by Kimberly Chapin, Pharm.D. at the Mills-Peninsula Cardiovascular Symposium in Burlingame CA on 9/30/2015

1. Anticoagulation
Pharmacology
Kimberly Chapin, Pharm.D.

2. Course Outline
• Review hemostatic mechanisms
• Review mechanisms of action of each class of
anticoagulant
• Compare and contrast pharmacology of
agents in each anticoagulant class
• Identify unique places in therapy for each
anticoagulant

3. Hemostasis
• Normal physiological
response that prevents
significant blood loss after
vascular injury
• Clot formation involves
multiple system responses:
– Vasoconstriction
– Platelet plug formation
– Coagulation
• Once the vessel heals,
primary fibrinolysis is
triggered and clot formation
processes are inhibited
Image source: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/hypercoagulable-states/

4. Hemostasis: A Balancing Act
Prohemorrhagic
Natural Anticoagulants
(Protein C, Protein S, AT)
Fibrinolytic proteins
•Illness (i.e. Infection, Malignancy,
CV Disease)
•Medications
•Inherited and acquired
bleeding disorders
•Immune Reactions
•Trauma
•Patient factors (i.e. Obesity,
immobility, pregnancy)
•Toxins
Platelets
Coagulation Factors
Fibrinolytic Inhibitors
Prothrombotic

5. Medications That Affect Hemostasis
• Antithrombotics prevent or interfere with the formation and
growth of blood clots.
•Anticoagulants—interfere with clotting factors
»Examples: heparin, low molecular weight heparins (LMWH),
warfarin, factor Xa inhibitors, direct thrombin inhibitors
•Antiplatelet agents—decrease platelet activation and
aggregation
»Examples: Aspirin, thienopyridines, glycoprotein IIb/IIIa
Inhibitors, P2Y12 platelet receptor inhibitors, Protease-Activated
Receptor-1 (PAR-1) Antagonist
• Antifibrinolytics inhibit clot dissolution
»Example: Aminocaproic Acid, tranexamic acid
• Thrombolytics dissolve existing clots
»Example: Alteplase (tPA)

6. Clotting Cascade
• Anticoagulants inhibit clotting
factors
• The clotting cascade is a
complex set of reactions
involving approximately 30
different proteins.
• Tissue and Blood Vessel
damage stimulate the
Intrinsic and Extrinsic
pathways, which converge at
factor Xa activation.
• These reactions convert
fibrinogen to insoluble
strands of fibrin, which,
together with platelets, forms
a stable clot.

7. Anticoagulation Therapy:
General Principles
• Weigh benefits of treatment against risk of bleeding
• Monitor for signs and symptoms of bleeding
– Labs
– Physical assessment
– Patient reporting
• Check dose adjustments for renal impairment, hepatic
dysfunction, age, body weight, interactions, and special
patient populations
• Check recommended hold times around invasive procedures,
particularly those involving neuraxial injection or catheters
• Follow recommended guidelines for use of agents in specific
indications

8. Antithrombin (AT) Enhancers:
Heparin, LMWH, Fondaparinux
• Most commonly used
anticoagulants in the
hospital setting
• Extensive clinical data
to support use in
multiple indications
• Years of experience
using these agents
Anticoagulant Approval
Unfractionated Heparin (UFH) 1939
Low Molecular Weight
Heparins (LMWHs)
Dalteparin (Fragmin®)
Enoxaparin (Lovenox®)
Nadroparin (Fraxiparine®)*
Tinzaparin (Inohep®)*
1980s
Indirect Factor Xa Inhibitors
Fondaparinux (Arixtra®)
2000s
*Not Available in the United States

9. AT Enhancers: Mechanism of Action
Unfractionated Heparin (UFH)
•Inhibits Thrombin (IIa), IXa, Xa, XIa
and XIIa
•Therapeutic action: Xa, thrombin
Low Molecular Weight Heparin
(LMWH)
•Predominantly inhibit factor Xa
Fondaparinux
•Purely inhibits factor Xa
All Agents:
–Require AT cofactor to exert
anticoagulant effect
–Do not affect thrombin bound to fibrin
or Xa bound to platelets (only fluid form)

10. Antithrombin (AT) Enhancers:
Heparin, LMWH, Fondaparinux
• Antithrombin (AT) inhibits factor Xa
and thrombin (natural
anticoagulant)
• UFH, LMWH, and Fondaparinux
bind to AT, causing a
conformational change.
• Activated complex increases
Factor Xa inactivation by several
fold over endogenous AT
• Longer chain polysaccharides:AT
complexes irreversibly binds to an
inhibits the active site of thrombin
–UFH>>>LMH
–Fondaparinux does not bind
thrombin
Image Source: Am J Health-Syst Pharm. 2002. American Society of Health System Pharmacists.

