1. Anticoagulation and Associated Disorders
Mikaela Elwell, Pharm.D.
Jordan Light, Pharm.D.
PGY1 Pharmacy Residents

2. 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.

3. 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

4. “Blood thinners” and Antiplatelets
Anticoagulants

5. Blood Clot Formation Injury to tissue / blood vessel
Platelets adhere to damaged tissue/vessels
Coagulation Cascade
Platelet Plug = Clot Formed
Blood clotting, or coagulation, is an important process that prevents excessive bleeding when a blood vessel is injured. Platelets (a type of blood cell) and proteins in your plasma (the liquid part of blood) work together to stop the bleeding by forming a clot over the injury. Typically, your body will naturally dissolve the blood clot after the injury has healed.
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6. When Bad Clots Arise Clot in a vein Venous Thromboembolism (VTE)
Clot in an Artery
Clot in a vein
Atherosclerosis
Sometimes, however, clots form on the inside of vessels without an obvious injury or do not dissolve naturally.
Clotting that occurs in arteries is usually associated with atherosclerosis (hardening of the arteries), a deposit of plaque that narrows the inside of the vessel. As the arterial passage narrows, the strong arterial muscles continue to force blood through the opening, and the high pressure can cause the plaque to rupture. Molecules released in the rupture cause the body to overreact and form an unnecessary clot in the artery, potentially leading to a heart attack or stroke.
An abnormal clot that forms in a vein may restrict the return of blood to the heart and can result in pain and swelling as the blood gathers behind the clot. Deep vein thrombosis (DVT) is a type of clot that forms in a major vein of the leg or, less commonly, in the arms, pelvis, or other large veins in the body. In some cases, a clot in a vein may detach from its point of origin and travel through the heart to the lungs where it becomes wedged, preventing adequate blood flow. This is called a pulmonary (lung) embolism (PE) and can be extremely dangerous.
Heart - chest heaviness or pain, discomfort in other areas of the upper body, shortness of breath, sweating, nausea, light-headedness
Brain - weakness of the face, arms or legs, difficulty speaking, vision problems, sudden and severe headache, dizziness
Arm or Leg - sudden or gradual pain, swelling, tenderness and warmth
Lung - sharp chest pain, racing heart, shortness of breath, sweating, fever, coughing up blood
Abdomen - severe abdominal pain, vomiting, diarrhea
Venous Thromboembolism (VTE)
Deep vein thrombosis (DVT)
Pulmonary Embolism (PE)
Stroke
Heart Attack
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7. Risky Business Smoking Immobility Obesity Hypertension
airplane or car trips
Hypertension
> 60 years old
Hyperlipidemia
Family History
Diabetes
Certain cancers or surgeries
Pregnancy
Oral contraception
Trauma

8. 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

9. Heart Attack Also called a ‘myocardial infarction’
Occurs when blood flow in the arteries going to the heart become blocked

10. Stroke
Occurs when a blood clot blocks the arteries going to the brain

11. 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

12. Prevention is Key Risk of Stroke Risk of Heart Attack
Prevent blocking the flow of blood to the brain
Risk of Heart Attack
Prevent blocking the flow of blood to the heart
After heart valve replacement
Atrial fibrillation
Reduced mobility
Prior history of a VTE
American Society of Hematology. Blood Clots. 07/1/2015 Available at:

