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60 Anticoagulation Therapy
https://t.me/med1917
• If the correct amount of heparin being
administered is unclear, consider replacing with
a new bag or syringe that has been verified for
accuracy and re-measure laboratory.
•
Bleeding: Consider turning off the infusion;
reverse with protamine or other blood products as
necessary
..31
• Reversal: See Chapter 9. Post administration
of protamine, a heparin rebound from tissue
redistribution back into the plasma can occur
after very high doses (cardiothoracic surgery),
warranting repeat protamine administration
and assessment of continued anticoagulation
effects by aPTT or anti-factor Xa activity
measurements.
32
Heparin-Induced Thrombocytopenia (See Chapter 18)
SPECIAL POPULATION CONSIDERATIONS
•
Low-weight/elderly: Low-weight or elderly patients can potentially be more
sensitive or responsive to UFH. Preset or fixed, non-weight-based dosing thus
has the potential for higher than expected levels of anticoagulation.
•
Obesity: See Table 3-8.
•
Pregnancy: See Chapter 19.
•
Pediatrics: See Chapter 20.
•
Heparin-induced thrombocytopenia: See Chapter 18.
•
Mechanical devices: See Chapter 17.
•
Combined with thrombolysis: See Chapter 6.
•
Reversal required: See Chapters 8 and 9.
UNFRACTIONATED HEPARIN 61
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TABLE 3-18: ACCP 2012 Recommendations for Platelet Count
Monitoring of UFH and LMWH
ACCP 2012 Guidelines for Platelet Count Monitoring
Heparin Risk Platelet Count
Yes >1% Every 2 or 3 days from
Yes <1% Not recommended 2C
Yes UFH past 100 days Baseline and within 24 hr
Yes Acute inflammatory reaction
Heparin Risk Platelet Count
Within 30 min
of UFH bolus
(30 min) after an IV bolus (fever,
chills and/or cardiorespiratory
symptoms such as hypertension,
tachycardia, dyspnea, chest pain,
cardiorespiratory arrest)
ACCP 2012 Guidelines for Platelet Count Monitoring
Anaphylactoid reaction Immediate and compare
33,a
Monitoring
day 4 to day 14 (or until
heparin is stopped,
whichever occurs first)
if feasible
Request immediate
platelet count to assess
for acute onset HIT
Monitoring
to prior count
Level
2C
Suggested,
not graded
Suggested,
not graded
Level
1C
Therapeutic
UFH
Prophylactic
UFH
Prophylaxis Medical/OB (HIT risk 0.1% to 1%) Every 2–3 days (day 4–14
a
Note: The 2015 ACCP guidelines did not address specifics on heparin dosing.
HIT: heparin-induced thrombocytopenia, hr: hour, LMWH: low molecular weight heparin, OB:
obstetric, UFH: unfractionated heparin
Postoperative
(HIT risk >1%)
Medical/OB or UFH catheter flush
(HIT risk 0.1% to 1%)
Every 2–3 days (day 4–14
or until stopping UFH)
Every other day (day 4–14
or until stopping heparin)
or until stopping heparin)
Not recommended 2C
2C
2C
2C
62 Anticoagulation Therapy
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REFERENCES AND KEY ARTICLES*
*1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrom-
botic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest
Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl
2):e24S-e43S.
2. Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin
Pharmacokinet. 1992;22:359-374.
3. Lexi-Comp Inc. Heparin. Accessed August 3, 2017.
Roberts J, Dager W. Heparin, low-molecular-weight heparin and fondaparinux. In:
4.
Murphy J, ed. Clinical Pharmacokinetics. 6th ed. Bethesda, MD: American Society of
Health-System Pharmacists; 2017.
5.
Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low
molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous
and subcutaneous administration. Thromb Res. 1985;39:631-636.
Smythe MA, Nutescu EA, Wittkowsky AK. Changes in the USP heparin monograph and
6.
implications for clinicians. Pharmacotherapy. 2010;30:428-431.
7. Yusuf S, Mehta SR, Chrolavicius S, et al.; Fifth Organization to Assess Strategies in
Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin
in acute coronary syndromes. N Engl J Med. 2006;354:1464-1476.
*8.
Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram
compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern
Med. 1993;119:874-881.
Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA. 1980;244:
9.
1209-1212.
10. Anand SS, Yusuf S, Pogue J, et al.; Organization to Assess Strategies for Ischemic
Syndromes Investigators. Relationship of activated partial thromboplastin time to
coronary events and bleeding in patients with acute coronary syndromes who receive
heparin. Circulation. 2003;107:2884-2888.
