Hemostasis

Question 1

What is the major process in primary hemostasis?

Answer 1

FIRST vessel reflexively constricts

platelets form a plug to minimize blood loss

Question 2

What is the major process in secondary hemostasis?

Answer 2

Clotting cascade forms a fibrin clot that anchors and stabilizes the platelet plug

Question 3

______ is central to the hemostatic response because i tis a potent platelet activator and it converts soluble fibrinogen to an insoluble fibrin clot

Answer 3

thrombin

Question 4

The _________ surface is an important site for assembly and localization of the membrane bound enzyme complexes of coagulation

Answer 4

Activated platelet surfac

Question 5

Gradual transition to ______ facilitates removal of a clot and wound healing

Answer 5

fibrinolysis

Question 6

List three pro-thrombotic components

Answer 6

1. Platelets/ vWF: formation of hemostatic plug
2. Coagulation cascade: thrombin–> fibrin clot formation
3. Fibrinolysis inhibitors: soluble protease inhibitors that down regulate fibrinolysis and prevent degradation of the clot

Question 7

List three anti-thrombotic components

Answer 7

1. Intact endothelium
2. Fibrinolysis: second enzyme cascade converts plasminiogen to plasmin which lyses the fibrin clot
3. Coagulation inhibitors: soluble protease inhibitors that down-regulate the coagulation cascade and remove activated coagulation factors

Question 8

List three classes of drugs that can be used to prevent hemostasis and their major targets

Answer 8

1. antiplatelet drugs: target formation of primary platelet plug
2. anticoagulants: prevent formation of fibrin clot
3. antifibrinolytics: prevent breakdown of fibrin clot

Question 9

List the steps in primary hemostasis

Answer 9

1. Platelet adhesion: interaction of platelet Gp-Ib with vWF
2. Platelet activation: by thrombin, collagen, ADP
3. Platelet aggregation: cross linking of activated platelets by fibrinogen binding to Gp IIb/IIIa
4. Secretion of platelet granules
5. Retraction of the newly formed thrombus

Question 10

Platelet ______ results in conformational change and activation of Gp IIb/IIIa, granule release, and thrombus contraction

Answer 10

activation

Question 11

Megakaryocyte differentiation is characterized by _____ in which DNA replication occurs but the nucleus does not divide

Answer 11

endomitosis

Question 12

The production of platelets is controlled by the cytokine _____

Answer 12

TPO, thrombonpoietin

Question 13

About 30% of platelets are stored in the spleen and can be released in response to _____

Answer 13

epinephrine

Question 14

There is usually an ____ relationship between platelet number and mean platelet volume

Answer 14

inverse

Question 15

Describe the relationship between platelet sequestration, platelet desttruction, and megakaryocyte hyperplasia

Answer 15

As platelets are sequestered, but not destroyed, in a large spleen, there is no compensatory megakaryocyte hyperplasia in the marrow in patients with thrombocytopenia due to hypersplenism. In contrast, when the platelet count is reduced due to rapid destruction, there is megakaryocytic hyperplasia.

Question 16

Large circulating platelets on the blood smear in a patient with thrombocytopenia suggests:

Answer 16

peripheral destruction of platelets

Rapid platelet production leads to increased size of circulating platelets

Question 17

List the two hemostatic functions of vWF

Answer 17

• major carrier of VIII, prolongs half life of VIII

- mediates platelet tethering and adhesion to exposed subendothelium

Question 18

Where is vWF found/ stored

Answer 18

endothelial cells, megakaryocytes, subendothelial connective tissue

Question 19

wVW is released by endothelial cells in the blood, which can be enhanced by ________

Answer 19

DDAVP

Question 20

If there is inherited or acquired deficiency of________, large VWF-platelet aggregates can form
in the circulation and occlude small blood vessels causing tissue injury.

Answer 20

ADAMTS13

This causes the disease thrombotic thrombocytopenic purpura (TTP)

Question 21

_______ promotes vWF unfolding

Answer 21

high shear stress- as in arterial circulation

Question 22

List platelet agonists that trigger platelet activation

Answer 22

collagen (in ECM)
thrombin (generated by TF)
epinephrine
ADP
serotonin
TXA2 produced by COX1

Question 23

Describe the contents of a granules and dense granules

Answer 23

a granules: proteins such as fibrinogen, vWF and factor V that promote clot formation as well as chemokines that recruit inflammatory cells

Dense granules: ADP/ATP and serotonin which activates additional platelets

Question 24

______ is normally sequestered on the inner membrane of a platelet but is exposed after platelet activation. It enhances the assembly of membrane bound coagulation enzyme complexes

Answer 24

phosphatidylserine

Question 25

Describe the terms intrinsic pathway and extrinsic pathway

Answer 25

Extrinsic pathway: plasma clotting in response to addition of tissue homogenates- factors "extrinsic to the blood". Measured by PT Intrinsic pathway: clotting of plasma in a glass tube using only factors intrinsic to the blood. Measured by aPTT

Question 26

What is the initiation phase of the clotting cascade?

Answer 26

formation of TF-VIIa complex, must exceed a specific threshold in order to trigger clotting mechanism

Question 27

What occurs in the propagation phase of the clotting casdcade

Answer 27

Amplifies clotting response through factor IXa-VIIIa complex

Question 28

Which components of the coagulation cascade are vitamin K dependent?

Answer 28

II, VII, IX, X, C and S

Question 29

Describe how the phospholipid platelet surface is involved in activation of zymogens

Answer 29

Acts as a surface to bring a protease, a cofactor/ helper protein, and a zymogen into close contact

Question 30

Describe factor XI

Answer 30

a serine protease but not vitamin K dependent

Question 31

Describe factor XIII

Answer 31

enzyme that is activated by thrombin, works by cross linking fibrin to stabilize a thrombus

Question 32

What is the function of antithrombin?

