Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3687_Библиотеки_им_академика_М_И_Перельмана
.pdf
382 Chapter 43/Conventional Treatment of Deep Venous Thrombosis
https://t.me/med1917
Unfractionated heparin from either porcine or bovine
sources has been used clinically for several decades, yet,
although studied extensively, much remains uncertain about
heparin’s mode of action, particularly those related to its
nonanticoagulant properties.
The anticoagulant activity of UFH depends upon a unique
pentasaccharide, which binds to antithrombin and potentiates the inhibition of thrombin and activated factor X (Xa)
by antithrombin.
cules contain the unique pentasaccharide sequence.
12–14
About one-third of all heparin mole-
12–14
It is
the pentasaccharide sequence that confers the molecular
high affi nity for antithrombin.
12–14
In addition, heparin catalyzes the inactivation of thrombin by another plasma
co-factor, (co-factor II), which acts independently of
antithrombin.
12
Heparin has a number of other effects.13 These include
the release of tissue factor pathway inhibitor, binding to
numerous plasma and platelet proteins, endothelial cells,
and leukocytes, suppression of platelet function and an
increase in vascular permeability. The anticoagulant response
to a standard dose of heparin varies widely between patients.
This makes it necessary to monitor the anticoagulant
response of heparin, using either the activated partial thromboplastin time (APTT) or heparin levels and to titrate the
dose to the individual patient.
12
One accepted approach to anticoagulant therapy for VTE
is a combination of continuous intravenous heparin and oral
warfarin. The length of the initial intravenous heparin
therapy has been reduced to fi ve days, thus shortening the
hospital stay and leading to signifi cant cost saving.
15,16
The
simultaneous use of initial heparin and warfarin has become
clinical practice for all patients with venous thromboembolism who are medically stable.12 Exceptions include patients
who require immediate medical or surgical intervention,
such as in thrombolysis or insertion of a vena cava fi lter, or
patients at very high risk of bleeding. Heparin is continued
until the INR has been within the therapeutic range (2 to 3)
for two consecutive days.
12
It has been established from experimental studies and
clinical trials that the effi cacy of heparin therapy depends
upon achieving a critical therapeutic level of heparin within
the fi rst 24 hours of treatment.
17–19
Data from double blind
clinical trials indicate that failure to achieve the therapeutic
APTT threshold by 24 hours was associated with a 23.3%
subsequent recurrent venous thromboembolism rate, compared with a rate of 4 to 6% for the patient groups who were
therapeutic at 24 hours.
18,19
The recurrences occurred throughout the three-month follow-up period and could not be attributed to inadequate oral anticoagulant therapy.18 The critical
therapeutic level of heparin, as measured by the APTT, is
1.5 times the mean of the control value or the upper limit of
17–19
the normal APTT range.
This corresponds to a heparin
blood level of 0.2 to 0.4 U/ml by the protamine sulphate
titration assay, and 0.35 to 0.70 by the anti-factor Xa assay.
However, there is wide variability in the APTT and
heparin blood levels with different reagents and even with
12,20
different batches of the same reagent.
It is, therefore,
vital for each laboratory to establish the minimal therapeutic
level of heparin, as measured by the APTT, that will provide
a heparin blood level of at least 0.35 U/ml by the anti-factor
Xa assay for each batch of thromboplastin reagent being
used, particularly if a new batch of reagent is provided by a
different manufacturer.
12
Although there is a strong correlation between subtherapeutic APTT values and recurrent thromboembolism, the
relationship between supratherapeutic APTT (APTT ratio
2.5 or more) and bleeding is less defi nite.18 Indeed, bleeding
during heparin therapy is more closely related to underlying
clinical risk factors than to APTT elevation above the therapeutic range.18 Weight and age >65 are independent risk
factors for bleeding on heparin.
Numerous audits of heparin therapy indicate that administration of intravenous heparin is fraught with diffi culty,
and that the clinical practice of using an ad hoc approach to
heparin dose-titration frequently results in inadequate
therapy. The use of a prescriptive approach or protocol for
administering intravenous heparin therapy has been evaluated in two prospective studies in patients with venous
thromboembolism.
17,19
In one clinical trial for the treatment of DVT, patients
were given either intravenous heparin alone followed by
warfarin, or intravenous heparin and simultaneous warfarin.18 The heparin nomogram is summarized in Tables 43.1
and 43.2. Only 1 and 2% of the patients were undertreated
for more than 24 hours in the heparin group and in the
heparin and warfarin group, respectively. Objectively documented recurrent venous thromboembolism occurred infrequently in both groups (7%), at rates similar to those
previously reported. These fi ndings demonstrated that subtherapy was avoided in most patients and that the heparin
protocol resulted in effective delivery of heparin therapy in
both groups.
In another clinical trial, a weight-based heparin dosage
nomogram was compared with a standard-care nomogram
19
(see Table 43.3). Patients on the weight-adjusted heparin
nomogram received a starting dose of 80 U/kg as a bolus and
18 U/kg/h as an infusion. The heparin dose was adjusted to
maintain an APTT of 1.5 to 2.3 times control. In the weightadjusted group, 89% of patients achieved the therapeutic
range within 24 hours compared with 75% in the standardcare group. Recurrent VTE was more frequent in the standard-care group; supporting the previous observation that
subtherapeutic heparin during the initial 24 hours is associated with a higher incidence of recurrences. This study
included patients with unstable angina and arterial thromboembolism in addition to VTE, which suggests that the principles applied to a heparin nomogram for the treatment of
VTE, may be generalizable to other clinical conditions.
Complications of Heparin Therapy 383
https://t.me/med1917
TABLE 43.1 Heparin Protocol
1. Administer initial intravenous heparin bolus: 5000 U.
2. Administer continuous intravenous heparin infusion: commence at
42 mL/h of 20,000 U (1680 U/h) in 500 mL of two-thirds dextrose
and one-third saline (a 24-hour heparin dose of 40,320 U), except in
the following patients, in whom heparin infusion is commenced at a
rate of 31 mL/h (1240 U/h, a 24-hour dose of 29,760 U):
1. Patients who have undergone surgery within the previous 2
weeks.
2. Patients with a previous history of peptic ulcer disease or
gastrointestional or genitourinary bleeding.
3. Patients with recent stroke (i.e., thrombotic stroke within 2
weeks previously).