11. Laslett L, White R. Predictors of the effect of heparin during cardiac catheterization.
Cardiology. 1995;86:380-383.
12. Cipolle RJ, Rodvold KA. Heparin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied
Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 2nd ed. Spokane, WA:
Applied Therapeutics; 1986:908-943.
13. Morabia A. Heparin doses and major bleedings. Lancet. 1986;1:1278-1279.
14. O’Gara PT, Kushner FG, Ascheim DD, 2013 ACCF/AHA guideline for the management
of ST-elevation myocardial infarction: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2013;61(4):e78-140.
15. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the
management of patients with non-ST-elevation acute coronary syndromes: executive
summary: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;130:2354-2394.
*16. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for venous
thromboembolic disease: Antithrombotic Therapy and Prevention of Thrombosis. 9th
ed. American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e419S-e494S.
UNFRACTIONATED HEPARIN 63
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17. Tanaka KA, Thourani VH, Williams WH, et al. Heparin anticoagulation in patients
undergoing off-pump and on-pump coronary bypass surgery. J Anesth. 2007;21:297-
303.
Yee WP, Norton LL. Optimal weight base for a weight-based heparin dosing protocol.
18.
Am J Health-Syst Pharm. 1998;55:159-162.
19. Rosborough TK, Shepherd MF. Achieving target anti-factor Xa activity with a heparin
protocol based on sex, age, height, and weight. Pharmacotherapy. 2004;24:713-719.
20. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical Impact of Heparin Kinetics
During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression. J
Cardiovasc Electrophysiol. 2016 Jun;27(6):683-693.
Myzienski AE, Lutz MF, Smythe MA. Unfractionated heparin dosing for venous
21.
thromboembolism in morbidly obese patients: case report and review of the literature.
Pharmacotherapy. 2010;30:105e-112e.
22.
Riney JN, Hollands JM, Smith JR, et al. Identifying optimal initial infusion rates for
unfractionated heparin in morbidly obese patients. Ann Pharmacother. 2010;44:1141-
1151.
Fan J, John B, Tesdal E. Evaluation of heparin dosing based on adjusted body weight
23.
in obese patients. Am J Health-Syst Pharm. 2016;73:1512-1522.
*24. Olson JD, Arkin CF, Brandt JT, et al.; College of American Pathologists Conference
XXXI on Laboratory Monitoring of Anticoagulation Therapy. Laboratory monitoring of
unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122:782-788.
25.
Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower
limit of the APTT therapeutic range and recurrent venous thromboembolism during
heparin treatment for deep vein thrombosis. Arch Intern Med. 1997;157:2562-2568.
Anand SS, Bates S, Ginsberg JS, et al. Recurrent venous thrombosis and heparin
26.
therapy: an evaluation of the importance of early activated partial thromboplastin time
results. Arch Intern Med. 1999;159:2029-2032.
27.
Anand S, Ginsberg JS, Kearon C, et al. The relation between the activated partial
thromboplastin time response and recurrence in patients with venous thrombosis
treated with continuous intravenous heparin. Arch Intern Med. 1996;156:1677-1681.
28. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated
heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med.
2003;138:720-723.
29. Smith ML, Wheeler KE. Weight-based heparin protocol using anti-factor Xa
monitoring. Am J Health-Syst Pharm. 2010;67:371-374.
30. Decousus HA, Croze M, Levi FA, et al. Circadian changes in anticoagulant effect of
heparin infused at a constant rate. Br Med J. 1985;290:341-344.
31. Fischer KG. Essentials of anticoagulation in hemodialysis. Hemodial Int. 2007;11:178-
189.
32. Teoh KH, Young E, Blackall MH, et al. Can extra protamine eliminate heparin
rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg.
2004;128(2):211-219.
33. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced
thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e495S-e530S.
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4
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Chapter
LOW MOLECULAR WEIGHT
HEPARIN AND FONDAPARINUX
Zachary Stacy and Sara K. Richter
INTRODUCTION
The low molecular weight heparins (LMWHs) and the synthetic pentasaccharide,
fondaparinux, offer several advantages over unfractionated heparin (UFH). Enoxaparin and dalteparin were approved in the United States in 1993 and 1994, respectively, followed by fondaparinux in 2001. Tinzaparin was approved and available in
2000, but was subsequently withdrawn from the market in 2011. These injectables
have been traditionally used as prophylaxis for venous thromboembolism or as a
bridge therapy to therapeutic oral anticoagulation. Based on their relative ease
of dosing and monitoring, these agents frequently replace UFH in many clinical
situations. This chapter will focus on those agents currently available in the United
States, including enoxaparin, dalteparin, and fondaparinux.
