clotting of blood ©copyright 1999-2004 by gene c. lavers no part of this presentation may be...

Clotting of BloodClotting of BloodClotting of BloodClotting of Blood

©Copyright 1999-2004 by Gene C. Lavers

No part of this presentation may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without written permission from the publisher.

©Copyright 1999-2004 by Gene C. Lavers

No part of this presentation may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without written permission from the publisher.

Lecture in Lecture in Basic TissuesBasic Tissues 2004 2004

Baynes & Dominiczak, Chapter 6Baynes & Dominiczak, Chapter 6

Gene C. Lavers, Ph.D.Gene C. Lavers, [email protected]@nyu.edu

Lecture in Lecture in Basic TissuesBasic Tissues 2004 2004

Baynes & Dominiczak, Chapter 6Baynes & Dominiczak, Chapter 6

Gene C. Lavers, Ph.D.Gene C. Lavers, [email protected]@nyu.edu

© Copyright 1999-2004 by Gene C. Lavers

2

Hemostasis (arrest of bleeding) Hemostasis (arrest of bleeding) Blood Blood ClottingClotting Balancing Events Balancing Events IntroductionIntroduction

Hemostasis (arrest of bleeding) Hemostasis (arrest of bleeding) Blood Blood ClottingClotting Balancing Events Balancing Events IntroductionIntroduction

VASOCONSTRICTIONVASOCONSTRICTION

PLATELET PLUG FORMATIONPLATELET PLUG FORMATION

BLOOD COAGULATION BLOOD COAGULATION

FIBRIN CLOT FORMATIONFIBRIN CLOT FORMATION

DISSOLUTION OF CLOTDISSOLUTION OF CLOT

PROTECTING THE CLOTPROTECTING THE CLOT

PREVENTING CLOT FORMATIONPREVENTING CLOT FORMATION

VASOCONSTRICTIONVASOCONSTRICTION

PLATELET PLUG FORMATIONPLATELET PLUG FORMATION

BLOOD COAGULATION BLOOD COAGULATION

FIBRIN CLOT FORMATIONFIBRIN CLOT FORMATION




Normal hemostasis is a balance between Normal hemostasis is a balance between coagulation and fibrinolytic systems.coagulation and fibrinolytic systems.Normal hemostasis is a balance between Normal hemostasis is a balance between coagulation and fibrinolytic systems.coagulation and fibrinolytic systems.


3

VaVasoconstrictionsoconstriction Blood Blood ClottingClotting PlateletPlatelets & Thromboxanes & Thromboxane OvervieOvervieww

VaVasoconstrictionsoconstriction Blood Blood ClottingClotting PlateletPlatelets & Thromboxanes & Thromboxane OvervieOvervieww

VASOCONSTRICTIONVASOCONSTRICTION – occurs immediately after vessel wall injury – occurs immediately after vessel wall injury

Diminished blood flow Diminished blood flow into and out of the vessel.into and out of the vessel. Initiated Initiated by local nerve reflexesby local nerve reflexes Sustained through biochemical mediators, Sustained through biochemical mediators, serotonin and serotonin and

histaminehistamine released from released from plateletsplatelets in the damaged in the damaged subendothelial.subendothelial.

Thromboxane AThromboxane A22 (TXA (TXA22) – A C) – A C2020 polyunsaturated fatty acid polyunsaturated fatty acid released from the activated platelets, released from the activated platelets, causes smooth muscle causes smooth muscle contraction and prolonged vasoconstriction.contraction and prolonged vasoconstriction.

The larger the portion of vessel traumatized, The larger the portion of vessel traumatized, the more the more extensive the degree of spasm.extensive the degree of spasm.

A sharply cut vessel (clean cut with sharp razor) undergoes A sharply cut vessel (clean cut with sharp razor) undergoes less spasm, i.e., bleeds longer, than a crushed vessel.less spasm, i.e., bleeds longer, than a crushed vessel.

VASOCONSTRICTIONVASOCONSTRICTION – occurs immediately after vessel wall injury – occurs immediately after vessel wall injury

Diminished blood flow Diminished blood flow into and out of the vessel.into and out of the vessel. Initiated Initiated by local nerve reflexesby local nerve reflexes Sustained through biochemical mediators, Sustained through biochemical mediators, serotonin and serotonin and

histaminehistamine released from released from plateletsplatelets in the damaged in the damaged subendothelial.subendothelial.

Thromboxane AThromboxane A22 (TXA (TXA22) – A C) – A C2020 polyunsaturated fatty acid polyunsaturated fatty acid released from the activated platelets, released from the activated platelets, causes smooth muscle causes smooth muscle contraction and prolonged vasoconstriction.contraction and prolonged vasoconstriction.

The larger the portion of vessel traumatized, The larger the portion of vessel traumatized, the more the more extensive the degree of spasm.extensive the degree of spasm.

A sharply cut vessel (clean cut with sharp razor) undergoes A sharply cut vessel (clean cut with sharp razor) undergoes less spasm, i.e., bleeds longer, than a crushed vessel.less spasm, i.e., bleeds longer, than a crushed vessel.


4

Platelet Plug Formation Platelet Plug Formation Blood Blood ClottingClottingCollagen & von Collagen & von Willebrand FactorWillebrand Factor OvervieOvervieww

Platelet Plug Formation Platelet Plug Formation Blood Blood ClottingClottingCollagen & von Collagen & von Willebrand FactorWillebrand Factor OvervieOvervieww

PLATELET PLUG FORMATIONPLATELET PLUG FORMATION – occurs within seconds after vessel – occurs within seconds after vessel wall injurywall injury

Primary hemostasis, platelets Primary hemostasis, platelets aggregate to control blood loss from aggregate to control blood loss from capillaries, arterioles, and venules.capillaries, arterioles, and venules.

If damage is small, platelet plug If damage is small, platelet plug can arrest bleeding completely by can arrest bleeding completely by closing minute ruptures in vessels that occur hundreds of times a day. closing minute ruptures in vessels that occur hundreds of times a day.

EExposure to collagen and other foreign substancesxposure to collagen and other foreign substances (antigen- (antigen-antibody complexes, thrombin, proteolytic enzymes, endotoxins, and antibody complexes, thrombin, proteolytic enzymes, endotoxins, and viruses),viruses), platelets platelets undergo dynamic change in appearance and begin the undergo dynamic change in appearance and begin the process of adheprocess of adhesion and activationsion and activation..

In adhesion, platelets swell, become sticky and adhere to collagen In adhesion, platelets swell, become sticky and adhere to collagen fibril on the basement membrane - fibril on the basement membrane - requires von Willebrand factor requires von Willebrand factor (vWF) adhere to collagen fibril(vWF) adhere to collagen fibrilss on the basement membrane (vWF on the basement membrane (vWF deficiency ideficiency is s aassociated bleeding ssociated bleeding didisordersorder).).

Activated platelets Activated platelets release granules containing vWF, factor V, release granules containing vWF, factor V, PDGF*, heparin-neutralizing protein, and ADPPDGF*, heparin-neutralizing protein, and ADP (attracts other (attracts other platelets)platelets)

PLATELET PLUG FORMATIONPLATELET PLUG FORMATION – occurs within seconds after vessel – occurs within seconds after vessel wall injurywall injury

Primary hemostasis, platelets Primary hemostasis, platelets aggregate to control blood loss from aggregate to control blood loss from capillaries, arterioles, and venules.capillaries, arterioles, and venules.

