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Therapeutics II > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Clot formation in hemostasis

A

-strong clot
-cascade mech that activates thrombin which converts fibrinogen to fibrin
-slide 3

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2
Q

Clotting (coagulation) factors

A

-serine proteases
-glycoproteins
-Ca2+ (factor IV)
-Transglutaminase
-Fibrinogen/Fibrin

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3
Q

Serine proteases

A

-coag factors
-cleave down-stream factors to activate them
-Factors XII, XI, X, IX, VII, II (procaogulants)
-cleave factors Va and VIIIa to inactivate them
-Protein C (anticoagulant)

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4
Q

Glycoproteins

A

-co-factors for activation of proteases
-Factors VIII, V, III (tissue factors), protein S
-bind/inhibt thrombin (anti-thrombin III

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5
Q

Ca2+ (Factor IV)

A

-links some factors to phospholipid membranes

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6
Q

Fibrinogen/Fibrin

A

-substrate protein for factor IIa (thrombin) that polymerizes to form clot

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6
Q

Transglutaminase

A

-coag factor
-cross-links fibrin fibers (factor XIII)

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7
Q

Genetic clotting factor diseases

A

Hemophilia A: def in factor VII (X-linked)
-B: factor IX (X-linked)
-Factor V Leidin: resistance to activated protein C
-Queen victoria carrier of hemophilia B

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8
Q

Where are clotting factors produced

A

-liver
-except vWF which is in the sub/endothelium and megakaryocytes
-factor VIII also produced in endothelium
-liver disease can have unpredictable effects on coagulation!

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9
Q

Where does coagulation occur

A

-extrinsic pathway
-intrinsic pathway

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10
Q

Extrinsic pathway of coagulation

A

-requires a factor (tissue factor) extrinsic to the blood
-initiated by release of tissue thromboplastin
-rapid (15sec to start clot formation)

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11
Q

Intrinsic pathway

A

-triggered when collagen is exposed on the wall of the blood vessel
-all components in blood
-initiated by contact w negatively charged collagen of diseased or injured vessel
-blood in test tube clots by this mech

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12
Q

Activation of extrinsic pathway

A

-tissue factor expressed on cells near blood vessels
-TF binds Factor VII in blood
-Factor VIIa binds and cleaves factor X

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13
Q

Activation of Intrinsic pathway

A

-factor IXa binds factor VIIIa on surface of platelets and activates Factor X

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14
Q

Common pathway in coagulation cascade

A

-prothrombin activator
-slide 12
-thrombin activation
-converts fibrinogen to long strands on insoluble fibrin
-activates factor XII that cross-links fibrin to form stable clot incorporated into platelet plug

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15
Q

Feedback mech that increase coagulation

A

-Thrombin activates V and VIII and enhances platelet activation
-platelet activation inc activation of VII, X and cleavage of prothrombin

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16
Q

Feedback mech that DECREASES coagulation

A

-antithrombin neutralizes procoagulants (thrombin, Xa, IXa) rx accelerated by heparin!
-protein C activated by thrombin binding thrombomodulin, APC forms complex w protein S to inactivate Va and VIIIa
-factor Xa activates tissue factor pathway inhibitor (TFPI) to block initital activation of factor VII

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17
Q

Common tests of hemostatic function

A

-platelet count
-prothrombin time (PT/INR)
-aPTT
-Fibrinogen
-D-dime

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18
Q

Platelet count test

A

-too low = thrombocytopenia (bone marrow and nutrition probs)
-too high = thrombocytosis

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19
Q

Prothrombin time (PT/INR)

A

-plasma + thromboplastin + Ca
=clots in 12-14 sec
-INR normal for each lot of thromboplastin

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20
Q

aPTT

A

-plasma + phospholipid (No TF) + activating agent
-clots 26-33 sec
-monitor heparin therapy

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21
Q

Fibrinogen testing

A

-less common
-200-400

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22
Q

D-dimer test

A

-product of fibrin breakdown

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23
Q

tests ordered for coagulation profile (DIC panel)

A

-Platelet count
-Prothrombin time (PT/INR)
-aPTT

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24
Q

In vitro measurement of coagulation

A

-add EDTA/citrate
-calcium only (recalcification time 2-4 minutes)
-calcium and partial thromboplastin (just phospholipids) and kaolin (aPTT 26-33sec) INTRINSIC
-ca and thromboplastin (tissue factor and phospholipids) (PT 12-14sec) EXTRINSIC

