The n e w e ng l a n d j o u r na l of m e dic i n e
the CYP2C9 and VKORC1 genotypes accounted for vocates both for the introduction of genotyping
6.5% of the variability in the warfarin dose.2
Thus, additional studies will be required to define
the independent contributions of the genotype and
phenotype for guiding warfarin dosing.
Mannucci and colleagues suggest that geno-
typing patients who are treated with warfarin is
not clinically justified until randomized trials
have shown that it decreases the outcome of bleed-
ing or thrombosis. Evidence this strong would be
ideal; however, many recommendations regard-
ing the modification of the dose of a drug for an
individual patient are based on pharmacokinetic
or pharmacodynamic observations. For example,
few (if any) randomized trials with clinical end
points have provided data on the adjustment of
drug doses in renal or hepatic dysfunction, de-
spite the widespread and appropriate use of this
information in patient care. Thus, there are ad-
Acute Pulmonary Embolism
To the Editor: We were surprised that the ne-
phrotic syndrome was omitted from the list of
underlying prothrombotic conditions in the re-
view of acute pulmonary embolism by Tapson
(March 6 issue).1 The nephrotic syndrome is rela-
tively common in comparison with some of the
prothrombotic conditions listed by the author.2
Thrombotic events, including pulmonary embo-
lism, may be the first presentation of the nephrotic
syndrome. In our experience, diagnosis of the ne-
phrotic syndrome is often delayed despite the pres-
ence of peripheral edema and abundant protein-
uria and hypoalbuminemia at the time of hospital
admission. This delay may result in further throm-
botic events or a deterioration in kidney function,
both of which could have been avoided.3 Timely
diagnosis of the nephrotic syndrome can help in
the identification of underlying glomerular dis-
ease and, where appropriate, the initiation of im-
munotherapy to induce remission of the nephrotic
syndrome and the accompanying prothrombotic
state.
Emily P. Fraser, M.B., Ch.B.
Colin C. Geddes, M.B., Ch.B.
Western Infirmary
Glasgow G11 6NT, United Kingdom
emilypf@hotmail.com
2744 n engl j med 358;25  www.nejm.org  june 19, 2008
The New England Journal of Medicine
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
into warfarin-dosing algorithms and for ran-
domized clinical trials to compare genotyping
with the standard of care, and both approaches
are being studied.
C. Michael Stein, M.B., Ch.B.
Dan M. Roden, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232-6602
michael.stein@vanderbilt.edu
Ute I. Schwarz, M.D.
University of Western Ontario
London, ON N6A 5A5, Canada
1. Millican EA, Lenzini PA, Milligan PE, et al. Genetic-based
dosing in orthopedic patients beginning warfarin therapy. Blood
2007;110:1511-5.
2. Michaud V, Vanier MC, Brouillette D et al. Combination of
phenotype assessments and CYP2C9-VKORC1 polymorphisms
in the determination of warfarin dose requirements in heavily
medicated patients. Clin Pharmacol Ther 2008;83:740-8.
1. Tapson VF. Acute pulmonary embolism. N Engl J Med 2008;
358:1037-52.
2. Ritz E. The nephrotic syndrome. N Engl J Med 1998;338:
1202-11.
3. Nandish SS, Khardori R, Elamin EM. Transient ischemic at-
tack and nephrotic syndrome: case report and review of litera-
ture. Am J Med Sci 2006;332:32-5.
To the Editor: Tapson does not mention concern
about deep venous thromboembolism during preg-
nancy and does not discuss certain specifics con-
cerning this disorder in women who become preg-
nant with the use of assisted reproductive
techniques. Although Tapson cites causes of false
positive d-dimer tests, the presence of d-dimer
during pregnancy indicates coagulation activa-
tion that is actually present throughout normal
pregnancy.1 Therefore, during pregnancy and in
the postpartum period, d-dimer testing may be
unhelpful and should not be used as a prelimi-
nary laboratory measure for the presence of deep
venous thromboembolism.
Women who become pregnant with the use
of assisted reproductive techniques have an in-
creased thrombophilic risk, especially if the
ovarian hyperstimulation syndrome occurs. Deep
venous thromboembolism involving upper-arm
veins is a well-recognized complication.2 In such
 correspondence
women, monitoring the level of activity against
activated factor X is warranted during the second
and third trimesters.
Finally, Tapson cautions against the use of war-
farin for long-term anticoagulation during preg-
nancy, since it is a teratogen. Spanish doctors al-
most never use warfarin. There is occasional use
of acenocumarol, except during weeks 6 to 12 of
gestation, when it should not be used.3,4
Jaume Alijotas-Reig, M.D., Ph.D.
Vall d’Hebron University Hospital
08035 Barcelona, Spain
jalijotas@vhebron.net
1. Hoke M, Kyrle PA, Philipp K, et al. Prospective evaluation of
coagulation activation in pregnant women receiving low-molec-
ular weight heparin. Thromb Haemost 2004;91:935-40.
2. Chan WS, Ginsberg JS. A review of upper extremity deep vein
thrombosis in pregnancy: unmasking the ‘ART’ behind the clot.
J Thromb Haemost 2006;4:1673-7.
3. Santamaria A, Fontcuberta J. Anticoagulación y embarazo.
Med Clin (Barc) 2008;130:57-9.
4. Jilma B, Kamath S, Lip GYH. Antithrombotic therapy in spe-
cial circumstances. I. Pregnancy and cancer. BMJ 2003;326:37-
40.
To the Editor: Would Tapson comment on the
use of low-dose warfarin during and after elective
joint replacement, a common preventive practice
used by orthopedists? I have yet to find any evi-
dence-based guidelines to support this prophylac-
tic regimen. My concern is that the perioperative
use of warfarin in the absence of heparin or enoxa-
parin for use in the prevention of deep venous
thrombosis and pulmonary embolism may result
in a hypercoagulable state through the initial re-
duction of proteins C and S and result in a higher
incidence of venous thromboembolism.
Thomas F. Castiglione, M.D.
South Shore Medical Center
Kingston, MA 02364
thomas_castiglione@ssmedcenter.com
To the Editor: Tapson does not mention the
role of subcutaneous heparin in the treatment of
pulmonary embolism. Heparin that is given sub-
cutaneously in a fixed dose adjusted according to
weight appears to be as effective and safe as low-
molecular-weight heparin for the treatment of ve-
nous thromboembolism, and monitoring of the
activated partial thromboplastin time may not be
an important therapeutic goal.1
The author encourages prophylaxis for venous
thromboembolism, but data supporting this prac-
n engl j med 358;25  www.nejm.org  june 19, 2008
The New England Journal of Medicine
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
tice for pulmonary embolism in medical patients
are controversial at best. Although a recent meta-
analysis of studies of prophylaxis for venous
thromboembolism showed decreases in both the
frequency of pulmonary embolism and associated
mortality, 400 patients would need to be treated
to prevent one death.2 Which medical patient
should receive prophylaxis for venous thrombo-
embolism: an asymptomatic and ambulatory
young man who is hospitalized to undergo che-
motherapy for testicular cancer or a malnourished
and bedridden patient with metastatic pancreatic
cancer? The challenge is to identify patients who
are at high risk rather than provide general rec-
ommendations.
Harris V. Naina, M.B., B.S.
Fernando J. Quevedo, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
naina.harris@mayo.edu
1. Kearon C, Ginsberg JS, Julian JA, et al. Comparison of fixed-
dose weight-adjusted unfractionated heparin and low-molecu-
lar-weight heparin for acute treatment of venous thromboembo-
lism. JAMA 2006;296:935-42.
2. Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA.
Meta-analysis: anticoagulant prophylaxis to prevent sympto-
matic venous thromboembolism in hospitalized medical pa-
tients. Ann Intern Med 2007;146:278-88.
The author replies: As Fraser and Geddes sug-
gest, the nephrotic syndrome is prothrombotic.
It increases the risk of venous thromboembolism
through loss of anticoagulant proteins, increased
synthesis of thrombogenic factors, or local acti-
vation of the hemostasis system within the glo-
merulus. Although the nephrotic syndrome is an
uncommon cause of thrombosis,1 the frequency
of the association is sufficient for venous throm-
boembolism to be considered in patients with
this condition, and vice versa.
Alijotas-Reig emphasizes several issues involv-
ing pregnancy. During pregnancy and the post-
partum period, there is ongoing coagulation acti-
vation, so a positive d-dimer test result may be
expected. As is the case in trauma, surgery, and
cancer, this result often does not represent patho-
logic thromboembolism (i.e., it is a false positive
result). It has been estimated that venous throm-
bosis in the upper arm occurs in about 1 in 1000
women who have become pregnant with the use
of assisted reproductive techniques, and this event
is not always preceded by the ovarian hyperstimu-
2745
 The n e w e ng l a n d j o u r na l of m e dic i n e

