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66 Cards in this Set

  • Front
  • Back

Pathway activated by tissue injury?

Extrinsic pathway

Extrinsic pathway

Pathway activated by contact?

Intrinsic pathway

Intrinsic pathway

Common pathway

What converts fibrin to CLF? What is CLF?

Fibrin --> CLF (cross-linked fibrin) via XIIIa

Cross-linking stabilizes fibrin (otherwise transient)

Intrinsic vs extrinsic pathway

Extrinsic pathway is initial activation

Intrinsic pathway is an amplification

Factor II

Prothrombin (converted to IIa - thrombin)

Clotting cascade feedback

Positive feedback

Reactions in clotting cascade w/out cofactors?

Slow, but they do proceed

Most factors are activated or inactivated by...

proteolytic cleavage

Factors II, VII, IX, X (and protein C and S) have ____ domains which are ____ charged and attach to _____

Gla domains

Negatively charged

Attach to platelet surface

Factors II, VII, IX, X are _____ dependent factors

Vitamin K

Conversion of X --> Xa requires...

IXa w/ cofactor VIIIa

VIIa w/ cofactor Tissue Factor

Platelets bind to collagen with the help of ____

Tiny amount of factor ____ is in form of _____

Injury exposes _____. ____ and ____ bind to ____.

Platelets bind to collagen with help of vWF

Tiny amount of VII is in form of VIIa

Injury exposes TF, VII and VIIabinds to TF (extrinsic pathway)

TF-VIIa is called _____

TF-VIIa converts a little ____ to ____ and ____ to ____

Extrinsic tenase (Xase)

IX --> IXa (intrinsic pathway)

X --> Xa (common pathway)

Xa feedback higher up

Main action is to convert II --> IIa

Also feeds back to convert V--> Va and VIII --> VIIIa

Complex of Xa/Va called....convert ___ to ___

prothrombinase (prothrombin --> thrombin)

VIIIa and IXa called _____ and convert more ____ to ____

Intrinsic tenase or Xase - convert more X to Xa

Once thrombin is active, it activates _____

lots of factors (V, VII, VIII) this is the amplification

Also converts XI to XIa - amplifying the intrinsic pathway (converts more IX to IXa)

Thrombin effect on platelets

Thrombin activates platelets (via binding to PAR 1, 3, 4) - cause secretion of granules (vWF, fibrinogen, Factor Va)

Cross-linker for platelets?


What converts fibrinogen to fibrin? What also needs to happen to help cross-link fibrin?

IIa (thrombin) converts fibrinogen to fibrin

IIa also converts XIII to XIIIa which is needed to cross-link fibrin

Extrinsic pathway

  • TF exposed upon exposure of subendothelium

  • Binding of TF to VIIa allows activation of small amount of both X and IX

  • VIIa is present in small amounts in the plasma and cannot initiate hemostasis w/out TF

Extrinsic pathway - thrombin production?

•The extrinsic pathway produces only asmall amount of thrombin, which is insufficient (in isolation) for hemostasisin most situations

Complete deficiencies of VII/TF?

Not compatible with life

Tissue factor

-Cell bound initiator of homeostasis, some soluble

-Transmembrane protein

1) Extracellular portion interacts w/ VIIa

2) Serves as cofactor for VIIa

3) Has no intrinsic protease activity

4) Found on fibroblasts, smooth muscle, microparticles

5) Expressed in endothelial cells in inflammation and other diseases (atherosclerosis)

-Necessary to maintain vascular integrity

Factor VII

-Extrinsic pathway

-Shortest half-life of any hemostatic factor

-Small amount of circulating VIIa that is available to bind with TF

-TF does not activate VII

-Complete loss of VII incompatible w/ life

-Thrombin can activate VII --> VIIa

Intrinsic pathway - function

-Feedback/amplification loop

-Significantly increases the production of thrombin

-Required for hemostasis in most situation

"Intrinsic" factors


Complete deficiencies of intrinsic factors?

•Complete deficiencies of intrinsicfactors are compatible withlife,unlike extrinsicandcommon pathway factors

Factor IXa activates _____. Activation process?

