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REVIEW ARTICLE

LOW-MOLECULAR-WEIGHT HEPARIN IN THE TREATMENT OF ACUTE


DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM*

Geno J. Merli, MD

ABSTRACT
There are more than 170 000 hospital admissions each year for deep vein thrombosis (DVT) in
the United States. Moreover, there are approximately 90 000 readmissions for recurrent venous
thromboembolic events, with an average length
of hospital stay between 5 days and 7 days. This
article reviews the clinical evidence related to
inpatient and outpatient treatment options and
their efficacies in achieving therapeutic goals for
the clinical management of DVT. It also reports
the medical evidence relating to eligibility criteria
and dosing, as well as the American College of
Chest Physicians recommendations regarding
duration of therapy.
(Advanced Studies in Medicine. 2002;2(12):445-451)

eep vein thrombosis (DVT) is a pervasive health problem, affecting 2 million


people in the United States annually.1
As many as 60 000 deaths are caused by
pulmonary embolism (PE) every year.
As many as 600 000 pulmonary emboli will occur
with approximately 60 000 deaths from these throm-

*Based on a presentation given by Dr Merli at the


American College of Physicians Annual Session.
The Ludwig A. Kind Professor of Medicine, Director of
the Division of Internal Medicine, Thomas Jefferson
University, Philadelphia, Pennsylvania.
Address correspondence to: Geno J. Merli, MD,
Director, Division of Internal Medicine, Jefferson Medical
College, Thomas Jefferson University, Walnut Towers, 1025
Walnut St, 8th Floor, Room 822, Philadelphia, PA 19107.

Advanced Studies in Medicine

botic events. Secondary complications such as postphlebitic syndrome and pulmonary hypertension contribute significantly to long-term morbidity and
mortality in this patient population. While the death
toll is tragic, the financial burden is significant; the
cost of care for patients with DVT is an estimated $1.5
billion annually.2
Clinical evidence documents the prevalence of undetected PE in patients with acute DVT. In a study of 622
patients with acute DVT but without PE, Meignan et al3
reported that radionuclide lung scanning revealed abnormalities in 82% of the patients; PE was thought to be
present in 40% to 50% of the patients. These findings
have strong implications for the clinical management of
DVT, with the goals of preventing thrombus extension,
thrombus embolization, early and late thrombus recurrence, and possibly postthrombotic syndrome (although
clinical evidence in this last area is inconclusive).
Prompt administration of anticoagulant therapy
is essential to preventing clot propogation and pulmonary emboli. Clinical evidence suggests that if
patients achieve a therapeutic activated partial
thromboplastin time quickly with heparin, the less
recurrent disease occurs subsequently.4 An examination of the current armamentarium for treating DVT
may offer insights as to which treatment modalities
are most efficacious.
Figure 1 illustrates the efficacy of various approaches to DVT clinical management in accomplishing
treatment goals, according to the current medical literature. In the United States, many physicians are
placing inferior vena cava filters in patients who have
extensive thrombosis in the deep femoral system up to
the iliacs, in addition to administering anticoagulation
therapies. However, using inferior vena cava filters in
such circumstances in advance has not been supported

445

REVIEW ARTICLE

by the medical literature. In terms of anticoagulation


therapies, both heparin and low-molecular-weight
heparin (LMWH) have proven effective in preventing embolization and extension as well as reducing
recurrence. Hypothetically, LMWH and heparin
may also prevent postthrombotic syndrome.
LMWH may restore patency, but at this time insufficient clinical evidence exists to confirm these suppositions. Thrombolysis has proven effective in
achieving 4 of the 5 treatment goals, but the extent
to which it prevents embolization is questionable at
this point. Following is a review of the clinical evidence related to the treatment options and their efficacies in achieving therapeutic goals for the clinical
management of DVT. Excluded from the following
trials were patients with hereditary or acquired coagulation disorders, creatinine clearance less than 30
cc/min, pregnancy, or cancer and unspecified concomitant chemotherapy.

