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Therapeutics P2 > Module 2 exam 1 lecture 3 > Flashcards

Module 2 exam 1 lecture 3 Flashcards

1
Q

What kind of protease is thrombin

A

Seriine protease

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2
Q

WHat are the two main proteins involved in clotting

A

Serine protease(thrombins)
Glycoproteins

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3
Q

name the serine pro-coagulant factors

A

XII, XI, X, IX, VII, II

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4
Q

protein C acts as an

A

anticoagulant

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5
Q

what factors does protein C cleave

A

cleaves factors Va, VIIIa and inactivates them

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6
Q

what are glycoproteins

A

Cofactors that localize factors to a particular region, they are procoagulatory

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7
Q

example of glycoproteins

A

factors VIII, v, III

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8
Q

Protein C and protein S complex

A

ANticoagulatory complex

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9
Q

what is the target for heparins

A

Anti-thrombin

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10
Q

is anti thrombin pro or anti coagulatory

A

anticoagulatory

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11
Q

how is antithrombin anticoagulatory

A

because It binds to a number of different factors and inactivate them and target them to be degraded

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12
Q

Calcium is sometimes referred to as

A

Factor IV

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13
Q

Why is calcium important in this context

A

It is an important co factor because it links different protease factors to phospholipid membrabne

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14
Q

What does transglutaminase do? Also called

A

Cross-links fibrin-fibers (factors XIII)

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15
Q

what is fibrinogen/fibrin

A

The substrate protein for factor IIa that polymerizes to form a clot

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16
Q

Where are CF (clotting factors ) produced?

A

CF (except for VWF) are made in liver

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17
Q

what is VWF

A

is a circulating factor that binds to collagen in damaged BV and recruits platelets

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18
Q

where is VWF made?

A

Endothelium (Factor VIII is also produced in endothelium)

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19
Q

Can liver disease affect coagulation?

A

yes, clotting factors are produced there.

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20
Q

What are the two different scenarios that lead to coagulation

A

Intrinsic and extrinsic pathway.

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21
Q

Explain the extrinsic pathway

A

Requires a protein or factor that is not present in bloodstream to come into contact with the blood. (important when vessel is damaged and blood leaks out)

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22
Q

Explain the intrinsic pathway

A

Triggered when collagen is exposed on the wall of the BV

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23
Q

What is the most important step in intrinsic pathway

A

activation of factor IX (9)

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24
Q

Extrinsic pathway MOA

A

Blood encounters tissue factor C (thromboplastin), which recognizes factor 7, leading to activation of factor 10

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25
Q

where do extrinsic and intrinsic pathways merge

A

activation of factor X

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26
Q

what does faxtor X do?

A

cleaves pro-thrombin to thrombin

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27
Q

how long does it take extrinsic pathway to start clot formation

A

15 seconds

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28
Q

where are factors VII and x found

A

in blood.

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29
Q

how is TF activated?

A

by binding to factor VII

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30
Q

what does factor VII do?

A

cleaves factor X and activates it to factor Xa

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31
Q

summarize actions of factor VII and x

A

factor x and factor VII are contents of the blood. IIf they are in BV, they will not encounter any TF. Once there is damage to the blood and it leaks, factor VII binds TF. Factor VII is actiavted and it can cleave factor x to factor Xa

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32
Q

how is factor X turned on in intrinsic pathway?

A

by factor ix (9)

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33
Q

the initiator of common pathway os factor

A

X

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34
Q

factor x does what?

A

cleaves prothrombin to thrombin

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35
Q

What happens once thrombin is activated

A

cleaves fibrinogen to fibrin, fibrin forms clot

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36
Q

thrombin also activates

A

factor 13 (transglutainase)

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37
Q

what does factor 13 (transglutaminase do?)

A

Crosslinks the fibrin strands and stabilizes the clot

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38
Q

examples of positive feedback activity in clotting

A

-thrombin has a positive feedback activity in the activation of coagulation
-platelet activation increases activation of factors VII and factor X

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39
Q

How does thrombin activation have a positive feedback

A

activates cofactors factor V and factor VIII, enhancing activity

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40
Q

feedback mechanisms that dcerease coagulation

A

Antithrombin
Protein C system
Factor Xa

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41
Q

use of calcium chelators in collecting blood smaple?

A

preserves platelet function in storage.