•Factor IXaactivates factor X

–IXa is a slow activator of X withoutits cofactor: VIIIa

–Remember: X is activated byboth factor VIIIa/IXa andthe TF/VIIa complex

Factor VIII is activated to Factor VIIIa (cofactor for...?) by ______.

Factor VIII is normally bound by ____ which extends the half-life of VIII. Activation _______.

•FactorVIII is activated (VIIIa) by thrombin

VIIIa is the cofactor for IXa activation of X)

•FactorVIII bound by vWF, which extends the ½ life of VIII. VIII --> VIIIa dissociates it from vWF

Common pathway - why is it called common, important factors/substrate, common pathway deficiencies

•Called “common” as it is the portion ofthe cascade that is common to both the intrinsic and extrinsic pathways

•Factors X, V, prothrombin, and fibrinogen

•Complete deficiencies of X, V, orprothrombin are not compatible with life

Factor X is activated to Xa by ______.

Xa activates ______. Cofactor?

Xa is a therapeutic target for _____ because of ______.

•Factor X is activated to Xa byeither the extrinsic “Xase” complex (TF/VIIa) orthe intrinsic “Xase” complex

•Xa activatesprothrombin (to thrombin) relatively slowly until factor V is activated bythrombin (Va is acofactor)

•Xa is a therapeutic target foranticoagulation because of its central role in hemostasisC

Common pathway: prothrombin + thrombin

-Activation of prothrombin --> thrombin via Xa with cofactor Va

-IIa is considered master effector and regulator of hemostatic cascade

-Thrombin upregulates its own production (XI, VIII, V)

-Thrombin downregulates its own production (activation of protein C when associated w/ thrombomodulin)

Thrombin interacts with/cleaves many proteins

–Fibrinogen (I), V, VII, VIII, XI

–Factor XIII (stabilizes fibrin)


–Thrombin activatablefibrinolysis inhibitor (TAFI)

–PARs 1, 3, 4 (on platelets)

–C5 and Osteopontin (Th 1cytokine) for lymphocyte activation

Almost all coagulation is initiated by the _____ with a positive feedback loop from the _____

•Almostall coagulation is initiated by the “extrinsic” cascade(TF/VIIa)with apositive feedback loop from the “intrinsic” cascade

Factors important for contact activation (on an anionic surface) include:

–Prekallikrein(enzyme, activates XII) 
–High Molecular Weight Kininogen(co-factor)
–Factor XII (Enzyme, activates factor XI)

–Prekallikrein(enzyme, activates XII)

–High Molecular Weight Kininogen(co-factor)

–Factor XII (Enzyme, activates factor XI)

Deficiencies of contact pathway?

do NOT result in a bleeding disorder

In vitro vs in vivo contact pathway

•Initiates fibrin formation invitro (i.e.aPTT)

•In vivo, may be involved in production ofbradykinin(vasodilator) and fibrinolysis onendothelial cells

Structure of fibrinogen + cleavage by thrombin

•Dimer consisting of three pairs ofchains: Aα, Bβ, andγ

•Thrombin cleaves fibrinopeptides Aand B from the Aα and Bβchains, respectively

•Cleavage of fibrinopeptide A isall that is required for formation of the fibrin polymer

•Fibrin polymers formed from thisthrombin-mediated process are unstable and easily lysed

Factor XIII

•Plasma transglutaminase

•Cross-links fibrin polymers via acovalent bond between the glutamine to lysine residues of the γ-chainof fibrin

•Also slowly crosslinks the α-chain

•Will also crosslink inhibitors offibrinolysis (α2-antiplasmin)into the fibrin clot, this stabilizes the clot

•Activated by thrombin

Vitamin K dependent factors

-Coagulant factors: II, VII, IX, X

-Anticoagulant proteins: C and S

-Glutamyl carboxylase - microsomal enzyme, requires Vit K as cofactor, converts Glutamate residues in the "Gla domain" on precursor proteins to y-carboxyglutamyl (Gla) residues via addition of CO2

-Gla domain: Ca2+ dependent binding of phospholipids

____ is added to glutamate to create gamma-carboxy-glutamate


Recycling of Vitamin K - drug significance and enzyme significance

  • Vitamin K must be converted back toreduced form by epoxide reductase torecycle
  • Warfarin (coumadin) blocks epoxide reductase
  • Also note many isoforms of epoxide reductase withdifferent activities, so Warfarin mustbe titrated and monitored, a PitA for both patient and physician