If damage is small, platelet plug If damage is small, platelet plug can arrest bleeding completely by can arrest bleeding completely by closing minute ruptures in vessels that occur hundreds of times a day. closing minute ruptures in vessels that occur hundreds of times a day.

EExposure to collagen and other foreign substancesxposure to collagen and other foreign substances (antigen- (antigen-antibody complexes, thrombin, proteolytic enzymes, endotoxins, and antibody complexes, thrombin, proteolytic enzymes, endotoxins, and viruses),viruses), platelets platelets undergo dynamic change in appearance and begin the undergo dynamic change in appearance and begin the process of adheprocess of adhesion and activationsion and activation..

In adhesion, platelets swell, become sticky and adhere to collagen In adhesion, platelets swell, become sticky and adhere to collagen fibril on the basement membrane - fibril on the basement membrane - requires von Willebrand factor requires von Willebrand factor (vWF) adhere to collagen fibril(vWF) adhere to collagen fibrilss on the basement membrane (vWF on the basement membrane (vWF deficiency ideficiency is s aassociated bleeding ssociated bleeding didisordersorder).).

Activated platelets Activated platelets release granules containing vWF, factor V, release granules containing vWF, factor V, PDGF*, heparin-neutralizing protein, and ADPPDGF*, heparin-neutralizing protein, and ADP (attracts other (attracts other platelets)platelets)

* PDGF Platelet-derived growth factor* PDGF Platelet-derived growth factor


5

Clotting ProceClotting Processss Blood Blood ClottingClottingZymogen CaZymogen Cascades scades IntroductionIntroduction

Clotting ProceClotting Processss Blood Blood ClottingClottingZymogen CaZymogen Cascades scades IntroductionIntroduction

CLOTTINGCLOTTING – stops bleeding and hemorrhage. – stops bleeding and hemorrhage.

2 zymogen activation cascades – 2 zymogen activation cascades – both convert inactive both convert inactive Stuart factor (X) to active Stuart factor Xa.Stuart factor (X) to active Stuart factor Xa.

Xa + Va Xa + Va activates prothrombin (II) to thrombin IIa.activates prothrombin (II) to thrombin IIa. Thrombin Thrombin activates activates soluble soluble fibrinogenfibrinogen (I) to in (I) to insoluble soluble

fibrin (Iafibrin (Ia)) Fibrin Fibrin aggregates forming enormous numbers of fibers aggregates forming enormous numbers of fibers

thatthat entangle one and other into a meentangle one and other into a meshwork that shwork that yieldyieldss a a soft clotsoft clot..

Transglutaminase (Transglutaminase (XXIIIa) IIIa) cross-links fibrin threads to cross-links fibrin threads to yield a yield a hard clothard clot..

Vitamin K and CaVitamin K and Ca2+2+ are essential for liver are essential for liver synthesis of synthesis of effective protein factors (II, IX, X, XI) that can bind effective protein factors (II, IX, X, XI) that can bind efficiently to membrane phospholipids exposed by wound efficiently to membrane phospholipids exposed by wound or trauma.or trauma.

CLOTTINGCLOTTING – stops bleeding and hemorrhage. – stops bleeding and hemorrhage.

2 zymogen activation cascades – 2 zymogen activation cascades – both convert inactive both convert inactive Stuart factor (X) to active Stuart factor Xa.Stuart factor (X) to active Stuart factor Xa.

Xa + Va Xa + Va activates prothrombin (II) to thrombin IIa.activates prothrombin (II) to thrombin IIa. Thrombin Thrombin activates activates soluble soluble fibrinogenfibrinogen (I) to in (I) to insoluble soluble

fibrin (Iafibrin (Ia)) Fibrin Fibrin aggregates forming enormous numbers of fibers aggregates forming enormous numbers of fibers

thatthat entangle one and other into a meentangle one and other into a meshwork that shwork that yieldyieldss a a soft clotsoft clot..

Transglutaminase (Transglutaminase (XXIIIa) IIIa) cross-links fibrin threads to cross-links fibrin threads to yield a yield a hard clothard clot..

Vitamin K and CaVitamin K and Ca2+2+ are essential for liver are essential for liver synthesis of synthesis of effective protein factors (II, IX, X, XI) that can bind effective protein factors (II, IX, X, XI) that can bind efficiently to membrane phospholipids exposed by wound efficiently to membrane phospholipids exposed by wound or trauma.or trauma.


6

Clot Prevention/InhibitionClot Prevention/Inhibition Blood Blood ClottingClottingAntithrombin III Antithrombin III IntroductionIntroduction


INHIBITING CLOT FORMATIONINHIBITING CLOT FORMATION

PreventionPrevention unscheduled clotsunscheduled clots clots beyond local trauma area.clots beyond local trauma area.

Anti thrombin III (AT III) Anti thrombin III (AT III) binds irreversibly to thrombin (IIa).binds irreversibly to thrombin (IIa).

Also binds to IXa, Xa, and XIa of the intrinsic Also binds to IXa, Xa, and XIa of the intrinsic pathway.pathway.


PreventionPrevention unscheduled clotsunscheduled clots clots beyond local trauma area.clots beyond local trauma area.

Anti thrombin III (AT III) Anti thrombin III (AT III) binds irreversibly to thrombin (IIa).binds irreversibly to thrombin (IIa).

Also binds to IXa, Xa, and XIa of the intrinsic Also binds to IXa, Xa, and XIa of the intrinsic pathway.pathway.


7



DISSOLUTION OF CLOTDISSOLUTION OF CLOT – removing unscheduled clots – removing unscheduled clots

and fostering healing.and fostering healing.

Tissue Plasminogen Activator (TPA) Tissue Plasminogen Activator (TPA) activates activates plasminogen to plasmin.plasminogen to plasmin.

Plasmin (a protease) Plasmin (a protease) hydrolyzes fibrin to peptides…clot hydrolyzes fibrin to peptides…clot dissolvesdissolves

DISSOLUTION OF CLOTDISSOLUTION OF CLOT – removing unscheduled clots – removing unscheduled clots

and fostering healing.and fostering healing.

Tissue Plasminogen Activator (TPA) Tissue Plasminogen Activator (TPA) activates activates plasminogen to plasmin.plasminogen to plasmin.

Plasmin (a protease) Plasmin (a protease) hydrolyzes fibrin to peptides…clot hydrolyzes fibrin to peptides…clot dissolvesdissolves


8

Topics-subtopicsTopics-subtopics Blood Blood ClottingClotting IntroductionIntroduction

Topics-subtopicsTopics-subtopics Blood Blood ClottingClotting IntroductionIntroduction

PROTECTING THE CLOT – PROTECTING THE CLOT – during healingduring healing

AntiplasminAntiplasmin inhibits fibrin hydrolysis. inhibits fibrin hydrolysis.

PREVENTING CLOT FORMATION – PREVENTING CLOT FORMATION – fail safe agentfail safe agent Heparin Heparin acts as a catalyst for inactivation of thrombin acts as a catalyst for inactivation of thrombin

by antithrombin III.by antithrombin III.

Citrate Citrate acts to chelate* Ca acts to chelate* Ca 2+2+

Oxalate Oxalate also chelates Ca also chelates Ca 2+2+

PROTECTING THE CLOT – PROTECTING THE CLOT – during healingduring healing

AntiplasminAntiplasmin inhibits fibrin hydrolysis. inhibits fibrin hydrolysis.