4. Patients with a platelet count <150 * 10º/L.
5. Patients with miscellaneous reasons for a high risk of bleeding
(e.g., hepatic failure, renal failure, or vitamin K defi ciency).
3. Adjust heparin dose by use of the aPTT. The aPTT test is
performed in all patients as follows:
1. 4–6 hours after commencing heparin; the heparin dose is then
adjusted.
2. 4–6 hours after the fi rst dosage adjustment.
3. Then, as indicated by the nomogram for the fi rst 24 hours of
therapy.
4. Thereafter, is once daily, unless the patient is subtherapeutic,* in
which case the aPPT test is repeated 4–6 hours after the heparin
dose is increased.
aPTT = activated partial thromboplastin time.
*Subtherapeutic = aPTT <1.5 times the mean normal control value for
the thromboplastin reagent being used.
Adapted from Reference 17.
TABLE 43.2 Intravenous Heparin Dose Titration Nomogram
According to the APTT
APTT Rate change Dose change
(sec) (ml/h) (IU/24h)a Additional action
≤45 +6 +5760 Repeated APTTb in 4–6 h
46–54 +3 +2880 Repeated APTT in 4–6 h
55–85 0 0 None
86–110 −3 −2880 Stop heparin sodium
treatment for 1 h;
repeated APTT
4–6 h after restarting
heparin treatment
>110 −6 −5760 Stop heparin treatment
for 1 h; repeated
APTT 4–6 h after
restarting heparin
treatment
a
Heparin sodium concentration 20,000 IU in 500 ml–40 IU/ml.
b
With the use of Actin-FS thromboplastin reagent (Dade, Mississauga,
Ontario, Canada).
c
During the fi rst 24 h, repeated APTT in 4–6 h. Thereafter, the APTT
will be determined once daily, unless subtherapeutic.
APTT = activated partial thromboplastin time.
Adapted from Reference 17.
c
TABLE 43.3 Weight-based Nomogram for Initial
Intravenous Heparin Therapy (fi gures in parentheses show
comparison with control)
Dose (IU/kg)
Initial dose 80 bolus, then 18/h
APTT < 35 sec (<1.2×) 80 bolus, then 4/h
APTT 35–45 sec (1.2–1.5×) 40 bolus, then 2/h
APTT 46–70 sec (1.5–2.3×) No change
APTT 71–90 sec (2.3–3.0×) Decrease infusion rate by 2/h
APTT > 90 sec (>3.0×) Hold infusion 1 h, then decrease
infusion rate by 3/h
APTT = activated partial thromboplastin time
Adapted from Reference 19.
Continued use of the weight-based nomogram has been
similarly effective.
20
Adjusted dose subcutaneous UFH has been used in the
initial treatment of VTE. One concern with giving UFH
subcutaneously every 12 hours is that there is diffi cultly in
achieving therapeutic APTT levels.21 Indeed, that was true
in a previous clinical trial comparing subcutaneous UFH
with intravenous UFH where therapeutic heparin levels and
APTT values were achieved at 24 hours in 37% of patients
receiving subcutaneous UFH, compared with 71% of those
who received intravenous UFH.21 These fi ndings are of
concern in view of the fact that recurrent VTE occurs more
frequently in patients who failed to achieve therapeutic
heparin levels in terms of APTT values within the fi rst 24
to 48 hours of therapy as compared with those who achieve
therapeutic levels.
18,19
Four randomized clinical trials compared the effi cacy of
subcutaneous UFH with subcutaneous LMWH in patients
with proven VTE.
22–25
Nomograms have been developed for
subcutaneous UFH.26 The largest of these trials compared
subcutaneous UFH dose adjusted with the use of APTT by
means of a weight adjusted algorithm with fi xed dose lowmolecular-weight heparin for the initial treatment of patients
with VTE, 16% of whom presented with PE.
25
Subcutaneous
UFH was shown to be similar to fi xed dose LMWH in terms
of effi cacy and safety.25 It is worth noting, however, that the
rate of recurrence VTE was three times lower in patients
who did achieve a therapeutic APTT threshold within the
fi rst 24 hours of therapy, than in those who did not, similar
to results from previous studies.
25
COMPLICATIONS OF
HEPARIN THERAPY
The main adverse effects of heparin therapy include
bleeding, thrombocytopenia, and osteoporosis. Patients at
particular risk of bleeding are those who have had recent
384 Chapter 43/Conventional Treatment of Deep Venous Thrombosis
https://t.me/med1917
surgery or trauma, or who have other clinical factors which
predispose to bleeding on heparin, such as peptic ulcer,
occult malignancy, liver disease, hemostatic defects, age
>65 years, and female gender.
The management of bleeding on heparin will depend on
the location and severity of bleeding, the risk of recurrent
VTE and the APTT; heparin should be discontinued temporarily or permanently. Patients with recent VTE may be
candidates for insertion of an inferior vena cava fi lter. If
urgent reversal of heparin effect is required, protamine sulphate can be administered.
12
Heparin-induced thrombocytopenia is a well-recognized
complication of heparin therapy, usually occurring within
fi ve to 10 days after heparin treatment has started.
27,28
Approximately 1 to 2% of patients receiving unfractionated
heparin will experience a fall in platelet count to less than
the normal range or a 50% fall in the platelet count within
the normal range. In the majority of cases, this mild to
moderate thrombocytopenia appears to be a direct effect
of heparin on platelets and is of no consequence. However,
approximately 0.1 to 0.2% of patients receiving heparin
develop an immune thrombocytopenia mediated by IgG
antibody directed against a complex of PF4 and heparin.29
In some cases neutrophil acting peptide 2 (NAP-2) and interleukin 8 (IL8) also play a role in pathogenesis.
The incidence of heparin-induced thrombocytopenia
(HIT) is lower with the use of LMWH;
28,30
however, the
clinical manifestations may be as or more severe than those
seen with UFH.31 Furthermore, the nadir of the platelet
count, onset, and duration of thrombocytopenia have been
shown to be somewhat different.32 Recently, delayed onset
of HIT has been described with the onset being as long as
several weeks after the end of exposure to heparin, thus,
making this syndrome sometimes more diffi cult to diagnose.33 Furthermore, the incidence and severity of HIT varies
among different patient populations being more prevalent in
patients having cardiac or orthopedic procedures than for
medical patients.34 The development of thrombocytopenia
may be accompanied by arterial or DVT, which may lead to
serious consequences such as death or limb amputation.
