enzyme regulation ii blood clotting - oregon state...

EnzymeRegulationIIBloodClotting

Dr.KevinAhern

BloodClotting

BloodClotting

Cellular Response

BloodClotting

Cellular Response

Molecular Response

BloodClotting

Cellular Response

Molecular Response

Focus of Activity

BloodClotting-CellularResponse

1.Damagetoepithelialtissueexposescollagen


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors3.Plateletintegrinsgetactivatedandbindtightlytoextracellularmatrixtoanchortositeofwound.


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors3.Plateletintegrinsgetactivatedandbindtightlytoextracellularmatrixtoanchortositeofwound.4.vonWillebrandfactor(abloodglycoprotein)formsadditionallinksbetweentheplatelets’glycoproteinandthefibrilsofthecollagen


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors3.Plateletintegrinsgetactivatedandbindtightlytoextracellularmatrixtoanchortositeofwound.4.vonWillebrandfactor(abloodglycoprotein)formsadditionallinksbetweentheplatelets’glycoproteinandthefibrilsofthecollagen5.Amplificationbeginswithreleaseofplateletfactor4(inhibitsheparin)andthromboxaneA2(increasesplateletstickiness).


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors3.Plateletintegrinsgetactivatedandbindtightlytoextracellularmatrixtoanchortositeofwound.4.vonWillebrandfactor(abloodglycoprotein)formsadditionallinksbetweentheplatelets’glycoproteinandthefibrilsofthecollagen5.Amplificationbeginswithreleaseofplateletfactor4(inhibitsheparin)andthromboxaneA2(increasesplateletstickiness).6.Calciumreleasedfromintracellularstores(Gqcascade)


1.Damagetoepithelialtissueexposescollagen2.Plateletsbindcollagen-bindingsurfacereceptors3.Plateletintegrinsgetactivatedandbindtightlytoextracellularmatrixtoanchortositeofwound.4.vonWillebrandfactor(abloodglycoprotein)formsadditionallinksbetweentheplatelets’glycoproteinandthefibrilsofthecollagen5.Amplificationbeginswithreleaseofplateletfactor4(inhibitsheparin)andthromboxaneA2(increasesplateletstickiness).6.Calciumreleasedfromintracellularstores(Gqcascade)(Throughoutthislecture,the‘a’subscript,suchasTFVIIa,indicatetheactivatedformofafactor


BloodClotting-MolecularResponse

Molecularresponseconvergesonpolymerizationoffibrin(resultingfromintrinsicandextrinsicpathways)tomakethebloodclot.


Molecularresponseconvergesonpolymerizationoffibrin(resultingfromintrinsicandextrinsicpathways)tomakethebloodclot.Theintrinsicpathwayisalsoknownasthecontactactivationpathwayandtheextrinsicpathwayisknownasthetissuefactorpathway(moreimportant).


BloodClotting-MolecularResponse-InitiationPhase

1.TissuedamagestimulatesformationofTF-FVIIacomplexBloodClotting-MolecularResponse-InitiationPhase

1.TissuedamagestimulatesformationofTF-FVIIacomplex2.TF-FVIIa,FIXa,PlateletMembranePhospholipid(PL)andcalcium(fromthecellularresponse)inefficientlyconvertFXtoFXa


1.TissuedamagestimulatesformationofTF-FVIIacomplex2.TF-FVIIa,FIXa,PlateletMembranePhospholipid(PL)andcalcium(fromthecellularresponse)inefficientlyconvertFXtoFXa3.FXa,FV,PL,andcalciuminefficientlyconvertprothrombin(zymogen)toatinyamountofthrombin.


1.TissuedamagestimulatesformationofTF-FVIIacomplex2.TF-FVIIa,FIXa,PlateletMembranePhospholipid(PL)andcalcium(fromthecellularresponse)inefficientlyconvertFXtoFXa3.FXa,FV,PL,andcalciuminefficientlyconvertprothrombin(zymogen)toatinyamountofthrombin.4.Thrombiniskeytotheamplificationphaseofthemolecularresponse.