lation syndrome.2 Although its occurrence is un-
common, recognition of the association is impor-
tant. I agree that warfarin should be avoided
during pregnancy. Low-molecular-weight heparin
preparations do not cross the placenta, but levels
of antifactor Xa should be monitored when such
agents are used during pregnancy. Recommen-
dations that focus on anticoagulation in pregnancy
are offered by the American College of Chest Physi-
cians.3
Castiglione notes the potential for detrimental
prothrombotic effects with the use of low-dose
warfarin in elective joint replacement. Hyperco-
agulability may result because the anticoagulant
protein C has a half-life similar to that of factor
VII (6 to 8 hours). Without the use of concomi-
tant heparin or low-molecular-weight heparin,
warfarin may decrease protein C levels before
factors II and X reach desired levels, resulting in
a transient prothrombotic state.4 This is of most
concern in patients with established thrombosis
and those at high risk. Evidence-based recommen-
dations strongly support the use of low-molecular-
weight heparin in joint replacement (grade 1A).5
The use of warfarin to achieve a target interna-
tional normalized ratio of 2.0 to 3.0 is also rec-
ommended (grade 1A), rather than the use of
“low-dose warfarin.” Adherence to current rec-
ommendations would appear to be prudent.
Newer oral anticoagulants that include antithrom-
bin and anti–factor Xa inhibitors may soon replace
this drug.
Naina and Quevedo remind us that subcuta-
neous standard heparin can be used to treat acute
venous thromboembolism. They cite a randomized
trial with compelling data, although that trial took
a number of years to recruit patients. Substantially
more data (and specific advantages) support the
use of low-molecular-weight heparin, as compared
with standard heparin by the subcutaneous route.
The criteria for prophylaxis in the medically ill are
clearly outlined in reports of clinical trials.5 One
must consider risk factors and then individualize
treatment for affected patients, realizing that ve-
nous thromboembolism may have devastating
consequences and that prophylaxis is generally
safe.5
Victor F. Tapson, M.D.
Duke University Medical Center
Durham, NC 27710
tapso001@mc.duke.edu
1. Samama MM. An epidemiologic study of risk factors for
deep vein thrombosis in medical outpatients: the Sirius study.
Arch Intern Med 2000;160:3415-20.
2. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrom-
botic agents during pregnancy: the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest 2004;126:3
Suppl:627S-644S.
3. Viganò S, Mannucci PM, Solinas S, Bottasso B, Mariani G.
Decrease in protein C antigen and formation of an abnormal
protein soon after starting oral anticoagulant therapy. Br J Hae-
matol 1984;57:213-20.
4. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous
thromboembolism: the Seventh ACCP Conference on Anti-
thrombotic and Thrombolytic Therapy. Chest 2004;126:3 Suppl:
338S-400S.
5. Francis CW. Prophylaxis for thromboembolism in hospital-
ized medical patients. N Engl J Med 2007;356:1438-44. [Erratum,
N Engl J Med 2007;357:203.]

