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PHAR121 > 3.B-Venous Thromboelism > Flashcards

3.B-Venous Thromboelism Flashcards

1
Q

What is primary hemostasis?

A

involves vasoconstriction and platelet adhesion/aggregation

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2
Q

What is secondary hemostasis?

A

process where fibrin is formed
classic clot production

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3
Q

What is fibrin?

A

small insoluble proteins that form tight complexes

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4
Q

What are the general causes of clot formation?

A

hypercoaguable state
venous stasis
vascular wall injury

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5
Q

What causes hypercoagulability?

A

coagulation exceeds natural mechanisms
genetic causes
malignancies

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6
Q

What causes venous stasis?

A

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

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7
Q

How does vascular wall injury promote clot formation?

A

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

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8
Q

Describe the clotting process.

A

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

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9
Q

Describe the intrinsic pathway.

A

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

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10
Q

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

A

activated platelets
circulating molecules
foreign bodies

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11
Q

Describe the extrinsic pathway.

A

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

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12
Q

What are the properties of thrombin?

A

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

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13
Q

True or false: thrombin can activate its own inhibition

A

true

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14
Q

What are the two classes of orally administered anticoagulants?

A

vitamin K antagonists
direct oral anticoagulants (DOACs)

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15
Q

What are examples of vitamin K antagonists?

A

warfarin
acenocoumarol

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16
Q

What do vitamin K antagonists do?

A

inhibit the production of vitamin-K dependent clotting factors

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17
Q

How are vitamin K clotting factors activated?

A

carboxylation reaction via reduced vitamin K

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18
Q

Where are vitamin K dependent factors synthesized?

A

liver
-not active until carboxylation

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19
Q

Which vitamin K factors are coagulation factors?

A

II
VII
IX
X

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20
Q

Which vitamin K factors are anti-coagulant factors?

A

proteins C and S

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21
Q

Which enzyme does warfarin target?

A

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

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22
Q

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

A

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

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23
Q

What is the mechanism of action for warfarin?

A

inhibits synthesis of vit K-dependent factors

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24
Q

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

A

false
the onset of anti-coagulation is therefore slow

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25
Q

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

A

VII (half life of 6 hours)
fools the INR

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26
Q

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

A

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

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27
Q

Is there a set dose for warfarin?

A

no
dosing requirements are highly variable
individuals require close monitoring

28
Q

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

A

polymorphisms in CYP2C9 and vitamin K reductase

29
Q

Which pathway does warfarin impact more completely?

A

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

30
Q

What is the ratio used to monitor warfarin?

A

international normalized ratio (INR)

31
Q

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

A

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

32
Q

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

A

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

33
Q

Which compounds can accelerate clotting?

A

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)

34
Q

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

A

PT
aPTT

35
Q

What are some differences between DOACs and warfarin?

A

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

36
Q

What are some DOACs?

A

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

37
Q

What do all DOACs end in?

A

-aban

38
Q

Which factor does each DOAC target?

A

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

39
Q

Which DOAC is a prodrug?

A

dabigatran

40
Q

What are the two main advantages of DOACs over warfarin?

A

single dose-no need for monitoring
fast onset

41
Q

True or false: DOACs work on existing clotting factors

A

true

42
Q

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

A

antithrombotic substances
prevents extension of clot to healthy cells

43
Q

What are the endogenous anti-thrombotic substances?

A

thrombomodulin
herparan sulfate
fibrinolytic factors

44
Q

What does thrombomodulin do?

A

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

45
Q

What does heparan sulfate do?

A

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

46
Q

What do plasminogen activators do?

A

converts plasminogen to plasmin
classified as a fibrinolytic

47
Q

What does plasmin do?

A

degrades fibrin into soluble products

48
Q

What are the two types of plasminogen activators?

A

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

49
Q

What are common parenteral anticoagulants?

A

heparin
low molecular weight heparin
fondaparinux

50
Q

What are some characteristics of unfractionated heparin?

A

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

51
Q

What is the mechanism of action of UFH?

A

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

52
Q

What are LMWH and Fondaparinux derivatives of?

A

UFH

53
Q

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

A

no
3:1 inhibitory effect on Xa:IIa

54
Q

True or false: Fondaparinux has Xa and IIa activity

A

false
only Xa activity

55
Q

What are some characteristics of LMWH?

A

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

56
Q

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

A

kidney disease

57
Q

What are some characteristics of Fondaparinux?

A

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

58
Q

What are the direct thrombin inhibitors?

A

lepirudin
desirudin
bivalirudin
argatroban

59
Q

What is the mechanism of action of direct thrombin inhibitors?

A

inhibit IIa

60
Q

True or false: all direct thrombin inhibitors are parenteral formulations

A

true

61
Q

What is venous thrombosis?

A

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

62
Q

Which areas of the body are common for venous thrombosis?

A

calf
thigh

63
Q

What does venous thrombosis result in?

A

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

64
Q

What is venous thrombosis mainly composed of?

A

fibrin and RBCs

65
Q

How is venous thrombosis managed/prevented?

A

anticoagulants

66
Q

How can we monitor the effect of UFH?

A

aPTT

67
Q

True or false: PT may be used for dabigatran

A

false
aPTT may be used for dabigatran

PHAR121 (17 decks)

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