Anticoagulants Flashcards
Clot formation in hemostasis
-strong clot
-cascade mech that activates thrombin which converts fibrinogen to fibrin
-slide 3
Clotting (coagulation) factors
-serine proteases
-glycoproteins
-Ca2+ (factor IV)
-Transglutaminase
-Fibrinogen/Fibrin
Serine proteases
-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)
Glycoproteins
-co-factors for activation of proteases
-Factors VIII, V, III (tissue factors), protein S
-bind/inhibt thrombin (anti-thrombin III
Ca2+ (Factor IV)
-links some factors to phospholipid membranes
Fibrinogen/Fibrin
-substrate protein for factor IIa (thrombin) that polymerizes to form clot
Transglutaminase
-coag factor
-cross-links fibrin fibers (factor XIII)
Genetic clotting factor diseases
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
Where are clotting factors produced
-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!
Where does coagulation occur
-extrinsic pathway
-intrinsic pathway
Extrinsic pathway of coagulation
-requires a factor (tissue factor) extrinsic to the blood
-initiated by release of tissue thromboplastin
-rapid (15sec to start clot formation)
Intrinsic pathway
-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
Activation of extrinsic pathway
-tissue factor expressed on cells near blood vessels
-TF binds Factor VII in blood
-Factor VIIa binds and cleaves factor X
Activation of Intrinsic pathway
-factor IXa binds factor VIIIa on surface of platelets and activates Factor X
Common pathway in coagulation cascade
-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
Feedback mech that increase coagulation
-Thrombin activates V and VIII and enhances platelet activation
-platelet activation inc activation of VII, X and cleavage of prothrombin
Feedback mech that DECREASES coagulation
-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
Common tests of hemostatic function
-platelet count
-prothrombin time (PT/INR)
-aPTT
-Fibrinogen
-D-dime
Platelet count test
-too low = thrombocytopenia (bone marrow and nutrition probs)
-too high = thrombocytosis
Prothrombin time (PT/INR)
-plasma + thromboplastin + Ca
=clots in 12-14 sec
-INR normal for each lot of thromboplastin
aPTT
-plasma + phospholipid (No TF) + activating agent
-clots 26-33 sec
-monitor heparin therapy
Fibrinogen testing
-less common
-200-400
D-dimer test
-product of fibrin breakdown
tests ordered for coagulation profile (DIC panel)
-Platelet count
-Prothrombin time (PT/INR)
-aPTT
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
INR
-international normalized ratio
=(PTtest/PTnorm)^ISI
-PTnorm = 11-14 sec
-TF producers must assign ISI (sensitivity index) to product
INR values
-normal: 0.8-1.2
-therapeutic: 2-3
->3 risk of hemorrhage
Therapeutic Indications for Anticoagulants
-prevent excessive clotting that can lead to occlusion of blood vessels
-stroke
-post MI
-unstable angina
-DVT
-PE
-artificial surfaces
Anticoagulant drug classes
-Vit K antagonists
-Direct thrombin inhibitors
-Heparin
-Fondaparinux
-Direct factor Xa inhibitors
Vitamin K antagonists
-Coumarin anticoagulants
-Warfarin
Coumarin anticoagulants
-warfarin
-originally found in spoiled clover hay that caused hemorrhage in cattle
-all derivatives are water soluble lactones
Warfarin
-S-isomer more potent
-vit k antagonist
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
Warfarin MOA
-inhibits Vit K epoxide reductase (VKORC1)
=block reduction of vit k epoxide back to its active form
-inhibits II, VII, IX, X
Role odf y-carboxylation of clotting factors
-slide 21
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)
Warfarin metabolism
-CYP2C9
-t1/2 36-48h
-termination of action not related to plasma levels of drug but reestablishment of normal clotting factors
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
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
How to prevent warfarin necrosis
-heparin
Adverse
effects of warfarin
-hemorrhage (close monitoring when starting tx and during heparin coadmin)
-drug-drug interactions
Warfarin drug interactions
-99% is bound to plasma albumin
-long half life
-CYP2C9
-coadmin w albumin-bound drugs or drugs that influence P450
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)
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)
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)
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
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
Heparin drugs (IIa/Xa inhibitors)
-Unfractionated heparin (UFH)
-enoxaparin (low weight)
-daltaparin (LWMH)
-fondaparinux (non-heparinoids)
-pentasaccharide unit
-IIa/Xa inhibitors
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
Heparin conformational change
-binds AT
-ternary complex
-heparin-AT-target factor
LMWH specificity
-inhibiting Xa
-too small to bind thrombin and antithrombin
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
Heparin testing
-aPTT
-aPTT therapeutic range: 1.5-2x normal
-cleared rapidly from blood (t1/2=30-180min)
Adverse effects of heparin
-latrogenic hemorrhage
-Thrombocytopenia (HIT)
-Osteoporosis
Latrogenic hemorrhage risk factors (heparin)
-pt over 50
-ulcer pt
-severe HTN
-antiplatelet drugs
Latrogenic hemorrhage from heparin tx
-stop heparin (short t1/2)
-life threatening bleeding: admin specific antagonist
-PROTAMINE SULFATE!
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
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
Osteoporosis from heparin
-associated w extended therapy
-3-6 months
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
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
Low molecular weight heparins (LMWH)
-dalteparin (2-9k daltons)
-enoxaprin (2-8k daltons)
-obtained from depolymerization of UFH from porcine
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
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
Slide 40
Slide 40
INDIRECT Factor Xa inhibitor
-Fondaparinux sodium
Fonaparinux sodiuam
-factor Xa inhibitor
-synthetic sulfated pentasaccharide
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
Fondaparinux use
-venous thromboembolism (acute DVT and PE)
-prophylaxis in hip, knee, or ab surgery
Direct Oral AntiCoagulants (DOAC)
-direct factor Xa inhibitors (RAEB)
-direct thrombin inhibitors (DAB)
-NOAC =novel
-TSOAC= target specific
Orally available DIreCT Factor Xa inhibitor drugs
-Rivaroxaban
-Apixaban
-Edoxaban
-Betrixaban
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
Edoxaban
-10-14h t1/2
-tx of VT and PE after 5-10days w parenteral anticoagulant
-prevent thrombosis in AFIB
-fixed dose, no monitoring
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
Betrixaban
-19-27h t1/2
-prevention of VTE in at risk hospital pt
-no monitoring
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
Antidote for factor Xa inhibitors
-Andexanet
-IV to pt w uncontrolled/lifethreatening bleeding after admin of apixaban or rivaroxaban
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
Andexanet black box
-inc risk for thromboembolic events
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
Non-heparinoid DTI
-Hirudin
-Lepirudin
-do not act through AT-III
-inhibit free thrombin and fibrin-bound thrombin
Hirudin
-DTI
-peptide from leech saliva
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
DTI drugs
-Bivalirudin (angiomax)
-Argatroban
-Dabigatran
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
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
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
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
reversal of DTIs
-Idarucizumab
-only dabigatran
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