27,34
When a clinical diagnosis of HIT is made heparin in all
forms must be stopped immediately. In most centers the
confi rmatory laboratory test is an ELISA assay for the PF4heparin complex, but, where possible, this should be confi rmed with a functional assay, such as the serotonin release
assay.34 In those patients requiring ongoing anticoagulation,
an alternative form of anticoagulation must be undertaken
immediately because of the high incidence of thrombosis
when heparin is stopped.35 Some authorities recommend the
use of alternative anticoagulants in all patients once a diagnosis is made. The most common alternative agents are the
34,35,36
specifi c antithrombin argatroban
inhibitor lepirudin.
35,38,39
Both agents are given by intrave-
or the direct thrombin
nous infusion. Lepirudin has the advantage that it can be
given to patients with renal insuffi ciency,
34,35
but it has the
disadvantage that with prolonged use antibodies develop
and some of these can have serious deleterious effects,
including anaphylaxis.
40,41,42
Argatroban is primarily excreted
by the kidney so that it cannot be used in people with severe
renal failure but it can be used in patients with signifi cant
hepatic insuffi ciency.
34,35,36
Both agents can be used in conjunction with vitamin K antagonists but it should be noted
that argatroban by itself increases the INR beyond that
observed with warfarin alone and this must be taken into
account in controlling the vitamin K antagonist.37 The alternative antithrombotic agents should be continued until the
platelet count is at least back to 100 × 109/L and/or the INR
is therapeutic for two consecutive days.34 Danaparoid has
been used in the past but is no longer available for many
countries. The pentasaccharide fondaparinux has been used
as an alternative antithrombotic agent in HIT patients and it
has the advantage that it is given by a once daily subcutaneous injection.
43,44
Insertion of an inferior vena cava fi lter is
seldom indicated.
Osteoporosis has been reported in patients receiving
unfractionated heparin in dosages of 20,000 U/day (or more)
for more than six months.12 Demineralization can progress
to the fracture of vertebral bodies or long bones, and the
defect may not be entirely reversible.12 Laboratory and clinical studies indicate that the incidence of osteoporosis with
use of long-term LMWH is low.
12
LOW-MOLECULAR-WEIGHT HEPARIN
(LMWH) FOR THE INITIAL
TREATMENT OF VTE
Heparin currently in use clinically is polydispersed
unmodifi ed heparin, with a mean molecular weight ranging
from 10 to 16 kDa. Low molecular weight derivatives of
commercial heparin have been prepared that have a mean
molecular weight of 4–5 kDa.
The LMWHs commercially available are made by different processes (such as nitrous acid, alkaline, or enzymatic
depolymerization) and they differ chemically and pharmacokinetically.
45,46
The clinical signifi cance of these differences, however, is unclear, and there have been very few
studies comparing different LMWHs with respect to clinical
outcomes.46 The doses of the different LMWHs have been
established empirically and are not necessarily interchangeable. Therefore, at this time, the effectiveness and safety of
each of the LMWHs must be tested separately.
The LMWHs differ from unfractionated heparin in
numerous ways. Of particular importance are the following:
increased bioavailability (>90% after subcutaneous injection), prolonged half-life and predictable clearance enabling
once- or twice-daily injection, and predictable antithrombotic response based on body weight permitting treatment
45,46
46
Pharmacology 385
https://t.me/med1917
without laboratory monitoring.
12,45,46
Other possible advantages are their ability to inactivate platelet-bound factor Xa,
resistance to inhibition by platelet factor IV and their
decreased effect on platelet function and vascular permeability (possibly accounting for less hemorrhagic effects at comparable antithrombotic doses).
There has been a hope that the LMWHs will have fewer
serious complications such as bleeding, heparin-induced
thrombocytopenia and osteopenia, when compared with
unfractionated heparin.
45,47
Evidence is accumulating that
these complications are indeed less serious and less frequent
with the use of LMWH. LMWH has been approved for the
prevention and treatment of venous thromboembolism in
pregnancy. These drugs do not cross the placenta and large
case series suggest they may be both effective and safe. The
LMWHs all cross-react with unfractionated heparin; therefore they cannot be used as alternative therapy in patients
who develop heparin-induced thrombocytopenia. The heparinoid danaparoid possesses a 10 to 20% cross-reactivity
with heparin and it can be used safely in patients who have
no cross-reactivity.
Four LMWHs are approved for clinical use in Canada,
and three LMWHs have been approved for use in the United
States.
In a number of early clinical trials (some of which were
dose-fi nding), LMWH given by subcutaneous or intravenous injection was compared with continuous intravenous
unfractionated heparin with repeat venography at day 7 to
10 being the primary endpoint.12 These studies demonstrated
that LMWH was at least as effective as unfractionated
heparin in preventing extension or increasing resolution of
thrombi on repeat venography.
Subcutaneous unmonitored LMWH has been compared
with continuous intravenous heparin in a number of clinical
trials for the treatment of proximal DVT using long-term
follow-up as an outcome measure.
48–51,55–57
These studies
have shown that LMWH is at least as effective and safe as
unfractionated heparin in the treatment of proximal DVT.
Pooling of the most methodologically sound studies suggests a signifi cant advantage for LMWH in the reduction of
major bleeding and mortality.
52,53
Further recent studies have
indicated that LMWH used predominantly out-of-hospital
was as effective and safe as intravenous unfractionated
heparin given in-hospital.
55–57
Two clinical trials showed that
LMWH was as effective as intravenous heparin in the treatment of patients presenting with PE.
54,58
Economic analysis
of treatment with LMWH versus intravenous heparin demonstrated that LMWH was cost-effective for treatment inhospital as well as out-of-hospital.59 As these agents have
become more widely available for treatment, they have
replaced intravenous unfractionated heparin in the initial
management of patients with VTE.
Long-term LMWH has been compared with warfarin
60
therapy in patients presenting with proximal DVT.
Although
these studies differ in design and doses of LMWH, they do
indicate that LMWH is a useful alternative to warfarin
therapy, particularly in patients who have recurrence of VTE
while on therapeutic doses of warfarin (e.g., in the cancer
population).60 More recently long-term low-molecularweight heparin has been compared with long-term vitamin
K antagonists for the treatment of a broad spectrum of
patients and patients presenting with cancer and proximal
61,62
DVT.
