
17
-1.16 ± 0.11
2667 ± 252
8000
26
-1.083 ± 0.207
2489 ± 475
Dextran T10
24
-1.287 ± 0.113
2958 ± 260
PVP 40
NA
- 1.314 ± 0.176
3028 ± 404
Water Transfer by Osmotic Stress Technique with Polymers of Different Size and Chemical Structure
A
B
PI
C-sheet
RCL
hH B-sheet hG hD
hA
hB
hl
hE A-sheet
hF hC
C
1 140
RATE s-1 X103
120 1 1 100
80 60 40 20 0
0
20
40
60
Dermatan Sulfate, μM
80
100
120
120
RATE s-1 X 103
100 80 60 40 20 0
0
5
10
15
20
Dermatan Disulfate, μM
25
30
35
GAG solution
Standard
Osmotic Stress (0.5 atm)
CSE in:
K1/2, (µΜ)
Vsat (s-1 x 103)
K1/2, (µΜ)
Vsat (s-1 x 103)
0.15 N, NaCl
3.3 ± 1.9
5.3 ± 1.3
4.3 ± 1.6
16 ± 3
0.15 N, NaCl, 2mM CaCl2
2.7 ± 0.8
5.7 ± 0.7
2.9 ± 0.4
20 ± 1
0.075 N NaCl
4.3 ± 2.8
6.1 ± 1.8
5.2 ± 2.3
15 ± 3
0.075 N NaCl,2mM CaCl2
1.3 ± 0.4
13.8 ± 0.1
0.34 ± .05
44 ± 1
0.15 N NaCl, 5mM CaCl2
4.8 ± 0.8
13.2 ± 0.1
2.7 ± 0.4
34 ± 2
0.15 N, NaCl
4.0 ± 0.6
48 ± 4
5.5 ± 0.9
104 ± 10
15 N, NaCl, 2mM CaCl2
6.9 ± 0.9
97 ± 5
6.3 ± 0.4
189 ± 5
.075 N NaCl
6.6 ± 0.8
78 ± 4
4.8 ± 0.3
119 ± 3
.075 N NaCl, 2mM CaCl2
9.2 ± 1.8
204 ± 19.4
5.1 ± 0.8
283 ± 17
HS in:
Standard
GAG solution DS in:
K1/2, (µΜ)
Vsat (s-1 x 103)
Osmotic Stress (0.5 atm) K1/2, (µΜ)
Vsat (s-1 x 103)
0.15 N, NaCl
74 ± 7
84 ± 5
37 ± 6
120 ± 8
0.15 N, NaCl, 2mM CaCl2
17 ± 3
97 ± 6
16 ± 1
136 ± 5
0.075 N NaCl
62 ± 4
125 ± 5
26 ± 2
136 ± 5
0.075 N NaCl,2mM CaCl2
19 ± 6
163 ± 21
3±1
116 ± 8
0.15 N, NaCl
17 ± 3
56 ± 5
9.4 ± 2
104 ± 10
15 N, NaCl, 2mM CaCl2
5.1 ± 0.4
73 ± 2
1.7 ± 0.3
106 ± 5
.075 N NaCl
7.5 ± 0.6
56 ± 2
3.8 ± 0.2
97 ± 2
.075 N NaCl, 2mM CaCl2
2.1 ± 0.2
73 ± 2.5
0.4 ± 0.8
107 ± 1
DDS in:
TABLE 3 Disaccharide Structure and Anticoagulant Function. Increased Efficiency with Osmotic Stress and Calcium Dermatan Sulfate Dermatan Disulfate Chondroitin Sulfate E Heparan Sulfate
Hexuronic Acid Hexosamine sulfation pattern Iduronic C4 Iduronic C4, C6 Glucuronic C4, C6 Iduronic C2, N (variable)
Efficiency M-1 s-1 4 X 104 (34) 2 X 105 (81) 1 X 105 (81) 5 X 104 (5)
Efficiency was estimated as the ratio between Vsat and K1/2 determined in titrations of antithrombin activity, under an osmotic stress of 0.5 atm, with the indicated glycosaminoglycans in TRIS buffer pH 7.4, 0.075 N NaCl and 2mM CaCl2 The increases in efficiency relative to reactions in standard TRIS buffer pH 7.4, 0.15N NaCl are indicated in parentheses.
