Physiologulation
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Transcript of Physiologulation
The Physiology of The Physiology of coagulationcoagulation
How to clotHow to clot
But not too muchBut not too much
BasisBasis
Blood flows through intact vesselsBlood flows through intact vessels– Resting state is designed to keep blood Resting state is designed to keep blood
flowingflowing– Arteries: rapid flow. Injury requires a plugArteries: rapid flow. Injury requires a plug
Rapid, localised, controlled. Rapid, localised, controlled. minimise blood flow compromiseminimise blood flow compromise
– Veins: slower, intermittent flowVeins: slower, intermittent flow Systemic anticoagulantSystemic anticoagulant clot dissolving systemclot dissolving system
Complex activating and inhibition Complex activating and inhibition systemsystem
Five componentsFive components– VesselsVessels– PlateletsPlatelets– Coagulation factors (clot forming) Coagulation factors (clot forming) – Coagulation inhibitors (clot controlling)Coagulation inhibitors (clot controlling)– Fibrinolysis (clot dissolving)Fibrinolysis (clot dissolving)
HaemostasisHaemostasis
1.1. VasoconstrictionVasoconstriction
2.2. Platelets activated by thrombin Platelets activated by thrombin form a platelet plugform a platelet plug
3.3. Fibrin mesh forms via activation Fibrin mesh forms via activation of the coagulation system to of the coagulation system to strengthen the clotstrengthen the clot
4.4. Clot dissolution via plasminClot dissolution via plasmin
5.5. Normal blood flow past the clotNormal blood flow past the clot
Platelet shape changePlatelet shape change
Pseudopod formationPseudopod formation Interact with adjacent plateletsInteract with adjacent platelets Contract later to consolidate the Contract later to consolidate the
platelet plug in process of clot platelet plug in process of clot retractionretraction
Platelet adhesionPlatelet adhesion
Platelet receptors (integrins)Platelet receptors (integrins)– Glycoprotein Glycoprotein Ib/IXIb/IX– Glycoprotein Ia/IIaGlycoprotein Ia/IIa
Ligands interact with receptorsLigands interact with receptors– Von Willebrand factorVon Willebrand factor
Large (high molecular weight) Large (high molecular weight) multimersmultimers
– collagencollagen
Platelet release Platelet release reaction reaction StimuliStimuli
– Adrenaline, collagen, ADP, thrombinAdrenaline, collagen, ADP, thrombin Release of preformed active substances Release of preformed active substances
from granulesfrom granules– ADP, serotonin, lysozyme,factor V, ADP, serotonin, lysozyme,factor V,
thrombospondin thrombospondin Activate the prostaglandin pathwayActivate the prostaglandin pathway
– Thromboxane A2 via cyclooxygenaseThromboxane A2 via cyclooxygenase Calcium releaseCalcium release Glycoprotein IIb/II activationGlycoprotein IIb/II activation
Platelet
Phospholipid
Arachadonic acid
Endoperoxidases
Thromboxane A2
Calcium flux
Phospholipase A2
Cyclooxygenase
Thromboxane synthase
Phosphodiesterase
Platelet aggregationPlatelet aggregation
Platelet receptorPlatelet receptor– Glycoprotein Glycoprotein IIb/IIIaIIb/IIIa
LigandsLigands– Von Willebrand factorVon Willebrand factor– FibrinogenFibrinogen
IRREVERSIBLE aggregation -> PlugIRREVERSIBLE aggregation -> Plug
Coagulation forms Coagulation forms fibrin meshfibrin mesh Biological amplification system which Biological amplification system which
converts soluble fibrinogen to an converts soluble fibrinogen to an insoluble fibrin meshwork which coverts insoluble fibrin meshwork which coverts the primary platelet plug to a firm, the primary platelet plug to a firm, definitive stable clot.definitive stable clot.
Required local concentration of clotting Required local concentration of clotting factors at site of injuryfactors at site of injury
Surface mediated reactions on exposed Surface mediated reactions on exposed collagen, platelet phospholipid or tissue collagen, platelet phospholipid or tissue factorfactor
General conceptsGeneral concepts Coagulation factors act as proteases Coagulation factors act as proteases
when activated (serine proteases)when activated (serine proteases) Zymogens (inactive eg fibrinogen) Zymogens (inactive eg fibrinogen)
converted to enzymes/proteins by limited converted to enzymes/proteins by limited proteolysisproteolysis
Complex formation requiring calcium,Complex formation requiring calcium,phospholipid surface, cofactorsphospholipid surface, cofactors
Thrombin converts fibrinogen to fibrin Thrombin converts fibrinogen to fibrin monomermonomer
Fibrin monomer crosslinked to fibrinFibrin monomer crosslinked to fibrin Forms "glue" for platelet plugForms "glue" for platelet plug
Cascade effect -> Cascade effect -> amplificationamplification
XIIa
XIa
XI a
IX a
IX a
IX a
IX a
Xa
Xa
Xa
Xa
Xa
Xa
Xa
II a
II a
II a
II a
II a
II a
II a
II a
II a
II a
II a
II a
2x108mol
Fibrin
mesh
1 mol
Coagulation cascadeCoagulation cascade
XII
XI
IX
XVIII
Prothrombin (II)
thrombin
