Anticoagulation Therapy

and Monitoring
Shiela May Jayme Nacabu-an, RPh, MHPEd
UP Department of Pharmacy
 Objectives:
At the end of the session, you must be able to:

1. Review the coagulation cascade

2. Compare the anticoagulation drugs and the
monitoring parameters for each
3. Compute for appropriate dose using the
nomograms
Coagulation Cascade Review:
Etiology of Thromboembolism
ANTICOAGULANT THERAPY
Advances in AC Therapy in the US
 Tests Used to Monitor
Antithrombotic Therapy
• Assessment of baseline hemostatic status
prior to initiation of drug therapy
– Platelet count
– Hgb and/or Hct
– PT (warfarin) and aPTT (heparin)
– INR
 PT
• Prolonged by deficiencies of clotting factors II,
V, VII, and X; low levels of fibrinogen; very
high levels of heparin
• Reflects alterations in extrinsic and common
pathways of clotting cascade
• Measured by adding Ca and tissue
thromboplastin to a sample plasma
(platelets removed by centrifugation)
• Mean normal: ~12 s
 Prothrombin Time and
International Normalized Ratio
• PT > 20 seconds
– Prolonged bleeding, hematoma at puncture site,
hemorrhage, blood in stool, bleeding gums, shock
– Monitoring vital signs and neurologic changes
until PT is within normal range, administration of
vitamin K (potent coagulant)
 INR
• Internationally recognized standard for
monitoring warfarin therapy
• ISI: used to mathematically convert PT to INR
• INR: 0.8-1.2
• INR 2.5 (2.0-3.0) for regular-intensity therapy
• INR 3.0 (2.5-3.5) for high-intensity therapy
 aPTT
• Reflects alterations in intrinsic pathway of
clotting cascade
• Used to monitor heparin therapy
• Surface-activating agent (kaolin or micronized
silica) + partial thromboplastin reagent
(phospholipid; platelet substitute) + Ca to
plasma sample
• Mean normal: 24-36 s
 Activated Partial
Thromboplastin Time (aPTT)
• Critical values
– > 70 seconds
• Prolonged bleeding, hematoma at puncture site,
hemorrhage, blood in stool, bleeding gums, shock
• Monitor vital signs and neurologic changes until values
are within normal range, administer protamine sulfate
– < 53 seconds in a patient receiving heparin
therapy
• Therapy is providing inadequate anticoagulation
 Anti-Factor Xa Activity
• Patients with renal failure may accumulate
LMWHs leading to increased risk of
hemorrhagic complications
• Obese patients weighing > 150 kg
• Unexpected bleeding complications secondary
to anticoagulation with LMWH
• Pregnant patients using LMWHs for treatment
or prevention of thrombosis
 Anticoagulation Therapy
• Mainstay of therapy for patients with VTE
– Rapid-acting anticoagulant (e.g., UFH, LMWH,
fondaparinux) overlapped with warfarin for at
least 5 days until INR > 2
– Continued for a minimum of 3 months
• Does not dissolve a formed clot but prevent its
propagation and growth (vs. thrombolytics)
• Duration based on patient’s risk of VTE
recurrence and major bleeding
Anticoagulant Therapy
Risk Factors for Major Bleeding while
on Anticoagulation Therapy
• Anticoagulation intensity • History of GI bleeding
(e.g., INR > 5, aPTT > 120
sec) • Recent surgery or
• Initiation of therapy (1st trauma
few days and weeks)
• High risk for fall/trauma
• Unstable anticoagulation
response • Heavy alcohol use
• Age > 65 years • Renal failure
• Concurrent antiplatelet
drug use • Cerebrovascular disease
• Concurrent NSAID or ASA • Malignancy
use
 Contraindications to
Anticoagulation Therapy
• Active bleeding
• Hemophilia or other hemorrhagic tendencies
• Severe liver disease with elevated baseline PT
• Severe thrombocytopenia (< 20 x 103/mm3)
• Malignant hypertension
• Inability to meticulously supervise and
monitor treatment
ANTICOAGULANTS
Unfractionated Heparin (UFH)

Drug of choice for indications requiring a rapid

anticoagulation (e.g., acute treatment of VTE)

Continuous infusion vs. Intermittent IV bolus

dosing
Routes of administration Significant reduction of bioavailability with SC
IM not recommended