GLYCOSAMINOGLYCANS REGULATE REACTIONS IN BIOGELS
Qui alium sequitur, nihil invenit, immo nee quaerit. SENECA
(“He who follows another not only discover nothing, but is not even investigating.” Translation by RG Gummere)
©2006 UpToDate®
e-mail this to a colleague
©2006 UpToDate® • www.uptodate.com • Contact Us
©2006 UpToDate®
e-mail this to a colleague
©2006 UpToDate® • www.uptodate.com • Contact Us
FUSTER et al, 2005
FUSTER et al., 2005
Local homeostasis maintained by continuous adjustments to changes
threshold Tissue PERTURBATION RESPONSE “COAGULATION” Hemostasis thrombophilia hemophilia Disseminated coagulation
REACTION RATE CHANGE
“INFLAMMATION” Immunity hypersensitivity autoimmunity Immunodeficiency
PLASMA COAGULATION/FIBRINOLYSIS
FLOW
PROCOAGULANT SURFACES
COAGULATION CONTROL INHIBITORS HEPARIN (Glycosaminoglycans) Warfarin (Vit.-K antagonist) Anti-platelets PROCOAGULANTS COAGULATION FACTORS BLOOD TRANSFUSIONS
STATINS ? Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A Reduce cholesterol levels and cardiovascular disease
but Under the best circumstances 2/3 cardiovascular events remain.
Bradikinin -tPA Plasminogen Fibrin Plasmin FIBRINOLYSIS Hereditary angioedema
Contact activator “autoactivation of fXII Pre to kallikrein H-kininogen to bradikinin B1 and B2 receptors Of endothelial cells PLA2->PG->cAMP Ca2+->eNOS->NO-> cGMP RELAXATION
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
Spaan J. A. E. et al., 2003
A + B ↔ AB →PRODUCT (1nmol ~ 1014 molecules)
FLUX : convective → pressure gradient diffusive→ concentration gradients FLOW-DEPENDENT TRANSFER?
SURFACE DIFFUSION ON CELLS?
PROTOTYPE REACTION SCHEME
Kf
KA A+B
PRODUCTS
[AB] Kd
K eff = KA.Kf / Kd + Kf
K f >>
Kd
K eff = K A
MODULAR STRUCTURE OF COAGULATION ZYMOGENS
Growth factor-like domain
Gla Domain Gamma-carboxylated Glutamic acid residues
Serine proteinase Domain Aspartic acid Histidine SERINE
DIFFUSION-CONTROLLED REACTIONS IN BIOLOGICAL SYSTEMS Soluble enzyme kinetics Steady-state diffusion-controlled reaction (Smoluchowski) Influence of intermolecular forces (Kramers, Debye) Hydrodynamics effects (Friedman, Deutch) (osmotic stress techniques?) Convective flow (Levich, Delichatsios) Diffusion toward an array of reactive traps. Spherical Influence of chemical reaction on diffusion in the reactive system
Mean first passage times.
Glycosaminoglycans role in the local regulation of interstitial fluid volume
Local hydration = competitive affinity of macromolecules for water Glycosaminoglycans form hydrophilic gels that store “dehydration energy” In vivo manifested as a dehydrating potential. In vitro detected as swelling pressure CARTILAGE VASCULATURE
Polymer rubber elasticity
Polymerpolymer affinity H20 H+ Pressure
OSMOTIC FORCES
GALACTOSAMINOGLYCANS
Vsat
K1/2
AT + GAG
AT·GAG+fXa
AT·GAG-fXa
GAG
AT-fXa
Antithrombin surface
Water activity
1.4 Å under 4.0 Å
K ΔG/Π = ΔV
20 18 16 DS (0.5 atm) DS (standard)
14
DD (0.5 atm)
Factor Xa nM
DD (standard)
