Review of Antiplatelet and
Anticoagulation Therapy
Steven W. Harris MHS, PA-C
Coagulation system
• Two pathways
– Intrinsic
– Extrinsic
– Combine into the final common pathway
• Intrinsic: clotting factors are intrinsic to the blood
– Measured by aPTT
• Extrinsic: triggered by the addition of
thromboplastin (tissue factor)
– Measured by PT
What happens?
• Damage to endothelium:
1. platelets adhere
2. Trigger formation of factor VII and X
3. VII and X facilitate conversion of prothrombin to
thrombin
4. Converts fibrinogen to fibrin
5. Activation of more platelets
6. Platelets release thromboxane A2,serotonin, and
ADP which enhance platelet aggregation.
What Happens?
• Direct tissue damage in the body
– Release of thrombin which activates the
fibrinogen system
– Aids in activation of platelets
– Continue cascade.
Why and What
• Prevention and treatment of thromboembolic
events
–
–
–
–
CVA
MI
DVT
PE
• Types of drugs
– Heparins
– Anticoagulants
– Antiplatelets
Heparins
•
•
•
•
Heparin sodium:
Enoxaparin sodium:
Fondaparinux:
Dalteparin:
generic
Lovenox
Arixtra
Fragmin
• Have no effect on existing clots, but prevents
or retards formation of new thrombi.
Oral Anticoagulants: only one
• Warfarin
• Jantoven
• Coumadin
• Blocks vitamin K binding sites inhibiting synthesis
of vit-K dependent factors
– II, VII, IX, X
• Do not lyse existing thrombi, but prevent extension
and formation
Antiplatelets
•
•
•
•
•
•
•
•
•
Acetylsalicylic acid (ASA)
Clopidogrel
Ticlodipine
Dipyridamole
Tirofiban *
Eptifibatide*
Anagrelide*
Abciximab*
Dipyridamole + ASA
*IIb/ IIIa Inhibitors
Aspirin, Ecotrin
Plavix
Ticlid
Persantine
Aggrastat
Integrilin
Agrylin
ReoPro
???
Antiplatelets
• ASA: inhibits cyclooxygenase
– Prevents formation of thromboxane A2
• Clopidogrel: inhibits ADP binding to platelet
receptor
Prevent platelet aggregation
Effect is irreversible
Antiplatelets
• IIb/ IIIa Inhibitors: newest group of
antiplatlets
– Reversibly inhibit platelet aggregation through
blocking the binding site of glycoprotein IIb/IIIa
and fibrinogen.
Heparins: Indications
• Acute treatment of thromboembolic event
– (DVT, PE, CVA, ACS)
•
•
•
•
•
Early treatment of AMI
Cardiac surgery
Vascular surgery
During and after PTCA, PCI
Select pts with acute stroke, unstable angina,
atrial fibrillation, precardioversion, prophylaxis of
DVT and PT in high risk pts.
Heparin
• Begin with standard loading dose of 5000 U IV
– Then follow appropriate dosing schedule
– Commonly 15-25 U/kg/hr.
• Monitor with aPTT
• Caution: HIT
– Treat with direct thrombin inhibitors
• argatroban or bivalirudin (angiomax)
Low Molecular Weight Heparins
(LMWH)
• Enoxaparin, Fondaparinux
– Advantages of predictable anticoagulant effect
– Dosing
– Inhibits generation of thrombi higher in the clotting
cascade
• Prophylaxis
– Lovenox 30 mg
– Lovenox 40 mg
• Therapeutic Dose
– Lovenox
Warfarin: Mechanism of Action
• Warfarin interrupts the ability to recycle
Vit K
• Vitamin K dependent procoagulants:
– Prothrombin (Factor II)
– Factor VII
– Factor IX
– Factor X
• Vitamin K dependent Anticoagulants:
– Proteins S and C.
Pharmacokinetics
Therpeutic challenges
– Delayed optimal anticoagulant effect
• Has no effect on available clotting factors
• No anticoagulant effect until these decay
– 5-7 days until clotting factors are at a minimal level
– Warfarin half-life of 36 to 48 hours
• Persistent anticoagulant effect after warfarin is
discontinued
Considerations
• hepatitis, cirrhosis, and cancers that degrade
liver function result in a deficiency of clotting
factors
• green leafy vegetables & fish oil contain
Vitamin K
• normal flora
– produce Vitamin K (broad spectrum antibiotic
effects)
• Multiple Drug interactions
Monitoring
• Prothrombin Time
– Used to assess Extrinsic Pathway
– Normal range 12-15 seconds
– Must be used with INR for Coumadin Dosing to
“Standardize Test”
• The normal range for the INR is 0.8-1.2
– Patients fondly refer to this test as “Pro-time”
– Adjusted from the INR value
Monitoring
• Warfarin is a narrow therapeutic index drug (NTI). When the INR falls
below 2.0 thrombosis risk increases and when the INR rises above 4.0
serious bleeding risk increases.
