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30 Anticoagulation Therapy
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TABLE 2-12: Management Strategies for Complications of
Warfarin Therapy
Clinical Scenario Strategy
Thromboembolic recurrence despite
adequate anticoagulation with warfarin
INR <1.5 •
Elevated INR <4.5 and no evidence of
bleeding
INR 4.5-10 and no evidence of
bleeding
>10 and no evidence of bleeding • Hold warfarin until INR < upper limit of
Serious or life threatening bleeding • Hold warfarin.
INR: international normalized ratio, LMWH: low molecular weight heparin
Treat with full intensity heparin/LMWH/fondaparinux
or switch to a direct-acting oral anticoagulant with or
without bridging depending on agent selected.
Increase maintenance dose if appropriate.
•
Avoid bridging for a single subtherapeutic INR.
Hold warfarin until INR < upper limit of therapeutic
range.
• Hold warfarin until INR < upper limit of
therapeutic range.
Consider low dose oral vitamin K.
•
therapeutic range.
•
Give low dose oral vitamin K.
Give 4-factor prothrombin complex concentrate
•
for rapid reversal. See Chapters 8 and 9.
Give vitamin K 5-10 mg IV by infusion. See
•
Chapters 8 and 9.
• Injectable vitamin K can be given orally when
doses less than 2.5 mg are desired. Many
hospital pharmacies use parenteral vitamin K for
oral administration due to the high cost of oral
vitamin K tablets.
HEMORRHAGIC RISK ASSESSMENT
Bleeding is the most significant adverse effect associated with warfarin
therapy. Several scoring systems have been developed to assess the risk
of major bleeding in patients taking warfarin. These scoring systems can
be helpful in determining risk versus benefit of oral anticoagulation and
in guiding the management of over-anticoagulation in individual patients
(Table 2-13).
12-17
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TABLE 2-13: Bleeding Risk Scoring Systems
Scoring System Criteria Point Scores Risk of Major Bleeding
Outpatient
bleeding risk
index (validated
in outpatients
taking warfarin)
HEMORR
(validated in
AF patients)
HAGES
2
AGE >65 1 point
History of GI bleed 1 point
History of stroke 1 point
One or more of diabetes,
Hct <30, Scr >1.5, or
recent MI
Hepatic or renal disease 1 point Score
Ethanol abuse 1 point
Malignancy 1 point
Older (age >75) 1 point
Reduced platelet count or
function
Rebleeding risk 2 points
Hypertension (uncontrolled) 1 point
Anemia 1 point
Genetic factors (CYP2C9
polymorphism)
Excessive fall risk 1 point
Stroke 1 point
1 point
1 point
1 point
Score
0
1–2
3–4
0
1
2
3
4
≥5
Major bleeding
0.8%/pt yr
2.6%/pt yr
9.7%/pt yr
Major bleeding
1.9%/pt yr
2.5%/pt yr
5.3%/pt yr
8.4%/pt yr
10.4%/pt yr
12.3%/pt yr
HAS-BLED
(validated in
AF patients)
Hypertension 1 point
Abnormal renal or hepatic
function
Stroke 1 point
Bleeding 1 point
Labile INRs 1 point
Elderly (age >65) 1 point
Concurrent antiplatelet/
NSAIDs or alcohol use
1−2 points
1−2 points
Score
0
1
2
3
4
≥5
Major bleeding
1.13%/pt yr
1.02%/pt yr
1.88%/pt yr
3.74%/pt yr
8.7%/pt yr
12.5%/pt yr
(continued)
32 Anticoagulation Therapy
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TABLE 2-13: (Continued)
Scoring System Criteria Point Scores Risk of Major Bleeding
ATRIA
(validated in
AF patients)
Findings from
REITE Registry
(validated in
patient with
acute venous
thromboembolism)
AF: atrial fibrillation, GI: gastrointestinal, Hct: hematocrit, INR: international normalized ratio,
MI: myocardial infarction, NSAIDs: nonsteroidal anti-inflammatory drugs, Pt yr: patient year, Scr:
serum creatinine
Anemia 3 points
Severe renal disease 3 points
Age >75 2 points
Prior bleeding 1 point
Hypertension 1 point
Recent major bleeding 2 points
Creatinine >1.2 mg/dL 1.5 points
Anemia 1.5 points
Cancer 1 point
Pulmonary embolism 1 point
Age >75 years 1 point
Score
Major bleeding
0–3
0.8%/pt yr (low risk)
4
2.6%/pt yr
(intermediate risk)
5–10
5.8%/pt yr (high
risk)
Score
Major bleeding
0
0.1%/pt yr (low risk)
1–4
2.8%/pt yr
(intermediate risk)
>4
6.2%/pt yr (high
risk)
• Patient education on bleeding: minor nose bleeds,
gum bleeding after brushing, and increased
bruising are common for warfarin patients.