ing was similar in the 3 groups. A report from


Lindmarker7 showed dalteparin sodium administered
at 200 units/kg once per day to a maximum of 18 000
units resulted in fewer instances of recurrent thromboembolic disease (12%), as compared to heparin
(17%). All 3 investigators report no differences
between LMWH and heparin in major bleeding
episodes.
Additional evidence suggesting that LMWH
therapy results in fewer recurrences of DVT and PE
has been reported by Hull in the New England
Journal of Medicine.8 This double-blind clinical trial
compared fixed-dose subcutaneous LMWH (tinzaparin), once daily with adjusted-dose intravenous
heparin, given by continuous infusion for the initial
treatment of patients with proximal-vein thrombosis. Six of 213 patients who received tinzaparin 175
units/kg (2.8%) and 15 of 219 patients who received
intravenous heparin (6.9%) experienced new
episodes of VTE (P = .07). Major bleeding associated with initial therapy occurred in 1 patient receiving tinzaparin (0.5%) and in 11 patients receiving
intravenous heparin (5.0%), showing a reduction in
risk of 91% (P = .006). However, this apparent protection against major bleeding was lost during longterm therapy. Another clinical trial comparing
reviparin with UFH9 showed no statistically signifi-

ENOXAPARIN VERSUS UNFRACTIONATED HEPARIN


A report by Simonneau5 et al shows that thromboembolic disease recurred in 1.5% (N=67) of
patients in an enoxaparin treatment arm, as compared to 10.4% (N=67) of subjects in the heparin
group. In a study, de Valk et al6 compared the efficacy and safety of 2 subcutaneous doses of danaparoid, a long-acting agent, with that of
continuous intravenous administration of
unfractionated heparin (UFH) in the treatment
of 209 patients believed to have venous thromboembolism (VTE). Patients were randomly
assigned to either low-dose danaparoid (intravenous loading dose of 1250 U followed by
1250 U administered subcutaneously twice
daily [N=65]); high-dose danaparoid (intravenous loading dose of 2000 U followed by
2000 U administered subcutaneously twice
daily [N= 63]); or UFH (intravenous loading
dose of 2500 U followed by dose-adjusted continuous infusion [N=60]). Treatment lasted at
least 5 days. A significant reduction in recurrence or extension of VTE was seen in patients
receiving high-dose danaparoid (8 of 63
[13%]), as compared with patients receiving
intravenous UFH (17 of 60 [28%]; relative risk
was 0.45 [0.21 to 0.96 (95% confidence interval [CI]). Occurrence of major and minor bleed-

446

Figure 1.Therapeutic Goals and Treatment Options for DVT

Goals of
therapy
Prevent
embolization
Prevent extension
Reduce
recurrence

Supportive
care

IVC
filter

Heparin

LMWH

Thrombolysis

Restore patency
Prevent
postthrombotic
syndrome

DVT = deep vein thrombosis; IVC = inferior vena cava; LMWH = low-molecularweight heparin.