PHARMACOLOGY AND PHARMACOKINETICS
Traditionally, unfractionated heparin was the parenteral anticoagulant used in the
inpatient setting. Active unfractionated heparin compounds are composed of an
inconsistent number of sugars, each ending in a specific pentasaccharide sequence.
Using a consistent and shorter sequence of sugars improved the variability in the
anticoagulant effect, giving rise to fractioned LMWH products.
Mechanism of Action
•
LMWHs and fondaparinux are indirect inhibitors of clotting factors requiring antithrombin to exert an anticoagulant effect (
•
A specific pentasaccharide sequence binds to antithrombin to potentiate its activity.
•
LMWHs inhibit both Factor Xa and IIa (thrombin) activity.
•
Fondaparinux selectively inhibits only Factor Xa.
•
Refer to Tables 4-1 and 4-2 for comparison of the specific clotting factors inhibited.
1-9
Figure 4-1).
65
66 Anticoagulation Therapy
Xa
LMWH
Xa
Fondaparinux
Thrombin
AT
AT
AT
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AT
UFH
AT AT AT
AT
AT
AT
Xa
Thrombin
Thrombin
FIGURE 4-1. Mechanism of Action for LMWH and
Fondaparinux in Comparison to UFH
AT: antithrombin, LMWH: low molecular weight heparin, UFH: unfractionated heparin
Source: Adapted from Weitz J. Low molecular weight heparins. N Engl J Med.
1997;337:688–698. Copyright ©1997 Massachusetts Medical Society. Used with
permission from Massachusetts Medical Society.
TABLE 4-1: Commercially Available Agents in the United States
Drug Therapeutic
Class
Generic Version
Available
Product Source Clotting Factors
Inhibited
Dalteparin
(Fragmin)
Enoxaparin
(Lovenox)
Fondaparinux
(Arixtra)
LMWH: low molecular weight heparin, UFH: unfractionated heparin
LMWH No Chemical or
Xa>IIa
enzymatic
depolymerization
of UFH
LMWH Yes Chemical or
Xa>IIa
enzymatic
depolymerization
of UFH
Pentasaccharide Yes Chemical synthesis Xa
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 67
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TABLE 4-2: Pharmacologic and Pharmacokinetic Properties of
LMWH and Fondaparinux
Property Dalteparin Enoxaparin Fondaparinux
Molecular weight (daltons) 5,000 4,500 1,728
Anti-Xa: anti-IIa 2.7:1 3.8:1 100% anti-Xa
Subcutaneous bioavailability ~87% ~100% ~100%
Volume of distribution 40–60 mL/kg 4.3 L 7–11 L
Protein binding (outside target) Limited Limited Limited
Time to peak concentration
(subcutaneous route)
Primary route of elimination Renal Renal Renal
Half-life (subcutaneous route) 3–5 hr 4.5–7 hr 17–21 hr
Effects of protamine Partial neutralization Partial neutralization No effect
~ 4 hr 3–5 hr ~ 2–3 hr
• Because fondaparinux is a synthetic product, it
may be an option in individuals with allergies to
animal products or in those who have religious
preferences to avoid select animal-derived
products.
INDICATIONS, DOSING, AND
ADMINISTRATION
Route of Administration
•
Due to their quick onset of action, LMWHs and fondaparinux can be initiated
and administered via the subcutaneous (sub-Q) route for most indications.
•
Intravenous bolus doses have been used in the setting of acute arterial thrombosis and in hemodialysis to protect against thrombosis of the dialysis circuit.
•
Refer to Table 4-3 for FDA-approved dosing and route of administration recom-
mendations.
Dosing
•
When dosing LMWHs and fondaparinux, remember the following:
Actual body weight should be used for dose determination (see
Restricting doses to a maximum limit or dose capping is not recom-
1-10
Special Populations for Guidance in Obese and Underweight
Patients section).
mended when treating acute venous thromboembolism because it
may lead to underdosing in obese patients.
