Download Blood Cancers

Anticoagulation and
Associated Disorders
Mikaela Elwell, Pharm.D.
Jordan Light, Pharm.D.
PGY1 Pharmacy Residents
Disclosure
We do not have (nor does any immediate family
member have) a vested interest in or affiliation with
any corporate organization offering financial support or
grant monies for this continuing education activity, or
any affiliation with an organization whose philosophy
could potentially bias our presentation.
Objectives
• Describe how clot formation occurs and list the risk
factors for developing a clot
• Identify and discuss the unique attributes of the
most commonly used anticoagulant
• Explain the utility of reversal agents and identify
which anticoagulant they reverse
• Recall important medication safety points for the
common anticoagulants
“Blood thinners” and Antiplatelets
ANTICOAGULANTS
Blood Clot Formation
Injury to tissue /
blood vessel
Platelets adhere to
damaged tissue/vessels
Coagulation Cascade
Platelet Plug = Clot
Formed
Image from: http://www.nlm.nih.gov/medlineplus/ency/imagepages/19462.htm
When Bad Clots Arise
Clot in an Artery
Clot in a vein
Venous Thromboembolism (VTE)
– Deep vein thrombosis (DVT)
– Pulmonary Embolism (PE)
Atherosclerosis
 Stroke
 Heart Attack
Right Image from: http://nymethodist.adam.com/content.aspx?productId=10&pid=10&gid=000003
Left Image from: http://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis
Risky Business
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Smoking
Obesity
Hypertension
Hyperlipidemia
Diabetes
Pregnancy
Oral contraception
Trauma
 Immobility
– airplane or car trips
 > 60 years old
 Family History
 Certain cancers or
surgeries
Venous Thromboembolism
• Caused by blood clot forming in the venous
circulation
– Deep vein thrombosis (DVT): blood clot that blocks the
veins to the lower extremities
– Pulmonary embolism (PE): blood clot that breaks off and
travels to the lungs, blocking the pulmonary arteries
Heart Attack
• Also called a ‘myocardial infarction’
• Occurs when blood flow in the arteries going to the
heart become blocked
Stroke
• Occurs when a blood clot blocks the arteries going to
the brain
Atrial Fibrillation
• Most common type of abnormal
heart rhythm
– Periods of rapid and irregular beating
• Caused by an electrical problem in
the heart
• Irregular heartbeats can result in
blood pooling in the heart  blood
clot  stroke
Prevention is Key
 Risk of Stroke
 Prevent blocking the flow of blood to the brain
 Risk of Heart Attack
 Prevent blocking the flow of blood to the heart
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After heart valve replacement
Atrial fibrillation
Reduced mobility
Prior history of a VTE
American Society of Hematology. Blood Clots. 07/1/2015 Available at: http://www.hematology.org/Patients/Clots/
Blood Clot Formation
Injury to tissue /
blood vessel
Platelets adhere to
damaged tissue/vessels
Coagulation Cascade
Platelet Plug = Clot
Formed
Image from: http://www.nlm.nih.gov/medlineplus/ency/imagepages/19462.htm
Anticoagulants in the Clotting Cascade
Warfarin
Rivaroxaban
Apixiban
Dabigatran
Argatroban
Unfractionated heparin
Low-molecular weight heparin
CLOT
Image from: http://www.nature.com/nrd/journal/v8/n5/fig_tab/nrd2851_F1.html
Unfractionated Heparin (UFH)
• Discovered: 1922
– Isolated from pig livers
– Greek “Hepar” meaning liver
• Used in humans: 1940’s
PROS
Reversal Agent: Protamine
Monitoring available
Cons
Unpredictable patient response
• Mixed chain lengths
• 1/3 of UFH molecules active
Monitoring required
• aPTT (activated partial
thromboplastin time)
• 1.5-2.5x patient’s baseline
• Mechanism of action (MOA):
– Potentiates antithrombin
• Route: IV, SQ
1.
2.
Wardrop D, et.al. BJH. 2008.141:757-763
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
Heparin Products
Caution: Several strengths available – always double check
Left and Middle Image from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc26e3c-aee9-4c0d-bdb1-bf350308fbce
Right Image from: http://www.ismp.org/NAN/files/NAN-20130610.pdf
Low-Molecular Weight Heparin
(LMWH)
• Discovered: 1980’s
– Chemical/enzymatically
changing UFH
PROS
• Predictable patient response
• No frequent lab monitoring
• Longer acting – dosed 1 -2
times daily
• Given at home
Cons
• Subcutaneous injection
• Renal dose adjustment
• Enoxaparin (Lovenox)
• Mechanism of action (MOA):
– Potentiates antithrombin
• Route: SQ
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
Heparin Induced Thrombocytopenia
(HIT)
• Uncommon
– UFH:
• 5 days: 1-3%
• 14 days: 6%
– LMWH: <1%
Exposure
to Heparin
Production
of
Antibodies
AntibodyHeparin
complex
activates
platelets
• Life-threatening
• Treatment:
– Discontinue ALL sources of heparin
– Start alternative anticoagulant:
• Argatroban – IV infusion
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
Increased
clot
formation
Warfarin
PROS
• Discovered: 1941
– Wisconsin Alumni
Research Foundation
(WARF)
• Reversal Agent: Vitamin K
• Oral tablet
• Monitoring for bleed/clot risk
• International Normalized
Ratio (INR)
• Standardized worldwide
• 1948: used as a
rodenticide
• MOA:
Warfarin
Dysfunctional
Vitamin K
reductase
Coagulation
Factors II, VII, IX, X,
Protein C & S
Dietary
Vitamin K
Functional
1.