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42
Q

What are the 3 different lab tests for coagulation

A

Calcium only
Calcium and partial thromboplastins (just phospholipids and kaolin)
Calcium and thromboplastins

43
Q

Give the time ranges for the different lab tests for coagulation

A

Calcium only -2-4 minutes
calcium and partial thromboplastins -26-33 seconds
calcium and thromboplastins- 12-14 seconds

44
Q

What is INR? What is its use?

A

international normalized ratio. It is used to normalize the prothrombin time test from lab to lab to set standard.

45
Q

What is normal INR

A

0.8-1.2

46
Q

INR number that makes pt at risk for hemorrhage

A

> 3

47
Q

why do we use anticoagulants

A

Preventing excessive clotting that can lead to stroke, MI, unstable angina, DVT, pulmonary embolism

48
Q

Vitamin K is an antagonist for

A

Warfarin

49
Q

MOA of coumadin (warfarin) inhibiting vit K

A

Coumadin inhibits vit-K epoxide reductase, blocking reduction of vitK epoxide to its active form.

50
Q

Warfarin acts by inhibiting synthesis of

A

Factors VII, IX, X, II

51
Q

How does warfarin inhibit factors VII, IX, X, II

A

dirsupts ability of calicum to bring these factors to phospholipid membrane

52
Q

Why does warfarin have a delayed action of onset? how long does it take?

A

It has to deplete the circulatory pool of clotting factors before it has an effect. takes 3-5 days

53
Q

Why is dosing warfarin so tricky

A

Warfarin is metabolized by CYP2C9, which is the most variable CYP in pt population.

54
Q

what to do if bleeding on warfarin

A

DX warfarin, give vit K (in serious hemorrhage, plasma replaces CF faster than vit K)

55
Q

Direct target of warfarin? which enantiomer is active?

A

vit K epoxide reductase (VKORCL)
S enantiomer

56
Q

How does warfarin necrosis happen? What do we do to combat this?

A

Protein C becomes depleted 1st before other CFs. This leads to pro coag state. Heparin can be given along side warfarin to combat this

57
Q

ADE of warfarin

A

Hemorrhage, drug-drug i/a

58
Q

contraindications of warfarin

A

dementia, psychosis, alcohol/drug abuse

59
Q

What are drugs that diminish warfarins anticoag effect?

A

VIT K, antibiotics that kill intestinal flora, SSRIs, anabolic steroids

60
Q

for emergency situations like acute major bleeding, how do we reverse warfarins effects?

A

exogenous vit K with prothrombin complex via IV

61
Q

Heparin ROA

A

IV or SQ

62
Q

How do heparins work?

A

via activation of a protein called antithrombin-3

63
Q

What does antithrombin 3 do?

A

it has the ability to bind to factors IIa (thrombin) and factor X (10a) and inactivate them, anti coag effect

64
Q

heparin structure? synthetic version name

A

long chain polysaccharide with negatively charged sulfates that bind to antithrombin 3. Fondaparine is synthetic part

65
Q

How does heparin change the interaction between thrombin and factor X?

A

Usually, this interaction is very slow. Heparin increases the speed by 100x.

66
Q

Where are heparins usually found? LMWH action?

A

Heparins are usually found on mast cells.
LMWH are too small to bind antithrombin and thrombin. They will have a greater specificity for inhibition of factor Xa

67
Q

Heparins act by accelerating

A

antithrombin rxns to inactivate thrombin and factor Xa

68
Q

do heparins bind directly to Xa or thrombin?

A

No, they bind to antithrombin and accelerate the interaction of antithrombin with either thrombin or factor Xa, causing them to be inactive and cleared.

69
Q

Clinical use of heparin? t1/2? onset?

A

Anticoagulant effective immediately for 30 min-180 mins. anticoag effect when therapy is dx

70
Q

adverse effects of heparin?

A

Type 1 HIT- type 1, mild, decrease in platelets by 25%
Type 2 HIT- severe, develops 7-12 days after starting therapy
osteoporosis

71
Q

How to reverse effects of heparin during life threatening bleeding? MOA?

A

Use protamine sulfate because it has positive charges that will bind tightly to heparin.
It can NOT reverse fondaparinux

72
Q

How does type 2 heparin induced thrombocytopenia occur?

A

develops 7-12 days after starting heparin. Occurs as a result of interaction of heparin and a protein called PF-4

73
Q

MOA of thrombocytopenia

A

PF4 on surface of platelet binds heparin. Heparin removes the pF4 from the platelet and form a complex that can be recognized by antibodies. In type 1 platelets are removed. in type 2 it causes thrombosis

74
Q

rank HIT risk in LMWH, Fondaparinux, and heparin

A

Heparin>LMH>fondaparinux

75
Q

name the two LMWH. How is LMWH obtained?