Dose-dependent t1/2 = 30 – 150 mins

 Reversal of Heparin Effect
• Protamine sulfate infused slowly over 3-5
mins, as a 1% solution at a dose of 1 mg for
each 100 units of heparin administered
– Max of 50 mg; Repeated doses if bleeding not
controlled or anticoagulant effect rebounds
– If delayed, dosing based on estimated amount of
heparin remaining (consider half-life of heparin)
– Effects of UFH neutralized in 5 mins
– Effects of protamine persist for 2 h
 Heparin-Associated
Thrombocytopenia (HAT)
• Occurs as a direct effect of heparin on platelet
function, causing transient platelet sequestration
and clumping with reductions in platelet count
(but usually > 100,000/uL)
• Within first several days of heparin therapy
• Px remains asymptomatic, platelet counts return
to normal even when heparin therapy is
continued
• Daily monitoring of platelet count + continue
heparin
 Heparin-induced thrombocytopenia
(HIT)
• Reductions in platelet count of >50% from
baseline
• Delayed-onset HIT
– More severe immune-mediated reaction with a typical
delay in onset of 5-10 days after initiation of heparin
therapy
– Develops several days after stopping heparin therapy
in patients naive to UFH
• Immediate-onset HIT
– Occurs rapidly (within 24 h of UFH initiation) in
patients previously exposed to heparin
 Heparin-induced thrombocytopenia
(HIT)
• Overall incidence of HIT < 3% after 5 days of
UFH use; cumulative incidence of 6% after 14
days of continuous heparin use
• More frequent with bovine lung heparin than
porcine gut-derived heparin
• Heparin therapy should be stopped
immediately; treatment with an alternative
anticoagulant should be initiated (argatroban,
lepirudin)
 Low Molecular Weight Heparins (LMWH)
• Dalteparin (Fragmin), Enoxaparin(Clexane), Tinzaparin
(Innohep)
• Less protein binding
– More predictable anticoagulant response
– Dose adjustments and routine monitoring not required in
majority of patients
– Improved bioavailability at low doses
• Dose-independent renal clearance
• Longer plasma t1/2 → once- or twice-daily dosing
• Elimination half-life: 2-6 h → in general, administered SC
every 12 to 24 h at fixed doses
• More favorable SE profile
 Fondaparinux
• Selective indirect factor Xa inhibitor
• t1/2 17 – 21 h → once-daily dosing SC at a
fixed dose
• No routine coagulation monitoring or dose
adjustments
• Anticoagulant effects up to 2 to 4 days after
discontinuation
Comparative Mechanism of Action:
Fondaparinux and the Heparins
Fondaparinux Advantages
Direct Thrombin Inhibitors
 Direct Thrombin Inhibitors
• IV: Argatroban, Lepirudin and Bivalirudin
– Continuous infusion; aPTT monitoring for dosing
adjustments
• PO Dabigatran
– Given at a fixed dose without need for routine coagulation
monitoring or dosing adjustments
– AF: 150 mg bid (CrCl > 30 mL/min); 75 mg bid (15-30);
– CI in CrCl < 15 ml/min
– Half-life 14 h (normal CL), > 27 h (severe renal impairment)
– GI absorption by PgP; not metabolized by CYP enzymes
Anticoagulant Targets
Absorption
Pharmacokinetics
Effect of Renal Function on Half-life
Dosing for Renal Dysfunction
Apixaban in ESRD
Use of Rivaroxaban and Dabigatran in
ESRD
Edoxaban in Patients with CrCl> 95
ml/min
Dabigatran
Effect on Coagulation Testing
Drug Interactions
Pre-Operative Management for
invasive procedures
Post-operative Management
Management of DOAC Major
Bleeding
Concentrated Blood Factor Products
 Warfarin
• Anticoagulant of choice when long-term or
extended anticoagulation is required
• Dose adjustment to maintain INR 2 – 3
– Determined by patient’s individual response to
therapy and the desired intensity of anticoagulation
• approximately 5-7 days to reach a steady state of
anticoagulation after warfarin therapy is initiated
or after dosing changes.
• (+): oral administration and low drug cost
• (-): frequent monitoring and periodic dose
adjustments
Warfarin Pharmacodynamics
Vitamin K Recycling
Comparison of Drugs and Regimens
DOSING NOMOGRAMS
Weight-based Dosing for UFH Administered by Continuous IV Infusion for VTE
Initial Loading Dose Initial Infusion Rate

80 units/kg (max = 10,000 units) 18 units/kg/h (max = 2,300 units/h)

Maintenance Infusion Rate

APTT (seconds) Dose Adjustment

< 37 (or less than 12 sec below 80 units/kg bolus then increase
institution-specific therapeutic range) infusion by 4 units/kg/h
37 – 47 (or 1 -12 sec below 40 units/kg bolus then increase
institution-specific therapeutic range) infusion by 2 units/kg/h
48 – 71 (within institution-specific No change
therapeutic range)
72 – 93 (or 1 – 22 sec above Decrease infusion by 2 units/kg/h
institution-specific therapeutic range)
> 93 (or greater than 22 sec above Hold infusion for 1 h then decrease by
institution-specific therapeutic range) 3 units/kg/h
 Heparin Dosing Nomogram
(University of Washington Medical Center)