However, they may also indicate an elevated
INR in a patient not used to these experiences
while therapeutic on warfarin. Patients require
education on how to manage these symptoms
and advice on specific symptoms requiring
medical attention. Patients prone to minor nose
bleeds should be informed of nasal moisturizers
that reduce this occurrence. Patients tend to
bruise easily on warfarin; however, bruises
should not continue to grow after several days.
• Red or brown urine as well as red or black
tarry stools are often symptoms of more serious
bleeding. These require medical attention and
INR check. Patients with hemorrhoids or frequent
constipation may have blood on toilet paper.
Stool softeners can be helpful in this situation.
These symptoms, however, should also be
WARFARIN 33
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evaluated by a physician in patients recently
starting warfarin or for those not having this
problem previously. Positive stool guaiacs and
red or black tarry stools can be symptoms of a
more serious condition such as malignancy or
the result of excessive anticoagulation. Warfarin
patients who develop occult gastrointestinal
(GI) bleeding have a 5–25% chance of finding
a malignant source with further evaluation.
Any bleeding regardless of source, which doesn’t
resolve quickly with minor attention, requires
medical attention and check of the INR.
REFERENCES AND KEY ARTICLES*
*1. Ageno W, Gallus AS, Wittkowsky AK, et al. Oral anticoagulant therapy: Antithrombotic
Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e89S-e119S.
Eckhoff CD, DiDomenico RJ, Shapiro NL. Initiation warfarin therapy: 5 mg versus 10
2.
mg. Ann Pharmacotherapy. 2004;38:2115-2121.
*3. Wittkowsky AK. Warfarin. In: Murphy JE, ed. Clinical Pharmacokinetics. 6th ed.
Bethesda, MD: ASHP; 2017.
4. Johnson JA, Cavallari LH. Warfarin pharmacogenetics. Trends Cardiovasc Med.
2015;15:33-41.
*5. Wittkowsky AK. Drug interactions with oral anticoagulants. In: Colman RW, Marder VJ,
Clowes AW, et al. Hemostasis and Thrombosis. Basic Principals and Clinical Practice.
5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
6.
Kovacs MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for
the initiation of oral anticoagulant therapy for outpatient treatment of venous
thromboembolism. Pathophysiol Haemost Thromb. 2002;32:131-133.
7. Fennerty A, Dolben J, Thomas J, et al. Flexible induction dose regimen for warfarin and
prediction of maintenance dose. Br J Med. 1984;288:1268-1270.
8. Roberts GW, Helboe T, Nielsen CBM, et al. Assessment of an age-adjusted warfarin
initiation protocol. Ann Pharmacotherapy. 2003;37:799-803.
9. Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better. Ann Intern Med.
1997;127:332-333.
10. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation
Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin
Pharmacol Ther. 2011;90:625-629.
*11. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of
antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis. 9th
ed. American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e152S-e184S.
34 Anticoagulation Therapy
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12. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting
risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105:91-99.
13. Aspinall SL, DeSanzo BE, Trilli LE, et al. Bleeding risk index in an anticoagulation
clinic: assessment by indication and implications for care. J Gen Intern Med.
2005;20:1008.
Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting
14.
hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart
J. 2006;151:713-719.
Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to
15.
assess 1 year risk of major bleeding in patients with atrial fibrillation. The Euro Heart
Survey. Chest. 2010;138:1093-1100.
16.
Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated
hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
J Am Coll Cardiol. 2011;58:395-401.
Ruiz-Gimenez N, Suarez C, Gonzalez R, et al. Predictive variables for major bleeding
17.
events in patients presenting with documented acute venous thromboembolism.
Findings from the REITE Registry. Thromb Haemost. 2008;100:26-31.
3
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Chapter
UNFRACTIONATED HEPARIN
William E. Dager
INTRODUCTION
Unfractionated heparin (UFH) is one of the most commonly used parenteral
anticoagulants. Heparin is used in a wide variety of settings to prevent or treat
thromboembolism. It can be used systemically, instilled in catheters, used to sustain
device functions, or coat artificial surfaces and lines to prevent thrombotic complications. As one of the oldest anticoagulant agents in use, many of its applications
developed over time and had limited assessment of efficacy from rigorous trials.