11. Antithrombin (AT) Enhancers:
Heparin, LMWH, Fondaparinux
Heparin LMWH (enoxaparin) Fondaparinux
Source Endogenous
Polysaccharide
(bovine and porcine
lung/intestine)
Derived from UFH Synthetic
(small molecule)
Chain Length ~45 saccharide units ~15 saccharide units 5 saccharide units
Route IV, Subcutaneous Subcutaneous, IV Subcutaneous, IV
Time to Cmax SC: 20-30 min
(erratic absorption)
SC: 3-4.5 hours
(predictable absorption)
SC: 2-3 hours
(predictable absorption)
Half Life 0.5 to 2 hours ~4 to 7 hours
(Daily to BID dosing)
15-17 hours
(Daily SC dosing)
Dosing in Renal
Impairment
No adjustment needed;
Preferred agent for
ESRD/dialysis patients
Adjust doses;
Not recommended for
dialysis patients
Adjust doses;
Contraindicated when
CrCl<30 mL/min
Laboratory
monitoring
aPTT, ACT,
anti-factor Xa
Platelet monitoring
Not routinely
recommended; optional
anti-factor Xa assay
Platelet monitoring
Not routinely
recommended; optional
anti-factor Xa assay

12. Antithrombin (AT) Enhancers:
Heparin, LMWH, Fondaparinux
Heparin LMWH (enoxaparin) Fondaparinux
Additional
Binding
Proteins, macrophages,
platelets, osteoblasts
Less protein, osteoblast,
platelet binding than UFH
No additional binding
Bleeding
Incidence
Higher than LMWHs
(rates vary based on
indication and patient)
0-13% Any bleeding
0-4% Major bleeding
2-3 % Minor bleeding
1-3% Major bleeding
Incidence of
thrombocytopenia
1-5% HIT
30% Non-HIT
<1%HIT
3-5% Non-HIT
0% HIT
3% Non-HIT
Pregnancy Preferred anticoagulant Preferred anticoagulant Category B
(not routinely used)
Body Weight Caution with obese
Initial doses often
capped, and/or adjusted
body weights are used
Caution in extremes of
weight
(<45kg and >~180kg)
Actual body weight used
for weight-based doses
Treatment dose tiered
according to body
weight.
Contraindicated for
body weight <50kg
Reversal Protamine (100%) Protamine (~60 to 75%) No specific reversal
agent available
Generic
Available
Yes Yes (Biosimilar) Yes

13. Unfractionated Heparin (UFH):
Pros and Cons
• Pros:
– Rapid onset and clearance, titratable, monitoring readily
available, rapidly reversed with protamine
– Preferred for anticoagulation during procedures
• Cons:
– Narrow window of adequate anticoagulation without bleeding
– Highly variable dose-response
– Hematologic side effects (including HIT)
– Not easily used in outpatient setting/no oral formulation
– Reduced ability to inactivate thrombin bound to fibrin or factor
Xa bound to activated platelets within a thrombus Potential
extension of thrombus

14. Low Molecular Weight Heparins (LMWHs):
Pros and Cons
• Pros:
– Does not require routine monitoring
– Subcutaneous administration and predictable dose response
allows for easier dosing and outpatient use
– Lower risk of HIT and osteoporosis than UFH
– Preferred agent for pregnancy, malignancy
• Cons:
– Prolonged half-life in patients with renal failure, challenging
dosing at extremes of body weight
– Generic availability challenging because of biologic status
– If monitoring is required, anti-factor Xa activity testing with a
rapid turnaround time may be less widely available
– No oral LMWH

15. Fondaparinux (Arixtra®):
Pros and Cons
• Pros:
– Synthetic small molecule
– Little to no risk of HIT (some use in history of HIT)
– Long duration of action Daily administration
– No routine monitoring, easy dosing
– No effect on thrombin or platelets
• Cons
– No reversal agent
– Limited to parenteral administration
– Significantly longer half-life in renal insufficiency
– Contraindicated with low body weight

16. Vitamin K Antagonists
• Warfarin (Coumadin®) –Oral
– IV formulation no longer available on the US market
• Medical use started in the 1955
– Originally found in sweet clover that was responsible for
hemorrhagic death in cattle in the 1930s
– Similar compound marketed as rat poison
• Only oral anticoagulant on the market for over 50
years
– Extensive clinical trial data and provider experience for
multiple indications