12
Heparan (0.5 atm) Heparan (standard)
10 8 6 4 2 0
0
5
10
15 20 25 30 TIME (seconds)
35
40
45
50
20.2 20
G ( kcal/mol)
19.8 19.6 19.4 19.2 19 18.8
0
.5
1
1.5
Osmotic Pressure (atm)
2
2.5
TABLE 1 (kcal/mol/atm)
(water mol/mol)
Probe radius, (Å) PEG: 300
4
-0.072 ± 0.011
165 ± 25
600
7
-0.221 ± 0.060
508 ± 138
1500
9
-0.336 ± 0.031
772 ± 71
3400
17
-1.16 ± 0.11
2667 ± 252
8000
26
-1.083 ± 0.207
2489 ± 475
Dextran T10
24
-1.287 ± 0.113
2958 ± 260
PVP 40
NA
- 1.314 ± 0.176
3028 ± 404
Water Transfer by Osmotic Stress Technique with Polymers of Different Size and Chemical Structure
A
B
PI
C-sheet
RCL
hH B-sheet hG hD
hA
hB
hl
hE A-sheet
hF hC
C
1 140
RATE s-1 X103
120 1 1 100
80 60 40 20 0
0
20
40
60
Dermatan Sulfate, μM
80
100
120
120
RATE s-1 X 103
100 80 60 40 20 0
0
5
10
15
20
Dermatan Disulfate, μM
25
30
35
GAG solution
Standard
Osmotic Stress (0.5 atm)
CSE in:
K1/2, (µΜ)
Vsat (s-1 x 103)
K1/2, (µΜ)
Vsat (s-1 x 103)
0.15 N, NaCl
3.3 ± 1.9
5.3 ± 1.3
4.3 ± 1.6
16 ± 3
0.15 N, NaCl, 2mM CaCl2
2.7 ± 0.8
5.7 ± 0.7
2.9 ± 0.4
20 ± 1
0.075 N NaCl
4.3 ± 2.8
6.1 ± 1.8
5.2 ± 2.3
15 ± 3
0.075 N NaCl,2mM CaCl2
1.3 ± 0.4
13.8 ± 0.1
0.34 ± .05
44 ± 1
0.15 N NaCl, 5mM CaCl2
4.8 ± 0.8
13.2 ± 0.1
2.7 ± 0.4
34 ± 2
0.15 N, NaCl
4.0 ± 0.6
48 ± 4
5.5 ± 0.9
104 ± 10
15 N, NaCl, 2mM CaCl2
6.9 ± 0.9
97 ± 5
6.3 ± 0.4
189 ± 5
.075 N NaCl
6.6 ± 0.8
78 ± 4
4.8 ± 0.3
119 ± 3
.075 N NaCl, 2mM CaCl2
9.2 ± 1.8
204 ± 19.4
5.1 ± 0.8
283 ± 17
HS in:
Standard
GAG solution DS in:
K1/2, (µΜ)
Vsat (s-1 x 103)
Osmotic Stress (0.5 atm) K1/2, (µΜ)
Vsat (s-1 x 103)
0.15 N, NaCl
74 ± 7
84 ± 5
37 ± 6
120 ± 8
0.15 N, NaCl, 2mM CaCl2
17 ± 3
97 ± 6
16 ± 1
136 ± 5
0.075 N NaCl
62 ± 4
125 ± 5
26 ± 2
136 ± 5
0.075 N NaCl,2mM CaCl2
19 ± 6
163 ± 21
3±1
116 ± 8
0.15 N, NaCl
17 ± 3
56 ± 5
9.4 ± 2
104 ± 10
15 N, NaCl, 2mM CaCl2
5.1 ± 0.4
73 ± 2
1.7 ± 0.3
106 ± 5
.075 N NaCl
7.5 ± 0.6
56 ± 2
3.8 ± 0.2
97 ± 2
.075 N NaCl, 2mM CaCl2
2.1 ± 0.2
73 ± 2.5
0.4 ± 0.8
107 ± 1
DDS in:
TABLE 3 Disaccharide Structure and Anticoagulant Function. Increased Efficiency with Osmotic Stress and Calcium Dermatan Sulfate Dermatan Disulfate Chondroitin Sulfate E Heparan Sulfate
Hexuronic Acid Hexosamine sulfation pattern Iduronic C4 Iduronic C4, C6 Glucuronic C4, C6 Iduronic C2, N (variable)
Efficiency M-1 s-1 4 X 104 (34) 2 X 105 (81) 1 X 105 (81) 5 X 104 (5)
Efficiency was estimated as the ratio between Vsat and K1/2 determined in titrations of antithrombin activity, under an osmotic stress of 0.5 atm, with the indicated glycosaminoglycans in TRIS buffer pH 7.4, 0.075 N NaCl and 2mM CaCl2 The increases in efficiency relative to reactions in standard TRIS buffer pH 7.4, 0.15N NaCl are indicated in parentheses.
GLYCOSAMINOGLYCANS REGULATE REACTIONS IN BIOGELS
Qui alium sequitur, nihil invenit, immo nee quaerit. SENECA
(“He who follows another not only discover nothing, but is not even investigating.” Translation by RG Gummere)
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