BloodClotting-MolecularResponse-AmplificationPhase

The amplification phase of the molecular response requires factors from the intrinsic and extrinsic response.


1. FVIII is normally bound in a complex with the von Willebrand factor and is inactive until it is released by action of thrombin.



2. FXIa helps favor production of more FIXa.




3. FIXa plus FVIIIa stimulate production of a considerable amount of FXa (3-4 orders of magnitude).




3. FIXa plus FVIIIa stimulate production of a considerable amount of FXa (3-4 orders of magnitude).

4. FVa joins FXa and calcium to make a much larger amount of thrombin (3-4 orders of magnitude).

BloodClotting-HardeningofClot

BloodClotting-HardeningofClot

Transglutaminase (FXIIIa)

HardeningoftheClot

Prothrombin

1.Convertsfibrinogentofibrin

Prothrombin

1.Convertsfibrinogentofibrin2.Serineprotease

Prothrombin

1.Convertsfibrinogentofibrin2.Serineprotease3.Mustbindcalciumtobeatsiteofwound

Prothrombin

1.Convertsfibrinogentofibrin2.Serineprotease3.Mustbindcalciumtobeatsiteofwound4.CarboxylationofglutamatesidechainsrequiresvitaminK

Prothrombin

1.Convertsfibrinogentofibrin2.Serineprotease3.Mustbindcalciumtobeatsiteofwound4.CarboxylationofglutamatesidechainsrequiresvitaminK5.Carboxylatedglutamatesidechainsbindcalcium

Prothrombin

1.Convertsfibrinogentofibrin2.Serineprotease3.Mustbindcalciumtobeatsiteofwound4.CarboxylationofglutamatesidechainsrequiresvitaminK5.Carboxylatedglutamatesidechainsbindcalcium6.BlockingvitaminKactionreducesclotting(bloodthinner)

Prothrombin

BloodClotting-Summary

1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.


1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.2.Tissuedamagesignalsinitiationoftheintrinsicandextrinsicpathways(molecularresponse).


1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.2.Tissuedamagesignalsinitiationoftheintrinsicandextrinsicpathways(molecularresponse).3.Theintrinsicpathwayandextrinsicpathwayaremolecularresponsesthatconvergetofavorpolymerizationoffibrin


1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.2.Tissuedamagesignalsinitiationoftheintrinsicandextrinsicpathways(molecularresponse).3.Theintrinsicpathwayandextrinsicpathwayaremolecularresponsesthatconvergetofavorpolymerizationoffibrin4.Themolecularresponsesinvolveaninitiationphasethatactivatesasmallamountofthrombin


1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.2.Tissuedamagesignalsinitiationoftheintrinsicandextrinsicpathways(molecularresponse).3.Theintrinsicpathwayandextrinsicpathwayaremolecularresponsesthatconvergetofavorpolymerizationoffibrin4.Themolecularresponsesinvolveaninitiationphasethatactivatesasmallamountofthrombin5.ThesmallamountofactivethrombinresultsinamplificationoffactorsFXaandFVabymanyfold,whichinturnactivatethrombinbymillionsoffold.


1.Tissuedamageinitiatesacellularresponsethatstartsaprocesstoplugthewound(stickyplatelets)andreleasescalciumnecessaryforthecellularresponse.2.Tissuedamagesignalsinitiationoftheintrinsicandextrinsicpathways(molecularresponse).3.Theintrinsicpathwayandextrinsicpathwayaremolecularresponsesthatconvergetofavorpolymerizationoffibrin4.Themolecularresponsesinvolveaninitiationphasethatactivatesasmallamountofthrombin5.ThesmallamountofactivethrombinresultsinamplificationoffactorsFXaandFVabymanyfold,whichinturnactivatethrombinbymillionsoffold.6.Thrombinactivatesfibrinogentomakefibrinandformtheclot


Hemophilia

Hemophilia1. Deficiency of FVIII leads to Hemophilia A (about 1 in 5000 to 10,000 male births)


2. Deficiency of FIX produces Hemophilia B (about 1 in 20,000 to 35,000 male births).


2. Deficiency of FIX produces Hemophilia B (about 1 in 20,000 to 35,000 male births).

3. In 1960, the life expectancy of a hemophiliac was about 11 years. Today, it is over 60.

vonWillebrand’sdisease

1.Similartohemophilia


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.3.Anchorsplateletsnearthesiteofthewoundinthecellularresponse


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.3.Anchorsplateletsnearthesiteofthewoundinthecellularresponse4.Bindstoaplateletglycoprotein.