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25
Q

INR

A

-international normalized ratio
=(PTtest/PTnorm)^ISI
-PTnorm = 11-14 sec
-TF producers must assign ISI (sensitivity index) to product

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26
Q

INR values

A

-normal: 0.8-1.2
-therapeutic: 2-3
->3 risk of hemorrhage

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27
Q

Therapeutic Indications for Anticoagulants

A

-prevent excessive clotting that can lead to occlusion of blood vessels
-stroke
-post MI
-unstable angina
-DVT
-PE
-artificial surfaces

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28
Q

Anticoagulant drug classes

A

-Vit K antagonists
-Direct thrombin inhibitors
-Heparin
-Fondaparinux
-Direct factor Xa inhibitors

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29
Q

Vitamin K antagonists

A

-Coumarin anticoagulants
-Warfarin

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30
Q

Coumarin anticoagulants

A

-warfarin
-originally found in spoiled clover hay that caused hemorrhage in cattle
-all derivatives are water soluble lactones

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31
Q

Warfarin

A

-S-isomer more potent
-vit k antagonist

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32
Q

Vit K action

A

-essential for post-translational mods of VII, IX, X, prothrombin, protein C and S
-carboxylase catalyzes y-carboxylation of Glu in prothrombin
-vit k oxidized

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33
Q

Warfarin MOA

A

-inhibits Vit K epoxide reductase (VKORC1)
=block reduction of vit k epoxide back to its active form
-inhibits II, VII, IX, X

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34
Q

Role odf y-carboxylation of clotting factors

A

-slide 21

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35
Q

Warfarin therapeutic actions

A

-delayed onset
-must deplete pool of circulating clotting factors
-max effect 3-5days after initiation
-loading dose 5mg/day
-maintenance dose 2.5 or 5
-after dc therapy, factors must be re-synthesized to return to normal PT (several days)

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36
Q

Warfarin metabolism

A

-CYP2C9
-t1/2 36-48h
-termination of action not related to plasma levels of drug but reestablishment of normal clotting factors

37
Q

Warfarin overdose

A

-latrogenic hemorrhage
-dc warfarin
-admin vit k to activate warfarin-inhibited reductase
-plasma instead of vit k in serious hemorrhage replaces clotting factors faster

38
Q

Warfarin necrosis

A

-pt w protein C deficiency
-protein C is ANTIcoagulant that needs vit k mediated carboxylation for activity
-warfarin dec protein C fastest
= inc coagulation when tx begins
-give pt heparin to combat
-protein S deficiency would be same necrosis

39
Q

How to prevent warfarin necrosis

A

-heparin

40
Q

Adverse

A
41
Q

effects of warfarin

A

-hemorrhage (close monitoring when starting tx and during heparin coadmin)
-drug-drug interactions

42
Q

Warfarin drug interactions

A

-99% is bound to plasma albumin
-long half life
-CYP2C9
-coadmin w albumin-bound drugs or drugs that influence P450

43
Q

Warfarin contraindications

A

-when risk of hemorrhage worse than potential benefits
-uncontrolled alcohol/drug use
-unsupervised dementia and psychosis
-never use in pregnancy (hemorrhage fetus = facial deformaties)

44
Q

Drugs that diminish warfarin’s anticoagulant effect

A

-Vitamin K (bypasses warfarin-induced epoxidase reductase inhibition)
-cholestyramine (blocks GI absorption)
-barbituates, carbamazepine, rifampin? (accelerates metabolism)
-nephrotic syndrome/hypoproteinemia (dec 1/2)
-pregnancy (more clotting factors)

45
Q

Drugs that enhance warfarins effect

A

-Antibiotics (reduce availability of vitamin K in GI tract)
-choral hydrate (displaces from plasma albumin)
-chloramphenicol, SSRIs, amiodarone (dec metabolism)
-anabolic steroids (testosterone)(blocks synthesis and inc degradation of clotting factors)

46
Q

Vit K

A

-fat-soluble
-post-translational mods of prothrombin, VII, IX, X (vit k dependent)
-tx individuals w abnormal fat absorption
-reverse anticoagulant effects of excess warfarin
-structure slide 27

47
Q

Reversing Warfarin effects

A

-admin EXOGENOUS VITAMIN K and prothrombin complex concentrates IV (II, VII, IX, X, protein C and S, Kcentra) for emergent situations (acute major bleeding)
-oral vit K for OD and no acute major bleeding

