Factor Vii a Slides

8/3/2019 Factor Vii a Slides

http://slidepdf.com/reader/full/factor-vii-a-slides 1/39

CONTROL OF

HEMOSTASIS Jerrold H. Levy, MD

Professor of AnesthesiologyDeputy Chair for Research

Emory University School of MedicineDivision of Cardiothoracic Anesthesiology and

Critical CareEmory HealthcareAtlanta, Georgia



COMPONENTS OFHEMOSTASIS

VasculatureCoagulation proteins

Platelets



COAGULATIONPATHWAYS



Contact Tissue Factor + VII

XIIIa

XIII

Thrombin

Fibrin(strong)

Fibrinogen Fibrin(weak)

IXXI

XIaIXa

XaVa

XIIaProthrombin

TF-VIIa

(Prothrombinase)

PL

PL(Tenase)

VIIIaPL

X

Intrinsic Pathway

HKa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation Pathways

Protein C, Protein S,Antithrombin III



Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.

TF-Bearing Cell

Activated Platelet

Platelet

TF

VIIIa Va

VIIIa Va

Va

VIIa

TF VIIa Xa

X

II IIa

IXV Va

II

VIII/vWF

VIIIa

II

IXa

XIX

X

IXa

IXaVIIa

Xa

IIa

IIa

Xa

Normal Hemostasis: Pivotal role of TF/VIIa



PLATELETACTIVATIONPATHWAYS



Adhesion

GpIIb/IIIa

Platelet Activation Pathways (1)

GpIIb/IIIa GpIIb/IIIa Aggregation

ADP

Adrenaline Platelet

Exposed Collagen

Endothelium

vWF

COLLAGEN

GpIIb/IIIa GpIIb/IIIa AggregationGpIIb/IIIa GpIIb/IIIa Aggregation

AdhesionAdhesion

ADP

Adrenaline

THROMBIN



Platelet Activation Pathways (2)

Platelet Aggregation

FibrinogenFibrinogen Binding Site

Thrombin

Platelet

Herbert. Exp Opin Invest Drugs 1994;3:449-455.



FibrinolysisPlasminogen

Plasmin

Fibrin, fibrinogen

ActivationExtrinsic: t-PA, urokinase

Intrinsic: factor XIIa, HMWK, kallikrein

Exogenous: streptokinase

Fibrin, fibrinogendegradation products



FIBRINOLYSIS



Fibrinolysis



CONDITIONS

PRODUCINGCOAGULOPATHY



Conditions of coagulopathy

HemophiliaPlatelet disorders

Liver diseaseDICDilution coagulopathyAnticoagulant treatment



CAUSES OF COAGULOPATHY inLIVER DISEASE

Decreased coagulation factors II,VII, IX, and X synthesis

FibrinolysisPlatelet dysfunctionDecreased physiologicanticoagulant synthesis (AT III,Protein C and S)



HEMOSTASIS:ROLE OF FACTORVII and TISSUE

FACTOR



TF-Bearing Cell

Activated Platelet

PlateletTF

Va

VaTF VIIa Xa

X

IIIIa

V Va

IIX

IIaXaVIIa

FVIIa Mechanism of Action

Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.



FACTOR VIIa Mechanism ofAction

• Increases the tissue factor (TF)occupancy

• In pharmacological doses binds toactivated platelets

• Activates Factor X independent oftissue factor

Proceedings of the National Academy of Sciences 97(10):5255-60, 2000. Circulation. 103(21):2555-9,2001. Blood Coagulation & Fibrinolysis. 11 Suppl 1:S107-11, 2000.

Proceedings of the National Academy of Sciences. 96(16):8925-30, 1999.Haemostasis. 30 Suppl 2:41-7, 2000. Thrombosis Research. 98(4):311-21, 2000.



CONTACTACTIVATION ANDCARDIOPULMONAR

BYPASS

f l d



Contact Activation of BloodProteins

Blood/Surface Interaction Thrombin Plasmin Kallikrein

Clotting Fibrinolysis Kinins

Platelets White Cells

Systemic Inflammatory Response

Cytokines/Adhesion Molecules

Serine Protease Inhibitors Heparin

Complement



Negative Charged SurfaceXII

FXIIa

Bradykinin

Thrombin Generatio

XIa

XII

FXIIa

FXI

HK

PKK

HK

FXIIa

Kallikrein

XII

Kallikrein

FXIIa

PKK

HK

Contact Activation - The Role of Kallikrei

Factor XII



KininGeneration

AngiotensinSystem

ComplementSystem

HMW-Kininogen

Bradykinin

Renin

Prorenin

C1

PrekallikreinFactor XIIa

Factor XII

Factor XIIa

Factor XII

Factor XIa

Factor XI

CoagulatioSystem

PlasminPlasminogen FibrinolytSystem

C1

_

Kallikrein



ANTICOAGULANTANTITHROMBINS

ANTITHROMBINS/



ANTITHROMBINS/ANTICOAGULANTS

ArgatrobanBivalirudin (Angiomax)

