deck_4983227

Question 1

Write out the intrinsic clotting pathway.

Answer 1

1) exposure to - charged surface2) X11 to X11a3) XI to XIa4) IX to IXa5) IXa binds to VIIIa

Question 2

What happens when damage disrupts endothelium?

Answer 2

circulating vMF binds exposed collagen, which alters its tertiary structure to expose platelet binding sites (and also bind VIII)

Question 3

T or F. vMF is a large multimer of homo-dimers that must be trimmed to an optimal length

Answer 3

T.

Question 4

How do platelets bind to vMF?

Answer 4

GP1b

Question 5

Binding of platelets to vMF causes what to happen?

Answer 5

activation and release of alpha and dense granules

Question 6

What are the contents of the alpha granules?

Answer 6

-TxA2-fibrinogen-factor VIII and V

Question 7

What are the contents of the dense granules?

Answer 7

-calcium-magnesium-histamine-ADP

Question 8

What role does Ca2+ play in clotting?

Answer 8

Calcium ions cause fatty acids to precipitate by binding their anionic head regions; this forces the hydrophobic tail regions to the outside of the complex, where they are free to interact with other similar complexes to form large insoluble complexes. Factor VII, and some of the other coag factors, responds to the presence of calcium according to the same principles. Exposure of more hydrophobic residues result in the protein becoming membrane bound.

Question 9

What reaction facilitates factor binding to Ca2+?

Answer 9

-gamma carboxylation of AA residues via vitamin K

Question 10

What factors require gamma carboxylation (and thus vitamin K)?

Answer 10

II, VII, IX, and X

Question 11

Once endothelial damage occurs and TF is exposed, what protease activates VII?

Answer 11

Unknown. What is clear is that after binding of TF, VII is much, much more susceptible to activation by any of several proteases in the coag cascade, including VIIa itself.

Question 12

What does the TF/VIIa complex do?

Answer 12

activates X, which in turn activates a small amount of factor V and complexes with it

Question 13

What does the small amount of Xa/Va do?

Answer 13

convert II to IIa (prothrombin to thrombin) - which does not, at this point, cleave a lot of fibrinogen

Question 14

Why doesn’t this thrombin cleave a lot of fibrinogen?

Answer 14

Because its activity is localized to the surface of damaged endothelial cells. Thrombin activation in an environment loaded with other coag factors – in the middle of a bunch of activated platelets – will be needed to get that job done.

Question 15

What else does thrombin do at this point?

Answer 15

Thrombin activates the intrinsic pathway by generating an activated IXa/VIIIa complex (sometimes called “tenase”). The factor VIII is released from activated platelets.

Question 16

What does the activated IXa/VIIa do?

Answer 16

It diffuses from the site on which it is generated (damaged endothelial cells) to the site at which more of its substrate (factor X) is located – on the surface of immobilized platelets to activate more Xa.There is some ambiguity in the literature about whether it does this primarily while complexed with VIIIa, or whether it acquires factor VIIIa after diffusing over to the platelet side.

Question 17

What happens what a lot of thrombin is built up?

Answer 17

-gradually more and more fibrinogen is produced to fibrin-it converts XIII to XIIIa to facilitate cross-linking multiple fibrin-platelet-fibrin chains-it facilitates yet more conversion of V to Va this is called on propagation phase

Question 18

What happens what a lot of thrombin is built up?

Answer 18

gradually more and more fibrinogen is produced to fibrin

Question 19

Where is antithrombin made?

Answer 19

liver

Question 20

What does antithrombin attach to on cell surfaces?

Answer 20

a complex polysaacharide called heparin

Question 21

What does antithrombin do?

Answer 21

inactivates thrombin (IIa) and Xa

Question 22

What cofactor does protein C use?

Answer 22

protein S

Question 23

T or F. Protein C and S are both gamma carboxylated

Answer 23

T. Thus, their function is both vitamin K dependent

Question 24

What is the function of Protein C?

Answer 24

inactivate factor V and VIII

Question 25

What activates plasmin?

Answer 25

t-PA, a protease on the surface of UNDAMAGED endothelial cells

Question 26

What does prothrombin time measure?

Answer 26

how long it takes plasma to form fibrin

Question 27

How does the prothrombin time assay work?

Answer 27

The “prothrombin” mixture is mixed with plasma. We collect blood for this in the presence of citrate (blue top), which chelates any Ca++ in plasma (i.e. its an anticoagulant). Prothrombin includes enough Ca++ to saturate the citrate and start this portion of the coag cascade.

Question 28

Prothrombin time assays are particularly sensitive to what?

Answer 28

The effects of drugs that inhibit gamma carboxylation of coag factors and cofactors, i.e. to vitamin K antagonists like warfarin. Most textbooks describe this as an assay of the extrinsic and common pathways; the latter term refers to the portion of the coagulation cascade involving factors Va, Xa, and Iia. But bear in mind that in vivo, activation of factor VII only generates a small amount of fibrin. We are exaggerating that part of the pathway in this test in order to generate an easily measurable readout

Question 29

T or F. VII is the vitamin-K dependent factor with the fastest normal turnover rate.

Answer 29

T.

Question 30

The activated partial thromboplastin (aPTT) assay is particularly sensitive to reductions in?

Answer 30

the level of IIa, VIIIa, and IXa.

Question 31

What drug can target VMF disease and how does it work?

Answer 31

We can augment vMF secretion with a drug called DDAVP. This will both increase circulating vWF and increase circulating factor VIII

Question 32

Defect in Gp1b leads to what?

Answer 32

Bernard-Soulier syndrome

Question 33

What drug blocks ADP release from dense granules of activated platelets?

Answer 33

Clopidogrel

Question 34

Defect in the binding of GPIIb/IIIa leads to what disease?

Answer 34

Glanzman-Thrombasthenia

Question 35

What drugs can treat GT?

Answer 35

abciximab, eptifibatide tirofiban

Question 36

What are some direct factor Xa inhibitors?

Answer 36

apixaban,rivaroxaban

Question 37

What are some direct thrombin inhibitors?

Answer 37

dabigatranhirudin

Question 38

What does warfarin do?

Answer 38

blocks vitamin-K dependent gamma carboxylation.First factor to show the effect is VII because it turns over fastest.

Question 39

Heparin is an anticoagulant. What happens to PT when it is given?

Answer 39

the PT will become abnormal when the warfarin starts to be effective

Question 40

What test is affected by factory VIII or IX deficiency, PT or aPTT?

Answer 40

aPTT only

Question 41

What test is affected by heparin, PT or aPTT?

Answer 41

the aTTP test is particularly dependent on activated thrombin, so it’s very sensitive to the effects of heparin

Question 42

What are the subtypes of vMF disease?

Answer 42

I- poor expression of vMF gene (recessive)IIa/c- increased degradation of appropriate sized vMFIIb- increased binding of appropriate sized vMF to plts IIN- reduced binding to VIIIa (normally stabilizes it)IIM- reduced binding of appropriate sized vMF to plts III-nonsense/frameshift in vMF gene

Question 43

What is INR?

Answer 43

way of standardizing prothrombin time(time with warfarin/ normal)^(coefficient)