Calcium - clotting factor ____; role in hemostasis; anticoagulants that target Ca2+

•Originally described as “clotting factorIV”

•Absolutely required for hemostasis

•Citrate or EDTA (calcium chelators) arepotent anticoagulants

•Vitamin K-dependent factors require Ca2+ binding to function

•Three Ca2+ bindingsites on fibrinogen that are important for maintaining its stability/structure

Most of the clotting factors are synthesized in the ______

liver - liver diseases affect clotting

What can cure VIII deficiency?

Liver transplant (cure hemophilia A)

Inhibitors of coagulation

  • The coagulation cascade is tightly controlled to prevent pathologic thrombus formation
  • Multiple inhibitors of coagulation
  • Coagulation is inhibited primarily at three points:
  • 1) Activation of X by TF/VIIa complex (TFPI)
  • 2) Activity of thrombin (thrombomodulin, antithrombin)
  • 3) Cofactor activity of VIIIa and Va (proteins S and C)


-Tissue factor pathway inhibitor

-Exists as both soluble and membrane bound forms (membrane bound is predominant in humans, mainly on endothelial cells)

-TFPI binds to complex of TF, VIIa, and Xa

-Inhibits extrinsic pathway of coagulation, especially in areas adjacent to clot where endothelium is intact


-Cell-associated factor (mostly endothelial cells) that binds thrombin and alters its activity

-Main role is to prevent clot/thrombus on endothelial cells

-Decreases activity against/affinity for: Fibrinogen, factors V, VIII, and XI, PARs (platelet receptors)

-Increases (significantly) activity for: protein C, thrombin activatable fibrinolysis inhibitor (TAFI)

Proteins C and S

•Protein C is activated by the thrombin-thrombomodulincomplex, binds to endothelial protein C receptor (EPCR)

•Protein S is a cofactor for protein C

•Activated protein C inactivates factors Va and VIIIa,especially on endothelial surfaces

•Vitamin K dependent proteins. ½ life of protein C is short (6-10 hours) so Warfarincauses paradoxical clotting, so give heparin for first 4 days

•APC (activated protein C) is also anti-inflammatory–Can be used for the treatment of severesepsis


-SerPIn (serine protease inhibitor) attached to endothelial surface

-Inhibits activity of both Xa and thrombin (IIa)

-Activity of antithrombin is greatly increased by heparins

Factor V Leidan

Factor V Leiden is mutation infactor V that is resistant to protein C inactivation


endogenous sulfated glycosaminoglycan

produced by mast cells in mammals

enhances activity of antithrombin

Antithrombin and ____ Combine together to inhibit _____


Xa (prevents conversion of II to IIa)

Unfractionated heparin blocks...

Thrombin AND Xa

Fibrin is degraded by...

plasmin - cleaves fibrin and other proteins at lysine-arginige bonds

Plasminogen is primarily activated by plasmin by...

tissue plasminogen activator (tPA) - from endothelial cells or uPA - urokinase-type plasminogen activator (from kidneys, bind endothelial cells via uPAR)

Both ____ and ____ bind to fibrin, increasing the fibrinolytic potential of both enzymes



What on endothelial cells binds tPA an dplasminogen?

Annexin A2

Fibrinolytic system (w/out inhibitors)


Not from dissolution of fibrin polymer - from dissolution of cross-linked fibrin (end pieces) - measure of clot formation

Inhibition of fibrinolysis

-a2-antiplasmin directly inhibits plasmin

-plasminogen activator inhibitor 1 (PAI-1) directly inhibits plasminogen activity

-fibrinolysis is indirectly inhibited by thrombin/thrombomodulin activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI)

-TAFI cleaves the C-terminal Lys residues from fibrin - these are the sites of binding for plasmin and tPA

Fibrinolytic system with inhibitors? (draw)

What do deficiencies in these inhibitors cause?

Deficiencies of VIII or IX are known as ____


Hemophilia A - factor VIII deficiency

Hemophlia B - factor IX deficiency

Extrinsic vs intrinsic Xase