Anticoagulation Drugs Flashcards
Clot Formation
1) vasospasm of injured blood vessel ___ passage
2) platelets release chemical making nearby platelets sticky; platelet ___forms
3) a strong clot forms by a cascade mechanism that culminates in activation of ___ , an enzyme that converts fibrinogen to fibrin
4) plasminogen is coverted to ___ by plasminogen activators
5) ___ is digested, blood flow restored
1) consitrictis
2) plug
3) thrombin
4) plasmin
5) fibrin
Clotting Factors
Serine Proteases
- ___ down-stream factors to ___ them
- Examples - Factors: XII, XI, X, IX, VII, II (pro-___)
- cleave factors ___ and ___
- Protein ___ (Anti-coagulants)
- cleave, activate
- pro-coagulants
- coagulant
- Va, VIIIa
- C
Clotting Factors
Glycoproteins
- Co-factors for activation of ___
- Examples - Factors: VIII, V, III (tissue factor), protein ___
- bind to and inhibit ___ (anti - ___ III)
- proteases
- S
- thrombin, thrombin
Clotting Factors
- Ca2+ (Factor ___ ) - links certain factors to ____
- transglutaminase - ___ fibrin fibers (Factor ___ )
- fibrinogen/fibrin - ultimately, the substrate protein for thrombin (Factor ___ ) that ___ to form clot
- IV, phospholipid membranes
- cross-links, XIII
- IIa, polymerizes
Genetic Clotting Factor Disease
Hemophilia A - deficiency in factor ___ - 1 in 5,000 males
Hemophilia B - deficiency in factor ___ - 1 in 25,000 males
Factor V Leiden - resistance to cleavage protein ___ (5% of Caucasians)
- VIII
- IX
- C
Where are clotting factors produced?
- all except for von Willebrand factor are made in the ___
- vWF is produced in the ___ , subendothelium, and megakaryocytes
- factor ___ is also produced in the endothelium
- ___ can have unpredicable effects on coagulation
- liver
- endothelium
- VIII
- liver disease
Where does coagulation occur?
Extrinsic - required a ___ factor extrinsic to the blood. Important when vessel is damaged and blood leaks out
Intrinsic - triggered when ___ in exposed on the wall of the blood vessel
- tissue
- collagen
Coagulation Cascade - Intrinsic Pathway
- all components in the blood
- initiated by contact with negatively charged collagen of diseased or injured vessel
- blood in ___ clots by this mechanism
- all
- collagen
- test tube
Coagulation Cascade - Extrinsic pathway
- relies on factors outside blood stream for activation
- release of tissue ___ initiates pathway
- rapid (about ___ secs) to start clot formation)
- thomboplastin
- 15
Activation of the Extrinsic of Tissue Factor Pathway to coagulatoin
- ___ is expressed on the surface of cells outside of but near blood vessels
- factor ___ normally resides in blood
- TF binding to factor ___ activates it
- factor ___ binds and cleaves actor ___
- tissue factor
- VII
- VII
- VIIa, X
Common Pathway
- ___ activation plays a central role in final steps of clot formation
- converts ___ into long strands of insoluble ___
- activates Factor ___ which then ___ fibrin to form a stable clot incorporated into platelet plug
- thrombin
- fibrinogen, fibrin
- XIII, crosslinks
Convergence with intrinsic pathway
Factor ___ binds Factor ___ on the surface of platelets and activates Factor ___
IXa, VIIa, X
Feedback mechanism which increase coagulation
Thrombin
- activates factor ___ and ___
- enhances platelet activation
Platelet activation - increases activation of Factor ___, Factor ___ , and cleavage of ____
- V, VIII
- VII, X, prothrombin
Feedback mechanism which decrease coagulation
Anti-thrombin
- neutralizes procoagulant serine ____ (thrombin, Xa, IXa)
- reaction acelerated by ___
Protein C system
- activated by thrombin binding to ___
- activated protein ___ complex (APC) forms a complex with protein ___ to inactivate factors ___ and ___
Factor Xa
- activates tissue factor pathway inhibitor (TFPI) to block initial activation of factor ___
- protease
- heparin
- thrombomodulin
- C, S, Va, VIIIa
- VII
Common Tests of Hemostatic Function
Platelet Count
- too low = ___ = bone marrow malfunction, nutritional deficiencies
- too high = ___
Prothrombin Time (PT/INR)
- plasma + thromboplastin + Ca - clots in 12-14 seconds
- INR (internal normalized ratio) is a normalized value for each lot of ___
- used to monitor ___ therapy
aPTT
- plasma + phospholipid (no TF) + activating agent - clots in 26-33 seconds
- used to monitor ___ therapy
Fibrinogen
- less common. range from 200-400 mg/dL
D-dimer
- product of ___ breakdown
- thombocytopenia
- thrombocytosis
- thromboplastin
- warfarin
- heparin
- fibrin
In vitro measure of coagulation
1) calcium + blood = recalcification time 2-4 min
2) calcium + partial thromboplastin (just phospholipids) + kaolin + blood = activated partial thromboplastin time (aPTT; 23-33 seconds) = ____ pathway
3) calcium + thromboplastin + blood (T.P. is tissue factor and phospholipids) - prothrombin time (PT; 12-14 seconds) = ___ pathway
- intrinsic
- extrinsic
INR
a normal PT time is 11-14 seconds. Due to differences in patches of tissue factor, producers must assign an international sensitivity index (ISI) to their product.