Vol. 2, No. 12

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REVIEW ARTICLE

cant difference between the 2 drugs in the measure


of return episodes of VTE. (Table 1)
A landmark study by Levine et al in 1996 evaluated the safety and efficacy of enoxaparin administered
to outpatients.10 Patients with acute proximal DVT
were randomly assigned to receive either intravenous
standard heparin in the hospital (253 patients) or
LMWH (247 patients received 1 mg of enoxaparin
per kilogram of body weight subcutaneously twice
daily) administered primarily at home. The study
design allowed outpatients taking LMWH to go
home immediately and hospitalized patients taking
LMWH to be discharged early. All the patients
received warfarin starting on the second day. Of the
247 patients receiving LMWH, 13 (5.3%) had
recurrent thromboembolism, as compared with 17
(6.7%, 95% CI) of the 253 patients receiving standard heparin. Five patients (2%) receiving LMWH
had major bleeding, as compared with 3 patients
(1.2%) receiving standard heparin. In a separate
study reported simultaneously, Koopman et al11
also demonstrated the safety and efficacy of outpatient administration of LMWH. Patients were randomly assigned to 1 of 2 study arms: adjusted-dose
intravenous standard heparin administered in the
hospital (198 patients), or fixed-dose subcutaneous
LMWH administered at home (202 patients).
Seventeen (8.6%) of the 198 patients who received
standard heparin and 14 (6.9%) of the 202
patients who received LMWH experienced recurrent thromboembolism (95% CI). Major bleeding
occurred in 4 patients (2.0%) assigned to standard
heparin and in 1 patient (0.5%, 95% CI) assigned
to low-molecular-weight heparin, as shown in
Table 2. However, despite such convincing clinical
evidence, many physicians in the United States are
not using LMWH to treat patients with thromboembolic disease.
Table 3 shows findings from 3 separate metaanalyses of safety and efficacy of LMWH, as compared with UFH.12-14 Outcomes for recurrent VTE,
major bleeds, and mortality were consistently better
for LMWH, as compared to UFH. Once-a-day
administration was compared to twice-a-day dosing
of LMWH and UFH in a randomized controlled
trial of patients with proximal and distal clots.15
Investigators found that once-a-day dosing with
enoxaparin 1.5 mg/kg was equally as safe and efficacious as 1 mg/kg q 12h and constant infusion IV of

Advanced Studies in Medicine

heparin; in both regimens, safety and efficacy were


comparable to that of standard heparin therapy.
While most of the medical evidence regarding
the safety and efficacy of LMWH focuses on the
treatment of DVT, only limited data are available on
the use of LMWH to treat acute symptomatic PE.

Table 1. Clinical Outcomes Trials: LMWH Treatment


of DVT/PE

Study

Group

Hull8

Tinzaparin
(213)
UFH
(219)

Columbus21

Reviparin
(510)
UFH
(511)

RTE

DVT

PE

Maj Bld

6 (3%)

3 (1%)

3 (1%)

1 (0.5%)

15 (7%)

6 (3%)

9 (4%)

11 (5%)

27 (5%)

17 (3%)

10 (2%)

16 (3%)

25 (5%)

13 (3%)

12 (2%)

12 (2%)

LMWH = low-molecular-weight heparin; DVT = deep vein thrombosis; PE = pulmonary embolism; RTE = recurrent thromboembolism; Maj Bld = major bleeding; UFH = unfractionated heparin.

Table 2. Efficacy: Suitable Proximal DVT10

Levine et al10
Enoxaparin
UFH
(n = 247) (n = 253)

Koopman et al11
Nadroparin
UFH
(n = 202) (n = 198)

RTE

5.3

6.7

6.9

8.6

Major bleeding

2.0

1.2

0.5

2.0

Death

4.4

6.7

6.9

8.1

Hospital (days)

1.1*

6.5

2.7

8.1

*120 (48%) were exclusively treated in the outpatient setting.


DVT = deep vein thrombosis; UFH = unfractionated heparin; RTE = recurrent
thromboembolism.
Table adapted with permission from reference 10.

447

REVIEW ARTICLE

This subgroup of patients was selected for


analysis in a random controlled trial of 612
patients with symptomatic PE who did not
require thrombolytic therapy or embolectomy.9 Patients were randomly assigned to
either SC LMWH (tinzaparin) once daily, or
IV UFH. In the first 8 days of treatment,
2.9% of 308 patients assigned to receive
UFH reached at least 1 of the endpoints, as
compared with 3.0% of 304 patients
assigned to LMWH (95% CI). By day 90 of
the study, 7.1% of patients assigned to UFH
and 5.9% of patients assigned to LMWH
had reached at least 1 of the following endpoints: death, recurrent thromboembolism,
or major bleed (P = .54). However, the risk
of major bleeding was similar in the 2 treatment groups throughout the study. These
findings suggest that initial treatment of PE
with LMWH is at least as safe and effective
as is treatment with UFH.
Looking at randomized trials of dalteparin, another formulation of LMWH
currently in use, studies by Lindmarker et
al,7 Fiessinger et al,16 and Luomanmaki et al17
found no significant differences between
dalteparin and UFH for the variables of
morbidity, PE/DVT, major bleeding, or
thrombocytopenia.
In conclusion, a composite of all relevant
study findings suggests that LMWH outcomes for recurrent thromboembolic disease
and major bleeding are superior to those for
UFH (Figure 2). Yet within the United States
healthcare system, UFH is used more widely
than is LMWH, largely due to lack of protocol development for outpatient care with
LMWH.