2.
3.
Wardrop D, et.al. BJH. 2008.141:757-763
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
Image from: http://www.surgery.usc.edu/hepatobiliary/liversurgery.html
Warfarin
Cons
• Frequent monitoring: INR
• Consistently eat Vitamin K rich foods
o Leafy greens
o Kale
o Chickpeas
o Spinach
o Broccoli
o Tea – green & black
o Onions
o MANY drug interactions
Tablets:
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1mg – pink
2mg – lavender
2.5mg – green
3mg – brown
4mg – blue
5mg – peach
6mg – teal
7.5mg – yellow
10mg – white
Caution:
Dispensing Errors – dosing changes may be frequent (based on INR levels)
Strength Pneumonic: Please Let Greg Brown Bring Peaches to Your Wedding
New Oral Anticoagulants (NOAC)
• Direct Thrombin Inhibitor
– Dabigatran (Pradaxa) (2010)
• Daily
PROS
Oral tablets
Fewer interactions
No lab monitoring
Rapid Onset of Action
Cons
Miss a dose – risk of clot
No current approved reversal
agent for anti-Xa inhibitors
• Anti-Xa Inhibitors
– Rivaroxaban (Xarelto) (2011)
• Daily
– Apixaban (Eliquis) (2012)
• Twice daily
Caution:
Black Box Warning
Premature discontinuation increases the risk of clotting events
◦ Patients should never run out / miss refills
1.
2.
DailyMed. Dabigatran, Rivaroxaban, Apixaban Package Inserts. 2015
Idaruxizumab. Press Release Archive. Available at: http://us.boehringeringelheim.com/news_events/press_releases/press_release_archive/2015/4-232015-fda-grants-priority-review-boehringer-ingelheims-biologics-license-application-idarucizumab.html
Clot Busters
• Work by dissolving a clot that already exists
• Used in emergency settings (e.g. new onset stroke, heart
attack, or pulmonary embolism)
• “Thrombolytic” or “fibrinolytic”
• Alteplase (Activase)*
• Tenecteplase (TNKase)
• Reteplase (Retavase)
– IV infusions
• Must be prepared quickly
ANTIPLATELET AGENTS
Antiplatelets
 Aspirin – acetylsalicylic acid
– Willow bark – salicyclic acid
– Egyption’s recorded use 1534 BC
– Tablet form: 1904
 MOA:
– Inhibits Cyclooxygenase-1
• Prevents thromboxane A2 formation
– Prevents platelet aggregation
– Irreversible for life of the platelet
 Primary & Secondary Prevention:
– men age 45-79 to reduce risk of myocardial
infarction (MI)
– women age 55-79 to reduce risk of ischemic stroke
– previous stroke or MI
Caution:
◦ Non-steroidal anti-inflammatory (NSAID):
◦ risk of gastrointestinal bleed
1.
2.
Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000 Dec 23; 321(7276): 1591–1594.
Using Aspirin for the Primary Prevention of Cardiovascular Disease. AHRQ.June 2009.
Antiplatelets
Clopidogrel
• Clopidogrel (Plavix)
• MOA:
– Inhibits P2Y12  ADP
• Alters platelet membrane
• Prevents platelet aggregation
• Secondary Prevention:
– Previous stroke or MI
1.
2.
PROS
Less GI bleeding than aspirin
Cons
Prodrug - Liver must transform to active drug
• Efficacy decreased if liver enzyme is inhibited/reduced
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
Image from: http://archinte.jamanetwork.com/article.aspx?articleid=215618
High Alert Medications
• ALL anticoagulants and antiplatelets
– Serious risk of bleed
1.
2.
ISMP Medication Safety Alert. Jan. 11, 2000. Available at: https://www.ismp.org/newsletters/acutecare/articles/20070111.asp
Image from: http://libguides.usc.edu.au/risk
High Alert Medications
• ALL anticoagulants and antiplatelets
– Serious risk of bleed
• Risks:
 Duplicate or concurrent therapy
 Accidental stoppage
 Look-alike vials or syringes
 Look-alike names
 Dosing errors
 Drug and Food Interactions
1.
2.
ISMP Medication Safety Alert. Jan. 11, 2000. Available at: https://www.ismp.org/newsletters/acutecare/articles/20070111.asp
Image from: http://libguides.usc.edu.au/risk
REVERSAL AGENTS
Protamine
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Reverses: heparin
Binds to heparin to form a complex, and neutralizes its effects
Storage: refrigerator
Dose determined by amount of heparin given
– 1 mg protamine for every 100 units of heparin
Vitamin K
• “Phytonadione”
• Reverses: warfarin
• Competes with warfarin in binding to receptor on
vitamin K-dependent clotting factors
• Given either PO or IV depending on:
– How high is the INR?
– Is the patient bleeding?
Praxbind
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“Idarucizumab”
Reverses: dabigatran
FDA approved October 2015
Monoclonal antibody that binds with high affinity to
dabigatran and neutralizes it within minutes
• Given as two separate 2.5 g infusions
• Storage: refrigerator
• Do NOT tube!
Bad Blood: Common
Hematologic Diseases and
Their Management
Mikaela Elwell, Pharm.D.
Jordan Light, Pharm.D.
PGY1 Pharmacy Residents