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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
In vitro measurement of coagulation
-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
25
INR
-international normalized ratio =(PTtest/PTnorm)^ISI -PTnorm = 11-14 sec -TF producers must assign ISI (sensitivity index) to product
26
INR values
-normal: 0.8-1.2 -therapeutic: 2-3 ->3 risk of hemorrhage
27
Therapeutic Indications for Anticoagulants
-prevent excessive clotting that can lead to occlusion of blood vessels -stroke -post MI -unstable angina -DVT -PE -artificial surfaces
28
Anticoagulant drug classes
-Vit K antagonists -Direct thrombin inhibitors -Heparin -Fondaparinux -Direct factor Xa inhibitors
29
Vitamin K antagonists
-Coumarin anticoagulants -Warfarin
30
Coumarin anticoagulants
-warfarin -originally found in spoiled clover hay that caused hemorrhage in cattle -all derivatives are water soluble lactones
31
Warfarin
-S-isomer more potent -vit k antagonist
32
Vit K action
-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
33
Warfarin MOA
-inhibits Vit K epoxide reductase (VKORC1) =block reduction of vit k epoxide back to its active form -inhibits II, VII, IX, X
34
Role odf y-carboxylation of clotting factors
-slide 21
35
Warfarin therapeutic actions
-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)
36
Warfarin metabolism
-CYP2C9 -t1/2 36-48h -termination of action not related to plasma levels of drug but reestablishment of normal clotting factors
37
Warfarin overdose
-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
Warfarin necrosis
-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
How to prevent warfarin necrosis
-heparin
40
Adverse
41
effects of warfarin
-hemorrhage (close monitoring when starting tx and during heparin coadmin) -drug-drug interactions
42
Warfarin drug interactions
-99% is bound to plasma albumin -long half life -CYP2C9 -coadmin w albumin-bound drugs or drugs that influence P450
43
Warfarin contraindications
-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
Drugs that diminish warfarin's anticoagulant effect
-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
Drugs that enhance warfarins effect
-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
Vit K
-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
Reversing Warfarin effects
-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
Heparin drugs (IIa/Xa inhibitors)
-Unfractionated heparin (UFH) -enoxaparin (low weight) -daltaparin (LWMH) -fondaparinux (non-heparinoids) -pentasaccharide unit -IIa/Xa inhibitors
49
Heparin MOA
-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
Heparin conformational change
-binds AT -ternary complex -heparin-AT-target factor
51
LMWH specificity
-inhibiting Xa -too small to bind thrombin and antithrombin
52
Heparin dosing
-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
Heparin testing
-aPTT -aPTT therapeutic range: 1.5-2x normal -cleared rapidly from blood (t1/2=30-180min)
54
Adverse effects of heparin
-latrogenic hemorrhage -Thrombocytopenia (HIT) -Osteoporosis
55
Latrogenic hemorrhage risk factors (heparin)
-pt over 50 -ulcer pt -severe HTN -antiplatelet drugs
56
Latrogenic hemorrhage from heparin tx
-stop heparin (short t1/2) -life threatening bleeding: admin specific antagonist -PROTAMINE SULFATE!
57
Protamine sulfate
-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
Thrombocytopenia (HIT) from heparin
-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
Osteoporosis from heparin
-associated w extended therapy -3-6 months
60
Heparin-induced thrombocytopenia MOA
-UFH use in pt producing Ab to complex of heparin and platelet factor 4 -HIT risk: heparin >LMWH>fondaparinux -slide 36
61
Heparin chemistry
-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
Low molecular weight heparins (LMWH)
-dalteparin (2-9k daltons) -enoxaprin (2-8k daltons) -obtained from depolymerization of UFH from porcine
63
LMWH compared to heparin
-eq efficacy -inc bioavailability from SC route (only route) -less freq dosing (qd or BID) (longer t1/2) -no monitoring needed
64
Advantages of LMWH
-more predictable PK -good SQ availability -less protein binding = more uniform dosing -longer t1/2 = fewer injections -LOWER incidence of HIT and Osteoporosis
65
Slide 40
Slide 40
66
INDIRECT Factor Xa inhibitor
-Fondaparinux sodium
67
Fonaparinux sodiuam
-factor Xa inhibitor -synthetic sulfated pentasaccharide
68
Fondaparinux MOA
-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
Fondaparinux use
-venous thromboembolism (acute DVT and PE) -prophylaxis in hip, knee, or ab surgery
70
Direct Oral AntiCoagulants (DOAC)
-direct factor Xa inhibitors (RAEB) -direct thrombin inhibitors (DAB) -NOAC =novel -TSOAC= target specific
71
Orally available DIreCT Factor Xa inhibitor drugs
-Rivaroxaban -Apixaban -Edoxaban -Betrixaban
72
Rivaroxaban and Apixaban
-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
Edoxaban
-10-14h t1/2 -tx of VT and PE after 5-10days w parenteral anticoagulant -prevent thrombosis in AFIB -fixed dose, no monitoring
74
Edoxaban cautions
-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
Betrixaban
-19-27h t1/2 -prevention of VTE in at risk hospital pt -no monitoring
76
Betrixaban cautions
-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
Antidote for factor Xa inhibitors
-Andexanet -IV to pt w uncontrolled/lifethreatening bleeding after admin of apixaban or rivaroxaban
78
Andexanet
-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
Andexanet black box
-inc risk for thromboembolic events
80
Direct thrombin inhibitors (DTI) MOA
-bind to active or exosite or both of thrombin -inhibit soluble and fibrin-bound thrombin -reduce platelet aggregation -slide 49
81
Non-heparinoid DTI
-Hirudin -Lepirudin -do not act through AT-III -inhibit free thrombin and fibrin-bound thrombin
82
Hirudin
-DTI -peptide from leech saliva
83
Lepirudin (refludan)
-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
DTI drugs
-Bivalirudin (angiomax) -Argatroban -Dabigatran
85
Bivalrudin (angiomax) structure
-20 aa peptide -Phe-Pro-Arg-Pro binds active site -4 Gly chain cleaved by thrombin -Asn-Gly-9-Leu binds exosite I
86
Bivalrudin
-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
Argatroban
-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
Dabigatran (Pradaxa)
-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
reversal of DTIs
-Idarucizumab -only dabigatran
90
Idarcizumab (praxbind)
-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 (55 decks)

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