48
Q

Heparin drugs (IIa/Xa inhibitors)

A

-Unfractionated heparin (UFH)
-enoxaparin (low weight)
-daltaparin (LWMH)
-fondaparinux (non-heparinoids)

-pentasaccharide unit
-IIa/Xa inhibitors

49
Q

Heparin MOA

A

-accelarates AT rx to inactivate thrombin and Xa

-free antithrombin (AT) can inactivate Xa, IXa, XIa, XIIa, IIa, and Vlla at slow rate
-heparin binds AT (conformational change)
=inc interaction of AT w target factors
-ratio of AT is 3:1 thrombin:Xa
-LMWH too small to bind antithrombin and thrombin
=greater specificity and inhibition of Xa

50
Q

Heparin conformational change

A

-binds AT
-ternary complex
-heparin-AT-target factor

51
Q

LMWH specificity

A

-inhibiting Xa
-too small to bind thrombin and antithrombin

52
Q

Heparin dosing

A

-intermittent IV injection
-continuous IV infusion (easy to control)
-SC injection
-adjust dose according to coagulation tests (aPTT)
-anticoagulaant effect disappears within hours of therapy

53
Q

Heparin testing

A

-aPTT
-aPTT therapeutic range: 1.5-2x normal
-cleared rapidly from blood (t1/2=30-180min)

54
Q

Adverse effects of heparin

A

-latrogenic hemorrhage
-Thrombocytopenia (HIT)
-Osteoporosis

55
Q

Latrogenic hemorrhage risk factors (heparin)

A

-pt over 50
-ulcer pt
-severe HTN
-antiplatelet drugs

56
Q

Latrogenic hemorrhage from heparin tx

A

-stop heparin (short t1/2)
-life threatening bleeding: admin specific antagonist
-PROTAMINE SULFATE!

57
Q

Protamine sulfate

A

-binds tightly to heparin to neutralize anticoagulation action
-low weight POLYCATIONIC protein that forms stable complex w neg charged heparin via electrostatic interactions
-admin IV in life-threating hemorrhage or heparin excess
-not as effective with LMWH
-does not reverse fondaparinux

58
Q

Thrombocytopenia (HIT) from heparin

A

-type1: mild due to direct action on platelets
-type 2: severe, develops 7-12 days after therapy, Abs develop to platelet (PF4)-heparin complex

59
Q

Osteoporosis from heparin

A

-associated w extended therapy
-3-6 months

60
Q

Heparin-induced thrombocytopenia MOA

A

-UFH use in pt producing Ab to complex of heparin and platelet factor 4
-HIT risk: heparin >LMWH>fondaparinux
-slide 36

61
Q

Heparin chemistry

A

-straight chain of sulfated mucopolysaccharides produced by MAST cells and BASOPHILS
-extracted from porcine small intestine or bovine lung!
-120USP units/mg standard activity
-SULFATE groups (neg charge) reguired for binding to antithrombin

62
Q

Low molecular weight heparins (LMWH)

A

-dalteparin (2-9k daltons)
-enoxaprin (2-8k daltons)
-obtained from depolymerization of UFH from porcine

63
Q

LMWH compared to heparin

A

-eq efficacy
-inc bioavailability from SC route (only route)
-less freq dosing (qd or BID) (longer t1/2)
-no monitoring needed

64
Q

Advantages of LMWH

A

-more predictable PK
-good SQ availability
-less protein binding = more uniform dosing
-longer t1/2 = fewer injections
-LOWER incidence of HIT and Osteoporosis

65
Q

Slide 40

A

Slide 40

66
Q

INDIRECT Factor Xa inhibitor

A

-Fondaparinux sodium

67
Q

Fonaparinux sodiuam

A

-factor Xa inhibitor
-synthetic sulfated pentasaccharide

68
Q

Fondaparinux MOA

A

-indirect inhibition of Xa by selectively binding AT
-given SC (can take at home)
-qd (t1/2=17-21h)
-predictable PK and dose response = does not require monitoring of anticoagulant effect
–low potential for HIT
-NOT reversed by protamine sulfate

69
Q

Fondaparinux use

A

-venous thromboembolism (acute DVT and PE)
-prophylaxis in hip, knee, or ab surgery

70
Q

Direct Oral AntiCoagulants (DOAC)