PREVENTING CLOT FORMATION – PREVENTING CLOT FORMATION – fail safe agentfail safe agent Heparin Heparin acts as a catalyst for inactivation of thrombin acts as a catalyst for inactivation of thrombin

by antithrombin III.by antithrombin III.

Citrate Citrate acts to chelate* Ca acts to chelate* Ca 2+2+

Oxalate Oxalate also chelates Ca also chelates Ca 2+2+

CC

OO

O–O–

RR CC

CC

OOO–O–

Ca2+Ca2+

Chelate: clawChelate: claw

-carboxylate group-carboxylate group-carboxylate group-carboxylate groupCaCa22++

COO–COO–COO–COO–

COO–COO–COO–COO–COO–COO–COO–COO–

HOHOHOHO

CitrateCitrate

CaCa22++CaCa22++COO–COO–COO–COO–

COO–COO–COO–COO–

OxalateOxalate


9

Four Principle ComponentsFour Principle Components Blood Blood Clotting Clotting Introduction Introduction

Four Principle ComponentsFour Principle Components Blood Blood Clotting Clotting Introduction Introduction

Intact endothelial cellsIntact endothelial cells – – inhibit blood clotting by displaying inhibit blood clotting by displaying proteins that inhibit the clotting system, and they form proteins that inhibit the clotting system, and they form prostacyclin (PGIprostacyclin (PGI22) which they release ) which they release (t/2 ~ 3 min)(t/2 ~ 3 min) to to prevent platelet aggregation, adhesion, and thrombus prevent platelet aggregation, adhesion, and thrombus formation.formation.

Subendothelial tissuesSubendothelial tissues – – contain membrane proteins contain membrane proteins normally not in contact with the blood. When exposed after normally not in contact with the blood. When exposed after injury, platelets and clotting factors adhere to components injury, platelets and clotting factors adhere to components of the subendothelial tissue, where they become activated.of the subendothelial tissue, where they become activated.

PlateletsPlatelets – – bind to components of the subendothelial tissue. bind to components of the subendothelial tissue. Subsequently, clotting factors bind and are activated on Subsequently, clotting factors bind and are activated on their surface.their surface.

Clotting factorsClotting factors – – are soluble plasma proteins, most are are soluble plasma proteins, most are serine proteases, that circulate as inactive zymogens serine proteases, that circulate as inactive zymogens awaiting proteolytic cascade activations that trigger awaiting proteolytic cascade activations that trigger insoluble fibrin formation from soluble fibrinogen.insoluble fibrin formation from soluble fibrinogen.

Intact endothelial cellsIntact endothelial cells – – inhibit blood clotting by displaying inhibit blood clotting by displaying proteins that inhibit the clotting system, and they form proteins that inhibit the clotting system, and they form prostacyclin (PGIprostacyclin (PGI22) which they release ) which they release (t/2 ~ 3 min)(t/2 ~ 3 min) to to prevent platelet aggregation, adhesion, and thrombus prevent platelet aggregation, adhesion, and thrombus formation.formation.

Subendothelial tissuesSubendothelial tissues – – contain membrane proteins contain membrane proteins normally not in contact with the blood. When exposed after normally not in contact with the blood. When exposed after injury, platelets and clotting factors adhere to components injury, platelets and clotting factors adhere to components of the subendothelial tissue, where they become activated.of the subendothelial tissue, where they become activated.

PlateletsPlatelets – – bind to components of the subendothelial tissue. bind to components of the subendothelial tissue. Subsequently, clotting factors bind and are activated on Subsequently, clotting factors bind and are activated on their surface.their surface.

Clotting factorsClotting factors – – are soluble plasma proteins, most are are soluble plasma proteins, most are serine proteases, that circulate as inactive zymogens serine proteases, that circulate as inactive zymogens awaiting proteolytic cascade activations that trigger awaiting proteolytic cascade activations that trigger insoluble fibrin formation from soluble fibrinogen.insoluble fibrin formation from soluble fibrinogen.


10

Coordinated Four Functions Coordinated Four Functions Blood Blood ClottingClottingThrombosis vs. fibrinolysis Thrombosis vs. fibrinolysis

Coordinated Four Functions Coordinated Four Functions Blood Blood ClottingClottingThrombosis vs. fibrinolysis Thrombosis vs. fibrinolysis

Fig. 6.1 Overview of hemostatic mechanismsFig. 6.1 Overview of hemostatic mechanisms

11

1. Arteriolar vasoconstriction 1. Arteriolar vasoconstriction can can transiently reduce blood flow, transiently reduce blood flow, and can give some platelet and can give some platelet aggregation.aggregation.

1. Arteriolar vasoconstriction 1. Arteriolar vasoconstriction can can transiently reduce blood flow, transiently reduce blood flow, and can give some platelet and can give some platelet aggregation.aggregation.2. Activation of blood platelets 2. Activation of blood platelets for adhesion to traumatized for adhesion to traumatized vessel wall.vessel wall.

2. Activation of blood platelets 2. Activation of blood platelets for adhesion to traumatized for adhesion to traumatized vessel wall.vessel wall.

3. Activation of coagulation 3. Activation of coagulation cascade systems cascade systems for activation for activation of thrombinof thrombin. .

3. Activation of coagulation 3. Activation of coagulation cascade systems cascade systems for activation for activation of thrombinof thrombin. . 4. Activation of fibrin 4. Activation of fibrin polymerization and crosslinking polymerization and crosslinking of fibrin soft clot to stable hard of fibrin soft clot to stable hard clot after vasoconstriction clot after vasoconstriction lessens or traumatized tissue is lessens or traumatized tissue is disturbed; clot is anchored.disturbed; clot is anchored.

4. Activation of fibrin 4. Activation of fibrin polymerization and crosslinking polymerization and crosslinking of fibrin soft clot to stable hard of fibrin soft clot to stable hard clot after vasoconstriction clot after vasoconstriction lessens or traumatized tissue is lessens or traumatized tissue is disturbed; clot is anchored.disturbed; clot is anchored.

22

33

44

1.1. TPA TPA activates plasminogen.activates plasminogen.2.2. Plasmin Plasmin proteolytically digests proteolytically digests

clot clot peptide peptides s amino acids. amino acids.

1.1. TPA TPA activates plasminogen.activates plasminogen.2.2. Plasmin Plasmin proteolytically digests proteolytically digests

clot clot peptide peptides s amino acids. amino acids.

4 stages 4 stages Clotting Clotting 4 stages 4 stages Clotting Clotting

Dissolution Dissolution peptides peptides Dissolution Dissolution peptides peptides


11

Bleeding Disorders Bleeding Disorders Blood Blood ClottingClottingCongenital and acquiredCongenital and acquired HemophiliaHemophilia

Bleeding Disorders Bleeding Disorders Blood Blood ClottingClottingCongenital and acquiredCongenital and acquired HemophiliaHemophilia

Hemophilia AHemophilia A deficient VIIIdeficient VIII Hemophilia BHemophilia B

deficient Ideficient IX (ChriX (Christmas)stmas)

Hemophilia AHemophilia A deficient VIIIdeficient VIII Hemophilia BHemophilia B

deficient Ideficient IX (ChriX (Christmas)stmas)

Clotting is slow, slower, Clotting is slow, slower, absent absent Clotting is slow, slower, Clotting is slow, slower, absent absent

Fig. 6.2 Congenital and acquired causes of excessive bleeding.Fig. 6.2 Congenital and acquired causes of excessive bleeding.Fig. 6.2 Congenital and acquired causes of excessive bleeding.Fig. 6.2 Congenital and acquired causes of excessive bleeding.