17. Warfarin: Mechanism of Action
– Antagonist of Vitamin K
– Interferes with hepatic
synthesis of vitamin K-
dependent clotting
factors II, VII, IX, and X, as
well as natural
anticoagulants protein C
and protein S

18. Warfarin Pharmacology
• Onset of action:
– Dependent on clearance of existing
factors
– Earliest changes in INR seen 24-36 hours
after first dose
– Full antithromboitc effect not seen until
4-5 days (when prothrombin is depleted)
– Overlap with another anticoagulant is
required for immediate anticoagulation.
Must be continued for 5 days AND until
INR is at desired range.
• Duration of action:
– 2 to 5 days
Factors Half-Life
II 42-72 hours
VII 4-6 hours
IX 21-30 hours
X 27-48 hours
Protein C 8 hours
Protein S 60 hours

19. Warfarin Pharmacology
• Varied Dose Response
– Monitoring: PT/INR measures the intensity of anticoagulation
• Therapeutic target usually INR of 2-3
• Higher targets for certain types of heart valves and recurrent thrombosis
events
• Metabolism: Liver (Hepatic P450 enzymes, CYP2C19, CYP1A2, CYP3A4)
• Protein bound: 99% (albumin)—Only unbound drug is active
• Interactions:
– Medications
• Hepatic CYP interactions, interference with Vitamin K stores, protein
displacers
– Lifestyle factors affecting Vitamin K Stores
• Activity Level, Diet, Alcohol, Illness (diarrhea, fever)
• Adverse events
– Bleeding (variable rates)
– Skin necrosis (rare)

20. Warfarin Reversal
1. Vitamin K
– Oral preferred if bleeding is absent or not life-threatening
– IV preferred for life-threatening bleeds or non-PO
• Sub-Q has erratic absorption, delay in onset  Not recommended
• IM can lead to hematoma formation
– Administer in addition to FFP or PCC to prevent rebound INR rise
For Life-threatening bleeds, ADD:
2a. 4-Factor Prothrombin Complex Concentrate (PCC) KCentra
– FDA approved for warfarin reversal
– Preferred in guidelines for serious/life-threatening bleeds.
• Due to risk of thrombosis, not recommended in the absence of severe bleeding
– Less volume and faster to prepare than FFP
OR
2b. Fresh Frozen Plasma

21. Warfarin: Pros and Cons
• Pros:
– Years of experience, especially in special populations (i.e.
hypercoagulability, heart valves, ESRD)
– Measurable anticoagulation
– Cheap cost of medication
• Cons:
– Slow onset of action
– Varied response to dosing
• Caution advised for: elderly (>70 years), low body weight (<50kg),
malnourished (low albumin), liver impairment, decompensated
CHF, active malignancy, high risk of bleeding, drug interactions,
clinical hyperthyroidism, ESRD
– Patient must be knowledgeable about interactions
– Lots of interactions
– Monitoring requirements

22. Direct Thrombin Inhibitors (DTIs)
• Hirudin first
anticoagulant
• Places in therapy:
– Parenteral
formulations largely
limited to patients
with HIT/hx of HIT
and PCI
– Dabigatran was first
of the new oral
anticoagulants
Anticoagulant Route Approval
Hirudin IV 1909 (1920s)
(not available)
Lepirudin
(Refludan®)
IV Late 1990s
(discontinued
in 2012)
Argatroban IV 2000
Bivalirudin
(Angiomax®)
IV 2000
Desirudin
(Iprivask®)
Sub-Q/IV 2003
Dabigatran Etexilate
(Pradaxa®)
Oral 2010 (2008 in
Canada and
Europe)

23. Direct Thrombin Inhibitors (DTIs)
DTIs exert their
antithrombotic effect by
direct, selective, and
reversible binding to the
active site of thrombin
(factor IIa)
– Argatroban and Dabigatran
only bind the active site of
the thrombin enzyme
– Bivalirudin and Desirudin
also bind to Exosite I on
thrombin
• DTIs bind free and clot
bound thrombin