Hirudin: r-lepirudin, (Refludan)Low molecular weight heparin(LMWH)/Xa inhibitorsWarfarin

Levy JH: Novel IV antithrombins. Am Heart J 2001:141:1043



LMWH Anti-Xa activity greater than ATactivity, purified from UFH, MWt4500-6000

Long duration of action, notreversible with protamineIncluded enoxaparin (Lovenox),

dalteparin (Fragmin), tinzaparin(Innohep)



Thrombin Inactivation: Heparin

Pentasaccharidesequence

Heparin/ATIII/IIa Ternary complex acceleratesinactivation of IIa by ATIII

LMW Heparin/ATIII No acceleration of inactivation of IIa by ATIIIwithout ternary complex

IIa

ATIII IIa

ATIIIPentasaccharidesequence



Factor Xa Inactivation: LMWH/Heparin

Heparin/ATIII Ternary complex notnecessary to accelerateinactivation of Xa by ATI

XaATIII

LMW Heparin/ATIII Ternary complex notnecessary to accelerateinactivation of Xa by ATIII

Pentasaccharidesequence

Xa ATIII



LMWH—Clinical Applications

Prevention of DVT/PEIn patients undergoing hip replacement, during & followinghospitalization

In patients undergoing knee replacement

In patients undergoing abdominal surgery who are at risk of TEcomplications

Treatment of DVT/PE

Ischemic complications of unstable angina and non-Q wave MI

i l i l C f d d i di



Biological Consequences of Reduced Bindingof LMWH to Proteins and Cells

Binding Target Biological Effects Clinical ConsequencesThrombin Reduced anti-IIa to Unknown

anti-Xa ratioProteins More predictable Monitoring of anticoagulant

anticoagulant response effect unnecessaryMacrophages Cleared through renal Longer plasma half-life;

mechanism once daily subcutaneoustreatment effective

Platelets Reduced incidence of Reduced incidence of heparin-dependent heparin-inducedantibody thrombocytopenia

Osteoblasts Reduced activation of Lower incidence of osteoclasts osteopenia

Dalen JE, Hirsh J. Fifth ACCP Consensus Conferenc Antithrombotic Therapy. Chest 1998;114:



LMWHBleedingThrombocytopeniaHypersensitivity

Heparin/LMWH—Adverse Effects

HeparinBleedingThrombocytopeniaOsteoporosisHypersensitivity



W f i M h i f A i



Warfarin—Mechanism of Action

Vitamin K

Warfarin

Synthesis of DysfunctionalCoagulation

Factors

VII

IXX

II

Vitamin K UtilizationReduced



Warfarin—Indications

Prophylaxis and/or treatment of:Venous thrombosis and its extensionPulmonary embolism

Thromboembolic complications associated with AFand/or cardiac valve replacement

Reduce risk of death, recurrent MI, andthromboembolic events such as stroke or systemicembolization after MI

Elimination Half Lives of



Elimination Half-Lives of Vitamin K-Dependent Proteins

Protein Half-LifeFactor VII 4 – 6 hoursFactor IX 24 hoursFactor II 60 hoursFactor X 48 – 72 hours

Protein C 8 hoursProtein S 30 hours



Warfarin—Contraindications

Risk of hemorrhage is greater than benefits of therapyPregnancyHemorrhagic tendencies or blood dyscrasiasTraumatic surgery with large open areas, recent or

contemplated surgery of CNS or eyeBleeding tendencies with active ulceration or overtbleedingSenility, alcoholism, psychosis or other lack of patientcooperationSpinal puncture and procedures with potential for uncontrollable bleedingInadequate laboratory facilities



Warfarin—Adverse Effects

Fatal or non-fatal hemorrhage from any tissue or organNecrosis of skin and other tissues

Other adverse reactions reported less frequentlyinclude:Systemic cholesterol microembolization Alopecia

Purple toes syndrome, urticaria, dermatitis includinbullous eruptions



LOVE=HEMOSTASIS Everybody talksabout it, nobodyunderstands it.

JH Levy 2000

Factor Vii a Slides

Documents

Transcript of Factor Vii a Slides