In the latter study there was a signifi cant decrease
in the incidence of recurrent VTE with the use of long-term
LMWH62 and in the former study involving a broad spectrum of patients including those with cancer, there was a
signifi cant decrease in the incidence of bleeding complications.62 Based on these trials, LMWH has been recommended
for a period of at least three to six months for patients presenting with VTE or PE and cancer.
4
ANTICOAGULANT THERAPY:
WARFARINS AND RELATED
COMPOUNDS (VITAMIN
K ANTAGONISTS)
Warfarin and related compounds have been shown to be
effi cacious and safe in a wide variety of clinical thrombotic
disorders including venous thromboembolism, stroke prevention in nonvalvular atrial fi brillation, and prevention of
systemic emboli in patients who have myocardial infarction
or prosthetic heart valves. Although low-molecular-weight
heparin has been shown to be effi cacious and safe in the
long-term treatment of venous thromboembolism particularly in patients with cancer, wafarin and related vitamin K
antagonists remain the treatment of choice for the long-term
treatment of venous thromboembolism.
PHARMACOLOGY
The Vitamin K Cycle
Vitamin K is responsible for the post-translational conversion of glutamate residues into Gla in a limited number
of proteins, the best known of which are the blood coagulation factors II, VII, IX, X, protein C, protein S, and protein
Z, and bone matrix proteins. The best-known bone matrix
proteins are osteocalcin and matrix Gla-protein (MGP).
γ-Carboxyglutamic acid permits the binding of calcium
by these proteins, and in the presence of calcium the coagulation factors undergo a conformational change that is required
for their binding to various active cofactors on cell surfaces.64
The reduced form of vitamin K (KH2) acts as a coenzyme for
carboxylase. The oxidation of vitamin K (KH
) by oxygen
2
into vitamin K epoxide (KO) provides energy to fi x carbon
dioxide (CO2) at the γ-position of a glutamate residue (see
Figure 43.1). The vitamin KO is then recycled, fi rst by
63
386 Chapter 43/Conventional Treatment of Deep Venous Thrombosis
https://t.me/med1917
FIGURE 43.1 The vitamin K cycle: the effect of warfarin and exogenous vitamin K (phytomenadione). Vitamin K
(quinone) is covered to reduce vitamin K (KH2, hydroxyquinone) by vitamin K reductase. Vitamin KH2 is the substrate
for the carboxylation of prozymogens (e.g., factor II, VII, IX, X) to activate enzymes. Carbon dioxide and oxygen are
required for this reaction, and vitamin KH2 is converted to vitamin K epoxide (KO). Vitamin K is regenerated for vitamin
KO by vitamin K epoxide reductase. Warfarin inhibits vitamin K epoxide reductase and, to some extent, vitamin K
reductase (hatched areas). Exogenous vitamin K in large doses overcomes the blockage by warfarin, presumably because
vitamin K reductase is less sensitive to warfarin than is vitamin K expoxide reductase (arrow). Reproduced from reference 64, with permission.
vitamin K epoxide reductase to vitamin K (quinone) and then
by vitamin K reductase to vitamin KH2 (hydroquinone). It is
essential that each molecule of vitamin K is recycled several
hundred times before being metabolized.
The oral anticoagulants inhibit vitamin KO reductase and
possibly vitamin K reductase, thereby depleting vitamin
KH2 and causing the buildup of vitamin KO in the tissues
such as the liver and plasma (see Figure 43.1).
The most important forms of vitamin K are phylloquinones (vitamin K1) and menaquinones (vitamin K2).63 Phylloquinones are found in green, leafy vegetables such as
spinach, cabbage, and broccoli. Defi ciencies of these vegetables in the diet can cause vitamin K defi ciency, whereas
excessive amounts can reverse the effects of oral anticoagulants. The menaquinones occur in various foods such as
yogurt and organ meats. They are also produced by the
bacterial fl ora of the colon and possibly the small intestine.
Factors interfering with the production or absorption of
these menaquinones, for example, broad-spectrum antibiotics, may lead to vitamin K defi ciency65 and interference with
anticoagulant control. Also, certain cephalosporins containing a N-methyl-thiotetrazole side chain may interfere directly
with vitamin KO reductase in the liver,66 thereby leading to
vitamin K defi ciency. Most of the vitamin K stores in the
liver are menaquinones and it is thought that most of these
originate from the diet rather than intestinal fl ora.
63
Large doses of vitamin K can overcome the blockade of
vitamin KH2 by oral anticoagulants presumably because
vitamin K reductase is less sensitive to the coumarins than
is vitamin KO reductase (see Figure 43.1).63 This reversal of
oral anticoagulants applies to the fi rst generation agents such
as warfarin, but does not apply to the second generation
rodenticides known as the super warfarins, which have an
extremely long half-life. Accidental consumption of these
Pharmacology 387
https://t.me/med1917
agents requires repeated injections of vitamin K and fresh
frozen plasma for a prolonged period of time to completely
overcome their effects.
67,68
Pharmacokinetics and Pharmacodynamics
of Warfarin
There are two distinct chemical groups of oral anticoagulants: the 4-hydroxy coumarin derivatives (e.g., warfarin
sodium) and the indane-1, 3-dione derivatives (e.g., phenindione).69 The coumarin derivatives are the oral anticoagulants of choice because they are associated with fewer
nonhemorrhagic side effects than are the indanedione derivatives. In North America the most commonly used agent is
coumarin (Bristol-Myers Squibb), but in recent years various
generic forms of warfarin sodium have been introduced.
Warfarin is a racemic mixture of stereo-isomers (R & S
forms). Warfarin is highly water soluble and is highly bioavailable.70 Peak absorption occurs around 90 minutes and
the half-life is between 36 and 42 hours. Warfarin is highly
protein bound (primarily albumen), and only the nonprotein
bound material is biologically active. Any drug or chemical,
which is also bound to albumen, may displace warfarin from
its protein binding sites and thereby increase the biologically
active material.70 Warfarin is metabolized in the liver by the
p450 system of enzymes. Interference with the p450 enzymes
by various drugs or a mutation in the gene coding for one
of the common p450 enzymes can markedly interfere with
the metabolism of warfarin. Therefore, the half-life of warfarin can vary markedly from one patient to another and
individual laboratory monitoring to determine drug dosing
is mandatory.
