Block2 12.the Blood Coagulation Cascade

Front 1

The Blood Coagulation Cascade

Back 1

When a vessel is damaged, a clot forms from plateletes aggregating and a fibrin network being build that traps additional RBC's.

Front 2

Platelet Adhesion

Back 2

Injury exposes collagen and von Willebrand factor.
1. An integrin binds vWF and induces a change in cell shape.
2. GPIb binds to vFW
3. GPIb binding stimulates intercellular signals that activate the platelet and expose GPIIIa/GPIIb (integrin αIIbβ3), which binds to vWF and fibrinogen

Front 3

thromboxane A2 and low dose aspirin

Back 3

Activated platelets also begin synthesizing thromboxane A2, a vasoconstrictor that also activates more GPIIa/GPIIb. Low-dose aspirin inhibits the synthesis of thromboxane A2 by platelets.

Front 4

platelet activation

Back 4

By adhesion. Platelettes degranulate, release ADP (primary stimulator), ATP, growth factors, Ca2+, vWF (Von Villibrand Factor), Factors V and VIII, fibrinogen, serotonin, and more. Activation recruits more platelets to the site, which also degranuate. These platelets form a ‘plug’ by binding to fibrinogen. This provisional platelet ‘plug’ is reinforced by the transformation of fibrinogen to fibrin by a complex and very carefully controlled series of reactions known collectively as the Blood Coagulation Cascade.

Front 5

Two bleeding disorders:
1. von Willebrand factor deficiencies
2. Hemophilia A

Back 5

1. The most common cause of genetic bleeding disorders is a deficiency in van Willebrand Factor (not X-linked). vWF binds factor VIII and stabilizes it in circulation.
2. Hemophelia A is an X-linked disorder, characterized by a lack of Factor VIII altogether

Front 6

Protein-Protein Interactions in the Blood Coagulation Cascade involve enzymes and a co-enzyme "buddy" in a series of zymogen cleavages to make mature protein enzymes

Back 6

Protease-Buddy
Factor IXa - Factor VIIIa (hemophelia factor)
Factor Xa - Factor Va
Factor VII - Tissue Factor
Factor IIa (thrombin) - Thrombomodulin
Protein Ca - Protein S

Front 7

Extrinsic Pathway

Back 7

Needs some sort of trauma to be initiated.
Tissue Factor -> activates VII to VIIa -> complex activates X to Xa.
Both pathways converge at Xa

Front 8

Intrinsic Pathway

Back 8

Contains all that is needed intrinsically.
Same as extrinsic pathway except with an extra step, TF/VIIa complex activates IX to IXa, and IXa (with VIIIa buddy) activates X to Xa. Both pathways converge at Xa.

Front 9

Common pathway

Back 9

Xa plus Va buddy -> activate prothrombin to thrombin (II to IIa).
Thrombin -> activates fibrinogen to Fibrin aggregates (I to Ia), resulting in a soft clot. Note: Thrombin does a lot more: it has a positive feedback loop; accelerates its own activation by 100,000-fold, it activates Va, and it activates factor XIIIa, which is a fibrin cross-linker.

Front 10

Soft clot vs. Hard clot

Back 10

Fibrin aggregates make a soft clot that is still not completely resistant to the sheer forces of the blood stream, so a hard clot must be made. Factor XIII is activated by thrombin to XIIIa. This gives the clot cross-linking and makes it hard. Note: Factor XIIIa is the only factor of the Blood Coagulation Cascade that is NOT a serine protease

Front 11

Coagulation Factors and Ca2+ Binding. Vitamin K vs. Warfarin.

Back 11

Calcium very important in blood coagulation. Certain of the coagulation factors (II, VII, IX, X and Protein C) are post-translationally modified with gamma-carboxyl groups to increase their ability to bind calcium and localize on surfaces at the site of injury. These ones need Vitamin K and they need Calcium. This gamma-carboxylation reaction requires vitamin K as a cofactor. Certain anti-coagulants (warfarin) are vitamin K analogues that inhibit the gamma carboxylation reaction. Warfarin works against vitamin K. Specifically, warfarin reduces your liver's ability to use vitamin K to produce normally functioning forms of the blood clotting proteins. Warfarin is rat poison, rats die slowly of internal bleeding

Front 12

Control of the Coagulation Process: Non-covalent inhibitors and covalent factors

Back 12

Non-covalent inhibitors:
Tissue Factor Pathway Inhibitor (TFPI) - inhibits TF/VIIa
Antithrombin III - serpin (serine protease inhibitor) inhibits IIa,IXa, Xa, XIa.
Proteins Z and ZPI.
Covalent factors: Activated protein C (with protein S buddy and thrombomodulin)

Front 13

TFPI, what is its function?

Back 13

Inhibits the first part of the pathway, the Tissue Factor / VIIa / Xa complex, and can also bind IXa.

Front 14

Antithrombin III (ATIII) and heparin

Back 14

IMPORTANT: ATIII is a serpin (serine protease inhibitor) binds to and irreversibly inhibits Factors Xa, IIa, IXa, and XIa. Heparin catalytically stimulates the rate of inactivation between 500 and 1,000,000 fold, depending upon the Factor. Heparin structure can be modified to more specifically interact with individual Factors of the cascade.

Front 15

Protein C and Thrombomodulin (TM)

Back 15

TM binding to thrombin causes the activation of Protein C to Ca. Protein Ca and protein S hydrolyze and inactivate factors Va (but Va is protected by Factor V Leiden) and VIIIa (important as this is hemophelia factor)

Front 16

Factor V Leiden (the protector of Factor V)

Back 16

People with this have some hypercoagulation, also called thrombophelia. Approximately 5% of Caucasians in North America are thought to have the Factor V Leiden variant, and up to 30% of patients who present with deep vein thrombosis or pulmonary embolism have this condition.
Women with Factor V Leiden have a substantially increased risk of clotting in pregnancy and when taking estrogen-containing birth control pills.

Front 17

Fibrinolysis

Back 17

Plasminogen activated to Plasmin by tPA.
Alpha-2 antiplasmin inhibits it
Plasminogen activator inhibitor inhibits acvtivators
scu-PA (Urokinase) = exogenous protein that happens to hydrolyse plasmin to plasminogen
Streptokinase = bacterial protein that happens to bind to plasminogen and triggers a conformation change that activates to plasmin

Front 18

Important overall concepts regarding the BCC

Back 18

Clot formation must be fast, limited and reversible.
•Clotting reactions all occur on a membrane surface.
•Clotting factors are produced in a latent form and normally activated at the site of injury.
•Clot formation is vitamin K and Ca2+ dependent.
•There are many different ways to inhibit the blood coagulation cascade and many different kinds of inhibitors.