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.3.Anchorsplateletsnearthesiteofthewoundinthecellularresponse4.Bindstoaplateletglycoprotein.5.Bindstoheparinandhelpsmoderateitsaction.


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.3.Anchorsplateletsnearthesiteofthewoundinthecellularresponse4.Bindstoaplateletglycoprotein.5.Bindstoheparinandhelpsmoderateitsaction.6.Bindstocollagen


1.Similartohemophilia2.vonWillebrandfactorisalargemultimericglycoproteinpresentinbloodplasmaandalsoproducedintheendotheliumliningbloodvessels.3.Anchorsplateletsnearthesiteofthewoundinthecellularresponse4.Bindstoaplateletglycoprotein.5.Bindstoheparinandhelpsmoderateitsaction.6.Bindstocollagen7.BindstoFVIIIinthemolecularresponse,playingaprotectiveroleforit.IntheabsenceofthevonWillebrandfactor,FVIIIisdestroyed.


VitaminK

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone Health

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat Tissue

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, Collards

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in Sunlight

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in SunlightMultiple Forms

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in SunlightMultiple FormsVitamin K-related Modifications Facilitate Calcium Binding by Target Proteins

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in SunlightMultiple FormsVitamin K-related Modifications Facilitate Calcium Binding by Target ProteinsAbsence of Vitamin K Leads to Uncontrolled Bleeding

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in SunlightMultiple FormsVitamin K-related Modifications Facilitate Calcium Binding by Target ProteinsAbsence of Vitamin K Leads to Uncontrolled BleedingDeficiency Rare in Healthy Adults

Phylloquinone (K1)

VitaminKFat Soluble Vitamin With Roles in Blood Clotting and Bone HealthStored in Fat TissueMost Abundant in Green Leafy Vegetables - Kale, Spinach, CollardsStable in Air. Decomposes in SunlightMultiple FormsVitamin K-related Modifications Facilitate Calcium Binding by Target ProteinsAbsence of Vitamin K Leads to Uncontrolled BleedingDeficiency Rare in Healthy AdultsRequired for Bone Formation

Phylloquinone (K1)

VitaminK

VitaminK

Vitamin K is a Group of Molecules

VitaminK

Vitamin K is a Group of MoleculesK1 - Phylloquinone - Electron Acceptor in Plants (Photosystem I)

VitaminK


K1

MK-4

MK-

VitaminK


Found in Leaves of Green Plants

K1

MK-4

MK-

VitaminK


Found in Leaves of Green PlantsInvolved in Carboxylation of Glutamates of Blood Clotting Factors II, VII, IX, X

K1

MK-4

MK-

VitaminK


Found in Leaves of Green PlantsInvolved in Carboxylation of Glutamates of Blood Clotting Factors II, VII, IX, XInvolved in Carboxylation of Glutamates of Anticoagulation Factors Protein C and S

K1

MK-4

MK-

VitaminK



K2 - Menaquinone-n - A Group of Compounds Differing in Number of Isoprenes

Menaquinone-n (K2)

VitaminK



K2 - Menaquinone-n - A Group of Compounds Differing in Number of IsoprenesMK-4 and MK-7 are Subtypes of K2

Menaquinone-n (K2)

VitaminK



K2 - Menaquinone-n - A Group of Compounds Differing in Number of IsoprenesMK-4 and MK-7 are Subtypes of K2As Involved in Glutamate Carboxylations as K1

Menaquinone-n (K2)