12

Classic HemophiliaClassic Hemophilia Blood Blood ClottingClottingFactor VIII deficiencyFactor VIII deficiency

Classic HemophiliaClassic Hemophilia Blood Blood ClottingClottingFactor VIII deficiencyFactor VIII deficiency

Fig. 6.7 Severe bruising from minor fall in a 3-Fig. 6.7 Severe bruising from minor fall in a 3-yr oldyr old child with classic hemophilia.child with classic hemophilia.

Fig. 6.7 Severe bruising from minor fall in a 3-Fig. 6.7 Severe bruising from minor fall in a 3-yr oldyr old child with classic hemophilia.child with classic hemophilia.


13

Genetic DisordersGenetic Disorders Blood Blood ClottingClotting ClinicalClinical

Genetic DisordersGenetic Disorders Blood Blood ClottingClotting ClinicalClinical

Hemophilia A Hemophilia A (recessive, X-linked) - Females carry the (recessive, X-linked) - Females carry the defective gene, males express the phenotype of the defective gene, males express the phenotype of the disorder. disorder. 85% of cases, Factor VIII (intrinsic pathway) is missing.85% of cases, Factor VIII (intrinsic pathway) is missing. Because antihemophilic factor is missing, clotting is Because antihemophilic factor is missing, clotting is

blocked. Interaction with Ca-dependent IXa that yields Xa blocked. Interaction with Ca-dependent IXa that yields Xa does not occur. Thus, inactve IX fails to act on prothrombin does not occur. Thus, inactve IX fails to act on prothrombin (II) to yield thrombin (IIa).(II) to yield thrombin (IIa).

Occurs in about 1 in 10,000 males.Occurs in about 1 in 10,000 males. Treat with factor VIII or IX concentrates.Treat with factor VIII or IX concentrates.

Hemophilia BHemophilia B - Factor IX (Christmas) is missing, thereby - Factor IX (Christmas) is missing, therebylimiting normal blood clotting.limiting normal blood clotting.

Hemophilia A Hemophilia A (recessive, X-linked) - Females carry the (recessive, X-linked) - Females carry the defective gene, males express the phenotype of the defective gene, males express the phenotype of the disorder. disorder. 85% of cases, Factor VIII (intrinsic pathway) is missing.85% of cases, Factor VIII (intrinsic pathway) is missing. Because antihemophilic factor is missing, clotting is Because antihemophilic factor is missing, clotting is

blocked. Interaction with Ca-dependent IXa that yields Xa blocked. Interaction with Ca-dependent IXa that yields Xa does not occur. Thus, inactve IX fails to act on prothrombin does not occur. Thus, inactve IX fails to act on prothrombin (II) to yield thrombin (IIa).(II) to yield thrombin (IIa).

Occurs in about 1 in 10,000 males.Occurs in about 1 in 10,000 males. Treat with factor VIII or IX concentrates.Treat with factor VIII or IX concentrates.

Hemophilia BHemophilia B - Factor IX (Christmas) is missing, thereby - Factor IX (Christmas) is missing, therebylimiting normal blood clotting.limiting normal blood clotting.


14

Vessel Wall Vessel Wall Blood Blood ClottingClottingFour layered structure Four layered structure Functional Functional RolesRoles

Vessel Wall Vessel Wall Blood Blood ClottingClottingFour layered structure Four layered structure Functional Functional RolesRoles Thrombo-resistant endothelial cell lining: Thrombo-resistant endothelial cell lining:

produces produces two vasodilatorstwo vasodilators and inhibitors of and inhibitors of platelet function:platelet function: prostacyclin (prostaglandin prostacyclin (prostaglandin II22, PGI, PGI22, , nitric oxide nitric oxide (NO, also called Endothelium-(NO, also called Endothelium-

Derived Relaxing Factor, EDRF) produced from Derived Relaxing Factor, EDRF) produced from arginine by eNOS (synthase) controlled by arginine by eNOS (synthase) controlled by intracellular [Caintracellular [Ca2+2+]. ].

Vasoconstriction after vascular injury: Vasoconstriction after vascular injury: mediated in mediated in part by serotonin andpart by serotonin and thromboxane Athromboxane A22 (TXA (TXA22)) released from activated platelets.released from activated platelets.

Disruption of the endothelial layer exposes Disruption of the endothelial layer exposes subendothelialsubendothelial Tissue factor – activates the extrinsic pathway Tissue factor – activates the extrinsic pathway

of blood coagulation.of blood coagulation.

Collagen – activates the intrinsic pathway of Collagen – activates the intrinsic pathway of blood coagulation.blood coagulation.

Stimulates platelet activationStimulates platelet activation

Stimulates platelet binding to exposed Stimulates platelet binding to exposed collagen collagen via von Willebrand factorvia von Willebrand factor (vWF) released from (vWF) released from endothelial cells also bound to platelet GPIb-IX endothelial cells also bound to platelet GPIb-IX receptor.receptor.

Thrombo-resistant endothelial cell lining: Thrombo-resistant endothelial cell lining: produces produces two vasodilatorstwo vasodilators and inhibitors of and inhibitors of platelet function:platelet function: prostacyclin (prostaglandin prostacyclin (prostaglandin II22, PGI, PGI22, , nitric oxide nitric oxide (NO, also called Endothelium-(NO, also called Endothelium-

Derived Relaxing Factor, EDRF) produced from Derived Relaxing Factor, EDRF) produced from arginine by eNOS (synthase) controlled by arginine by eNOS (synthase) controlled by intracellular [Caintracellular [Ca2+2+]. ].

Vasoconstriction after vascular injury: Vasoconstriction after vascular injury: mediated in mediated in part by serotonin andpart by serotonin and thromboxane Athromboxane A22 (TXA (TXA22)) released from activated platelets.released from activated platelets.

Disruption of the endothelial layer exposes Disruption of the endothelial layer exposes subendothelialsubendothelial Tissue factor – activates the extrinsic pathway Tissue factor – activates the extrinsic pathway

of blood coagulation.of blood coagulation.

Collagen – activates the intrinsic pathway of Collagen – activates the intrinsic pathway of blood coagulation.blood coagulation.

Stimulates platelet activationStimulates platelet activation

Stimulates platelet binding to exposed Stimulates platelet binding to exposed collagen collagen via von Willebrand factorvia von Willebrand factor (vWF) released from (vWF) released from endothelial cells also bound to platelet GPIb-IX endothelial cells also bound to platelet GPIb-IX receptor.receptor.

Fig. 6.3 Structure of blood Fig. 6.3 Structure of blood vessel wall.vessel wall.Fig. 6.3 Structure of blood Fig. 6.3 Structure of blood vessel wall.vessel wall.