• Target INR ranges:
• Disease
INR Range
DVT/PE
2.0-3.0
Atrial Fibrillation
2.0-3.0
Myocardial Infarction
2.0-3.0
Mechanical Heart Valves
2.5-3.5
Initiating Therapy
• Contraindications
• Initiating a Plan:
– Rx for medication
• interactions
– Pt Education
• Diet
• Timing
• Warning signs
– Laboratory findings
• Baseline PT INR, aPTT, platelet count
• Follow-up PT INR
Drug Interactions
Drugs That May Lengthen
PT
• Antibiotics
• Antiarrhythmics
• Others
– Anabolic steroids
Omeprazole Cimetidine
Phenytoin Clofibrate
Tamoxifen Disulfiram
Thyroxine Lovastatin
Vitamin E (large doses)
Drugs That May Shorten PT
• Alcohol Penicillin
• Antacids Rifampin
• Antihistamines
Spironolactone
• Barbiturates Sucralfate
• Carbamazepine
Trazodone
• others
Dietary Interactions
• Patients taking warfarin should eat a diet that
is constant in vitamin K.
• Minimize changes in intake of green leafy
vegetables (spinach, greens, and broccoli),
green peas, and oriental green tea
– http://www.med.umich.edu/cvc/services/site_ant
icoag/healthprof.html
Co-morbid Conditions
• Expect a longer prothrombin time in patients with CHF, jaundice,
hepatitis, liver failure, diarrhea, or extensive cancer or connective
tissue disease.
• Expect a longer prothrombin time when patients receiving warfarin are
hospitalized for any reason.
• Metabolic alterations can affect the prothrombin time.
• Expect a longer prothrombin time in patients with hyperthyroidism or
high fever.
• Expect a longer prothrombin time in elderly patients.
• Expect a shorter prothrombin time in patients with hypothyroidism
Initiating Warfarin Therapy
• Large loading doses do not markedly shorten
the time to achieve a full therapeutic effect.
• Initiate therapy with the estimated daily
maintenance dose (2-5 mg daily)
• Elderly or debilitated patients often require
low daily doses of warfarin (2-4 mg daily).
Initiating Warfarin Therapy
• In Patient
• Check daily PT INR
–
–
–
–
5mg Day 1
5mg Day 2
2-5mg Day 3*
2-5 mg Day 4*
• Concurrent LMWH or Heparin management
Initiating Warfarin Therapy
• Out patient
• 2-5 mg daily
• Check INR on day 3-5
– Insure anticoagulation achieved and stable
• Recheck one week from initiation
• Additional anticoagulant?
– Urgent anticoagulation needed
• Concurrent LMWH or Heparin
– Non-urgent anticoaglation
• Start with anticipated daily dose
Initiating Therapy
• Contraindications
• Initiating a Plan:
– Rx for medication
• interactions
– Pt Education
• Diet
• Timing
• Warning signs
– Laboratory findings
• Baseline PT INR, aPTT, platelet count
• Follow-up PT INR
Case 1
• 70 y/o male with new dx atrial fibrillation.
Hemodynamically stable, HR 70 bpm.
• PMH: CAD
• Habits: occasional ETOH, eats a healthy diet.
Case 2
• 55 y/o healthy female. Recently returned
from visiting tour de France . Found to have
unilateral R leg swelling, U/S comes back
confirming R DVT.
• PMH: G2 P2
Case 3
• 80 y/o female with SOB, tachypnea,
tachycardia, hypoxia. Found to have massive
PE on CT angiogram.
• PMH: Prior DVT no workup, DM, HTN.
Case 3
• 80 y/o female with SOB, tachypnea, tachycardia, hypoxia.
Found to have massive PE on CT angiogram.
• PMH: Prior DVT no workup, DM, HTN.
• Day 3 INR is 2.0
• Day 4 INR is 3.2
Altering Chronic Therapy
• Significant changes in INR can usually be
achieved by small changes in dose (15% or
less).
• 4-5 days are required after any dose change or
any new diet or drug interaction to reach the
new antithrombotic steady state.
• Patients are confused by multiple dosages of
pills.
Antiplatelets
•
•
•
•
Aspirin
Clopidogrel
Aggrenox
Ticlid
Resources
Clotting Cascade
• Web based aid to help determine dose
http://warfarindosing.org/Source/Home.aspx
• ACC foundation guide to therapy
http://circ.ahajournals.org/cgi/content/full/107/12/1692
?eaf
• Excellent Resource for managing Warfarin
http://www.med.umich.edu/cvc/services/site_anticoag/
healthprof.html