13. Blood Clot Formation Injury to tissue / blood vessel
Platelets adhere to damaged tissue/vessels
Coagulation Cascade
Platelet Plug = Clot Formed
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14. Anticoagulants in the Clotting Cascade
Warfarin
Rivaroxaban
Apixiban
Dabigatran
Argatroban
Unfractionated heparin
Low-molecular weight heparin
CLOT
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15. Unfractionated Heparin (UFH)
Discovered: 1922
Isolated from pig livers
Greek “Hepar” meaning liver
Used in humans: 1940’s
Mechanism of action (MOA):
Potentiates antithrombin
Route: IV, SQ
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)
x patient’s baseline
Heparin, one of the oldest drugs still in widespread use – discovered/isolated back in 1922, naturally occurring glycosaminoglycan whos main function is to inhibit coagulation of blood. It was found in high concentrations in the lung and liver of animals such as cow and pigs and it where is gets name. Now it took a long time getting to popular use in humans because the first extraction protocols did not create a pure enough product and patients were getting HA, fevers and nausea from it. It wasn’t until the late 1940s that an efficient, low cost, high potency extraction technique was developed that allowed heparin to be used without the HA, fevers and nausea.
IV, SQ – not absorbed well from GI therefore
Dose expressed in units of activity
MOA: UFH binds with our naturally occurring antithrombin, and the UFH-antithrombin complex is 100-1,000 times more potent and an anticoagulant than antithrombin alone. Prevents the growth and propagation of a formed clot, and allows the patient’s own system to degrade the clot.
aPTT-activated partial thromboplastin time tells us the degree of anticoagulation. Too high and the patient is at risk for a bleed, too low and the patient is at risk for a clot. Typically we shoot for times the patient’s baseline.
Protamine binds with heparin and forms an inactive compound effectively reversing anticoagulation and neutralization can occur within 5 minutes of administration.
SQ Bioavilability / Absorption is relatively poor and erratic (30-70%) based on dose. Once absorbed into the body, the anticoagulation profile and clearance from the body varies based on length of the heparin molecules (range 3,000-30,000 DA). Only about 1/3 of the heparin molecules are able to interact with antithrombin.
Earlier this month we learned of a fatal heparin overdose for this very reason. A nurse and medical resident planned to administer an IV bolus dose of 3,000 units of heparin to a patient. Both mistakenly thought each 10 mL vial of heparin held a total of 1,000 units when, in fact, each vial contained 10,000 units (1,000 units/mL). Instead of 3,000 units, they gave the patient 30,000 units(3 vials). The patient died after developing an intracranial hemorrhage and brain stem herniation. The updated USP label standard became effective on May 1, New heparin vial labels(Figure 2) must express the amount per the entire container (e.g., 10,000 units per 10 mL) followed by the amount per mL in parentheses.
Wardrop D, et.al. BJH :
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011

16. Heparin Products
Caution: Several strengths available – always double check
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17. Low-Molecular Weight Heparin (LMWH)
Discovered: 1980’s
Chemical/enzymatically changing UFH
Enoxaparin (Lovenox)
Mechanism of action (MOA):
Potentiates antithrombin
Route: SQ
PROS
Predictable patient response
No frequent lab monitoring
Longer acting – dosed 1 -2 times daily
Given at home
Cons
Subcutaneous injection
Renal dose adjustment
Low-Molecular Weight Heparin derived by chemically or enzymatically changing unfractioned heparin.
Improvement in predictable patient response with increased bioavailability when given SQ (90%) compared with UFH
Predictability and longer duration of action (smaller molecules last longer in the body) allows for fixed and weight based dosing, therefore unlike UFH which was dosed based on units of activity, dose is expressed in mg for enoxaparin and may be given once to twice daily. Additionally the predictability of anticoagulation response when given SQ means monitoring is unnecessary to guide dosing.
IV, SQ – not absorbed well from GI therefore
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011

18. Heparin Induced Thrombocytopenia (HIT)
Uncommon
UFH:
5 days: 1-3%
14 days: 6%
LMWH: <1%
Life-threatening
Treatment:
Discontinue ALL sources of heparin
Start alternative anticoagulant:
Argatroban – IV infusion
Exposure to Heparin
Production of Antibodies
Antibody-Heparin complex activates platelets
Increased clot formation
Including flushes
Start alternative anticoagulant – choosing one that can rapidly act and that does not cross react with the heparin-antibodies. Argatroban is FDA approved
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011

19. Warfarin Discovered: 1941 1948: used as a rodenticide MOA:
PROS
Reversal Agent: Vitamin K
Oral tablet
Monitoring for bleed/clot risk
International Normalized Ratio (INR)
Standardized worldwide
Discovered: 1941
Wisconsin Alumni Research Foundation (WARF)
1948: used as a rodenticide
MOA:
Dysfunctional
Warfarin
Dietary
Vitamin K
Coagulation Factors II, VII, IX, X, Protein C & S
Vitamin K reductase
Functional
Warfarin most widely used anticoagulant in the world. It was seen in 1920’s, healthy cattle started dying of internal bleeding in Canada and US plains with no apparent cause. Now this was the time of the Great Depression and farmers who could not afford to throw away anything were using moldy hay as their feed. This hemorrhagic disease became known as “sweet clover disease”. Now it makes sense that researchers from Wisconsin, the dairy state, would try and isolate the compound that was causing all the hemorrhages in the cows, and when they did isolate the compound from moldy sweet clover it was named after the Wisconsin Alumni Research Foundation (WARF). Promoted at rat poison.
But because you could ingest warfarin and have it be effective, it was its oral bioavailability that brought it into use as an anticoagulant in humans, because heparins are given IV, SQ.
MOA: time for warfarin to achieve its effect takes time because we must run out of our functional coagulation factors. And typically takes anywhere from 8 – 15 days after starting to reach therapeutic effect.
Therapeutic effect is determined by a blood test known as the International Normalized Ratio. This measures the time to clot formation of a blood sample and the target range is typically an INR of 2-3.
Wardrop D, et.al. BJH :
Dipiro JT, et. al. Pharmacotherapy: A pathophysiological Approach. McGraw Hill Inc. 2011
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20. Warfarin 1mg – pink 2mg – lavender 2.5mg – green 3mg – brown
Cons
Frequent monitoring: INR
Consistently eat Vitamin K rich foods
Leafy greens
Kale
Chickpeas
Spinach
Broccoli
Tea – green & black
Onions
MANY drug interactions
Tablets:
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