24. Direct Thrombin Inhibitors (Parenteral)
Argatroban Bivalirudin (Angiomax®)
Source Derivative of amino acid
L-arginine
Synthetic analog of recombinant
hirudin (protein from leech saliva)
Route IV bolus and infusion IV bolus and infusion
Half Life 39-51 min 25 min
Metabolism/
Clearance
Hepatic*
*Requires adjustment for
impaired hepatic function
Metabolism: Blood proteases
Excretion*: Urine (20%)
*Adjust for severe impaired renal
function (CrCl<30 mL/min)
Laboratory monitoring aPTT , ACT
(prolongs PT/INR)
ACT, aPTT
Major non-bleeding
adverse events
Hypotension, Chest pain, GI upset,
arrhythmias, SOB, hypersensitivity
Hypotension, Headache, back pain,
GI upset
Bleeding rates 5.3% (major) 3.7% (major)
Reversal Supportive measures Supportive measures

25. Direct Thrombin Inhibitors (DTIs)
• Pros:
– Agents of choice for treatment of HIT or history of HIT
– Does not affect platelets
– Argatroban may be used in renal impairment (even ESRD)
• Cons
– Argatroban has a narrow therapeutic index and is
unpredictable in hepatic impairment, ICU patients
– Cardiovascular adverse events
– Requires continuous infusion and monitoring
– Agents unpredictably prolongs PT/INR, making transition
to warfarin difficult
– Expensive

26. Direct Factor Xa Inhibitors
• First oral agent approved in 2012,
most recent agent 2015
– No generic products available until
at least 2020
• FDA approvals for reduction of
stroke in non-valvular atrial
fibrillation, VTE prophylaxis, VTE
treatment, prevention of
recurrent VTE
Direct Factor Xa
Inhibitors (Oral)
FDA Approval
(initial)
Apixaban (Eliquis®) 2012
Betrixaban Not yet FDA-
approved
Edoxaban (Savaysa®) 2015
Rivaroxaban (Xarelto®) 2011

27. Direct Factor Xa Inhibitors
• Highly selective for Factor Xa
• Inhibits free, prothrombinase-
associated and clot-
associated Factor Xa
• No cofactors required (no AT)
• Indirect effect on platelet
aggregation

28. New Oral Anticoagulants
Dabigatran Apixaban Edoxaban Rivaroxaban
Bioavailability 3-7%
(Prodrug)
*Take with food
50% 62% 10mg: 80-100%
20 mg*: 66%
*Take with food
Time to Cmax 1 hour 3-4 hours 1-2 hours 2-4 hours
Half-Life 12-17 hours ~12 hours 10-14 hours 5-9 hrs
11-13 hrs (elderly)
Drug Interaction
concerns
P-gp Hepatic CYP and
P-gp
P-gp Dual CYP 3A4 and
P-gp
Adjustment for
renal function
Yes
AVOID if
CrCl <15 mg/mL
Yes
Adjust when SCr
>1.5 (including
ESRD w/HD) IF
≥ 80 yrs OR ≤60 kg
Yes
AVOID for NVAF if
CrCl >95 mg/mL;
AVOID if
CrCl <15 mg/mL
Yes
VTE: AVOID if
CrCl <30 mg/mL;
NVAF: AVOID if
CrCl <15 mg/mL
Other
Adjustments
Extreme caution if
>80 years old
AVOID in severe
hepatic
dysfunction
AVOID in
moderate to
severe hepatic
dysfunction
AVOID in
moderate to
severe hepatic
dysfunction

29. New Oral Anticoagulants
Dabigatran Apixaban Edoxaban Rivaroxaban
Bleed rates Any: 16.6%
Major: 3.3%
Any: 1-12%
Major: <2%
Any: 22%
Major: <2%
Any: 5-28%
Major: <6%
Major or
Common
side effects
GI distress (35%) Well tolerated Abnormal hepatic
function tests, skin
rash
Well tolerated
Effect on
common
Coagulation
labs
Prolongs PT, INR,
and PTT
ECT and TT reliable,
but not available
Prolongs PT, INR,
and PTT
Prolongs PT, INR,
and PTT
PT, INR, and PTT
Dosing
frequency
(NVAF)
BID BID Daily Daily
Unique
points
Not recommended
if previous MI;
5-10 days of
parenteral tx
recommended for
new VTE.
Concomitant
chronic NSAIDs
allowed in some
studies
5 -10 days of
parenteral tx
recommended for
new VTE
Concomitant
clopidogrel
allowed in some
studies

30. New Oral Anticoagulants
• Pros:
– Very close to “ideal” for an anticoagulant
• Rapid onset
• Predictable dose response, no routine monitoring
• Oral dosing
• Most have minimal/tolerable non-bleeding side effects
• Cons:
– Expensive
– Increased risk of bleeding with advancing age and decreased renal
function
– No reliable monitoring for adjustments or assessment of coagulation
status
– No data in special populations (i.e. Valvular disease, prosthetic heart
valves, hypercoagulable states, oncology, pediatrics, pregnancy)
– Reversal options are available, but limited (for now)

