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