The anticoagulant effect of warfarin is mediated by the
inhibition of the vitamin K-dependent gamma-carboxylation
of coagulation factors II, VII, IX, and X.
the synthesis of immunologically detectable but biologically
inactive forms of these coagulation proteins. Warfarin also
inhibits the vitamin K-dependent gamma-carboxylation of
proteins C and S.71 Protein C circulates as a proenzyme that
is activated on endothelial cells by the thrombin/thrombomodulin complex to form activated protein C. Activated
protein C in the presence of protein S inhibits activated
factor VIII and activated factor V activity.
vitamin K antagonists such as warfarin create a biochemical
paradox by producing an anticoagulant effect due to the
inhibition of pro-coagulants (factors II, VII, IX, and X) and
a potentially thrombogenic effect by impairing the synthesis
of naturally occurring inhibitors of coagulation (proteins C
71,72
and S).
Heparin or low molecular weight heparin and
warfarin treatment should overlap by four to fi ve days when
warfarin treatment is initiated in patients with thrombotic
disease.
73
The anticoagulant effect of warfarin is delayed until the
normal clotting factors are cleared from the circulation, and
69,70
This results in
71
Therefore,
the peak effect does not occur until 36 to 72 hours after drug
74–76
administration.
During the fi rst few days of warfarin
therapy, the prothrombin time (PT) refl ects mainly the
depression of factor VII which has a half-life of fi ve to seven
hours. Equilibrium levels of factors II, IX, and X are not
reached until about one week after the initiation of therapy.
75–77
The use of small initial daily doses (e.g., 5 mg) is the preferred approach for initiating warfarin treatment.
70,78
The
dose-response relationship to warfarin therapy varies widely
between individuals and, therefore, the dose must be carefully monitored to prevent overdosing or underdosing.
A number of factors infl uence the anticoagulant response
of warfarin in individual patients; these include inaccuracies
in laboratory testing and noncompliance of patients, but
more importantly refl ect the infl uence of dietary changes or
the infl uence of drugs that interfere with the metabolism of
warfarin. The availability of vitamin K can be infl uenced by
dramatic changes in dietary intake
antibiotics,
81–83
which interfere with the synthesis of vitamin
79,80
or by drugs such as
K in the gastrointestinal tract. A wide variety of drugs may
interact with warfarin.70 However, a critical appraisal of the
literature reporting such interactions indicates that the evidence substantiating many of the claims is limited.84 The
interactions of drugs and food with warfarin are reviewed
in detail elsewhere.70 Aspirin is particularly problematic
because it interferes with platelet function, displaces warfarin from its protein binding thus augmenting its biological
activities, and as with the NSAIDs it may cause gastric erosions thus creating a site for bleeding. Nonetheless, in certain
patients the use of aspirin and warfarin is indicated to
improve effi cacy even though minor bleeding may be somewhat increased. It is important that patients be warned
against taking any new drugs without the knowledge of their
attending physician and it is prudent to monitor the INR
more frequently when any drug (including natural compounds)85 is added or withdrawn from the regimen of the
patient being treated with an oral anticoagulant.
Laboratory Monitoring and
Therapeutic Range
The laboratory test most commonly used to measure the
effects of warfarin is the one-stage PT test. The PT is sensitive to reduced activity of factors II, VII, and X but is
insensitive to reduced activity of factor IX. Confusion about
the appropriate therapeutic range has occurred because the
different tissue thromboplastins used for measuring the PT
vary considerably in sensitivity to the vitamin K-dependent
clotting factors and in response to warfarin.
thromboplastin, which has been widely used in North
America, is less sensitive than is standardized human brain
thromboplastin, which has been widely used in the United
Kingdom and other parts of Europe. A PT ratio of 1.5 to 2.0
using rabbit brain thromboplastin is equivalent to the current
86,87
Rabbit brain
388 Chapter 43/Conventional Treatment of Deep Venous Thrombosis
https://t.me/med1917
therapeutic range (i.e., INR 2.0 to 3.0).
86,87
Conversely, a
two- to three-fold increase in the PT using standardized
human brain thromboplastin is equivalent to a 1.25- to 1.5fold increase in the PT using a rabbit brain thromboplastin
such as Simplastin or Dade-C.
86,87
In order to promote standardization of the PT for
monitoring oral anticoagulant therapy, the World Health
Organization (WHO) developed an international reference
thromboplastin from human brain tissue and recommended
that the PT ratio be expressed as the International Normalized Ratio or INR.70 The INR is the PT ratio obtained by
testing a given sample using the WHO reference thromboplastin. For practical clinical purposes, the INR for a given
plasma sample is equivalent to the PT ratio obtained using
a standardized human brain thromboplastin known as the
Manchester Comparative Reagent, which has been widely
used in the United Kingdom. In recent years thromboplastins with a high sensitivity have been commonly used. In
fact many centers have been using the recombinant tissue
factor, which has an ISI value 0.9 to 1.0, giving an INR
equivalent to the prothrombin time ratio.
Warfarin is administered in an initial dose of 5 to 7.5 mg
per day for the fi rst two days, and the daily dose is then
adjusted according to the INR. Heparin or low-molecularweight heparin therapy is discontinued on the fourth or fi fth
day following initiation of warfarin therapy, provided the
INR is prolonged into the recommended therapeutic range
(INR 2.0 to 3.0) for at least two consecutive days.4 Because
some individuals are either fast or slow metabolizers of the
drug, the selection of the correct dosage of warfarin must be
individualized. Therefore, frequent INR determinations are
required initially to establish therapeutic anticoagulation.
Once the anticoagulant effect and patient’s warfarin dose
requirements are stable, the INR should be monitored every
one to three weeks throughout the course of warfarin therapy.
However, if there are factors that may produce an unpredictable response to warfarin (e.g., concomitant drug therapy),
the INR should be monitored more frequently to minimize
the risk of complications due to poor anticoagulant
control.
70,88
ADVERSE EFFECTS OF ORAL
ANTICOAGULANTS
Bleeding
The major side effect of oral anticoagulant therapy is
bleeding.
that predispose to bleeding on oral anticoagulants.
most important factor infl uencing bleeding risk is the intensity of the INR.
ing, previous history of stroke or myocardial infarction,
hypertension, renal failure, diabetes, and a decreased he-
70,87,88
A number of risk factors have been identifi ed
87–90
Other factors include a history of bleed-
88,89,90
The
89
matocrit.
risk according to these underlying clinical factors.