Answer 32

Inhibits thrombin (IIa), Xa, IXa, XIa

Question 33

Describe the function of Protein C and Protein S

Answer 33

Protein C: proteolytic inactivation of V and VIII Protein S: supports inactivation of V and VIII

Question 34

What is the function of tissue factor pathway inhibitor?

Answer 34

Forms a complex with factor Xa that inactivates the TF-VIIa complex

Question 35

List the components of the coagulation cascade that are considered cofactors

Answer 35

tissue factor: membrane protein that binds VIIa to form a complex that activates X, does not require proteolytic activation for cofactor activity Factors V and VIII: require activation by thrombin to function. VIII binds IXa to form a complex that activates X Va binds to Xa to form a complex that activates prothrombin Protein S: vitamin K dependent cofactor for protein C

Question 36

How does TF initiate coagulation?

Answer 36

After vascular injury, TF is exposed to the blood and binds circulating VIIa. TF-VIIa generates additional VII and small amounts of IX and X before being inhibited by tissue factor pathway inhibitor A small amount of thrombin is generated by Xa which in turn activates V, VIII, and IX

Question 37

Activation of factors of VIII and V in the initiation phase allows for the formation of _____ and ______ complexes

Answer 37

IXa/VIIIa and Xa/Va --> explosive generation of thrombin in the propagation phase

Question 38

In the propagation phase, thrombin also cleaves/ activates factor ____ which activates additional factor IX and contributes to the final rate of thrombin generation

Answer 38

XI

Question 39

______ is an abundant plasma protein that is cleaved by thrombin to form an insoluble clot

Answer 39

fibrinogen (cleaved to fibrin)

Question 40

What is the role of factor XIII in the coagulation cascade?

Answer 40

Cross links fibrin strands to stabilize the fibrin clot

Question 41

List all of the pro-coagulant functions of thrombin

Answer 41

activation of factors V, VIII, XI and XIII,activation of platelets, and cleavage of fibrinogen to fibrin

Question 42

At very low concentrations, thrombin is bound to _______ on endothelial surfaces, which acts as an anti-coagulant by accelerating activation of protein C

Answer 42

thrombomodulin

Question 43

Describe the role of the contact factors in the coagulation cascade

Answer 43

Factor XII, HMWK, prekallikrein Deficiency does not lead to a bleeding phenotype but does show up as a prolonged aPTT These factors are not necessary for normal hemostasis

Question 44

What is the role of factor XI? What happens in factor XI deficiency?

Answer 44

XI is activated by thrombin and activates factor IX Deficiency causes a mild to moderate bleeding phenotype

Question 45

List three circulating coagulation inhibitors

Answer 45

- tissue factor pathway inhibitor: inhibits TF-VIIa complex so inhibits initiation phase - antithrombin III: markedly reduces rate of thrombin generation in the propagation phase by inhibiting thrombin - activated protein C: helps terminate propagation by inactivating Va and VIIIa

Question 46

______ inhibits IXa, Xa, and thrombin, acting as a scavenger of free proteases

Answer 46

AT3

Question 47

The activity of AT3 is markedly accelerated by the drug _____

Answer 47

heparin

Question 48

How is protein C activated?

Answer 48

Thrombin bound to thrombomodulin

Question 49

The _____ response predominates on the arterial side and the _____ response is more critical on the venous side

Answer 49

platelets on arterial side | clotting cascade on venous side

Question 50

List platelet inhibitory substances produced by normal endothelium

Answer 50

PGI2 Nitric oxide synthase- NO generated from arginine by eNOS CD39 aka ectoDAPase, degrades ADP and ATP

Question 51

List anticoagulant substances produced by normal endothelium

Answer 51

Heparin sulfate: binds AT3 to accelerate protease inhibition | Thrombomodulin: enhances generation of activated protein C

Question 52

How does intact endothelium act as a profibrinolytic surface?

Answer 52

Produces enzymes that activate plasminogen

Question 53

______ is a zymogen produced in the liver that is converted to activated protease then works to digest cross linked fibrin

Answer 53

plasminogen

Question 54

Endothelial cells secrete _____ which activates plasminogen to plasmin and binds specifically to fibrin

Answer 54

tPA

Question 55

Describe two fibrinolysis inhibitors

Answer 55

- a-antiplasmin: circulates in blood, inhibits circulating plasmin but is less effective at inhibiting plasmin bound to a fibrin clot- helps keep plasmin activity local to a fibrin clot and not systemic - plasminogen activator inhibitor-1: released by endothelial cells, helps stabilize blood clots by delaying the onset of fibrinolysis

Question 56

The PT measures factors:

Answer 56

VII, X, V, II, and fibrinogen

Question 57

Prolonged PT with normal aPTT occurs in factor ____ deficiency

Answer 57

VII

Question 58

The aPTT measures factors:

Answer 58

IX, XI, VIII, X, V, II, and fibrinogen

Question 59

The aPTT is sensitive to changes in the ______ which prolong aPTT but do not cause bleeding

Answer 59

contact factors

Question 60

The aPTT is commonly used to monitor the anticoagulant effects of ______

Answer 60

heparin

Question 61

Describe how to interpret the findings of a mixing test

Answer 61

if a single coagulation factor deficiency is present, the mixing test will completely correct prolongation of the clotting time. If a coagulation inhibitor is present, mixing will usually not correct the clotting time.

Question 62

A _____ test can be used to assess vWF activity because it causes conformational changes in vWF triggering binding to GpIb

Answer 62

Ristocetin

Question 63

The thrombin time test is very sensitive to the presence of _____

Answer 63

heparin