Anticoagulation Drugs

Question 1

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

Answer 1

1) consitrictis
2) plug
3) thrombin
4) plasmin
5) fibrin

Question 2

Clotting Factors

Serine Proteases
- ___ down-stream factors to ___ them
- Examples - Factors: XII, XI, X, IX, VII, II (pro-___)
- cleave factors ___ and ___
- Protein ___ (Anti-coagulants)

Answer 2

• cleave, activate
• pro-coagulants
• coagulant
• Va, VIIIa
• C

Question 3

Clotting Factors

Glycoproteins
- Co-factors for activation of ___
- Examples - Factors: VIII, V, III (tissue factor), protein ___
- bind to and inhibit ___ (anti - ___ III)

Answer 3

• proteases
• S
• thrombin, thrombin

Question 4

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

Answer 4

• IV, phospholipid membranes
• cross-links, XIII
• IIa, polymerizes

Question 5

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)

Answer 5

• VIII
• IX
• C

Question 6

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

Answer 6

• liver
• endothelium
• VIII
• liver disease

Question 7

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

Answer 7

• tissue
• collagen

Question 8

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

Answer 8

• all
• collagen
• test tube

Question 9

Coagulation Cascade - Extrinsic pathway

• relies on factors outside blood stream for activation
• release of tissue ___ initiates pathway
• rapid (about ___ secs) to start clot formation)

Answer 9

• thomboplastin
• 15

Question 10

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 ___

Answer 10

• tissue factor
• VII
• VII
• VIIa, X

Question 11

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

Answer 11

• thrombin
• fibrinogen, fibrin
• XIII, crosslinks

Question 12

Convergence with intrinsic pathway

Factor ___ binds Factor ___ on the surface of platelets and activates Factor ___

Answer 12

IXa, VIIa, X

Question 13

Feedback mechanism which increase coagulation

Thrombin
- activates factor ___ and ___
- enhances platelet activation

Platelet activation - increases activation of Factor ___, Factor ___ , and cleavage of ____

Answer 13

• V, VIII
• VII, X, prothrombin

Question 14

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 ___

Answer 14

• protease
• heparin
• thrombomodulin
• C, S, Va, VIIIa
• VII

Question 15

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

Answer 15

• thombocytopenia
• thrombocytosis
• thromboplastin
• warfarin
• heparin
• fibrin

Question 16

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

Answer 16

• intrinsic
• extrinsic

Question 17

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

Answer 17

0.8-1.2
2-3
3

Question 18

Therapeutic Indication for Anticoagulation

prevent excessing clotting that can lead to ___ of blood vessels
- stroke
- post MI
- unstable angina
- DVT
- pulmonary embolisms
- artificial surfaces

Answer 18

• occlusion

Question 19

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 ___

Answer 19

VII, IX, X
- warfarin

Question 20

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)

Answer 20

• K
• lactones
• S

Question 21

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

Answer 21

• VII, IX, X prothrombin II, C, S
• II, VII, IX, X
• prothrombin
• oxidized
• VKORC1, reduction

Question 22

Warfarin Therapeutic actions

___ onset of action
- must deplete the pool of circulating ___
- max effect in ___ - ___ days after start of therapy
- loading dose: 5 mg/day
- maintenance dose: 2.5-5 mg/day

After discontinuing therapy
- factors must be re-synthesized to return to normal PT (several ___ )

Answer 22

delayed, clotting factors
- 3-5 days
- days

Question 23

Warfarin Metabolism

• metabolized in the liver by CYP ___ (S-warfarin)
• t1/2 = ___ - ___ hrs
• termination of action is not correlated with plasma warfarin levels, but reestablishment of normal ___

over dose - latrogenic hemorrhage
- discontinue warfarin therapy
- administer Vit K1 (high levels can activate warfarin-inhibitied ___ )
- in serious hemorrhage - ____ replaces clotting factors faster than Vit K therapy

Answer 23

• CYP2C9
• 36-48
• clotting factors
• reductase
• plasma

Question 24

Warfarin Necrosis

• some patients have a deficiency of protein __
• this protein is an innate ___ that requires vitamin K dependent carboxylation for its activity
• since warfarin initaitally decreases protein ___ levels faster than the coagulation factors, it can paradoxically ___ the blood tendency to coagulate when treatment is begun
• many patients when starting on warfarin are given ___ in parallel to combat this
• a deficiency in protein ___ would lead to the same necrosis

Answer 24

• C
• anticoagulant
• C, increase
• heparin
• S

Question 25

# Drugs that Diminish warfarin's Anticoagulant Effect - cholestyramine - inhibits warfarin absorption in the ___ - barbiturates, carbamazepine, rifampin - accelerates warfarin metabolism by ___ P450 enzymes - Nephrotic syndrome/hypoproteinemia - decreased albumin, increased ___ warfarin, decreased t1/2 - **reduced vitamin K** - ___ warfarin-induced epoxide reductase inhibition - pregnancy (bad dr) - ___ levels of clotting factors

Answer 25

- GI tract - inducing - free - bypasses - increased

Question 26

# Drugs that enhance warfarins anticoagulant effect - chloral hydrate - displaces warfarin from plasma ___ - chloramphenicol, SSRIs, amiodarone - decreases warfarin metabolism by ___ hepatic P450 - **broad spectrum antibiotics** - reduce availability of vit K in the ___ - anabolic steroids - inhibits ___ and increases ___ of clotting factors

Answer 26

- albumin - inhibiting - GI tract - synthesis, degradation

Question 27

# Warfarin Adverse Effects - hemorrhage - drug-drug interactions Contraindications - when risk of ___ is greater than potential benefits (uncontrolled alcohol/drug abuse, unsupervised dementia/psychosis) - never use in ___ (teratogen)