Efforts have been made to quantify the bleeding
89,90
Introduction of a multicomponent intervention combining patient
education and alternative approaches to the maintenance of
the INR resulted in a reduced frequency of major bleeding
in the patients in this group.89 Furthermore, patients in the
intervention group were within the therapeutic INR a signifi cantly greater amount of time than were patients in the
standard care group. In a retrospective cohort study of
patients with an INR greater than 6.0, it was shown that a
prolonged delay in the return of the INR to the therapeutic
range was seen in patients who had an INR over 4.0 after
two doses of warfarin were withheld, patients with an
extreme elevation of the INR, and older age patients, particularly those with decompensated congestive heart failure
and active cancer.90 Numerous randomized clinical trials
have demonstrated that clinically important bleeding is
lower when the targeted INR is 2.0 to 3.0, and that bleeding
increases exponentially when the INR increases above 4.5
87,90,91
or 5.0.
There is a strong negative relationship between
the percentage of time that patients are within the targeted
INR and both bleeding and recurrent thrombosis.
Oral anticoagulant therapy in elderly patients presents
further problems.
92,93,94
Many of these patients require longterm anticoagulants because of their underlying clinical conditions that increase with age, while they are more likely to
have underlying causes for bleeding including the development of cancer, intestinal polyps, renal failure, and stroke,
and they are more prone to having frequent falls. The daily
requirements for warfarin to maintain the therapeutic INR
also decreases with age, presumably due to decreased clearance of the drug. Therefore, before initiating oral anticoagulant treatment in elderly patients, the risk/benefi t ratio of
treatment must be considered. If they are placed on oral
anticoagulant therapy, careful attention to the INR is
required.
Patients with cancer are more likely to bleed on oral
anticoagulant treatment.95 Compared with patients on oral
anticoagulants who do not have cancer, patients with cancer
have a higher incidence of both major and minor bleeding
and anticoagulant withdrawal is more frequently due to
bleeding. Patients with cancer have a higher thrombotic
complication rate and a higher bleeding rate regardless of
the INR, whereas bleeding in noncancer patients was seen
only when the INR was greater than 4.5. Safer and more
effective anticoagulant therapy is required for the treatment
of VTE in patients with cancer.
95
Management of Over-Anticoagulation
The approach to the patient with an elevated INR depends
on the degree of elevation of the INR and the clinical circumstances.
temporary discontinuation of warfarin treatment, admini-
70,96
Options available to the physician include
Adverse Effects of Oral Anticoagulants 389
https://t.me/med1917
stration of vitamin K or administration of blood products
such as fresh frozen plasma or prothrombin concentrate to
replace the vitamin K–dependent clotting factors or administration of activated Factor VII. If the increase is mild and
the patient is not bleeding, no specifi c treatment is necessary
other than reduction in the warfarin dose. The INR can be
expected to decrease during the next 24 hours with this
approach. With more marked increase of the INR in patients
who are not bleeding, treatment with small doses of vitamin
K1 (e.g., 1 mg), given either orally or by subcutaneous injection should be considered.
97,98
With very marked increase of
the INR, particularly in a patient who is either actively
bleeding or at risk for bleeding, the coagulation defect
should be corrected. Vitamin K can be given by the intravenous or subcutaneous route or by the oral route.
70,96
Where
possible the oral route is preferred. If ongoing anticoagulation with warfarin is planned, then repeated small doses of
vitamin K should be given, so that there is no problem with
warfarin resistance.
70,96,97
Reported side effects of vitamin K include fl ushing, dizziness, tachycardia, hypotension, dyspnea, and sweating.70
Intravenous administration of vitamin K1 should be performed with caution to avoid inducing an anaphylactoid
reaction. The risk of anaphylactoid reaction can be reduced
by slow administration of vitamin K1. In most patients, intravenous administration of vitamin K1 produces a demonstrable effect on the INR within six to eight hours and corrects
the increased INR within 12 to 24 hours. Because the halflife of vitamin K1 is less than that of warfarin sodium, a
repeat course of vitamin K1 may be necessary. If bleeding is
very severe and life threatening, vitamin K therapy can be
supplemented with concentrates of Factors II, VII, IX, and
X.
When bleeding occurs in a patient on oral anticoagulants
it is important to consider the site of bleeding. Bleeding from
the upper gastrointestinal tract commonly is seen in patients
on oral anticoagulants, and the concomitant use of other
medications is often an association. When the bleeding is
controlled, it is important to carry out the necessary investigations to identify bleeding lesions in the gastrointestinal or
genitourinary tract, which are often unsuspected.
98
Management of Patients Receiving Long-
term Anticoagulants Who Require
Temporary Interruption Therapy
Patients on long-term oral anticoagulant therapy may
require a temporary interruption of therapy for surgical
interventions, which may vary from dental extractions to
major surgery. In such cases the risk of arterial or venous
thromboembolism after anticoagulants have been discontinued must be weighed against the risk of bleeding if UFH or
LMWH is used for bridging anticoagulant therapy.
70,99
In the
absence of randomized clinical trials recommendations are
99
based on large, nonrandomized cohort studies,
which in
recent years have used low-molecular-weight heparin for
bridging therapy.
100,101
These studies have shown that LMWH
given in either prophylactic or therapeutic doses are effective and safe for bridging therapy. In addition this therapy
is cost effective when compared with UFH in hospital.
102,103
Thus, based on the current evidence recommendations can
be made depending on the anticipated risk of thromboembolism and the risk of major bleeding with anticoagulant
therapy. These recommendations range from temporary lowering of the INR for certain procedures such as dental extraction to discontinuation of oral anticoagulant therapy and
bridging with either unfractionated heparin or low-molecular-weight heparin in either prophylactic or therapeutic doses
until a therapeutic INR is reached post-operatively.
Long-term Treatment of VTE
Patients with established DVT or PE require long-term
anticoagulant therapy to prevent recurrent disease.70 Warfarin therapy is highly effective and is preferred in most
patients. Adjusted dose subcutaneous heparin or LMWH is
the treatment of choice where long-term oral anticoagulants
are contraindicated, such as in pregnancy or for the longterm treatment of patients in whom oral anticoagulant
therapy proves to be very diffi cult to control. In patients with
proximal DVT, long-term therapy with warfarin reduces the
frequency of objectively documented recurrent VTE from
47% to 2%.