TXATXA22 is a potent is a potent mediator of platelet mediator of platelet activation and activation and vasoconstrictionvasoconstriction

TXATXA22 is a potent is a potent mediator of platelet mediator of platelet activation and activation and vasoconstrictionvasoconstriction


15

Platelets (150-400 x 10Platelets (150-400 x 1099/L)/L) Activated by Activated by

ADP from endothelial, RBC, and ADP from endothelial, RBC, and plateletsplatelets

EpinephrineEpinephrine CollagenCollagen ThrombinThrombin Platelet Activating Factor, PAFPlatelet Activating Factor, PAF Immune complexes (infection)Immune complexes (infection) Shear stress from blood flowShear stress from blood flow

Platelet shape: disc to spherePlatelet shape: disc to sphere Release: Release: TXATXA22 (t/2, 30sec)(t/2, 30sec) and and

vWFvWF Aggregation via vWF and Aggregation via vWF and

fibrinogen fibrinogen binding to binding to GPIbIXGPIbIX and and GPIIa-IIIPGPIIa-IIIP receptors receptors

Adhesion to vessel wall linked Adhesion to vessel wall linked by vWFby vWF

Platelets (150-400 x 10Platelets (150-400 x 1099/L)/L) Activated by Activated by

ADP from endothelial, RBC, and ADP from endothelial, RBC, and plateletsplatelets

EpinephrineEpinephrine CollagenCollagen ThrombinThrombin Platelet Activating Factor, PAFPlatelet Activating Factor, PAF Immune complexes (infection)Immune complexes (infection) Shear stress from blood flowShear stress from blood flow

Platelet shape: disc to spherePlatelet shape: disc to sphere Release: Release: TXATXA22 (t/2, 30sec)(t/2, 30sec) and and

vWFvWF Aggregation via vWF and Aggregation via vWF and

fibrinogen fibrinogen binding to binding to GPIbIXGPIbIX and and GPIIa-IIIPGPIIa-IIIP receptors receptors

Adhesion to vessel wall linked Adhesion to vessel wall linked by vWFby vWF

Platelet Activation Platelet Activation Blood Blood ClottingClottingAntiplatelet drugsAntiplatelet drugs EicosanoidsEicosanoids

Platelet Activation Platelet Activation Blood Blood ClottingClottingAntiplatelet drugsAntiplatelet drugs EicosanoidsEicosanoids

Exposed Exposed collagencollagen

PlateletPlatelet

Fig. 6.4 Platelet activationFig. 6.4 Platelet activation pathways & antiplatelet drugspathways & antiplatelet drugs

drugsdrugs

drugsdrugs

OOOO

OHOHOHOH

COOHCOOHCOOHCOOHCHCH33CHCH33

TXATXA22 thromboxane thromboxaneFig 36.16Fig 36.16

TXATXA22TXATXA22

Endothelial liningEndothelial lining

ExposedExposed collagencollagen


16

Coagulation Factors Coagulation Factors Blood Blood ClottingClottingzymogens zymogens Plasma soluble Plasma soluble proteinsproteins

Coagulation Factors Coagulation Factors Blood Blood ClottingClottingzymogens zymogens Plasma soluble Plasma soluble proteinsproteins

Intrinsic pathwayIntrinsic pathway ( (••): activated ): activated by plasma components by plasma components

Clinical testsClinical tests APTT (30-50 sec) APTT (30-50 sec) Activated Partial Activated Partial

Thromboplastin Time, also known as the Thromboplastin Time, also known as the KCCT (kaolin-cephalin clotting time), intrinsic KCCT (kaolin-cephalin clotting time), intrinsic pathway.pathway.

PT (10-15 sec)PT (10-15 sec) Prothrombin time, Prothrombin time, extrinsic pathwayextrinsic pathway

Thrombin timeThrombin time

Extrinsic pathwayExtrinsic pathway (o): activated (o): activated by nonendothelial ‘surface’ tissue by nonendothelial ‘surface’ tissue factorfactor

Vitamin K deficiency Vitamin K deficiency reduces reduces hepatic synthesis of II, VII, IX, and hepatic synthesis of II, VII, IX, and X. Treat with vit K injectionsX. Treat with vit K injections

Oral anticoagulents – warfarin Oral anticoagulents – warfarin reduces hepatic factor synthesis. reduces hepatic factor synthesis. Excessive bleeding with warfarin Excessive bleeding with warfarin treated by stopping the drug, giving treated by stopping the drug, giving vit K or replacing II, VII, IX, and X vit K or replacing II, VII, IX, and X with fresh frozen plasma or with fresh frozen plasma or concentrates.concentrates.

Liver Disease – Factor syn reducedLiver Disease – Factor syn reduced; ; acetaminophen overdose acetaminophen overdose hepatic hepatic failure failure longer prothrombin time longer prothrombin time

Intrinsic pathwayIntrinsic pathway ( (••): activated ): activated by plasma components by plasma components

Clinical testsClinical tests APTT (30-50 sec) APTT (30-50 sec) Activated Partial Activated Partial

Thromboplastin Time, also known as the Thromboplastin Time, also known as the KCCT (kaolin-cephalin clotting time), intrinsic KCCT (kaolin-cephalin clotting time), intrinsic pathway.pathway.

PT (10-15 sec)PT (10-15 sec) Prothrombin time, Prothrombin time, extrinsic pathwayextrinsic pathway

Thrombin timeThrombin time

Extrinsic pathwayExtrinsic pathway (o): activated (o): activated by nonendothelial ‘surface’ tissue by nonendothelial ‘surface’ tissue factorfactor

Vitamin K deficiency Vitamin K deficiency reduces reduces hepatic synthesis of II, VII, IX, and hepatic synthesis of II, VII, IX, and X. Treat with vit K injectionsX. Treat with vit K injections

Oral anticoagulents – warfarin Oral anticoagulents – warfarin reduces hepatic factor synthesis. reduces hepatic factor synthesis. Excessive bleeding with warfarin Excessive bleeding with warfarin treated by stopping the drug, giving treated by stopping the drug, giving vit K or replacing II, VII, IX, and X vit K or replacing II, VII, IX, and X with fresh frozen plasma or with fresh frozen plasma or concentrates.concentrates.

Liver Disease – Factor syn reducedLiver Disease – Factor syn reduced; ; acetaminophen overdose acetaminophen overdose hepatic hepatic failure failure longer prothrombin time longer prothrombin time

prothrombin = II prothrombin = II IIa = thrombinIIa = thrombin fibrin I fibrin I Ia = Ia = fibrinogenfibrinogen prothrombin = II prothrombin = II IIa = thrombinIIa = thrombin fibrin I fibrin I Ia = Ia = fibrinogenfibrinogen

Fig. 6.5 Coagulation factors and someFig. 6.5 Coagulation factors and some of their propertiesof their propertiesFig. 6.5 Coagulation factors and someFig. 6.5 Coagulation factors and some of their propertiesof their properties


17

Topics Topics Blood Blood ClottingClotting IntroductionIntroduction

Topics Topics Blood Blood ClottingClotting IntroductionIntroduction

CLOT FORMATIONCLOT FORMATION











18

Die Die CO CO22 Die Die CO CO22

Activation Cascades Activation Cascades Blood Blood ClottingClottingIntrinsic, Extrinsic, Final pathways Intrinsic, Extrinsic, Final pathways

Activation Cascades Activation Cascades Blood Blood ClottingClottingIntrinsic, Extrinsic, Final pathways Intrinsic, Extrinsic, Final pathways