Normal INR = ___ - ___
Therapeutic INR ~ ___ - ___
INR > ___ = risk of hemorrhage
0.8-1.2
2-3
3
Therapeutic Indication for Anticoagulation
prevent excessing clotting that can lead to ___ of blood vessels
- stroke
- post MI
- unstable angina
- DVT
- pulmonary embolisms
- artificial surfaces
- occlusion
Vitamin K
- fat-soluble vitamin
- involved in post-translation modification of prothrombin, factors ___ , ___ , and ___ (vit K dependent)
Uses
- individuals with abnormalities in fat absorption
- reverse anticoagulant effect of excess ___
VII, IX, X
- warfarin
Vitamin K Antagonist - Warfarin
- Vitamin ___ Antagonists
- Coumarin anticoagulants
- originally found in spoiled clover hay as substances that caused hemorrhage in cattle
- all derivates are water soluble ___
- warfarin is the most commonly used
- racemic mixture ( __ isomer most potent)
- K
- lactones
- S
Warfarin - MOA
vitamin K is essential for post-translation modification of clotting factors ___ , ___ , ___ , and ___ and anticoagulation proteins ___ and ___
Warfarin acts by inhibiting the synthesis of clotting factors ___ , ___ , ___ , and ___
Vitamin K action
- carboxylase catalyzes the gama-carboxylation of Glu in ___
- Vitamin K is ___ in the process
- coumadin inhibits vit K-epoxide reductase ( ___ ), thus blocking ___of Vit K epoxide back to its active form
- VII, IX, X prothrombin II, C, S
- II, VII, IX, X
- prothrombin
- oxidized
- VKORC1, reduction
Mechanism of Heparin
- free antithrombin can slowly inactivate Factors ___ , ___ , ___ , ___ , ___ , and ___
- heparin binding to AT changed the protein conformation; this ___ interaction of AT with target factors
- the ratio of AT activity is typically ___ (thrombin:factor Xa)
- LMWH are too small to bind AT and ___ , thus have greater specificity for inhibiton of ____
- Overall, heparin acts by accelerating AT reactions to inactivate ___ and ___
- Xa, IXa, XIa, XIIa, IIa, VIIa
- increases
- 3:1
- thrombin, Factor Xa
- thrombin, Factor Xa
Hepatin Reversal
Heparin Inhibitor: protamine sulfate
- a low molecular weight ___ protein which forms a stable complex with ___ charged heparin through multiple electrostatic interactions
- administered IV to rapidly reverse the effects of heparins in situations of life threatening hemorrhage/great heparin excess
- not as effective with ___
- does not reverese effects of ___
- polycationic
- negatively
- LMWH
- fondaparinux
Heparin induced thrombocytopenia
unfractionated heparin can cause thrombocytopenia and thrombosis in patients producing an ___ to a complex of heparin and platelet factor 4
- HIT risk: unfractionated heparin > LMWH > fondaparinux
antibody
Heparin Chemistry
- straight chain sulfated mucopolysaccharides - produced by ___ cells and ___
- mixture of 5-30 kDa (mean ~ ___ kDa) compounds
- extracted from ___ small intestine or ___ lung
- anticoagulant activity standardized by bioassay - expressed as units ~ 120 USP units/mg is st activity
- sulfate groups (negatively charged) required for binding to ___ are indicated in blue
- mast cells, basophils
- 15 kDa
- porcine, bovine
- antithrombin
Factor Xa Inhibitor
Fondaparinux Sodium
- synthetic sulfated pentasaccharide
- mechanism: indirectly inhibits factor Xa by selectively binding ___
- route of administration: ___, can be given at home
- t1/2 ~ 17-21 hrs - can be given ___ daily
- predicatable PK and dose response; does not require monitoring
- anti-thrombin
- SQ
- once
Factor Xa Inhibitor
Fondaparinux sodium
Use:
- venous thromboembolism: acute ___ and ___
- ___ in patients undergoing hip fracture surgery, hip replacement, knee replacement or abdominal surgery
Low potential for ___
- action not reversed by ___
- DVT, PE
- prophylaxis
- HIT
- protamine sulfate