There have been attempts to improve the safety of warfarin therapy by using a lower INR target, but this results in
an increased thrombotic risk.
ment with warfarin to a target INR of 1.5 to 2.0 in patients
who have venous thromboembolism proved to be more
effective than placebo treatment,
pared a target INR of 1.5 to 2.0 the standard INR of 2.0 to
3.0 showed signifi cantly lower recurrence rate with the standard treatment, with no added risk of bleeding.
of other studies using less-intense warfarin (e.g., for the
prevention of thrombobosis in central venous catheters)
showed such treatment to be ineffective.
the target INR is greater than 3.0. For example, based on
retrospective studies, patients who have mechanical heart
valves have been treated with a target INR of 2.5 to 3.5. In
patients who have bioprosthetic heart valves or in low-risk
patients who have bileafl et mechanical valves in the aortic
position, the target INR is still 2.0 to 3.0.
spective studies suggested that patients who have antiphospholipid antibodies and recurrent thrombosis required an
INR of greater than 3.0,
paring an INR of 2.0 to 3.0 with an INR of 3.1 to 4.0 showed
that the incidence of recurrent thrombosis and major bleeding was comparable in the two groups.
104
105
Although long-term treat-
106
a similar study that com-
107
108–110
In some cases,
111
Although retro-
106–108
two randomized studies com-
112,113
A number
390 Chapter 43/Conventional Treatment of Deep Venous Thrombosis
https://t.me/med1917
Optimal Duration of Oral Anticoagulants
after a First Episode of Venous
Thromboembolism
It has been recommended that all patients with a fi rst
episode of VTE receive warfarin therapy for at least three
to six months. Attempts to decrease the treatment to four
weeks
114,115
or six weeks
116
resulted in higher rates of recurrent VTE in comparison with either 12 or 24 weeks of treatment (11 to 18% recurrent VTE in the following one to two
years). Most of the recurrent thromboembolic events
occurred in the six to eight weeks immediately after anticoagulant treatment was stopped, and the incidence was higher
in patients with continuing risk factors, such as cancer and
immobilization.
six months
115,116
116
Treatment with oral anticoagulants for
reduced the incidence of recurrent thromboembolic events, but there was a cumulative incidence of
recurrent events at two years (11%) and an ongoing risk of
recurrent VTE of approximately 5 to 6% per year. In patients
with a fi rst episode of idiopathic VTE treated with intravenous heparin followed by warfarin for three months, continuation of warfarin for 24 months led to a signifi cant
reduction in the incidence of recurrent DVT when compared
117
with placebo.
In a further recent trial comparing three
months with 12 months of oral anticoagulant therapy after
the occurrence of a fi rst episode of idiopathic proximal DVT
it was shown that patients treated for three months had a
higher incidence of recurrence of VTE during the subsequent 12 months compared with those patients who were
continued on anticoagulants for 12 months.
118
However, the
cumulative hazard of recurrent VTE at 36 months was the
same in both groups. The incidence of recurrence after discontinuation of treatment was 5.1% per patient year in
patients where oral anticoagulant therapy was discontinued
after three months and 5.0% per patient year in patients who
received an additional nine months of oral anticoagulant
therapy. The recurrence occurred in the initially unaffected
leg more than half the time. This suggests that the recurrences were related to a hypercoagulable state and the duration of anticoagulant therapy did not infl uence the ultimate
recurrence rate.
118
Optimal Duration of Oral Anticoagulant
Treatment in Patients with Recurrent VTE
In a multicenter clinical trial, Schulman et al. randomized
patients with a fi rst recurrent episode of VTE, to receive
either six months or continued oral anticoagulants indefi nitely, with a targeted INR of 2.0 to 2.85.
was reported at four years. In the patients receiving anticoagulants for six months, recurrent VTE occurred in 20.7%,
compared with 2.6% of patients on the indefi nite treatment
(p < .001). However, the rates of major bleeding were 2.7%
in the six months group, compared with 8.6% in the indefi -
119
The analysis
nite group. In the indefi nite group, two of the major hemorrhages were fatal, whereas there were no fatal hemorrhages
in the six month group. This study showed that extending
the duration of oral anticoagulants for approximately four
years resulted in a signifi cant decrease in the incidence of
recurrence, but a higher incidence of major bleeding. Without
a mortality difference, the risk of hemorrhage versus the
benefi t of decreased recurrent thromboembolism with the
use of extended warfarin treatment remains uncertain and
will require further clinical trials.
From the Seventh American College of Chest Physicians
Conference on Anti-thrombotic and thrombolytic Therapy
4
the following recommendations are made.
Oral anticoagulant therapy should be continued for at least three months to
prolong the prothrombin time to a targeted INR of 2.5 (range
2.0 to 3.0). Patients with reversible or time-limited risk
factors can be treated for three to six months. Patients with
a fi rst episode of idiopathic VTE should be treated for at
least six months. Patients with recurrent VTE or a continuing risk factor such as cancer, antithrombin defi ciency, or
the antiphospholipid syndrome, should be treated for at least
12 months and considered for indefi nite long-term therapy.
Patients with activated protein C resistance (Factor V
Leiden) should probably receive indefi nite treatment if they
have recurrent disease, are homozygous for the gene, or
have multiple thrombophilic conditions. Accumulated evidence indicates that symptomatic isolated calf vein thrombosis should be treated with anticoagulants for at least three
months.
4
Alternative Approaches to the Management
of Oral Anticoagulant Therapy
Anticoagulant Management Clinics
In recent years a large number of anticoagulation management clinics have been developed initially in Europe and
more recently in North America. These anticoagulation
management clinics provide coordinated services for patients
requiring long-term anticoagulation therapy.
though there have been no randomized clinical trials comparing routine medical care with care given in anticoagulant
management clinics, there is evidence that patients managed
in anticoagulation management clinics are within the targeted INR a larger percentage of the time and therefore there
would be expected to have a decrease in the incidence of
thromboembolism as well as the incidence of major bleed-
122
ing.
Cost analysis based on the data from a number of
reports comparing routine medical care with anticoagulation
management clinics indicate that anticoagulant management
clinics are capable of achieving cost saving that should be
equal to the cost of running the clinics themselves.