Despite availability of newer anticoagulants, UFH remains frequently used due to
its quick onset and offset and ease to reverse.
PHARMACOLOGY
•
UFH is a highly sulfated mucopolysaccharide, heterogeneous compound of which
one-third contains the pentasaccharide unit responsible for anticoagulant activity.
•
UFH is an indirect-acting anticoagulant that forms a complex with antithrombin, increasing the affinity and anticoagulant activity of antithrombin against clotting factors IIa
(18 saccharide sequence required) and Xa (5 saccharide sequence required). Factors
IXa, XIa, and XIIa are also inactivated.
•
At higher concentrations, heparin chains unrelated to the pentasaccharide sequence
can catalyze thrombin by inhibiting thrombin via heparin cofactor II, or separately by
factor Xa generation through antithrombin and heparin cofactor II.
•
UFH will not dissolve a formed clot but will prevent its propagation and growth.
•
No differences in antithrombotic activity have been demonstrated between the various
UFH preparations.
1,2
INDICATIONS
Approved indications for UFH are listed in Table 3-1.
PHARMACOKINETICS/PHARMACODYNAMICS
The pharmacokinetic properties of UFH are listed in Table 3-2.
•
The pharmacokinetics of UFH can be altered by factors such as age, thromboembolism
location, hepatic or renal impairment, and obesity.
35
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TABLE 3-1: Approved Indications for Unfractionated Heparin
• Anticoagulant in blood samples for laboratory purposes
•
Anticoagulant in blood transfusions, extracorporeal circulation, dialysis procedures
•
Atrial fibrillation with embolism
•
Diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated
intravascular coagulation [DIC])
Prevention of clotting in arterial and cardiac surgeries
•
•
Prophylaxis and treatment of peripheral arterial embolism
Prophylaxis and treatment of venous thromboembolism
•
• The activated partial thromboplastin time
(aPTT)/anti-factor Xa activity from UFH can
be checked to verify appropriateness of the
dose for a particular treatment dosing interval.
For subcutaneous administration with higher
treatment goals, a 12-hour (trough) value can
be assessed. If this value is too low, an 8-hour
dosing interval may be considered. Similarly, if
an 8-hour trough value is in the upper portion
of the target range or higher, a 12-hour dosing
interval can be considered for ease of use. A
repeat trough value can be considered to validate
the regimen. Risk assessment for thrombosis,
bleeding, and compliance should be considered
when determining a subcutaneous dosing
regimen.
Change in Calibrators for UFH and Potency
In 2009, the United States Pharmacopeia (USP) updated the monograph for
heparin to be consistent with the World Health Organization (WHO) standards.
This update resulted in up to a 10% reduction in heparin potency (potency
per USP unit of heparin was up to 10% less than International Units). This
conversion created a concern among clinicians for a potential underdosing
of heparin. Consensus to date suggests that impact of this change on clinical
outcomes is minimal.
•
Intramuscular administration is not
recommended due to erratic absorption and risk
of hematoma formation.
6
UNFRACTIONATED HEPARIN 37
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TABLE 3-2: Pharmacokinetic Properties of UFH
UFH Properties Comment
Source
Molecular weight (daltons)
Bioavailability
Activated clotting factors
inhibited
Binding to proteins other
than target
Extracted from porcine intestinal mucosa or beef lung (currently
not available in the United States).
Mean 15,000 (range 3,000–30,000)
Oral: UFH administered orally is not absorbed by the
gastrointestinal tract.
Intravenous: 100%—Rapid onset of anticoagulation action can
occur with an IV bolus followed by a continuous infusion; in
some situations (e.g., during cardiac procedures), IV bolus doses
may be repeated to maintain desired effects.
Subcutaneous: Highly variable (10–80%); generally,
approximately 20–30% but can be up to 80% with high doses.
•
Because of the nonspecific binding of UFH to various
cellular proteins and cells and unpredictable sub-Q
bioavailability, notable inter- and intra-patient variability in
anticoagulant dose-response can occur.
• Bioavailability when given sub-Q may decrease when
vasoconstrictors are in use or in the critically ill in general.
•
Effects from sub-Q injections typically have duration of
activity lasting 8–12 hr.
Factors IIa, IXa, Xa, XIa, XIIa
Nonspecific binding to proteins and other cells; presence of
heparin-binding proteins, including acute phase reactants, can
vary in concentration during acute illness and affect the aPTT.
