3.B-Venous Thromboelism

Question 1

What is primary hemostasis?

Answer 1

involves vasoconstriction and platelet adhesion/aggregation

Question 2

What is secondary hemostasis?

Answer 2

process where fibrin is formed
classic clot production

Question 3

What is fibrin?

Answer 3

small insoluble proteins that form tight complexes

Question 4

What are the general causes of clot formation?

Answer 4

hypercoaguable state
venous stasis
vascular wall injury

Question 5

What causes hypercoagulability?

Answer 5

coagulation exceeds natural mechanisms
genetic causes
malignancies

Question 6

What causes venous stasis?

Answer 6

immobility (hospitalized patients, bedrest, minimal activity)
obstruction
impaired circulation

Question 7

How does vascular wall injury promote clot formation?

Answer 7

exposure of blood to tissue factor, collagen, subendothelial tissue
-strong initiators of primary and secondary hemostasis

Question 8

Describe the clotting process.

Answer 8

platelets adhere and aggregate on injured/exposed area
clotting cascade activated by platelets and injury
generate fibrin clot–>reinforce platelet plug
as time passes:
-damaged tissue covered
-triggering signals reduced dramatically
-anticoagulant and fibrinolytic pathways predominate
-clot disappears, tissue heals

Question 9

Describe the intrinsic pathway.

Answer 9

XII–>XIIa (via intrinsic molecules)
XI–>XIa (via XIIa)
IX–>IXa (via XIa)
X–>Xa (via IXa)
promthrombin (II)–>thrombin (IIa)

Question 10

What are some intrinsic molecules that can activate the instrinc pathway?

Answer 10

activated platelets
circulating molecules
foreign bodies

Question 11

Describe the extrinsic pathway.

Answer 11

VII–>VIIa (via tissue factor)
X–>Xa (via VIIa)
prothrombin (II)–>thrombin (IIa)

Question 12

What are the properties of thrombin?

Answer 12

activates fibrinogen to a fibrin clot
amplifies its own product (+ve feedback)
activates platelets
pro-inflammatory effects
activates endogenous anticoagulant system

Question 13

True or false: thrombin can activate its own inhibition

Answer 13

true

Question 14

What are the two classes of orally administered anticoagulants?

Answer 14

vitamin K antagonists
direct oral anticoagulants (DOACs)

Question 15

What are examples of vitamin K antagonists?

Answer 15

warfarin
acenocoumarol

Question 16

What do vitamin K antagonists do?

Answer 16

inhibit the production of vitamin-K dependent clotting factors

Question 17

How are vitamin K clotting factors activated?

Answer 17

carboxylation reaction via reduced vitamin K

Question 18

Where are vitamin K dependent factors synthesized?

Answer 18

liver
-not active until carboxylation

Question 19

Which vitamin K factors are coagulation factors?

Answer 19

II
VII
IX
X

Question 20

Which vitamin K factors are anti-coagulant factors?

Answer 20

proteins C and S

Question 21

Which enzyme does warfarin target?

Answer 21

vitamin K reductase
-lowers the supply of reduced vit K available to active vit K
clotting factors

Question 22

What is the difference between S-warfarin and R-warfarin?

Answer 22

S-warfarin: most of the anticoagulant action, metabolized by
CYP 2C9
R-warfarin: 5x less potent, metabolized by CYP 3A4 and 1A2

Question 23

What is the mechanism of action for warfarin?

Answer 23

inhibits synthesis of vit K-dependent factors

Question 24

True or false: warfarin has an effect on clotting factors already in circulation

Answer 24

false
the onset of anti-coagulation is therefore slow

Question 25

Which clotting factor has a short half life? What is the implication of this?

Answer 25

VII (half life of 6 hours) fools the INR

Question 26

How long does it take for the full anticoagulation effect of warfarin? Which factor is mainly responsible for this?

Answer 26

6 days because there needs to be a reduction in all factors IIa (half life of 72 hours)

Question 27

Is there a set dose for warfarin?

Answer 27

no dosing requirements are highly variable individuals require close monitoring

Question 28

Why is the dosing so variable for each person with warfarin?

Answer 28

polymorphisms in CYP2C9 and vitamin K reductase

Question 29

Which pathway does warfarin impact more completely?

Answer 29

extrinsic pathway -effects can be monitored using PT (prothrombin time)

Question 30

What is the ratio used to monitor warfarin?

Answer 30

international normalized ratio (INR)

Question 31

What does an INR of 1 mean? What if it was 2-3?

Answer 31

1: no anticoagulant effect 2-3: intensity of anti-coagulation is increased

Question 32

What are the drug interactions to be aware of with warfarin?

Answer 32

metabolism: 2C9, 3A4/1A2 bleeding: antiplatelets, other anticoagulants, herbals vitamin K displacement: sulfonamides, ASA absorption: iron, magnesium, zinc (reduce warf absorption)

Question 33

Which compounds can accelerate clotting?