68 Anticoagulation Therapy
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TABLE 4-3: FDA-Approved Indications and Recommended
Doses for LMWHs and Fondaparinux
FDA-Approved
Indications
Enoxaparin
a
CrCl >30 mL/min CrCl <30 mL/min
Dalteparin
b
Fondaparinux
c
VTE prophylaxis
after hip
replacement
surgery
VTE prophylaxis
after hip fracture
surgery
VTE prophylaxis
after knee
replacement
surgery
VTE prophylaxis
after abdominal
surgery
30 mg sub-Q q
12 hr initiated
12–24 hr after
surgery
or
40 mg sub-Q q
24 hr initiated
10–12 hr prior to
surgery
30 mg sub-Q q
12 hr initiated
12–24 hr after
d
surgery
30 mg sub-Q q
12 hr initiated
12–24 hr after
surgery
40 mg sub-Q q
24 hr initiated
1–2 hr prior to
surgery
30 mg sub-Q q
24 hr
30 mg sub-Q q
d
24 hr
30 mg sub-Q q
24 hr
30 mg sub-Q q
24 hr
2,500 units
sub-Q given 4–8
hr after surgery,
then 5,000 units
sub-Q q 24 hr
or
5,000 units
sub-Q q 24 hr
initiated the
evening prior
(10–14 hr prior)
to surgery
2,500 units
sub-Q given 4–8
hr after surgery,
then 5,000 units
sub-Q q 24 hr
d
2,500 units
sub-Q given 4–8
hr after surgery,
then 5,000 units
sub-Q q 24 hr
d
2,500 units
sub-Q 1–2 hr
prior to surgery
then 2,500
units 12 hr after
surgery followed
by 5,000 units
sub-Q q 24 hr
2.5 mg sub-Q q
24 hr initiated
6–8 hr after
surgery
2.5 mg sub-Q q
24 hr initiated
6–8 hr after
surgery
2.5 mg sub-Q q
24 hr initiated
6–8 hr after
surgery
2.5 mg sub-Q q
24 hr initiated
6–8 hr after
surgery
VTE prophylaxis
in acute medical
illness
Treatment of
VTE (DVT +/PE)
40 mg sub-Q q
24 hr
1 mg/kg sub-Q q
12 hr
or
1.5 mg/kg sub-Q
e
q 24 hr
30 mg sub-Q q
24 hr
1 mg/kg sub-Q q
24 hr
5,000 units
sub-Q q 24 hr
100 units/kg
sub-Q q 12 hr
d
or
200 units/kg
sub-Q q 24 hr
for 1st month,
then 150 units/
kg sub-Q q 24
hr for months
f
2 to 6
2.5 mg sub-Q
d
q 24 hr
5 mg sub-Q q
24 hr if weight
<50 kg
7.5 mg sub-Q q
24 hr if weight
50–100 kg
10 mg sub-Q q
24 hr if weight
>100 kg
(continued)
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 69
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TABLE 4-3: (Continued)
FDA-Approved
Indications
Unstable angina
or non-Q-wave
MI
CrCl >30 mL/min CrCl <30 mL/min
1 mg/kg sub-Q
g
q 12 hr
Enoxaparin
1 mg/kg sub-Q
q 24 hr
a
Dalteparin
120 units/kg
sub-Q q 12 hr
(maximum dose
10,000 units)
b
Fondaparinux
2.5 mg sub-Q
d
q 24 hr
Note: UFH
was added
c
to prevent
thrombus
formation on
the guidewire
(see Table 3-4)
Acute STEMI If <75 years of
age:
30 mg single IV
bolus plus a
1 mg/kg sub-Q
dose followed by
1 mg/kg sub-Q
q 12 hr (first two
sub-Q doses
capped at
100 mg)
If ≥75 years of
age:
0.75 mg/kg
sub-Q q 12 hr
If <75 years of
age:
30 mg single IV
bolus plus a
1 mg/kg sub-Q
dose followed by
1 mg/kg sub-Q
q 24 hr (first two
sub-Q doses
capped at
100 mg)
If ≥75 years of
age:
1 mg/kg sub-Q
q 24 hr (no bolus)
Not
recommended
for this
indication.
Not
recommended
for this
indication.
(no bolus, first
two sub-Q doses
capped at 75 mg)
hr: hour, IV: intravenous, MI: myocardial infarction, PE: pulomonary embolism, Q: every, STEMI:
ST-segment elevation myocardial infarction, sub-Q: subcutaneous, UFH: unfractionated heparin,
VTE: venous thromboembolism
a
Enoxaparin dose conversion is 10 mg = 1,000 units (e.g., 30 mg = 3,000 units).
b
Dalteparin should be used with caution in patients with a CrCl <30 mL/min.
c
Fondaparinux is contraindicated in patients with a CrCl <30 mL/min and should be used with
caution when CrCl 30–50 mL/min.
d
Non-FDA approved for indication.
e
The 1.5 mg/kg dose should be avoided in obesity, pediatrics, pregnancy, and renal impairment.
f
Dosing regimen approved for VTE treatment in patients with malignancy.
g
An additional 30 mg IV bolus with the first sub-Q dose has been studied in clinical trials.
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