fibrinogen fibrin
STABILISED FIBRIN
V, Ca, P/L
VII
Intrinsic pathway
Extrinsic pathway
XIII
APTT
PT
VIIa
TF X Xa
II (Prothrombin)
IIa (Thrombin)
Va
VIIIa
VaXIa
INITIATION
IXa
AMPLIFICATION
Xa-Va-II
Prothrombinase
Platelet
IXa- VIIa-X
“tenase”
TF IX
VIIa
THROMBIN (IIa) FIBRIN
Fibrinogen -> fibrinFibrinogen -> fibrin
Thrombin cleaves fibrinogen Thrombin cleaves fibrinogen Fibrinopeptide releaseFibrinopeptide releaseFibrin monomersFibrin monomersSpontaneously link to form a loose Spontaneously link to form a loose
polymerpolymerFibrin meshwork is stabilised by Fibrin meshwork is stabilised by
factor XIIIa (activated by thrombin factor XIIIa (activated by thrombin and calcium)and calcium)
Inhibitors: ANTI-Inhibitors: ANTI-coagulantscoagulants Antithrombin IIIAntithrombin III
– Directly inactivates serine proteasesDirectly inactivates serine proteases– Thrombin and Xa. Also: IXa and XiaThrombin and Xa. Also: IXa and Xia– Potentiated by heparinPotentiated by heparin
Protein CProtein C– Inhibits (cleaves) the cofactors VIIIa and Inhibits (cleaves) the cofactors VIIIa and
VaVa– Significantly decreases the rate of clot Significantly decreases the rate of clot
formationformation– Needs to be activatedNeeds to be activated
Protein S:Protein S:– Enhances activity of protein CEnhances activity of protein C
ThrombomodulinThrombomodulin– Activated by thrombinActivated by thrombin– Binds to thrombin to alter its Binds to thrombin to alter its
conformationconformation– Complex activates protein CComplex activates protein C
Tissue pathway factor inhibitorTissue pathway factor inhibitor– Inhibits FVIIa-tissue factor complexInhibits FVIIa-tissue factor complex
AnticoagulantsAnticoagulants
Too little or ineffectiveToo little or ineffective– Extensive clotExtensive clot
Too muchToo much– BleedingBleeding
TherapeuticsTherapeutics– HeparinHeparin– Activated protein CActivated protein C– TPFI inhibitorTPFI inhibitor
FibrinolysisFibrinolysis
Prevents excessive fibrin Prevents excessive fibrin depositiondeposition
Allows closely coupled with fibrin Allows closely coupled with fibrin formationformation
Localised surface bound Localised surface bound phenomenon that is catalysed by phenomenon that is catalysed by fibrin formationfibrin formation
Components: Components: fibrinolysisfibrinolysis Plasminogen -> plasminPlasminogen -> plasmin
Plasminogen activatorsPlasminogen activators
Inactivators of plasminogenInactivators of plasminogen
Inhibitors of plasminInhibitors of plasmin
Effect of plasminEffect of plasmin
Lyses factor V and VIIILyses factor V and VIII Proteolysis of fibrinogenProteolysis of fibrinogen
– Removes small peptidesRemoves small peptides Degradation of fibrinDegradation of fibrin
– Fibrin degradation products (FDP)sFibrin degradation products (FDP)s– D-DimersD-Dimers
Blood Vessel: Blood Vessel: endotheliumendothelium ActiveActive Haemostasis factorsHaemostasis factors
– Von Willebrand factorVon Willebrand factor– Tissue factor – expressed after injuryTissue factor – expressed after injury
Anticoagulant factors Anticoagulant factors – ATIII, protein S, thrombomodulinATIII, protein S, thrombomodulin
FibrinolysisFibrinolysis– Tissue plasminogen activatorTissue plasminogen activator
Haemostatic responseHaemostatic response
1.1. VasoconstrictionVasoconstriction1.1. Initial slowing of blood flow to injured Initial slowing of blood flow to injured
areaarea2.2. Smooth muscle in arteriolesSmooth muscle in arterioles3.3. Vasoactive substancesVasoactive substances
2.2. Platelet primary plug formationPlatelet primary plug formation1.1. Collagen/VWFCollagen/VWF2.2. Glycoprotein Ib/IX and IIb/IIIaGlycoprotein Ib/IX and IIb/IIIa3.3. Aggregation with arachadonic acid Aggregation with arachadonic acid
pathwaypathway
Haemostatic responseHaemostatic response
3.3. Stabilsation of the platlelet plug Stabilsation of the platlelet plug with fibrinwith fibrin
1.1. Tissue factor activation of Tissue factor activation of coagulation cascadecoagulation cascade
2.2. Thrombin burstThrombin burst
3.3. Formation of fibrin meshworkFormation of fibrin meshwork
Haemostasis reactionHaemostasis reaction
4.4. Regulation of fibrin clotRegulation of fibrin clot1.1. Activation of fibrinolysisActivation of fibrinolysis
2.2. Tissue plasminogen activatorTissue plasminogen activator
3.3. Plasmin -> FDPsPlasmin -> FDPs
A test tube is not a A test tube is not a personperson Coagulation in vivoCoagulation in vivo
– TemperatureTemperature– pHpH– CalciumCalcium
That is: hypothermic , acidotic, That is: hypothermic , acidotic, hypocalcaemic patients don’t clothypocalcaemic patients don’t clot
-CARBOXYGLUTAMIC ACID
-carboxy Glu
COO-COO-
COO-
CH
CH2
CHNH3+
COO-
COO-
CH2
CH2
CHNH3+
Glu
O2,CO2
Vit KCarboxylase
VITAMIN K DEFICIENCY
• Almost always hospitalized patients• Require both malnutrition & decrease in
gut flora• PT goes up 1st, 2º to factor VII's short
half-life• Treatment: Replacement Vitamin K• Response within 24-48 hours
FIBRIN FORMATIONA
B
A
B
F XIIIa
T