VitaminK

VitaminK

γ-carboxyglutamate

Glutamate Carboxylase

O2 + CO2 H2O + H+

Vitamin K Vitamin K Epoxide

Needed for Carboxylation of Proteins

Ca++

VitaminK

Warfarin Blocks Vitamin K Recycling

Vitamin K Epoxide


Must be Recycled

Vitamin K Epoxide Vitamin K

H2O

Vitamin K Epoxide

Reductase


Vitamin K Epoxide Vitamin K

H2O

Vitamin K Epoxide

Reductase

Warfarin (Coumadin)


VitaminK

VitaminK

Vitamin K is Important for Bone Health

VitaminK

Vitamin K is Important for Bone HealthStimulates Carboxylation and Activates Many Proteins

VitaminK


Osteocalcin - Binds Bone Matrix, Stimulates Osteoblasts

VitaminK


Osteocalcin - Binds Bone Matrix, Stimulates OsteoblastsPeriostin - Involved in Cell Migration, Bone Development,

BloodThinning-Aspirin

Inhibitssynthesisofprostaglandins


InhibitssynthesisofprostaglandinsProstaglandinsareprecursorsofthromboxaneA2


InhibitssynthesisofprostaglandinsProstaglandinsareprecursorsofthromboxaneA2ThomboxaneA2helpsmakeplatelets“sticky”incellularresponse


ClotDissolving-Plasmin

ClotDissolving-Plasmin Blue arrows activate Red arrows inhibit

Plasmin

Serineprotease

Plasmin

SerineproteaseCleavesfibrinclots,fibronectin,thrombospondin,laminin,andthevonWillebrandfactor

Plasmin

SerineproteaseCleavesfibrinclots,fibronectin,thrombospondin,laminin,andthevonWillebrandfactorActivatescollagenasesbycleavagealso

Plasmin

MetabolicMelody

Thank Goodness My Blood is Clotting(to the tune of "Don't Sleep in the Subway Darling")

Copyright © Kevin Ahern

I’m feeling so sad‘Cuz I cut . . . . myself bad

Now I’m all worried ‘bout . . . . consequences

It’s starting to bleedThere’s some clo . . . . sure I need

So the body kicks . . . . in its defenses

It’s happened all so many times beforeThe blood flows out and then it shuts the door

Thank goodness my blood is clotting

Enmeshing the fibrin chainsThank goodness my blood is clotting

The zymogensAre activating and all is wellSo I’ll stop bleeding again

The vitamin K’s

Help to . . . . bind to cee-aysAdding C-O-. . . . O-H to amend things

Um-m-um-um-um-um

http://www.davincipress.com/professional.html

Thank Goodness My Blood is Clotting(to the tune of "Don't Sleep in the Subway Darling")

Copyright © Kevin Ahern

I’m feeling so sad‘Cuz I cut . . . . myself bad

Now I’m all worried ‘bout . . . . consequences

It’s starting to bleedThere’s some clo . . . . sure I need

So the body kicks . . . . in its defenses

It’s happened all so many times beforeThe blood flows out and then it shuts the door

Thank goodness my blood is clotting

Enmeshing the fibrin chainsThank goodness my blood is clotting

The zymogensAre activating and all is wellSo I’ll stop bleeding again

The vitamin K’s

Help to . . . . bind to cee-aysAdding C-O-. . . . O-H to amend things

Um-m-um-um-um-um

It hardens and staysWhen a glu. . . . taminase

Creates co. . . . valent bonds . . . . for cementing

In just a moment, things are good to goThe clot’s in place and it has stopped the flow

But what about clot dissolving?

Untangling fibrin chains?This calls for some problem solving

There is a wayJust activate up some t-PAGet plasmin active in veins

Oh, oh, oh.

And thanks to the dis-enclotting’As part of repairin’ veins

It’s part of my body’s plottingThe wound is gone

I’m back where I started andNothing’s wrong

My blood flow is normal again.

http://www.davincipress.com/professional.html

enzyme regulation ii blood clotting - oregon state...

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