XI XIa

IX IXa

IntrinsicExtrinsic

X Xa

XIIPrekalikrein

HMWK

Tissue Factor(III)VII + Ca2+

Final

ProProthrombin thrombin

fibrinogenogen fibrinStablefibrin

XIIa

XII

Fig. 6.6 Blood Coagulation Fig. 6.6 Blood Coagulation Fig. 6.6 Blood Coagulation Fig. 6.6 Blood Coagulation

VIII VIIIa

VaV


19

VIIVIIVIIVIIVIIVIIaaVIIVIIaa

XXXXXXaaXXaa

TissueTissuefactorfactor

TissueTissuefactorfactor

PreconvertinPreconvertinPreconvertinPreconvertinConvertinConvertinConvertinConvertin

Intrinsic and Extrinsic Converge at Xa Intrinsic and Extrinsic Converge at Xa Blood Blood Clotting Clotting Regulation Regulation Cascade*Cascade*

Intrinsic and Extrinsic Converge at Xa Intrinsic and Extrinsic Converge at Xa Blood Blood Clotting Clotting Regulation Regulation Cascade*Cascade*

Trauma DamageTrauma DamageTrauma DamageTrauma Damage

Trauma DamageTrauma DamageTrauma DamageTrauma Damage

Damaged SurfaceDamaged SurfaceDamaged SurfaceDamaged Surface

Intrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic Pathway

Extrinsic PathwayExtrinsic PathwayExtrinsic PathwayExtrinsic Pathway

PrekallikreinPrekallikreinPrekallikreinPrekallikrein

XIIXII XIIXIIaaXIIXIIaa

XIXI

IXIX

XX

XIXIaaXIXIaa

IXIXaaIXIXaa

VIIIVIIIaaVIIIVIIIaa

XXaaXXaa

KininogenKininogenKallikreinKallikrein

KininogenKininogenKallikreinKallikrein

HagemanHagemanHagemanHageman

PlasmaPlasmathromboplastinthromboplastinPlasmaPlasmathromboplastinthromboplastin ChristmasChristmasChristmasChristmas

AntihemophilicAntihemophilicAntihemophilicAntihemophilic

StuartStuartStuartStuart

* Other Cascades?* Other Cascades? GlycogenolysisGlycogenolysis cAMPcAMP

1111

2222

3333

4444

- - -- - -II

IIIIIIII IIaIIaIIaIIaProthrombinProthrombinProthrombinProthrombin ThrombinThrombinThrombinThrombin

FibrinogenFibrinogenFibrinogenFibrinogen

- + -- + -- + -- + -

- + -- + -- + -- + -

- + -- + -

- + -- + -IaIa

FibrinFibrinFibrinFibrin

Fibrin

Fibrin fiberfiber


20

Activation of Thrombin Activation of Thrombin Blood Blood ClottingClotting I I IIa IIa MoleculesMolecules

Activation of Thrombin Activation of Thrombin Blood Blood ClottingClotting I I IIa IIa MoleculesMolecules

323323323323

AA

ArgArgArgArg

275275275275 ThrThrThrThr

CC

SS

SS

BB

582582582582

324324324324 IleIleIleIle

IIII IIaIIa

NHNH22NHNH22

274274274274 ArgArgArgArg

10101010

SS SSSS SSAA

275275275275 ThrThrThrThrNHNH22NHNH22

CCCC 323323323323 ArgArgArgArg BB

CC 582582582582

NHNH22NHNH22324324324324IleIleIleIle

NHNH22NHNH22

CCCC

10101010

274274274274 ArgArgArgArg


21

Fibrinogen,Fibrinogen, Factor I Factor I Blood Blood ClottingClotting MoleculesMolecules

Fibrinogen,Fibrinogen, Factor I Factor I Blood Blood ClottingClotting MoleculesMolecules

Synthesized in the liver, Synthesized in the liver, t/2 = 4 dayst/2 = 4 days 0.3 mg% in human plasma0.3 mg% in human plasma Dimeric heterotrimer: Dimeric heterotrimer: 2 [3 different polypeptides] = [2 [3 different polypeptides] = [ ]]22

joined by S-S bonds, the middle disulfide knot.joined by S-S bonds, the middle disulfide knot. Each half contains an Each half contains an subunit subunit mostly in a rod-like triple-mostly in a rod-like triple-

helix where the halves join, but with random coils at the helix where the halves join, but with random coils at the outside ends (globular).outside ends (globular).

Fibrinogen is about 9 nm wide and 46 nm long Fibrinogen is about 9 nm wide and 46 nm long with two halves with two halves of 23 nm (230Å). of 23 nm (230Å).

Fibrinogen is trinodular Fibrinogen is trinodular (three-globule dumbbell-shape), (three-globule dumbbell-shape), central knob has three clusters of charges: -4 at each end and central knob has three clusters of charges: -4 at each end and -8 at the central knob: - 4 - 8 - 4-8 at the central knob: - 4 - 8 - 4

Charge repulsion prevents fibrinogen from self-associating, Charge repulsion prevents fibrinogen from self-associating, thus it remains a soluble monomer the circulating blood.thus it remains a soluble monomer the circulating blood.

Synthesized in the liver, Synthesized in the liver, t/2 = 4 dayst/2 = 4 days 0.3 mg% in human plasma0.3 mg% in human plasma Dimeric heterotrimer: Dimeric heterotrimer: 2 [3 different polypeptides] = [2 [3 different polypeptides] = [ ]]22

joined by S-S bonds, the middle disulfide knot.joined by S-S bonds, the middle disulfide knot. Each half contains an Each half contains an subunit subunit mostly in a rod-like triple-mostly in a rod-like triple-

helix where the halves join, but with random coils at the helix where the halves join, but with random coils at the outside ends (globular).outside ends (globular).

Fibrinogen is about 9 nm wide and 46 nm long Fibrinogen is about 9 nm wide and 46 nm long with two halves with two halves of 23 nm (230Å). of 23 nm (230Å).

Fibrinogen is trinodular Fibrinogen is trinodular (three-globule dumbbell-shape), (three-globule dumbbell-shape), central knob has three clusters of charges: -4 at each end and central knob has three clusters of charges: -4 at each end and -8 at the central knob: - 4 - 8 - 4-8 at the central knob: - 4 - 8 - 4

Charge repulsion prevents fibrinogen from self-associating, Charge repulsion prevents fibrinogen from self-associating, thus it remains a soluble monomer the circulating blood.thus it remains a soluble monomer the circulating blood.

PropertiesPropertiesPropertiesProperties

– – 88– – 88– – 44– – 44 – – 44– – 44


22

Fibrinogen (I) Fibrinogen (I) Fibrin (Ia) Fibrin (Ia) Blood Blood ClottingClottingVia thrombin (IIa)Via thrombin (IIa) MoleculesMolecules

Fibrinogen (I) Fibrinogen (I) Fibrin (Ia) Fibrin (Ia) Blood Blood ClottingClottingVia thrombin (IIa)Via thrombin (IIa) MoleculesMolecules

Hydrolysis by Thrombin (IIHydrolysis by Thrombin (IIaa) at Arg-) at Arg-glygly site yields site yields

Fibrin (IFibrin (Iaa) monomer + fibrinopeptides A and B) monomer + fibrinopeptides A and B Fibrin is Fibrin is insolubleinsoluble because its - 4 +5 - 4 charges allow it because its - 4 +5 - 4 charges allow it

to aggregate to form fibers.to aggregate to form fibers. The aggregated intertwined fibers trap cells yielding a soft clot.The aggregated intertwined fibers trap cells yielding a soft clot. The The soft clotsoft clot is is notnot stable. It is held together by electrostatic stable. It is held together by electrostatic

charges.charges. Soft clot is cross-linked by factor XIIISoft clot is cross-linked by factor XIIIaa with Ca with Ca2+2+ to yield hard clot to yield hard clot

fibrin fiber.fibrin fiber.