• Suggested LD
– Tx of DVT/PE: 80 units/kg (rounded to nearest 500
units)
– Prevention, including CV indications: 70 units/kg
(rounded to nearest 500 units)
• Suggested initial infusion
– Tx of DVT/PE: 18 units/kg/h (rounded to nearest 100
units)
– Prevention, including CV indications: 15 units/kg/h
(rounded to nearest 100 units)
• First aPTT check: 6 hours after initiating therapy
 Dosing Adjustments of Heparin (rounded to nearest 100 units)

aPTT (secs) Heparin bolus Infusion hold Infusion rate Next aPTT
time adjustment
<50 4,000 units 0 Increase by 200 In 6 h
units/h
50-59 2,000 units 0 Increase by 100 In 6 h
units/h
60-100 0 0 None Every AM

101-110 0 0 Decreased by In 6 h
100 units/h
111-120 0 0 Decreased by In 6 h
200 units/h
121-150 0 30 mins Decreased by In 6 h
200 units/h
151-199 0 60 mins Decreased by In 6 h
200 units/h
>200 0 PRN Hold until aPTT Every h until
< 100 <100
 Sample Problem
• 76 y/o, 92 kg, 6 ft male; heparin for DVT
Time aPTT (seconds) Heparin Dosage Order

0800 31 (baseline) 7,400 units bolus followed

by 1,700 units/h infusion

0900 130 Hold infusion for 30

minutes, then decrease to
1,500 units/h infusion rate
1500 40 Rebolus with 4,000 units,
then to increase to 1,700
units/h infusion rate
? 85 ?
 Duration of Therapy
• Adherence of thrombus to vessel wall and
subsequent endothelialization usually takes 7
to 10 days
• Anticoagulation therapy generally continued
for 3 months to prevent recurrent thrombosis
→ which anticoagulant can be used?
• Heparin continued for a minimum of 5 days
and until INR > 2 for 24 hours
 “Initiation” Dose of Warfarin
Higher (7.5 or 10 mg)
• Younger (<55) and
otherwise healthy patients
Conservative (5 mg or less)
• Elderly (>75)
• HF, liver disease, or poor
nutritional status
• Taking interacting meds
• High risk of bleeding

Loading doses of warfarin (e.g., 15 to 20 mg)

are NOT recommended.
false impression that a therapeutic INR has been achieved in 2 to 3
days and lead to potential future overdosing.
 Day INR Dose
Initiation of warfarin therapy with available daily PT/INR monitoring
1 -- Start warfarin with 5 mg daily (7.5 – 10 mg if patient’s
age <60, no concurrent use of interacting meds, and
bleeding risk is low)
2 < 1.5 No change
1.5 – 1.9 Decrease dose by 25 – 50%
2 – 2.5 Decrease dose by 50 – 75%
> 2.5 Hold next dose
3 < 1.5 Increase dose by 0 – 25%
1.5 – 1.9 No dose change
2 – 2.5 Decrease dose by 25 – 50%
> 2.5 Decrease by 50% or hold next dose
4 < 1.5 Increase dose by 0 – 25%
1.5 – 1.9 No dose change or increase by 10 – 25%
2–3 Decrease dose by 0 - 25%
>3 Decrease by 50% or hold next dose
5 < 1.5 Increase dose by 25%
1.5 – 1.9 Increase dose by 0 – 25%
2–3 No dose change or decrease dose by 10 – 25%
>3 Decrease by 25 – 50%
 Applying the Dosing Nomogram
Day INR Recommended Warfarin Dose
1 7.5 or 10 mg initiation dose for a 50
year-old male patient with DVT
Prescribed Warfarin Dose based on
recommendations
Start patient with warfarin 1 tab 10 mg
once daily with daily INR monitoring

2 2 Decrease dose by 50 – 75% Decrease dose of warfarin to 5 mg 1 tab

10 mg (0.5) = 5 mg → 5 mg once daily.
10 mg (0.75) = 7.5 mg → 2.5 mg
•Dosing range 2.5 – 5 mg
3 1 Increase dose by 0 – 25% Maintain dose of warfarin at 5 mg 1 tab
5 mg (0.25) = 1.25 mg → 6.25 mg once daily.
•Dosing range 5 – 6.25 mg
4 3.5 Decrease dose by 50% or hold next Hold next dose of warfarin.
dose
5 mg (0.5) = 2.5 mg → 2.5 mg
5 2 No dose change or decrease dose by Continue warfarin at 5 mg 1 tab once
10 – 25% daily.
5 mg (0.1) = 0.5 mg → 4.5 mg
5 mg (0.25) = 1.25 mg → 3.75 mg
•Dosing range 3.75 mg-5 mg
 Frequency of INR Monitoring and Patient
Assessment During Warfarin Therapy
Initiation Therapy
Inpatient initiation Daily