A

-direct factor Xa inhibitors (RAEB)
-direct thrombin inhibitors (DAB)

-NOAC =novel
-TSOAC= target specific

71
Q

Orally available DIreCT Factor Xa inhibitor drugs

A

-Rivaroxaban
-Apixaban
-Edoxaban
-Betrixaban

72
Q

Rivaroxaban and Apixaban

A

-tx DVT, PE, prophylaxis, AFIB
-dose reduction w impaired renal function
-risk of hematoma/paralysis in pt undergoing spinal puncture or epidural anethesia
-inc risk of thrombosis upon dc
-fixed dosing, anticoagulation monitoring not required
-R: 5-9h t1/2
-A:12h t1/2
-structures

73
Q

Edoxaban

A

-10-14h t1/2
-tx of VT and PE after 5-10days w parenteral anticoagulant
-prevent thrombosis in AFIB
-fixed dose, no monitoring

74
Q

Edoxaban cautions

A

-do NOT use in pt w CrCl > 95ml/min?
-inc risk of ischemic events upon premature dc
-risk of hematoma/paralysis in pt undergoing spinal puncture or epidural anesthesia
-no monitoring needed

75
Q

Betrixaban

A

-19-27h t1/2
-prevention of VTE in at risk hospital pt
-no monitoring

76
Q

Betrixaban cautions

A

-reduce dose in pt w renal impairment
-AVOID in mod-severe liver impairment
-risk hematoma/paralysis in pt undergoing spinal puncture or epidural anesthesia
-inc risk of ischemic events upon premature dc

77
Q

Antidote for factor Xa inhibitors

A

-Andexanet
-IV to pt w uncontrolled/lifethreatening bleeding after admin of apixaban or rivaroxaban

78
Q

Andexanet

A

-Antidote for factor Xa inhibitors
-apixaban and rivaroxaban
-recom protein that mimic Xa, binds drug but no enzymatic activity
-under ivestigation for edoxaban and enoxaparin

79
Q

Andexanet black box

A

-inc risk for thromboembolic events

80
Q

Direct thrombin inhibitors (DTI) MOA

A

-bind to active or exosite or both of thrombin
-inhibit soluble and fibrin-bound thrombin
-reduce platelet aggregation
-slide 49

81
Q

Non-heparinoid DTI

A

-Hirudin
-Lepirudin

-do not act through AT-III
-inhibit free thrombin and fibrin-bound thrombin

82
Q

Hirudin

A

-DTI
-peptide from leech saliva

83
Q

Lepirudin (refludan)

A

-recom hirudin grown in yeast
-small, give IV
-specific (active and exosite)
-IRREVERSIBLE inhibition of thrombin
-aPTT values inc dose-dependently
-can produce hypersensitivity rx
-excreted via kidney
-tx HIT

84
Q

DTI drugs

A

-Bivalirudin (angiomax)
-Argatroban
-Dabigatran

85
Q

Bivalrudin (angiomax) structure

A

-20 aa peptide
-Phe-Pro-Arg-Pro binds active site
-4 Gly chain cleaved by thrombin
-Asn-Gly-9-Leu binds exosite I

86
Q

Bivalrudin

A

-binds active and exosite I of thrombin
-REVERSIBLE binding
-rapid onset/short duration
-give IV during percutaneous coronary angioplasty
-eliminated renally
-25min t1/2
-low risk of bleeding, doesnt induce Ab formation

87
Q

Argatroban

A

-derived from L-arginine
-bind REVERSIBLY to active site
-does not require AT for activity
can inhibit free and clot-associated thrombin
-monitor using aPTT
-give IV (40-50min t1/2)
-metabolized by liver (CYP3A4/5)
-approved tx HIT or Coronary artery thrombosis in pt w HIT
-also for prophylaxis in PCI procedures

88
Q

Dabigatran (Pradaxa)

A

-DTI
-12-14h t1/2
-tx prevention of stroke and embolism in pt w Afib
-avoid in renal impairment
-lab assessment of coagulation state is not required
-reversed by praxbind (idarucizumab) IV

89
Q

reversal of DTIs

A

-Idarucizumab
-only dabigatran

90
Q

Idarcizumab (praxbind)

A

-humanized IgG1 FAB fragment against dabigatran
-mAb directly binds dabigatran with 350x greater affinity than thrombin
-does not bind jirudim, bivalrudin, or argatrobin

Therapeutics II (38 decks)

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