31. Reversal of New Oral Anticoagulants
• No specific antidote available for any of the
new OACs
• Limited studies with factor replacements
– Laboratory corrections not always indicative of
positive clinical outcomes (i.e. correction of
bleeding, thrombotic events)
– Dosing not established for all agents
• Minimize use to life-threatening bleeds

32. Recommended Dosing of Concentrated
Clotting Factor Products for Oral Anticoagulants
Repletion
Agent
Clotting
Factors
Replaced1,2
Dose(s) for
Repletion of
Specific
OACs†
Dose(s) for Repletion of Specific OACs†
Warfarin1 Dabigatran1 Rivaroxaban1/Apixaban2¶
PCC3 II, IX, X
(inactivated)
25-50 units/kg — 50 units/kg
PCC4
KCentra®
II, VII, IX, X
(inactivated)
25-50 units/kg 25-50 units/kg 25-50 units/kg
aPCC II, IX, X
(inactivated)
VII
(activated,
FEIBA)
500 units for INR <5;
1000 units for INR ≥5
Up to 25 units/kg initially; subsequent
doses based on response1
FEIBA:
50 IE/kg, up to 200 IE/kg/d3
Up to 25 units/kg initially; no data
available in patients with active
bleeding;
80 units/kg1
FEIBA: 50 IE /kg up to 200
IE/kg/day3
rFVIIa VII
(activated)
17.7-53.4 μg/kg 20-120 μg/kg 20-120 μg/kg
†Experience with doses listed in this table is limited; consult current references and product label for most current information.
¶Limited data are available for apixaban reversal; however, it may be rational to apply information from rivaroxaban because of their
similar mechanisms of action.
1. Nutescu EA et al. Am J Health Syst Pharm. 2013;70:1914-1929. ©2013, American Society of Health-System Pharmacists, Inc. All rights
reserved. Reprinted with permission.
2. Babilonia K et al. Thromb J. 2014;12:8.
3. Heidbuchel H et al. Europace. 2013;15:625-651.

33. Reversal Agents: The Future (?)
• Two new reversal agents in clinical trials
– Idarucizumab
• Reversal of dabigatran (Pradaxa)
• Analysis of Phase II trials underway
• Likely the first to market (currently under priority
review by the FDA)
– Andexanet alfa
• Currently under Phase III trials
• Positive results reversing Direct AND Indirect Factor Xa
inhibitors
1. Idarucizumab. Boehringer Ingelheim. http://us.boehringer-
ingelheim.com/content/dam/internet/opu/us_EN/documents/Media_Press_Releases/2015/Idarucizumab-Media-Fact-Sheet.pdf
2. Andexanet alfa: FXa Inhibitor Antidote. Portola Pharmaceuticals. https://www.portola.com/clinical-development/andexanet-alfa-prt4445-
fxa-inhibitor-antidote/.

34. Potential Future Anticoagulants
• Tissue factor pathway inhibitors
• Factor VIII inhibitor
• Thrombomodulin
• Factor IXa inhibitor
• Factor XI inhibitor
• Factor XIIa inhibitor
• Polyphosphate inhibitors

35. Summary
• Several clotting factors may be targeted to
achieve therapeutic anticoagulation
– Most approved agents focus on factor Xa and/or
thrombin
• Different agents all have a place in therapy
• Clinical data, pharmacology, bleed risk, and
patient specific factors must all be considered
for safe use of anticoagulation

36. Additional References
• American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th
Edition). February 2012.
• Angiomax® prescribing information. The Medicines Company. May 2013
• Apixiban® prescribing information. Bristol-Meyers Squibb Company. August 2014.
• Argatroban prescribing information. Teva. February, 2015.
• Arixtra® prescribing information. Glaxo SmithKline. August 2011.
• Dobesh PP, et al. New Oral Anticoagulants for the treatemtn of Venous Thromboembolism:
Understanding Differences and Similarities. Drugs (2014) 74:2015–2032.
• Facts and Comparisons Database. Accessed 9/2015
• Lovenox® prescribing information. Sanofi-Aventis US, LLC. April 2013.
• Lexi-Comp Online Database. Accessed 9/2015
• Pradaxa® prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. January
2015.
• Savasya® prescribing information. Daiichi Sankyo Co., LTD. September 2015.
• Xarelto® prescribing information. Janssen Pharmaceuticals. December 2014.