21. New Oral Anticoagulants (NOAC)
Direct Thrombin Inhibitor
Dabigatran (Pradaxa) (2010)
Daily
Anti-Xa Inhibitors
Rivaroxaban (Xarelto) (2011)
Apixaban (Eliquis) (2012)
Twice 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
Even though patients can be treated at home with enoxaparin, the daily SQ injections can be a significant barrier for some patient. Even though warfarin is an oral tablet it has its own challenges with delayed time to reach effectiveness, and the required lab monitoring as well as many interactions there was still obvious room in the market for something better.
The new oral anticoagulants or NOAC were developed for just this gap. First out on the market was Dabigatran, a direct thrombin inhibitor, stopping the 2nd to last step in the clotting cascade before the production of fibrin and subsequent clot development. Rivaroxaban and Apixaban followed the next 2 years. All three are
idarucizumab, an investigational fully humanized antibody fragment is currently in Phase III trial for approval as the antidote for dabigatran, and has received “breakthrough” therapy designation that will help fast track approval through the FDA. The phase III trial is projected to be completed in 2017 so we will have to stay tuned.
Caution:
Black Box Warning
Premature discontinuation increases the risk of clotting events
Patients should never run out / miss refills
DailyMed. Dabigatran, Rivaroxaban, Apixaban Package Inserts. 2015
Idaruxizumab. Press Release Archive. Available at:

22. 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

23. Antiplatelet Agents

24. 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 to reduce risk of myocardial infarction (MI)
women age to reduce risk of ischemic stroke
previous stroke or MI
An egyption pyprus dating back to 1534 BC describes the use of willow bark as a general-purpose tonic or antiinflammatory/pain reliever
In 1860’s Fridrich Bayer started a company that worked to modify salicyclic acid isolated from willow bark to improve efficacy and reduce side effects. In 1899, Aspirin was registered as a pure compound and became a stamped tablet in 1904.
Aspirin’s mechanism of action is still somewhat unknown for all of its effects and uses as a pain reliever, fever reducer, and anti-inflammatory.
Low dose aspirin quickly inhibits COX in all platelets in circulation and so its antiplatelet activity is seen in less than 60minutes. This is why in patients who are experiencing a stroke, a 325mg aspirin is one of the first things that you want to give a patient in order to prevent early recurrent stroke.
Caution:
Non-steroidal anti-inflammatory (NSAID):
risk of gastrointestinal bleed
Sneader W. The discovery of aspirin: a reappraisal. BMJ Dec 23; 321(7276): 1591–1594.
Using Aspirin for the Primary Prevention of Cardiovascular Disease. AHRQ.June 2009.

25. Antiplatelets Clopidogrel (Plavix) MOA: Secondary Prevention:
Inhibits P2Y12  ADP
Alters platelet membrane
Prevents platelet aggregation
Secondary Prevention:
Previous stroke or MI
An egyption pyprus dating back to 1534 BC describes the use of willow bark as a general-purpose tonic or antiinflammatory/pain reliever
In 1860’s Fridrich Bayer started a company that worked to modify salicyclic acid isolated from willow bark to improve efficacy and reduce side effects. In 1899, Aspirin was registered as a pure compound and became a stamped tablet in 1904.
Aspirin’s mechanism of action is still somewhat unknown for all of its effects and uses as a pain reliever, fever reducer, and anti-inflammatory.
Low dose aspirin quickly inhibits COX in all platelets in circulation and so its antiplatelet activity is seen in less than 60minutes. This is why in patients who are experiencing a stroke, a 325mg aspirin is one of the first things that you want to give a patient in order to prevent early recurrent stroke.
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
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26. High Alert Medications
ALL anticoagulants and antiplatelets
Serious risk of bleed
ISMP Medication Safety Alert. Jan. 11, Available at:
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27. 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
ISMP Medication Safety Alert. Jan. 11, Available at:
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28. Reversal Agents

29. Protamine 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

30. 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?

31. Praxbind “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!

32. Bad Blood: Common Hematologic Diseases and Their Management
Mikaela Elwell, Pharm.D.
Jordan Light, Pharm.D.
PGY1 Pharmacy Residents