Hemostasis (study in order, do not shuffle)

explain the endothelium (walls of the blood vessels) under normal conditions

we want blood to flow smoothly without clotting or obstruction

we have antiplatelet adhesion via NO, PGI2, and nucleoside diphosphatase

anticoagulation via heparin like molecules, tissue factor pathway inhibitor, and thrombomodulin

fibrinolytics: tPA

Explain the endothelium (walls of the blood vessels) under injurious conditions

when injured, the endothelium becomes prothrombotic (we want blood to stop and clot at sites of injury to reduce blood loss)

damaged endothelium cells release what? what does that cause?

endothelin which causes vasoconstriction (We want the blood to slow down so we can form a clot)

Where does the von Willebrand factor (vWF) come from/ get released from?

platelets (alhpa granules) and endothelial cells (Weibel-Palade bodies)

With primary hemostasis: explain the “foundation”, double-sided tape, and bricks that get stuck

the foundation is the collagen that get exposed dueing an injury

then vWF binds to the collagen and acts as “double-sided tape”

then the platelets are flowing past the vWF and they have GpIb receptors on the platelets that bind to the vWF and allow them to adhere

What happens to the platelets once they bind to vWF on the collagen?

they change shape and release positive feedback mediators/factors

the alpha granules release more vWF

the dense granules release ADP and calcium

and thromboxane A2 (TXA2) also gets released and causes vasoconstriction

What is the role of ADP in primary hemostasis?

once the platelets have bound to the vWF (via their GpIb receptor) then they release ADP which binds to the P2Y12 receptor on the platele and causes the platelets to expose another receptor that they have called GpIIb/IIa

Once the receptor GpIIb/IIIa is exposed due to ADP binding to the P2Y12 receptor, what happens?

the receptor binds fibrinogen from the plasma and this makes a fibrinogen network that allows all of the platelets that have been stuck on the double sided tape (vWF) to aggregate together, forming a platelet plug.

What are the receptor and ligand pairs?

receptors: GpIb, GpIIbIIIa, and P2Y12

ligands: Fibrinogen, ADP, and vWF

GpIb binds to vWF

P2Y12 binds to ADP

GpIIbIIIa binds to fibrinogen (not fibrin!)

So we left off with primary hemostasis creating a fibrinogen network with the platelets, now what is the goal of secondary hemostasis?

this is the coagulation cascade that leads to stablization of the platelet plug

it does this by: fibrinogen turning into fibrin which is more stable

Overview of primary hemostasis:

no specifics, just what are the steps we just went over?

vasoconstriction → adhesion (platelets + vWF) → activation (platelets release ADP, vWF, and TXA2)→ aggregation (GpIIbIIIa receptor binding to fibrinogen and forming network)

Secondary hemostasis: what pathway is activated by damage inside the vasculature?

intrinsic pathway (think internal injury)

Secondary hemostasis: what pathway is activated by endothelial damage that causes blood to leave the vasculature?

extrinsic pathway (think external injury)

Which pathway?

Tissue factor III is expressed

important factors: III, VII

extrinsic pathway

Which pathway?

contact activated: factor XII interacts with negatively charged collagen

important factors: XII, XI, IX, VIII

intrinsic pathway (think internal injury)

What pathway is associated with the aPTT lab? what is a normal value? what do we use it to monitor?

The intrinsic pathway (so if the time is longer then we know this is an issue with the intrisic pathway and the XII, XI, IX, and VIII factors)

a normal value typically between 25-40 seconds

used to monitor heparin therapy

What pathway is associated with the aPT lab? what is a normal value? what do we use it to monitor?

The extrinsic pathway (so if the time is longer then we know this is an issue with the extrinsic pathway and the III and VII factors)

a normal value typically between11-15 seconds

used to monitor warfarin therapy

Both the intrinsic and extrinsic pathway lead to the ___ pathway

common pathway

the common pathway (that both intrinsic and extrinsic pathways lead to) is associated with factor ___

Xa

Thw common pathway and Factor Xa leads to:

the conversion of prothrombin to thrombin, ultimately resulting in fibrin formation from fibrinogen

Describe the role of thrombin

thrombin changes roles based on the state of the endothelium

when endothelium is normal then thrombin activates protein C to promote anticogulation

when endothelium in injured then it promotes platelet aggregation and activation

What is the end result of the common pathway with retraction

the pletelets contract

the fibrin mesh shrinks

and it brings the edges of damaged vessels together to facilitate wound healing

What are the three clot regulators? (anticoagulation checks)

Protein C, protein S, antithrombin

Which clot regulator?

vitaminn K dependent, synthesized in the liver

binds to thrombin and thrombomodulin and inhibits factors Va and VIIIa

protein C and protein S

Which clot regulator?

binds to and degrades thrombin, and inhibits factor IXa and Xa

antithrombin

What is the last step of hemostasis? what is the goal?

fibrinolysis

goal is to get rid of/dissolve the clot

Explain the steps of fibrinolysis

goal: degrade the fibrin network by plasmin

plasminogen turns into plasmin through tPA, then the plasmin can make the fibrin mesh turn into soluble fibrin that can be dissolved (goodbye clot)

What enzyme os directly responsible for breaking down fibrin clots?

plasmin (plasminogen turns into plasmin via tPA)

What disorder is a deficiency of vWF?

Von Willebrand disease

What disease is a deficiency of GpIb receptor?

Bernard-Soulier syndrome

What disease is a deficiency of the GpIIbIIIa receptor?

Glanzmann's thrombasthenia

What disease is a low level of clotting factor VIII

Hemophilia A

What disease is a low level of clotting factor IX?

Hemophilia B

What do we expect if we see:

decreased platelet number and increased bleeding time

thrombocytopenia

What do we expect if we see:

normal platelet number and increased bleeding time

platelet dysfunction (think von Willebrand disease, Bernard-Soulier syndrome, or Glanzmann thrombasthenia)

What pathway and what factor are messed up?

elevated PT/INR

PT/INR = aPT

extrinsic pathway is messed up

associated with factor VII deficiency

What pathway and what factor are messed up?

elevated aPTT

intrinsic pathway is messed up

associated with factors VIII, IX, and XI

What pathway and what factor are messed up?

elevated PT/INR and aPTT

bith extrinsic and intrinsic pathways

deficiency of vitamin K dependent pathway

factors II, VII, IX, and X

If you see a poor diet you think what kind of deficiency?

this deficiency messes up what things? (6)

vitamin K deficiency

factors: II, VII, IX, and X

and protein C and S

What are the 2 antiplatelet drugs?

Aspirin and Clopidogrel

What are the 2 anticoagulant drugs?

Warfarin and Heparin

Which drug?

prevents platelet plug formation

inhibits COX-I → is required to make thromboxane in platelets → decreased platelet aggregation

Aspirin

Which drug?

binds the ADP (P2Y12) receptors → inhibits activation of GpIIbIIIa receptor complex → decreased platelet aggregation

Clopidogrel

Which drug?

binds to ATII → increases affinity for factor Xa and throbin → binds and inactivates them

heparin (aPTT monitored)

Which drug?

inhibits VKORC1 → depletes functional vitamin K → depletion of factors II, VII, IX, and X; inhibits protein C and S

warfarin (aPT/INR monitored)