Computer programs are now available for the data man-
agement for anticoagulant management clinics and one
120,121,122
Al-
References 391
https://t.me/med1917
system has been developed for the ongoing prescribing of
warfarin once patients have a stable INR on at least two
occasions. In an interesting report, it was shown that the
computer was superior to experienced hematologists in the
ordering of warfarin with a higher percentage of patients
achieving their targeted INR a greater amount of time with
the use of the computer program.
123
Point of Care INR Testing
A number of instruments are now available for the measurement of capillary INRs on fi nger sampling of whole
blood. INRs performed with these instruments compare well
with venous samples, and numerous studies have indicated
that many patients are capable of both self-testing and selfmanagement of their warfarin dosing.
124–126
Indeed, some
studies have indicated that self-management of warfarin
therapy using point of care INR testing has resulted in higher
INR compliance with fewer tests when compared with
physician-managed patients.
126
Self-managed vitamin-Kantagonist therapy compared with anticoagulant clinic management resulted in improved patient outcomes. Although
self-managed vitamin-K-antagonist therapy resulted in a
similar level of INR control, bleeding complications occurred
less frequently for self-managed patients.
127
References
1. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS.
Clinical risk factors and timing of recurrent venous thromboembolism
during the initial 3 months of anticoagulant therapy, Arch Intern Med.
2000. 160: 3431–3436.
2. Douketis JD, Kearon C, Bates B, Duk EK, Ginsberg JS. Risk of fatal
pulmonary embolism in patients with treated venous thromboembolism, JAMA. 1998. 279: 458–462.
3. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM,
Melton LJ III. Predictors of recurrence after deep vein thrombosis and
pulmonary embolism. A Population-Based Cohort Study, Arch Intern
Med. 2000. 160: 761–768.
4. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE.
Antithrombotic therapy for venous thromboembolic disease; The
Seventh ACCP Conference on Antithrombotic and Thrombolytic
Therapy, Chest. 2004. 126: 401S–428S.
5. Kahn SR, M’Lan CE, Lamping DL, Kurz X, Berards A, Abenhaim
L. The infl uence of venous thromboembolism on quality of life and
severity of chronic venous disease, J Thromb Haemost. 2004. 2:
2146–2151.
6. Brandjes DPM, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt
H, ten Cate JW. Randomised trial of effect of compression stockings
in patients with symptomatic proximal-vein thrombosis, Lancet.
1997. 349: 759–762.
7. Prandoni P, Lensing AWA, Prins MH, Frulla M, Marchiori A,
Bernardi E et al. Below-knee elastic compression stockings to prevent
the post-thrombotic syndrome: a randomized, controlled trial, Ann
Intern Med. 2004. 141: 249–256.
8. Kahn SR, Kearon C, Julian JA, Mackinnon B, Kovacs P, Crowther
MA et al., for the Extended Low-Intensity anticoagulation
for thrombo-embolism (Elate) Investigators. Predictors of the
post-thrombotic syndrome during long-term treatment of proximal
deep vein thrombosis, J Thromb Haemost. 2005. 3: 718–723.
9. Hull RD, Marder VJ, Mah AF, Biel RK, Brant RF. Quantitative
assessment of thrombus burden predicts the outcome of treatment for
venous thrombosis: A systematic review, Am J Med. 2005. 118:
456–464.
10. Van Dongen CJJ, Prandoni P, Frulla M, Marchiori A, Prins MH,
Hutten BA. Relation between quality of anticoagulant treatment and
the development of the postthrombotic syndrome, J Thromb Haemostasis. 3: 939–942.
11. Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute
vein thrombosis reduces post-thrombotic syndrome, Int Angiol. 2004.
23: 206–212.
12. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The
Seventh ACCP Conference on antithrombotic and thrombolytic
therapy, Chest. 2004. 126: 188S–203S.
13. Lane DA. Heparin binding and neutralizing protein. In: Lane DA,
Lindahl U, eds. Heparin, chemical and biological properties, clinical
applications. London: Edward Arnold, 189: 363–391.
14. Rosenberg RD, Lam L. Correlation between structure and function of
heparin, Proc Natl Acad Sci USA. 1979. 76: 1218–1222.
15. Gallus A, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and
effi cacy of warfarin started early after submassive venous thrombosis
or pulmonary embolism, Lancet. 1986. II: 1293–1296.
16. Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwards P,
Ginsberg JS et al. Heparin for 5 days as compared with 10 days in
the initial treatment of proximal venous thrombosis, N Engl J Med.
1990. 322: 1260–1264.
17. Hull RD, Raskob GE, Rosenbloom D, Lemaire J, Pineo GF, Baylis
B et al. Optimal therapeutic level of heparin therapy in patients with
venous thrombosis, Arch Intern Med. 1992. 152: 1589–1595.
18. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. The 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.
19. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The
weight based heparin dosing nomogram compared with a “standard
care” nomogram, Ann Intern Med. 1993. 119: 874–881.
20. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of
unfractionated heparin in comparative studies with low-molecularweight heparin, Ann Intern Med. 2003. 138: 720–723.
21. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH et al.
Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis, N
Engl J Med. 1986. 315: 1109–1114.
22. Faivre R, Neuhart Y, Kieffer Y, Apfel F, Magnin D, Didier D et al.
Un nouveau traitement des thromboses vein euses profondes: les
fractions d’heparine de bas poids moleculaire. Etude randomisee,
Presse Medicale. 1988. 17: 197–200.
23. Lopaciuk S, Meissner AJ, Filipecki S, Zawilska K, Sowier J, Ciesielski L. Subcutaneous low molecular weight heparin versus subcutaneous UFH in the treatment of DVT: A Polish multicenter trial, Thromb
Haemost. 1992. 68: 14–18.
24. Belcaro G, Nicolaides AN, Cesarone MR, Laurora G, De Sanctis MT,
Incandela L et al. Comparison of low-molecular-weight heparin,
administered primarily at home, with UFH, administered in hospital,
and subcutaneous heparin, administered at home for deep-vein thrombosis, Angiology. 1999. 50: 781–787.
25. Writing Committee for the Galilei Investigators. Subcutaneous
adjusted-dose UFH vs fi xed-dose low-molecular-weight heparin in
the initial treatment of venous thromboembolism, Arch Intern Med.
2004. 164: 1077–1083.
Соседние файлы в папке Библиотека им академика М.И. Перельмана