Hydrolysis by Thrombin (IIHydrolysis by Thrombin (IIaa) at Arg-) at Arg-glygly site yields site yields

Fibrin (IFibrin (Iaa) monomer + fibrinopeptides A and B) monomer + fibrinopeptides A and B Fibrin is Fibrin is insolubleinsoluble because its - 4 +5 - 4 charges allow it because its - 4 +5 - 4 charges allow it

to aggregate to form fibers.to aggregate to form fibers. The aggregated intertwined fibers trap cells yielding a soft clot.The aggregated intertwined fibers trap cells yielding a soft clot. The The soft clotsoft clot is is notnot stable. It is held together by electrostatic stable. It is held together by electrostatic

charges.charges. Soft clot is cross-linked by factor XIIISoft clot is cross-linked by factor XIIIaa with Ca with Ca2+2+ to yield hard clot to yield hard clot

fibrin fiber.fibrin fiber.

-4-4-4-4 +5+5+5+5 -4-4-4-4


23

Hard Clot FormationHard Clot Formation Blood Blood ClottingClotting Transglutaminase (XIIIa)Transglutaminase (XIIIa) Cross-linkingCross-linking

Hard Clot FormationHard Clot Formation Blood Blood ClottingClotting Transglutaminase (XIIIa)Transglutaminase (XIIIa) Cross-linkingCross-linking

The soft clot continues enlarging as platelets, other blood cells, and The soft clot continues enlarging as platelets, other blood cells, and debris from the wound, become enmeshed. debris from the wound, become enmeshed.

Factor Factor XIIIaXIIIa ( (transglutaminasetransglutaminase) cross-links the fibrin monomers ) cross-links the fibrin monomers comprising the thread-like fiberscomprising the thread-like fibers by forming sets of peptide (amide) by forming sets of peptide (amide) bonds between adjoining C-terminal peptides of the bonds between adjoining C-terminal peptides of the -chains thereby -chains thereby stabilizing and strengthening each fibrous thread along its length.stabilizing and strengthening each fibrous thread along its length.

– COOH region:COOH region: eetc tc ------------------------------------------------Gly Gly GlnGln Gln His His Leu Gly Gly AlaGln His His Leu Gly Gly Ala LysLys Gln Ala Gly Asp ValGln Ala Gly Asp Val COOHCOOH

| | | |

The soft clot continues enlarging as platelets, other blood cells, and The soft clot continues enlarging as platelets, other blood cells, and debris from the wound, become enmeshed. debris from the wound, become enmeshed.

Factor Factor XIIIaXIIIa ( (transglutaminasetransglutaminase) cross-links the fibrin monomers ) cross-links the fibrin monomers comprising the thread-like fiberscomprising the thread-like fibers by forming sets of peptide (amide) by forming sets of peptide (amide) bonds between adjoining C-terminal peptides of the bonds between adjoining C-terminal peptides of the -chains thereby -chains thereby stabilizing and strengthening each fibrous thread along its length.stabilizing and strengthening each fibrous thread along its length.

– COOH region:COOH region: eetc tc ------------------------------------------------Gly Gly GlnGln Gln His His Leu Gly Gly AlaGln His His Leu Gly Gly Ala LysLys Gln Ala Gly Asp ValGln Ala Gly Asp Val COOHCOOH

| | | | COOHCOOH Val Asp Gly Ala Gln Val Asp Gly Ala Gln LysLys Ala Gly Gly Leu His His Gln Ala Gly Gly Leu His His Gln GlnGln Gly Gly ------------------------------- ------------------------------- etc ofetc of COOHCOOH Val Asp Gly Ala Gln Val Asp Gly Ala Gln LysLys Ala Gly Gly Leu His His Gln Ala Gly Gly Leu His His Gln GlnGln Gly Gly ------------------------------- ------------------------------- etc ofetc of

As cross-linking proceeds, the As cross-linking proceeds, the soft clotsoft clot becomes more stable becomes more stable and a and a hard clothard clot develops: clot contracts, water is squeezed out. develops: clot contracts, water is squeezed out.

As cross-linking proceeds, the As cross-linking proceeds, the soft clotsoft clot becomes more stable becomes more stable and a and a hard clothard clot develops: clot contracts, water is squeezed out. develops: clot contracts, water is squeezed out.

Gamma chains cross-linkedGamma chains cross-linkedGamma chains cross-linkedGamma chains cross-linked


24

TopicsTopics Blood Blood ClottingClotting OutlineOutline













25

Antithrombin III Antithrombin III Blood ClottingBlood Clotting Antithrombin III Antithrombin III Blood ClottingBlood Clotting

Antithrombin III Antithrombin III –– always present in the serum.always present in the serum.

Binding between Antithrombin III and Thrombin (IIa) Binding between Antithrombin III and Thrombin (IIa)

prevents thrombin from proteolytically activating prevents thrombin from proteolytically activating

fibrinogen (I) to fibrin (Ia).fibrinogen (I) to fibrin (Ia).

Antithrombin III counteracts any unscheduled clot Antithrombin III counteracts any unscheduled clot

formation. formation.

Impact injury triggers clotting Impact injury triggers clotting at the injury-site by at the injury-site by

activating thrombin. activating thrombin.

Any thrombin that might escape the local clot is Any thrombin that might escape the local clot is

inactivated, inactivated, thus, clotting does not spread throughout thus, clotting does not spread throughout

the body.the body.

Antithrombin III Antithrombin III –– always present in the serum.always present in the serum.

Binding between Antithrombin III and Thrombin (IIa) Binding between Antithrombin III and Thrombin (IIa)

prevents thrombin from proteolytically activating prevents thrombin from proteolytically activating

fibrinogen (I) to fibrin (Ia).fibrinogen (I) to fibrin (Ia).

Antithrombin III counteracts any unscheduled clot Antithrombin III counteracts any unscheduled clot

formation. formation.

Impact injury triggers clotting Impact injury triggers clotting at the injury-site by at the injury-site by

activating thrombin. activating thrombin.

Any thrombin that might escape the local clot is Any thrombin that might escape the local clot is

inactivated, inactivated, thus, clotting does not spread throughout thus, clotting does not spread throughout

the body.the body.


26

Inhibiting Intrinsic Clot CascadeInhibiting Intrinsic Clot Cascade Blood Blood ClottingClotting ProcessProcess

Inhibiting Intrinsic Clot CascadeInhibiting Intrinsic Clot Cascade Blood Blood ClottingClotting ProcessProcess

Anti thrombin III binds irreversibly to Anti thrombin III binds irreversibly to

– IIIIaa (thrombin) active site. (thrombin) active site.

– also binds to IXalso binds to IXa a (Christmas)(Christmas)

– also binds to Xalso binds to Xa a (Stuart)(Stuart)

– also binds to XIalso binds to XIaa (Plasma Thromboplastin) (Plasma Thromboplastin)

Thus, the active factors exist brieflyThus, the active factors exist briefly!!