Imatinib as a Possible Cause of Severe Rhabdomyolysis

To the Editor: Imatinib mesylate (Gleevec
[Glivec], Novartis), a protein kinase inhibitor of
c-kit receptor tyrosine kinase (KIT) and platelet-
derived growth factor receptor α (PGFR-α), is
widely used for the treatment of chronic myeloid
leukemia and gastrointestinal stromal tumors.
Its common side effects (diarrhea, edema, asthenia,
myalgia, and skin reactions) are most often mild
and manageable.1
We describe the case of a 25-year-old woman
who received imatinib mesylate (at a daily dose
of 400 mg) in a clinical trial for the treatment of
aggressive fibromatosis (desmoid tumors) not
amenable to surgery.2 Shortly after the initiation
of treatment with imatinib, she had myalgia of
growing intensity and was subsequently admit-
ted with an extensive mucocutaneous rash, pru-
ritus, hypereosinophilia, and an elevated level of
serum creatine kinase (1068 IU per liter; upper
limit of the normal range, 110).
Myocardial infarction, stroke, and other med-
ications were ruled out as causes of the elevated
creatine kinase level. Common causes of rhabdo-
myolysis were also ruled out. A myopathic pattern
was seen on electromyography. Although the pa-
tient declined to undergo muscle biopsy, there was

2746 n engl j med 358;25  www.nejm.org  june 19, 2008

The New England Journal of Medicine

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