orally available factor Xa inhibitors - rivaroxaban and apixaban
- rivaroxaban t1/2 = ___ - ___ hrs
- apixaban t1/2 = __ hrs
- treatment and prevention: ___ and ___
- prevention of thrombosis in non-valvular ___
- dose reduction with impaired ___ function
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- increased risk of ___ upon discontinuation
- fixed dosing, monitoring not required
- 5-9 hrs
- 12 hrs
- VT, PE
- A-fib
- renal
- hematoma, paralysis
- thrombosis
orally available factor Xa inhibitors - edoxaban (Savaysa)
- t1/2 = ___ - ___ hrs
- treatment of ___ and ___ after 5-10 days with parenteral anticoagulant
- prevention of thrombosis in NV ____
- not used in patients with CrCl > ___ mL/min
- increased risk of ___ events upon premature discontinuation
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- fixed dose, anticoagulation monitoring not required
- 10-14
- VT, PE
- A-fib
- 95 mL/min
- ischemic
- hematoma, paralysis
cant use this drug if your kidneys work too well
orally available factor Xa inhibitors - betrixaban (Bevyxxa)
- t1/2 = ___ - ___ hrs
- prevention of ___ in hospitalized patients at risk
- dose reduction in patients with severe ___ impairment
- avoid in patients with moderate to severe ___ impairment
- fixed dose, no monitoring of coagulation required
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- increased risk of ___ events upon premature discontinuation
- 19-27 hrs
- VTE
- renal
- hepatic
- hematoma, paralysis
- ischemic
Antidote for Factor Xa inhibitors
Andexanet - reversal agent of Xa inhibitors ___ and ___.
- Recombinant protein that mimics factor ___. It can bind drug, but lacks enzymatic activity.
- under investigation or use with ___ and ___
- given ___ to patients with uncontrolled or life threatening bleeding
- black box warning: increased risk for ___ events
- apixaban, rivaroxaban
- Xa
- edoxaban, enoxaparin
- IV
- thromboembolic
Direct Thrombin Inhibitors (DTI): Mechanism
- DTIs can bind to the ___ site of thrombin, to ___ of thrombin, or both
- DTIs can inhibit both ___ and ___ bound thrombin
- direct thrombin inhibitors can also reduce platelet ___
- active, exosite
- soluble, fibrin
- aggregation
Direct Thrombin Inhibitors
Bivalirudin (Angiomax)
- ___ amino acid, synthetic peptide
- binds to the ___ site and ___ of thrombin
- Binding is ___ with ___ onset and ___ duration
- given ___ during percutaneous coronary angioplasty
- eliminated by ___ excretion
- t 1/2: ___
- low bleeding risk, doesn’t induce ___ formation
- 20
- catalytic, exosite I
- reversible, rapid, short
- IV
- renal
- 25 min
- antibody
Direct Thrombin Inhibitors
Argatroban
- derived from ___
- binds reversibly to the ___ site of thrombin
- does not require ___ for activity
- can ___ free and clot associated thrombin
- therapy monitored using ___
- given ___ , t1/2 ~40-50 min
- metabolized in liver (CYP ___ )
- approved treatment for ___ or coronary artery thrombosis in patients with ___
- ___ in PCI procedures
- L-arginine
- active
- anti-thrombin
- inhibit
- aPTT
- IV
- 3A4/5
- HIT, HIT
- prophylaxis
Orally administered direct thrombin inhibitor
dabigatran (Pradaxa)
- t1/2 = ___ - ___ hrs
- indicated for prevention of ___ and systemic ___ in patients with non-valvular ___
- eliminated by ___ excretion - avoid in cases of severe ___ impairment
- monitoring unnecessary
- anticoagulant activity reversed by ___ IV
- 12-14 hrs
- stroke, embolism, a-fib
- renal, renal
- idarucizumab (Praxbind)
Reversing the action of thrombin inhibitors
Idaruizumad (Praxbind)
- humanized monoclonal antibody that directly binds to ___ with ___ x greater affinity than thrombin
- does not bind other thrombin inhibitors such as ___ , ___ , or ___
- dabigatran, 350x
- hirudim, bivalirudin, argatroban
