cuagulation

8/14/2019 cuagulation

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BLOOD COAGULATION: AT

THE INTERFACE BETWEEN

PHYSICAL AND CHEMICALKINETICS


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2006 UpToDate

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2006 UpToDate

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FUSTER et al, 2005


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FUSTER et al., 2005


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Local homeostasis maintained by continuous adjustments to changes

threshold

Tissue PERTURBATION

RESPONSE

COAGULATION

Hemostasis

thrombophilia

hemophilia

Disseminated coagulation

INFLAMMATION

Immunity

hypersensitivity

autoimmunity

Immunodeficiency

REACTION

RATE CHANGE


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PLASMA COAGULATION/FIBRINOLYSIS

PROCOAGULANT

SURFACESFLOW


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COAGULATION CONTROL

INHIBITORS

HEPARIN (Glycosaminoglycans)

Warfarin (Vit.-K antagonist)

Anti-platelets

PROCOAGULANTSCOAGULATION FACTORS

BLOOD TRANSFUSIONS

STATINS ?Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme AReduce cholesterol levels and cardiovascular disease

but

Under the best circumstances 2/3 cardiovascular events remain.


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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

Bradikinin -tPA

Plasminogen

Fibrin

Plasmin

FIBRINOLYSIS

Hereditaryangioedema


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Spaan J. A. E. et al., 2003


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A + B ABPRODUCT

(1nmol ~ 1014 molecules)

FLUX :

convective pressure gradient

diffusive concentration gradients

FLOW-DEPENDENT TRANSFER?

SURFACE DIFFUSION ON CELLS?


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A + B

KA

Kd[AB]

Kf>>

PRODUCTS

PROTOTYPE REACTION SCHEME

K eff = KA.Kf/ Kd + Kf

K d Keff= KA

Kf


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Gla Domain

Gamma-carboxylated

Glutamic acid residues

Serine proteinase Domain

Aspartic acid

Histidine

SERINE

Growth factor-like domain

MODULAR STRUCTURE OF COAGULATION ZYMOGENS


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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.


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Glycosaminoglycans role in the local

regulation of interstitial fluid volume

Local hydration = competitive affinity of macromolecules for water

Glycosaminoglycans form hydrophilic gels that store dehydrationenergy

In vivo manifested as a dehydrating potential.

In vitro detected as swelling pressure

CARTILAGE

VASCULATURE


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Polymer rubber elasticity

H20

Polymer-polymeraffinity

H+

Pressure

OSMOTIC FORCES


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GALACTOSAMINOGLYCANS


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AT + GAG ATGAG+fXa ATGAG-fXa

AT-fXa

GAG

K1/2Vsat

Antithrombin surface 1 4 under 4 0


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G/ = V

K

Antithrombin surface 1.4 under 4.0

Wateractivity


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0

2

4

6

8

10

12

14

16

18

20

0 5 10 15 20 25 30 35 40 45 50TIME (seconds)

Heparan (standard)

Heparan (0.5 atm)

DD (standard)

DD (0.5 atm)

DS (standard)

DS (0.5 atm)

FactorX

anM


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18.8

19

19.2

19.4

19.6

19.8

20

20.2

0 .5 1 1.5 2 2.5

Osmotic Pressure (atm)

G

(kcal/mol)


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TABLE 1

3028 404- 1.314 0.176NAPVP 40

2958 260-1.287 0.11324Dextran T10

2489 475-1.083 0.207268000

2667 252-1.16 0.11173400772 71-0.336 0.03191500

508 138-0.221 0.0607600

165 25-0.072 0.0114PEG: 300

(water mol/mol)(kcal/mol/atm)Probe radius, ()

Water Transfer by Osmotic Stress Technique with Polymers of Different Size and Chemical Structure


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A B CPI

RCLC-sheet

hH

B-sheet

hD

hB

hE

A-sheet

hC

hF

hl

hA

hG


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0

20

40

60

80

100

120

140

0 20 40 60 80 100 120

Dermatan Sulfate, M

RATE

s-1X

103 1

1

1


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0

20

40

60

80

100

120

0 5 10 15 20 25 30 35

Dermatan Disulfate, M

RATE

s-1X

103


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283 175.1 0.8204 19.49.2 1.8.075 N NaCl, 2mM CaCl2

119 34.8 0.378 46.6 0.8.075 N NaCl

189 56.3 0.497 56.9 0.915 N, NaCl, 2mM CaCl2

104 105.5 0.948 44.0 0.60.15 N, NaCl

HSin:

34 22.7 0.413.2 0.14.8 0.80.15 N NaCl, 5mM CaCl2

44 10.34 .0513.8 0.11.3 0.40.075 N NaCl,2mM CaCl2

15 35.2 2.36.1 1.84.3 2.80.075 N NaCl

20 12.9 0.45.7 0.72.7 0.80.15 N, NaCl, 2mM CaCl2

16 34.3 1.65.3 1.33.3 1.90.15 N, NaCl

Vsat (s-1 x 103)K1/2, ()Vsat (s

-1 x 103)K1/2, ()CSE in:

Osmotic Stress (0.5 atm)StandardGAG solution


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107 10.4 0.873 2.52.1 0.2.075 N NaCl, 2mM CaCl2

97 23.8 0.256 27.5 0.6.075 N NaCl

106 51.7 0.373 25.1 0.415 N, NaCl, 2mM CaCl2

104 109.4 256 5 17 30.15 N, NaCl

DDS in:

116 83 1163 2119 60.075 N NaCl,2mM CaCl2

136 526 2125 562 40.075 N NaCl

136 516 197 617 30.15 N, NaCl, 2mM CaCl2

120 837 684 574 70.15 N, NaCl

Vsat (s-1 x 103)K1/2, ()Vsat (s

-1 x 103)K1/2, ()DS in:

Osmotic Stress (0.5 atm)StandardGAG solution


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TABLE 3

Disaccharide Structure and Anticoagulant Function.Increased Efficiency with Osmotic Stress and Calcium

Hexuronic Acid Hexosamine sulfation pattern Efficiency M-1 s-1

Dermatan Sulfate Iduronic C4 4 X 104 (34)

Dermatan Disulfate Iduronic C4, C6 2 X 105 (81)

Chondroitin Sulfate E Glucuronic C4, C6 1 X 105 (81)Heparan Sulfate Iduronic C2, N (variable) 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.


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GLYCOSAMINOGLYCANS REGULATE REACTIONS IN BIOGELS


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Qui alium sequitur, nihil invenit, immo nee quaerit.

SENECA

(He who follows another not only discover nothing, but is not eveninvestigating. Translation by RG Gummere)

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