3-5
Ratio anti-Xa activity:
anti-IIa activity
Onset of action Rapid if sufficient amounts administered; IV faster than sub-Q.
Primary route of elimination Enzymatic degradation at low doses and renal at higher dose;
Half-life (Sub-Q route) 30–150 min (dependent on dose and administration site, with
Volume of distribution 0.07 L/kg (range 0.04–0.14 L/kg); typically reflects blood
Effects of protamine Complete neutralization
aPTT: activated partial thromboplastin time, hr: hour, IV: intravenous, L: liters, kg: kilograms,
sub-Q: subcutaneous, UFH: unfractionated heparin
1:1
both zero-order and first-order processes can be present.
Clearance (Cl): 0.015–0.12 L/hr/kg
Higher clearance can occur in the setting of pulmonary
embolism.
slower clearance at higher doses); may be slightly prolonged in
liver disease and end stage renal disease.
volume; distribution into the tissues can occur with large doses
(during cardiac bypass surgery).
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INITIATING THERAPY
UFH is usually administered parenterally by intravenous (IV) or subcutaneous
injection. In some situations, heparin may be used by other purposes (such as
a bath) for instruments used in procedures, flushes in surgical processes, or
as a coating of dialyzers prior to use. It can also be imbedded into catheter
linings during their manufacture or locally infused to keep devices functional
(e.g., Impella catheters, see Chapter 17).
UFH for Flushing Catheters
•
Saline and heparin are frequently instilled into catheters to keep them from
clotting. Saline is the preferred agent in peripheral IV lines.
•
Depending on the manufacturer of the peripherally inserted central catheter
(PICC) line, heparin may or may not need to be instilled.
•
The concentration and volume of heparin instilled will vary between catheters
with suggestions potentially provided by the catheter’s manufacturer. The lowest
amount of heparin to maintain patency should be considered (see
for examples).
•
When using in the same line as an agent that is incompatible with heparin,
consider flushing first with saline prior to instilling the other agent.
•
In some cases, high amounts of heparin are used—where the possibility of a
sufficient amount reaching the circulation to cause systemic anticoagulant effects
should be considered.
Table 3-3
TABLE 3-3: Examples of Uses of Heparin Locks in Adults for
Selected Devices
Device Heparin Volume
Midline 10 units/mL 3 mL
PICC, non-tunneled and tunneled 10 units/mL 5 mL
Port 100 units/mL 3–5 mL
UNFRACTIONATED HEPARIN 39
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• Line flushing during percutaneous coronary
intervention (PCI): 200 units of IV heparin was
used to flush catheters in individuals receiving
fondaparinux undergoing PCI in the OASIS 5
trial to reduce thrombosis on the guidewire.
Recent observations suggest that narrow targetspecific agents (e.g., fondaparinux and direct
acting oral anticoagulants) may not adequately
protect artificial surfaces from thrombosis
formation.
•
The lack of more specific anticoagulants to
protect mechanical surfaces compared to heparin
may relate in theory to heparin’s effects of factors
XI and XII.
ADMINISTRATION: INTRAVENOUS OR
SUBCUTANEOUS
7
Bolus Dosing
•
A bolus is typically used when immediate anticoagulation is necessary. If immediate anticoagulation is not required (i.e., active thromboembolism is not present),
a bolus may not be necessary.
•
Dosing guidelines may consider specifying a maximum bolus and infusion rate
that triggers an additional assessment step for safety to prevent unintended
excessive doses of heparin (see Dose Capping section).
•
Continuous IV infusion is preferred over intermittent IV boluses. Intermittent
bolus injections result in high peak anticoagulant levels that may be associated
with a higher risk of major bleeding.
•
Dosing of UFH is generally based on patient’s weight (see Table 3-4).
Weight-based UFH dosing regimens are more likely to exceed
the therapeutic aPTT threshold in the first 24 hours after initiating
treatment compared to more traditional dosing regimens, such as
a 5,000-unit bolus dose followed by an infusion administered at
1,000 units/hr.
For continuous infusion, the dose and target aPTT/anti-Xa may
depend on the indicated use (
UFH products are available in a wide variety of concentrations.
Solutions for injection range from 1,000 units/mL to 20,000 units/
mL, while flushes may include 1 unit/mL to 100 units/mL. Institu
tional use of different concentrations should be avoided as much as
possible to minimize medication errors and ensure patient safety.
8
Table 3-5).
-
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