Answer 33

substances intrinsic to the plasma -reduce clotting time to 26-33s -activated partial thromboplastin time (aPTT) substances extrinsic to the plasma -reduce clotting time to 12-14s -prothrombin time (PT)

Question 34

What are the common blood tests to assess clotting ability based on blood samples?

Answer 34

PT aPTT

Question 35

What are some differences between DOACs and warfarin?

Answer 35

DOACs more predictable (INR monitoring not required) DOACs have faster onset (hours vs days) DOACs have lower risk of bleeding DOACs are more expensive

Question 36

What are some DOACs?

Answer 36

dabigatran etexilate (Pradaxa) rivaroxaban (Xarelto) apixaban (Eliquis) Edoxaban (Lixiana)

Question 37

What do all DOACs end in?

Answer 37

-aban

Question 38

Which factor does each DOAC target?

Answer 38

dabigatran: thrombin (IIa) rivaroxaban: Xa apixaban: Xa edoxaban: Xa

Question 39

Which DOAC is a prodrug?

Answer 39

dabigatran

Question 40

What are the two main advantages of DOACs over warfarin?

Answer 40

single dose-no need for monitoring fast onset

Question 41

True or false: DOACs work on existing clotting factors

Answer 41

true

Question 42

What will be secreted by an intact endothelium adjacent to damaged tissue?

Answer 42

antithrombotic substances prevents extension of clot to healthy cells

Question 43

What are the endogenous anti-thrombotic substances?

Answer 43

thrombomodulin herparan sulfate fibrinolytic factors

Question 44

What does thrombomodulin do?

Answer 44

converts Protein C to its active form aPC -aPC degrades vit K dependent clotting factors -uses protein S as a cofactor

Question 45

What does heparan sulfate do?

Answer 45

binds to antithrombin antithrombin inhibits IIa, Xa, and other activated clotting factors in the intrinsic pathway

Question 46

What do plasminogen activators do?

Answer 46

converts plasminogen to plasmin classified as a fibrinolytic

Question 47

What does plasmin do?

Answer 47

degrades fibrin into soluble products

Question 48

What are the two types of plasminogen activators?

Answer 48

tissue type plasminogen activators (t-PA) -predominant type secreted by endothelial cells -promotes intravascular fibrinolysis U-PA or urokinase -secreted in response to inflammatory stimuli -promotes extravascular fibrinolysis

Question 49

What are common parenteral anticoagulants?

Answer 49

heparin low molecular weight heparin fondaparinux

Question 50

What are some characteristics of unfractionated heparin?

Answer 50

obtained from gut mucosa of animals mixture of proteins short half life (<60min) IV or SQ

Question 51

What is the mechanism of action of UFH?

Answer 51

binds to antithrombin heparin-AT complex: inactivates IIa and Xa inactivates several factors in intrinsic pw

Question 52

What are LMWH and Fondaparinux derivatives of?

Answer 52

UFH

Question 53

Does LMWH have the same inhibitory effect on Xa and IIa?

Answer 53

no 3:1 inhibitory effect on Xa:IIa

Question 54

True or false: Fondaparinux has Xa and IIa activity

Answer 54

false only Xa activity

Question 55

What are some characteristics of LMWH?

Answer 55

smaller fragments lower binding affinity for plasma proteins/cells cleared by kidney (UFH unaffected by renal dysfunction) better bioavailability longer half life no monitoring of bleeding time needed

Question 56

Which people do you have to be careful about use of LMWH and Fondaparinux?

Answer 56

kidney disease

Question 57

What are some characteristics of Fondaparinux?

Answer 57

smaller pentasaccharide sequence anti-Xa only renal clearance predictable dose response SQ administration no monitoring of bleeding time

Question 58

What are the direct thrombin inhibitors?

Answer 58

lepirudin desirudin bivalirudin argatroban

Question 59

What is the mechanism of action of direct thrombin inhibitors?

Answer 59

inhibit IIa

Question 60

True or false: all direct thrombin inhibitors are parenteral formulations

Answer 60

true

Question 61

What is venous thrombosis?

Answer 61

pathologic clots in veins without obvious damage often occurs in areas of disturbed flow

Question 62

Which areas of the body are common for venous thrombosis?

Answer 62

calf thigh

Question 63

What does venous thrombosis result in?

Answer 63

poor tissue drainage-->edema and inflammation-->pulmonary embolism

Question 64

What is venous thrombosis mainly composed of?

Answer 64

fibrin and RBCs

Question 65

How is venous thrombosis managed/prevented?

Answer 65

anticoagulants

Question 66

How can we monitor the effect of UFH?

Answer 66

aPTT

Question 67

True or false: PT may be used for dabigatran

Answer 67

false aPTT may be used for dabigatran