A

dalteparin, enoxaparinFrom the depolymerization of unfractured heparin.

76
Q

COmpare LMH and heparin in terms of bioavailability, efficacy, dosing and monitoring, side effects?

A

Equal efficacy
less frequent dosing than heparin (longer half life)
no monitoring needed
increased bioavailability
lower incidence of side effects

77
Q

MOA of fondaparinx

A

indirectly inhibits factor Xa by selectively binding antithrombin

78
Q

ROA and use of fondaparinux

A

Given SQ and used for venous thromboembolism and prophylaxis in patinets undergoing surgery

79
Q

ROA of warfarin? onset? Reversal time?

A

Oral, longtime to onset, long time to reverse

80
Q

Heparin moa? onset?

A

works fast, binds antithrombin and accelerates its ability to inactivate thrombin

81
Q

Name DOAC/NOAC drugs

A

Direct factor Xa inhibitors
Rivaroxaban
apixaban
edoxaban
betrixaban

Direct thrombin inhibitors
Dabigatran

82
Q

RivaroXAban and apiXAban MOA? t1/2? indication?

A

Both small molecules that bind the active site of factor Xa serine protease. (its in the name)
rivaroxaban- 5-9hrs
apixanab- 12 hrs
Both indicated for the tx/prevention of VT and PE

83
Q

Rivaroxaban and apixaban excreted by?
When to not use them

A

renally, dose reduction in renally impaired patient needed. Risk of hematoma/paralysis in spine puncture/epidural

84
Q

Edoxaban MOA? Indication? ROA?

A

Xa inhibitor, indicated for tx/prophylaxis of VT and PE, orally available

85
Q

Edoxaban excreted by?

A

Renally, NOT IN USE in patients with CRCL>95

86
Q

side effects of edoxaban?

A

Risk of hematomal paralysis in pts undergoing soinal puncture or epidural.

87
Q

For every drug with Xa in it (direct Xa inhibitors)
indication
MOA

A

Moa- Xa inhibitor
indication- VT and PE
risk of ischemic event upon premature dx
paralysis in patients undergoing epidural and spinal puncture
fixed dosing
monitoring not required

88
Q

betrixaban excreted

A

renally and hepatially. Dose reduction in impairments in both

89
Q

antidote for reversal for apixaban and rivaroxaban

A

Andexanet

90
Q

How does andexanet work? ROA? blackbox warning?

A

mimics factor Xa and binds drug, but lacks enzymatic activity. Given IV. blackbox for increase risk for thromboembolic event

91
Q

when is andexanet given?

A

unconrolled bleeding after administration of apixaban or rivaroxaban

92
Q

besides factor X, the ultimate serine protease involved in cleaving fibrinogen to fibrin is

A

thrombin

93
Q

factor X cleaves

A

prothrombin to thrombin

94
Q

Name DTI drugs

A

Lepirudin
Bivalirudin
Argatroban
Dabigatran

95
Q

How do DTIs work? What do they do?

A

They bind to active site of thrombin, to the xosite or both. Inhibit platelet aggregation (anticoag)

96
Q

Difference between DTI and heparin

A

DTI can inhibit fibrin bound to thrombin, Heparin can not inhibit thrombin once bound to fibrin;

97
Q

Lepirudin MOA, ROA, indication, reversible or irreversible? Bivalent or no?

A

ROA- IV
MOA- bivalent (binds active and exosite)
used to treat heparin induced thrombocytopenia (HIT)
irreversible

98
Q

Bivalirudin ROA, MOA, indication, bivalent or no? irreversible or no? half life?

A

Bivalent short peptide
cleared in 25 minutes
given IV
reversible with rapid onset and short duration

99
Q

bivalirudin and argatroban bind in the

A

arg-pro motif. It is a recognition site for thrombin

100
Q

Argatroban indication? bivalent? reversible or irreversible? ROA?

A

DTI approved for HIT or coronary artery thrombosis
IV
Reversible
Not bivalent, binds active site

101
Q

Only DTI orally available

A

Dabigatran

102
Q

Dapigatran dosing and indication

A

Dosed BID
Prevents stroke
It is a prodrug

103
Q

Drug used to reverse effects of dabigatran

A

Idarucizumab (does not work for other DTIs)

104
Q

DOAC drugs and indication

A

rivaroxaban, apixaban, edoxaban, dabigatran
non-vascular A-fib, DVT, PE (tx or prevention)

Therapeutics P2 (41 decks)

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