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398 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 399

type of heparin, the dose and route of administration, and the indication CHOICE OF HEPARIN OR LOW-
for heparin anticoagulation (e.g., more common in “surgical patients”
than in “medical patients”). The “4T’ score is a clinical prediction tool MOLECULAR-WEIGHT HEPARIN
with good negative predictive value. Platelet counts should be moni-
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tored during treatment and heparin discontinued if thrombocytopenia The factors governing the choice of heparin or LMWH concern effec-
occurs, and an alternative anticoagulant that does not interact with the tiveness, safety, convenience, and cost. For treatment of venous throm-
heparin-platelet factor 4 complexes should be administered. Vitamin K boembolic disease, the safety and efficacy of heparin and LMWH are
antagonists should be given only after the platelet count has risen to comparable. A meta-analysis of 14 studies comparing unfractionated
greater than 150,000/μL. Long-term heparin therapy can also cause heparin to LMWH in 4754 patients showed that LMWH-treated
osteoporosis, and radiographic evidence of bone loss occurs in approx- patients had less recurrent venous thromboembolic complications (4.3
imately 15 percent of women who receive prolonged treatment during percent vs. 5.6 percent, odds ratio [OR] 0.76, 95 percent confidence
pregnancy, with symptomatic vertebrae fractures in approximately 2 interval 0.57 to 1.01) and fewer major bleeding events (1.3 percent vs. 2.1
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percent. The bone loss may resolve after heparin is discontinued. percent, OR 0.6, 95 percent confidence interval 0.39 to 0.93). LMWH
also offers better convenience because subcutaneous administration
permits outpatient treatment. However, LMWHs may be difficult to use
LOW-MOLECULAR-WEIGHT HEPARIN in patients with renal insufficiency because of decreased clearance, and
Limitations of unfractionated heparin led to studies correlating struc- intravenous heparin may offer advantages in such patients. LMWHs are
incompletely reversed by protamine sulfate, making them more difficult
tural and functional relationships of heparin, and this eventually to use for cardiac bypass surgery. Unfractionated heparin may be pref-
resulted in the development of LMWHs, several of which are available. erable in patients who require an invasive procedure on an urgent basis
LMWH preparations are produced by treating heparin chemically or because of its shorter half-life. LMWHs may offer some advantages for
enzymatically to decrease the size of the polysaccharide chains, yielding patients with acute coronary syndromes.
products with restricted molecular weight distributions with a mean
of approximately 4000 to 5000 daltons. Like heparin, LMWHs exert DANAPAROID
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antithrombotic effects through interaction with AT. In the presence of
LMWH, AT inactivates factor Xa in the same way as unfractionated Danaparoid is a mixture of glycosaminoglycans and is composed of
heparin, but it is less able to inactivate thrombin because the shorter approximately 84 percent heparan sulfate, 12 percent dermatan sulfate,
polysaccharide length does not allow formation of the necessary ternary and 4 percent chondroitin sulfate. It is an AT-dependent anticoagulant
complex. Consequently, LMWHs have a greater proportion of anti– with predominant anti–factor Xa activity. The plasma half-life is approx-
factor Xa than AT activity. imately 24 hours with predominant renal clearance. Danaparoid is not
LMWHs also have different pharmacokinetic properties than reversed by protamine sulfate. Danaparoid differs structurally from
unfractionated heparin. Following subcutaneous administration, heparin and it has been used successfully to treat patients with HIT.
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LMWHs are nearly completely absorbed, a clear benefit over unfrac- Although there is in vitro cross-reactivity of 10 to 20 percent of hepa-
tionated heparin, which exhibits variable and dose-dependent absorp- rin antibodies with danaparoid, this is of uncertain clinical relevance.
tion. LMWHs also exhibit less binding to plasma proteins and cells Danaparoid is administered subcutaneously, and levels may be mon-
than unfractionated heparin, resulting in more predictable blood levels itored with anti–factor Xa assays performed using a danaparoid stan-
and anticoagulant effects. LMWHs have a longer plasma half-life than dard curve. At the time of writing danaparoid has not been approved in
unfractionated heparins, allowing once- or twice-daily subcutaneous the United States, and availability elsewhere was limited.
administration.
LMWHs have significant renal clearance, and high levels can FONDAPARINUX
accumulate in patients with renal insufficiency. Care must be taken in Fondaparinux is a unique heparin-like anticoagulant with highly selec-
dosing LMWHs in patients with reduced renal function as bleeding tive AT-dependent anti–factor Xa activity. It is a completely synthetic
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risks are increased, and monitoring with anti–factor Xa levels may be pentasaccharide whose structure is based on the heparin sequence
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needed. Similarly, monitoring may be necessary to achieve appropriate that interacts with AT. It binds reversibly and with high affinity to AT,
levels in very obese patients, although weight-based dosing probably resulting in a conformational change that renders it effective in inhib-
achieves better anticoagulation. Protamine sulfate does not completely iting factor Xa, but because of its small size, does not inhibit thrombin.
reverse the anticoagulant effect of LMWH but is partially effective and Whereas unfractionated heparin and all LMWHs are derived from ani-
can be useful in patients with serious hemorrhage. Several LMWH mal sources, fondaparinux is synthesized in a structurally homogenous
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preparations are available and approved for both prophylaxis and treat- form containing no animal products. Consequently, fondaparinux does
ment of venous and arterial thrombotic diseases. Each preparation dif- not induce allergic responses. Because it inhibits factor Xa but has no
fers slightly and is pharmacologically unique, although the agents are direct action on thrombin, its mechanism of action depends on reduc-
likely similarly effective for the treatment and prevention of venous ing thrombin generation.
thrombosis. Pharmacologic studies show that maximum plasma levels are
Similar to unfractionated heparin, the most common adverse reached approximately 2 hours after subcutaneous administration with
effect is bleeding, which occurs at approximately the same frequency an elimination half-life of approximately 17 hours independent of the
and severity when used in similar patient groups for the same indica- dose. Bioavailability is nearly complete after subcutaneous or intrave-
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tion. HIT is much less common than with unfractionated heparin, nous administration. There is a low intra- and intersubject variability
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occurring only in 0.3 to 0.45 percent of patients. However, cross-reac- with little accumulation after multiple daily doses. Because elimination
tivity of the antibody occurs, and LMWH is not an acceptable choice for is primarily renal and the agent is excreted unchanged in the urine,
continued anticoagulation in patients with HIT induced by treatment fondaparinux is contraindicated in patients with severe renal impair-
with unfractionated heparin. Animal studies suggest that osteoporosis ment. Fondaparinux plasma levels can be measured with the anti–factor
may be less common with LMWH, and this is reported by several small Xa assay, but there is no effect on other coagulation assays including the
clinical trials. 63 activated clotting time (ACT), aPTT, or thrombin clotting time.

Kaushansky_chapter 25_p0393-0408.indd 398 9/19/15 12:19 AM