Answer 27

- hemorrhage - pregnancy

Question 28

# 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 ___

Answer 28

- Xa, IXa, XIa, XIIa, IIa, VIIa - increases - 3:1 - thrombin, Factor Xa - thrombin, Factor Xa

Question 29

# Heparin - Clinical Use administration - effective ___ - intermittenet IV inj - Continuous IV infusion - easiest to control - SC inj adjust dosing according to ___ tests - ___ therapeutic range = 1.5-2 x normal - cleared rapidly from blood (t1/2 = 30-180 min) anticoagulant effect disapprears within ___ of dicontinuation of therapy

Answer 29

- immediately - coagulation - aPTT - hours

Question 30

# Adverse Effects of Heparin latrogenic hemorrhage can occur at any site risk factors: - patients over ___ - ___ patients - severe ___ - ___ drugs Treatment - stop heparin (short t1/2) - life threatening bleeding: administer specific antagonist - ___ - binds tightly to heparin to neutralize the anticoagulant action

Answer 30

- 50 - ulcer - hypertension - antiplatelet - protamine sulfate

Question 31

# 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 ___

Answer 31

- polycationic - negatively - LMWH - fondaparinux

Question 32

# Adverse Effects - Heparin - thrombocytopenia (HIT) type 1: mild, transient due to direct action on ___ type 2: severe, develops ___ - ___ days after starting therapy - ___ develop to platelet (PF4)-heparin complex - ___ - associated with extended therapy (3-6 months)

Answer 32

- platelets - 7-12 - antibodies - osteoporosis

Question 33

# 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

Answer 33

antibody

Question 34

# 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

Answer 34

- mast cells, basophils - 15 kDa - porcine, bovine - antithrombin

Question 35

# LMWH Examples: ___ and ____ - obtained from ___ of unfractionated porcine heparin - equal efficacy to heparin - increased bioavailability for ___ site of adm (only route) - less frequent dosing (1-2x daily); ___ t1/2 than heparin - no monitoring of ___ needed

Answer 35

dalteparin enoxaparin - depolymerization - equal - SQ - longer - clotting

Question 36

# Advantages of LMWH more ___ pharmacokinetic profile - good bioavailability from ___ injection site - less ___ binding/more ___ dosing - ___ t1/2 (fewer inj) - ___ incidence of HIT/osteoporosis

Answer 36

predictable - SQ - protein, uniform - longer - lower

Question 37

# UFH - Heparin Summary routes of administration: ___ and ___ advantages - ___ onset and clearance - anticoagulation effect easily ___ - ok in ___ failure - can be rapidly reversed with ___ disadvantages - frequent ___ required - HIT

Answer 37

- IV, SQ - rapid - monitored - renal - protamine - monitoring

Question 38

# LMWH - Heparin Summary examples: ___ and ___ routes of administration: ___ only advantages: - ___ duration of action when administered ___ (as compared to heparin) - monitoring is generally ___ disadvantages: - relatively contraindicated in ___ failure - unknown optimal dosing in morbidly ___ patients - if monitoring is needed, it requires an ___ level (less available than aPTT) - HIT (mixed data on whether risk is equal to or lower compared to UFH)

Answer 38

dalteparin, enoxaparin SQ - longer, SQ - unnecessary - renal - obese - anti-factor Xa

Question 39

# 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

Answer 39

- anti-thrombin - SQ - once

Question 40

# 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 ___

Answer 40

- DVT, PE - prophylaxis - HIT - protamine sulfate

Question 41

# DOACs/NOACs Direct Factor Xa Inhibitors (4) Direct Thrombin Inhibitors

Answer 41

direct factor Xa inhibitors - rivaroxaban - apixaban - edoxaban - betrixaban direct thrombin inhibitors - dabigatran

Question 42

# 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

Answer 42

- 5-9 hrs - 12 hrs - VT, PE - A-fib - renal - hematoma, paralysis - thrombosis

Question 43

# 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

Answer 43

- 10-14 - VT, PE - A-fib - 95 mL/min - ischemic - hematoma, paralysis ## Footnote cant use this drug if your kidneys work too well

Question 44

# 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

Answer 44

- 19-27 hrs - VTE - renal - hepatic - hematoma, paralysis - ischemic

Question 45

# 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

Answer 45

- apixaban, rivaroxaban - Xa - edoxaban, enoxaparin - IV - thromboembolic

Question 46

# 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 ___

Answer 46

- active, exosite - soluble, fibrin - aggregation

Question 47

# Direct Thrombin Inhibitors non-heparinoid parenteral agents - do not act through ___. Inhibit ___ thrombin and ___ thrombin ___ - peptide from saliva gland of medicinal leach

Answer 47

- AT-III - free - fibrin bound - Hirudin

Question 48

# Direct Thrombin Inhibitors Lepirudin (Refludan) - recombinant hirudin grown in yeast - ___ protein (65 amino acids), given ___ - highly ___ direct inhibitor of thrombin ( ___ binding at active aite and exosite 1) - inhibition of thrombin is ___ - ___ values increase dose-dependently - can produce ___ reactions - excreted via the ___ - treatment of ___

Answer 48

- small, IV - specific, bivalent - irreversible - aPTT - hypersensitivity - kidney - HIT

Question 49

# 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

Answer 49

- 20 - catalytic, exosite I - reversible, rapid, short - IV - renal - 25 min - antibody

Question 50

# 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

Answer 50

- L-arginine - active - anti-thrombin - inhibit - aPTT - IV - 3A4/5 - HIT, HIT - prophylaxis

Question 51

# 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

Answer 51

- 12-14 hrs - stroke, embolism, a-fib - renal, renal - idarucizumab (Praxbind)

Question 52

# 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 ___

Answer 52

- dabigatran, 350x - hirudim, bivalirudin, argatroban