Outpatient flexible initiation method Daily through day 4, then within 3-5 days

Outpatient average daily dosing method Within 3-5 days, then within 1 week

After hospital discharge If stable, within 3-5 days

If unstable, within 1-3 days

First month of therapy Every 1-4 days until therapeutic, then

weekly
 Frequency of INR Monitoring and Patient
Assessment During Warfarin Therapy
Maintenance Therapy
Medically stable patients Every 1-3 days

Medically unstable patients Daily

After hospital discharge If stable, within 3-5 days

If unstable, within 1-3 days
Routine ff-up in medically stable and Every 4-6 weeks
reliable patients
Routine ff-up in medically unstable and Every 1-2 weeks
unreliable patients
Dose held today for significant In 1-2 days
overanticoagulation
Dosage change today Within 1-2 weeks

Dosage change < 2 weeks ago Within 2-4 weeks

 Guidelines for Reversal of an
Elevated INR
INR Recommendation

<5 Lower or hold dose

5-8.9 Hold 1 or 2 doses, or hold dose and give vit K (1-2.5 mg orally). If
more rapid reversal is required, give vit K (<5 mg) orally. Repeat vit K
(1-2 mg orally) if INR is still elevated at 24 h.
>/= 9 Hold warfarin and give vit K (2.5-5 mg orally). Use additional vit K, if
necessary.

Serious Hold warfarin and give vit K (10 mg slow IV infusion) supplemented
bleeding with with fresh-frozen plasma (FFP), prothrombin complex concentrates
high INR (PCC), or recombinant factor (RF) VIIa. May repeat vit K every 12 h
prn.
Life- Hold warfarin and give FFP, PCC, or RF VIIa supplemented with vit
threatening K(10 mg slow IV infusion). Repeat as necessary.
bleeding
 Warfarin Interactions with Disease States and Clinical Conditions

Clinical Condition Effect on Warfarin Therapy

Advanced age Inc sensitivity to warfarin due to reduced vit K stores

and/or lower Cp of vit-K-dependent clotting factors
Pregnancy Teratogenic; avoid exposure during pregnancy

Lactation Not excreted in breast milk; can be used postpartum by

nursing mothers
Alcoholism Acute: inhibits drug metabolism, with acute INR elevation
Chronic: induces drug metabolism, higher dose reqts
Liver disease May induce coagulopathy by dec production of clotting
factors, with baseline INR elevation; may reduce drug CL
Renal disease Reduced activity of CYP2C9, with lower drug dose reqts

Heart failure Reduced drug metabolism due to hepatic congestion

 Warfarin Interactions with Disease States and Clinical Conditions

Clinical Condition Effect on Warfarin Therapy

Cardiac valve Enhanced sensitivity to drug preoperatively due to

replacement hypoalbuminemia, lower oral intake, dec physical activity,
and reduced clotting factor concentrations after
cardiopulmonary bypass

Nutritional status Changes in dietary vitamin K intake (intentional or as the

result of disease, surgery, etc.) alter response to drug

Use of tube feedings Dec sensitivity to drug, possibly caused by changes in

absorption or vit K content of nutritional supplements

Thyroid disease Hypo: dec catabolism of clotting factors → inc doses

Hyper: inc catabolism of clotting factors → inc sensitivity
to drug
 Warfarin Interactions with Disease States and Clinical Conditions

Clinical Condition Effect on Warfarin Therapy

Smoking and tobacco use Smoking: may induce CYP1A2, inc drug dosing reqts
Chewing tobacco: may contain vit K, inc drug dosing reqts
Fever Inc catabolism of clotting factors, causing acute inc in INR

Diarrhea Reduction in secretion of vit K by gut flora, causing acute

inc in INR
Acute Inc sensitivity to warfarin
infection/inflammation
Malignancy Inc sensitivity to warfarin by multiple factors
Reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260295/

Nancy L. Shapiro, PharmD, FCCP, BCPS

Operations Coordinator, Antithrombosis Clinic
Clinical Associate Professor
Director, PGY2 Ambulatory Care Residency
The University of Illinois at Chicago
Chicago, IL

END OF LECTURE ☺