Table 3. Meta Analyses of LMWH vs IV UFH DVT Treatment

Leizorovicz et al12
10 d23 mo follow-up
VTE
recurrence

Major
bleed

Mortality

n = 2045
2.82% vs 4.63%
RR 0.66 (0.411.07)
P = .09
n = 2045
2.43% vs 4.04%
RR 0.65 (0.361.16)
P = .15
n = 2045
3.30% vs 4.83%
RR 0.72 (0.461.40)
P = .16

Lensing et al13
36 mo follow-up
n = 1086
3.1% vs 6.6%
RR 0.47 (0.270.82)
P < .01
n = 1512
0.8% vs 2.8%
RR 0.32 (0.150.69)
P< .005
n = 1086
3.9% vs 7.1%
RR 0.53 (0.310.90)
P< .04

Siragusa et al14
90 d follow-up
n = 1228
2.5% vs 4.5%
RR 0.5 (0.30.9)
P < .02
n = 1694
2.2% vs 4.7%
RR 0.44 (0.200.70)
P = .04
n = 1733
3.3% vs 5.9%
RR 0.51 (0.20.9)
P = .01

LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; DVT = deep


vein thrombosis; VTE = venous thromboembolism; RR = relative risk.

Figure 2. Clinical Efficacy: LMWH vs UFH Venous


Thromboembolism22

CRITERIA FOR SELECTING PATIENTS FOR


OUTPATIENT ANTICOAGULATION THERAPY
Figure 3 offers a graphic illustration of
combined clinical evidence regarding the
incidence of major bleeding and recurrent
thromboembolism in patients who are given
UFH and in patients who receive LMWH.
Based upon these study findings and their
exclusion criteria, the following should be

448

LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.


Reprinted with permission from reference 22.

Vol. 2, No. 12

August 2002

REVIEW ARTICLE

considered as absolute contraindications for


outpatient treatment with LMWH:

Figure 3. LMWH vs IV UFH

Active bleeding
Cardiopulmonary instability
Hereditary bleeding disorders
History of heparin induced
thrombocytopenia
Allergy to heparin.
Social and medical relative contraindications for outpatient treatment with LMWH
include the following:
Geographic inaccessibility
Potential for medication noncompliance
Inability to support cost of drug
Pregnancy
Hereditary or acquired thrombotic disorders
Peptic ulcer disease, gastrointestinal, or genitourinary bleeding within 6 weeks
Uncompensated comorbidities
Concomitant medical problems (eg, CrCl < 30
cc/min)
Pulmonary embolism (hemodynamically stable).
This was placed under the relative risk category
because many US physicians are not clinically
comfortable with treating patients with uncomplicated PE on an outpatient basis.
Koopman et al11 reported that 69% of the patients
were eligible for outpatient treatment of DVT; Levine et
al10 and Yusen et al18 respectively reported that only 33%
and 18% of the subjects met the criteria to be treated at
home. Within our facility at Thomas Jefferson University,
we find that approximately 45% of patients meet eligibility criteria for outpatient anticoagulation therapy.

LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

Table 4. Once- vs Twice-Daily Dosing

DOSING REGIMENS
Whether to administer once- or twice-a-day dosing
of therapy remains controversial. Table 4 summarizes
the incidence of major bleeding and recurrent DVT
under various dosing regimens, but it is important to
stress that these studies did not exclude patients on the
basis of weight. However, in studies where dosing was
fixed and not adjusted on actual body weight, outcomes for primary endpoints were less favorable (Table
5). In our study of once- versus twice-daily dosing

Advanced Studies in Medicine

WT

Major
Bleed

Simonneau5
(enoxaparin)

No limit

1/67
(1%) q12h

Hull8
(tinzaparin)

No limit

0.5%

6/213
(3%) qd

Levine10
(enoxaparin)

No limit

2%

13/247
(5.3%) q12h

Author

RVTE

RVTE = recurrent venous thromboembolism.

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with enoxaparin15 in which no weight limits were


placed upon subjects, we found no significant difference in the outcomes of recurrent VTED or major
bleeding within the qd and q12h study arms.
However, in a subgroup analysis there was a higher
incidence of recurrent VTED in obese patients and in
patients with cancer who received qd dosing than for
those patients who received q12h dosing, but the variance was not statistically significant. Nonetheless, it

Table 5. Once- vs Twice-Daily Dosing

Author

WT

Major
Bleed

RVTE

Koopman11

Fixed dose
(nadroparin)

0.5%

14/202
(6.9%) q12h

Lindmarker7

Fixed dose
(dalteparin)

0%

11/91
(12%) qd

de Valk6

Fixed dose
(danaparoid)

1%

8/63
(13%) q12h

Fixed dose
(reviparin)

1.9%

27/510
(5.3%) q12h

Columbus21

does raise some questions surrounding dosing, which


again surface in reports from Partsch et al.19 This study
of the safety and efficacy of dalteparin showed 5.3%
(N=67) of subjects within the qd (200 units/kg) study
arm experienced major bleeds and 5.3% experienced
recurrent PE. In the 12 h D (100 units/kg) study arm,
1.5% (N=64) experienced major bleeds and 1.6%
experienced recurrent PE.
Protocol for outpatient anticoagulation therapy at
Thomas Jefferson University is based on recommendations from the American College of Chest Physicians
(ACCP) consensus conference.20 The ACCP recommendations, as detailed in Table 6, call for administration of warfarin initiated on day 1 or day 2 with
continuation of LMWH for at least 5 days, until an
international normalized ratio (INR) value of 2 to 3 is
achieved for 2 consecutive days.
In summary, UFH has long been the mainstay of
therapy for DVT and PE. However, over the last 10
years, LMWHs have been replacing this therapy for
treating thrombotic events. LMWHs are better
absorbed, have a longer half-life, and do not require
monitoring.19 A number of studies have demonstrated
the safety and efficacy of LMWHs in treating patients
with thromboembolic events. LMWHs have changed
the paradigm of care for thromboembolic disease: outpatient treatment or shorter hospital stay for inpatients.

RVTE = recurrent venous thromboembolism.

REFERENCES
Table 6. ACCP Duration of Therapy26

 3 to 6 months
First event with reversible or time-limited risk factor

 > 6 months
Idiopathic VTE, first event

 12 months to lifetime
First event with
Cancer until resolved
Anticardiolipin antibody
Antithrombin deficiency
Recurrent event, idiopathic or with thrombophilia
Data adapted with permission from reference 26.

450

1. Hirsh J, Hoak J. Management of deep vein thrombosis and


pulmonary embolism: a statement for healthcare professionals from the council on thrombosis (in constitution with the
council on cardiovascular radiology), American Heart
Association. Circulation 1996;93:2212-2245.
2. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary
embolism: clinical outcomes in the International Cooperative
Pulmonary Embolism Registry (ICOPER). Lancet.
1999;353:1386-1419.
3. Meignan M, Rosso J, Gauthier H, et al. Systematic lung
scans reveal a high frequency of silent pulmonary embolism
in patients with proximal deep venous thrombosis. Arch
Intern Med. 2000;160:159-164.
4. Hull RD, Raskob GE, Brant R, 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.