* * All four have proteins contain N-terminal All four have proteins contain N-terminal -carboxyglutamate clusters with Ca-carboxyglutamate clusters with Ca2+2+

Anti thrombin III binds irreversibly to Anti thrombin III binds irreversibly to

– IIIIaa (thrombin) active site. (thrombin) active site.

– also binds to IXalso binds to IXa a (Christmas)(Christmas)

– also binds to Xalso binds to Xa a (Stuart)(Stuart)

– also binds to XIalso binds to XIaa (Plasma Thromboplastin) (Plasma Thromboplastin)

Thus, the active factors exist brieflyThus, the active factors exist briefly!!

* * All four have proteins contain N-terminal All four have proteins contain N-terminal -carboxyglutamate clusters with Ca-carboxyglutamate clusters with Ca2+2+


27

Inhibitors of Coagulation Inhibitors of Coagulation Blood Blood ClottingClottingPreventing harmful thrombi that cause strokes & infarcts Preventing harmful thrombi that cause strokes & infarcts

Inhibitors of Coagulation Inhibitors of Coagulation Blood Blood ClottingClottingPreventing harmful thrombi that cause strokes & infarcts Preventing harmful thrombi that cause strokes & infarcts

.. .. Die Die CO CO22 Die Die CO CO22

Fig. 6.8 Sites of inhibitorsFig. 6.8 Sites of inhibitorsFig. 6.8 Sites of inhibitorsFig. 6.8 Sites of inhibitors


28














29

Coagulation InhibitorsCoagulation Inhibitors Blood Blood ClottingClottingFibrinolytic System Components Fibrinolytic System Components HemostasisHemostasis

Coagulation InhibitorsCoagulation Inhibitors Blood Blood ClottingClottingFibrinolytic System Components Fibrinolytic System Components HemostasisHemostasis

Fig. 6.9 Fig. 6.9 Fig. 6.9 Fig. 6.9 Fig. 6.10 Fig. 6.10 Fig. 6.10 Fig. 6.10


30

Fibrinolytic System Fibrinolytic System Blood Blood ClottingClottingPlasminogenPlasminogen plasminplasmin Clot Clot DissolutionDissolution

Fibrinolytic System Fibrinolytic System Blood Blood ClottingClottingPlasminogenPlasminogen plasminplasmin Clot Clot DissolutionDissolution

Dissolving clotsDissolving clots

– UnscheduledUnscheduled Use tPA and Use tPA and

streptokinase streptokinase

– Wound healingWound healing

Plasminogen Plasminogen plasminplasmin(active)(active)

Fibrin proteolyized Fibrin proteolyized Fibrinogen degradation Fibrinogen degradation peptidespeptides

Saving clots: Saving clots: 22 antiplasmin antiplasmin inhibits inhibits

plasmin, thus the plasmin, thus the hydrolysis of fibrin clots is hydrolysis of fibrin clots is prevented.prevented.

Dissolving clotsDissolving clots

– UnscheduledUnscheduled Use tPA and Use tPA and

streptokinase streptokinase

– Wound healingWound healing

Plasminogen Plasminogen plasminplasmin(active)(active)

Fibrin proteolyized Fibrin proteolyized Fibrinogen degradation Fibrinogen degradation peptidespeptides

Saving clots: Saving clots: 22 antiplasmin antiplasmin inhibits inhibits

plasmin, thus the plasmin, thus the hydrolysis of fibrin clots is hydrolysis of fibrin clots is prevented.prevented.

Fibrin Fibrin Fibrinogen Degradation Products (FDP Fibrinogen Degradation Products (FDP peptides) peptides) Fibrin Fibrin Fibrinogen Degradation Products (FDP Fibrinogen Degradation Products (FDP peptides) peptides)

Fig. 6.11 Fibrinolytic system. Plasminogen Fig. 6.11 Fibrinolytic system. Plasminogen to plasmin by uPA, tPA or to plasmin by uPA, tPA or streptokinase streptokinase

Fig. 6.11 Fibrinolytic system. Plasminogen Fig. 6.11 Fibrinolytic system. Plasminogen to plasmin by uPA, tPA or to plasmin by uPA, tPA or streptokinase streptokinase


31

Topics Topics Blood Blood

ClottingClotting

OutlineOutline

Topics Topics Blood Blood

ClottingClotting

OutlineOutline












32

AnticoagulantsAnticoagulants Blood Blood ClottingClotting MoleculesMolecules

AnticoagulantsAnticoagulants Blood Blood ClottingClotting MoleculesMolecules

Vitamin K Antagonists Vitamin K Antagonists - Inhibit - Inhibit -carboxylase thereby -carboxylase thereby lessening lessening -carboxyglutamate formation.-carboxyglutamate formation.– DicumarolDicumarol - - present in hay, mimics Vitamin K.present in hay, mimics Vitamin K.

– WarfarinWarfarin (Coumadin)- (Coumadin)- a clinical anticoagulant (strokes/infarcts).a clinical anticoagulant (strokes/infarcts).

– Chelated CaChelated Ca2+2+ normally promotes binding of factors IIa, VIIa, normally promotes binding of factors IIa, VIIa, IXa, and Xa to trauma-exposed membrane phospholipids.IXa, and Xa to trauma-exposed membrane phospholipids.

– The fewer or absence of the The fewer or absence of the -carboxyglutamate cluster -carboxyglutamate cluster at the at the N-termini of these clotting factors slows or prevents these N-termini of these clotting factors slows or prevents these events and interferes with effective clotting.events and interferes with effective clotting.

HeparinHeparin - - A carbohydrate polymer that promotes thrombin A carbohydrate polymer that promotes thrombin inactivation by antithrombin IIIa.inactivation by antithrombin IIIa.

CitrateCitrate or oxalate - or oxalate - Chelates CaChelates Ca2+2+ thereby inhibiting thereby inhibiting clottingclotting..

Vitamin K Antagonists Vitamin K Antagonists - Inhibit - Inhibit -carboxylase thereby -carboxylase thereby lessening lessening -carboxyglutamate formation.-carboxyglutamate formation.– DicumarolDicumarol - - present in hay, mimics Vitamin K.present in hay, mimics Vitamin K.

– WarfarinWarfarin (Coumadin)- (Coumadin)- a clinical anticoagulant (strokes/infarcts).a clinical anticoagulant (strokes/infarcts).

– Chelated CaChelated Ca2+2+ normally promotes binding of factors IIa, VIIa, normally promotes binding of factors IIa, VIIa, IXa, and Xa to trauma-exposed membrane phospholipids.IXa, and Xa to trauma-exposed membrane phospholipids.

– The fewer or absence of the The fewer or absence of the -carboxyglutamate cluster -carboxyglutamate cluster at the at the N-termini of these clotting factors slows or prevents these N-termini of these clotting factors slows or prevents these events and interferes with effective clotting.events and interferes with effective clotting.

HeparinHeparin - - A carbohydrate polymer that promotes thrombin A carbohydrate polymer that promotes thrombin inactivation by antithrombin IIIa.inactivation by antithrombin IIIa.

CitrateCitrate or oxalate - or oxalate - Chelates CaChelates Ca2+2+ thereby inhibiting thereby inhibiting clottingclotting..


33

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