Coagulation - Simplified Intrinsic Pathway Extrinsic Pathway Factor XII Factor IX TF/Factor VII “fuel” - amplification “spark” - initiation Factor X Factor II Common Pathway Fibrin “clots”

Coagulation - Role of TF Step 1 Tissue injury Step 2 Exposure of tissue factor (TF) “the spark”

TF

Coagulation - Role of TF Step 3 TF binds to VII Step 4 VII is activated to VIIa

VII TF-VIIa

Coagulation - Role of TF VII Step 5 TF-VIIa activates 3

IX

zymogens IXa X Xa IX IXa VII VIIa

X TF-VIIa Xa

Coagulation - Generation of Thrombin Step 6 TF-VIIa and Xa form a complex TF-VIIa/Xa/Va Step 7 Xa forms a complex with circulating II IIa Va on platelet surface (prothrombinase) Step 8 Prothrombinase converts prothrombin (II) to thrombin (IIa)

Coagulation - Formation of Fibrin Clot Step 9 IIa converts fibrinogen (I) TF-VIIa/Xa/Va to fibrin (Ia) XIII Step 10 IIa activates II IIa XIII to form XIIIa XIIIa Step 11 XIIIa fibrinogen fibrin stabilizes the thrombus cross-linked fibrin

Control of Coagulation - TFPI 4Although coagulation is initiated by the TF-VIIa complex, the amount of Xa that can be generated is relatively limited because of rapid inhibition by tissue factor pathway inhibitor (TFPI)

TFPI + Xa

TFPI/Xa

TF-VIIa/TFPI/Xa

4Sustained coagulation requires activation by X by an augmenting pathway - “the fuel”

Coagulation - Intrinsic Pathway IIa

VII IX

XI

XIa

X TF-VIIa

IXa

Xa

4In the intrinsic pathway IX is activated by XIa 4XI is converted to XIa when some of the thrombin generated by extrinsic pathway feeds back on the intrinsic pathway 4IX is also activated by TF-VIIa

Coagulation - Amplification IIa

VII IX

XI

X

XIa

TF-VIIa IXa

Xa +

VIIIa Va X

IIa II 4VIIIa and IXa assemble on the platelet membrane to form “tenase” that activates X

Coagulation - Summary XIa

TF + VIIa IXa + VIIIa (tenase)

Xa + Va (prothrombinase) IIa

II

+feedback Fibrinogen

Fibrin

Coagulation - Role of Thrombin Thrombin (IIa) V Va VIII VIIIa XI XIa XIII XIIIa Fibrinogen Fibrin Activates platelets

Coagulation - Ca+2 Dependent Steps Ca+2 TF + VII V VIII IX X II Fibrin

TF-VIIa Va VIIIa IXa Xa IIa Cross-linked fibrin

Cellular Nature of Coagulation 4Phospholipid surfaces are required for effective coagulation hTF-VIIa (endothelial surface) h“Tenase” complex (platelet surface) −IXa/VIIIa/Ca+2/phospholipid h“Prothrombinase” complex (platelet surface) − Xa/Va/Ca+2/phospholipid

Tests - PT/INR PT measures how long it takes for TF + Ca+2 clot to form when TF and Ca+2 are added to the test tube to activate the extrinsic pathway

VII TF/VIIa X

Fibrinogen

Xa Va IIa

II Fibrin

Tests - PT/INR 4PT result can vary with reagent

hISI (International Sensitivity Index) was introduced to standardize PT results − Measures responsiveness of a given reagent to È vitamin K-dependent factors

4INR (International Normalized Ratio) standardizes PT results using ISI h(PT patient/PT controls)ISI

4Prolonged with È activity of VII, X, V, II hwarfarin hliver disease hvitamin K deficiency

Tests - aPTT aPTT measures how XI long it takes for Reagent Contact clot to form when IX Factors aPTT reagent XIa (activator, PL, Ca+2) IXa VIIIa II is added to the test tube to activate the X Xa intrinsic pathway IIa Fibrinogen Fibrin

Tests - aPTT 4aPPT result can also vary with reagent hNo INR equivalent exists

4Prolonged with

hÈ activity of contact factors, XII, XI, IX, VIII, V, II hvon Willebrand disease hUnfractionated heparin hInhibitors (nonspecific and specific)

41:1 Mixing test helps differentiate causes of isolated Ç aPTT hCorrection with factor deficiency hNo correction with inhibitor

Tests - Thrombin Clotting Time TCT measures how long it takes for a clot to form when thrombin is added to a test tube

IIa Fibrinogen

Prolonged when i Fibrinogen (DIC, liver disease) i Abnormal fibrinogen i Heparin is present

Fibrin

Inhibitors - TFPI XI

XIa TF/VIIa

TF + VII

IX IXa VIIIa TFPI interacts with X Xa X and inhibits Xa. The Va TFPI-Xa complex II IIa then binds to and inhibits TF-VIIa Fibrinogen Fibrin

Inhibitors - Antithrombin XI

XIa TF/VIIA IX VIIIa

TF + VII

IXa

AT binds to and X Xa X inactivates IIa, IXa , Va Xa, XIa, XIIa, and II IIa VIIa in TF/VIIa enhanced with heparin Fibrinogen Fibrin

Thrombin/Thrombomodulin 4Excess thrombin formed at sites of vascular injury is washed downstream and binds to thrombomodulin (TM) found on intact endothelium iConverts thrombin anticoagulant Protein C

IIa TM

from

procoagulant

to

Va Va fragments Activated Protein C VIIIa + VIIIa fragments Protein S

Inhibitors - Proteins C and S XI

XIa IX VIIIa

TF/VIIa

TF + VII

IXa X

Xa Va II

X IIa

Fibrinogen

Fibrin

Diseases - Hemophilia A XI

XIa TF/VIIa

TF + VII

IX IXa VIIIa X Xa X Factor VIII deficiency Va Sex-linked recessive II IIa Fibrinogen Fibrin

Diseases - Hemophilia B XI

XIa TF/VIIa

TF + VII

IX IXa VIIIa X Xa X “Christmas Disease” Va Factor IX deficiency II IIa Sex-linked recessive Fibrinogen Fibrin

Vitamin K Deficiency XI

XIa TF/VIIa IX VIIIa

TF + VII

IXa X

Xa Va II

X IIa

Fibrinogen Fibrin

Fibrinolysis 4Activation of fibrinolytic system maintains vessel patency by promoting dissolution of the fibrin clot Plasminogen tissue plasminogen activator (t-PA) Plasmin Endothelial Cell fibrin breakdown fibrinogen products

Inhibitors of Fibrinolysis 2 antiplasmin

2 macroglobulin

Plasminogen activator 1 antitrypsin inhibitor (PAI-1) Plasminogen t-PA Plasmin Endothelial Cell

fibrin breakdown fibrinogen products

Drugs 4Heparin/Low-molecular-weight heparin

hCatalyze AT-mediated inactivation of IIa, Xa, XIIa, XIa, and VIIa in TF VIIa

4Warfarin (Coumadin)

hInterferes with -carboxylation of vitamin-K dependent factors (II, VII, IX, X, protein C & S)

4Direct thrombin inhibitors

hBind to and inactivate thrombin

4Thrombolytics (e.g. t-PA, streptokinase) hActivate plasmin