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REVIEW ARTICLE

5. Simonneau G, Charbonnier B, Decousus H, et al.


Subcutaneous low-molecular-weight heparin compared with
continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med.
1993;153:1541-1546.
6. deValk HW, Banga JD, Wester JW, et al. Comparing subcutaneous danaparoid with intravenous unfractionated
heparin for the treatment of venous thromboembolism. A
randomized controlled trial. Ann Intern Med.
1995;123(1):1-9.
7. Lindmarker P, Holmstrom M, Granqvist S, et al. Comparison
of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein
thrombosis. Thromb Haemost. 1994;72:186-190.
8. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous lowmolecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.
N Engl J Med. 1992;326(15):975-982.
9. Simonneau G, Sors H, Charbonnier B, et al, for the THESEE Study Group. A comparison of low-molecular-weight
heparin with unfractionated heparin for acute pulmonary
embolism. N Engl J Med. 1997;337(10):663-669.
10. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with
unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334(11):
677-681.
11. Koopman MMW, Prandoni P, Piovella F, et al, for The
Tasman Study Group. Treatment of venous thrombosis with
intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight
heparin administered at home. N Engl J Med. 1996;
334(11):682-687.
12. Leizorovicz A, Simonneau G, Decousus H, et al.
Comparison of efficacy and safety of low molecular weight
heparins and unfractionated heparin in initial treatment of
deep venous thrombosis: a meta-analysis. BMJ.
1994;309(6950):299-304.
13. Lensing AW, Prins MH, Davidson BL, et al. Treatment of
deep venous thrombosis with low-molecular-weight
heparins. A meta-analysis. Arch Intern Med.
1995;155:601- 607.
14. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight
heparins and unfractionated heparin in the treatment of
patients with acute venous thromboembolism: results of a
meta-analysis. Am J Med. 1996;100:269-277.
15. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous

Advanced Studies in Medicine

unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134:191- 202.
16. Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. Oncedaily subcutaneous dalteparin, a low molecular weight
heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost. 1996;76:195-199.
17. Luomanmaki K, Grankvist S, Hallert C, et al. A multicentre
comparison of once-daily subcutaneous dalteparin (low-molecular-weight heparin) and continuous intravenous heparin
in the treatment of deep vein thromobosis. J Intern Med.
1996;240(2):85-92.
18. Yusen RD, Haraden BM, Gage BF, et al. Criteria for outpatient management of proximal lower extremity deep venous
thrombosis. Chest. 1999;115(4):972-979.
19. Partsch H, Kechavarz B, Mostbeck A, et al. Frequency of
pulmonary embolism in patients who have iliofemoral deep
vein thrombosis and are treated with once- or twice-daily
low-molecular-weight heparin. J Vasc Surg. 1996;
24(5):774-782.
20. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy
for venous thromboembolic disease. Chest. 2001;119
(suppl 1):176S-193S.
21. The Columbus Investigators. Low-molecular-weight heparin
in the treatment of patients with venous thromboembolism.
N Engl J Med. 1997;337:657-662
22. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparig low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism:
examining some unanswered questions regarding location
of treatment, product type, and dosing frequency. Arch
Intern Med. 2000;160(2):181-188.
23. Duroux P. A Collaborative European Multicentre Study: a
randomized trial of subcutaneous low-molecular-weight
heparin (CY216) compared with intravenous unfractionated
heparin in the treatment of deep vein thrombosis. Thromb
Haemost. 1991;65:251-256.
24. Prandoni P, Lensing AW, Buller HR, et al. Comparison of
subcutaneous low-molecular-weight heparin with intravenous
standard heparin in proximal deep vein thrombosis. Lancet.
1992;339:441-445.
25. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous
low-molecular-weight heparin in the treatment of deep vein
thrombosis: a Polish multicenter trial. Thromb Haemost.
1992;68:14-18.
26. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy
for venous thromboembolic disease. Chest. 2001;
119(suppl 1);176S-193S.

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