Day 2, 19 February 2005, Special Lecture 4 (14.00-15.

15) Mutiara 2 Gran Melia Jakarta

2nd Annual Meeting of Indonesian Society of Obstetric Anesthesia
and Indonesian Society of Regional Anesthesia and Pain Medicine
in conjunction with Recent Advances in Anesthesia Symposia

DVT: INCIDENCE, PATHOGENESIS & PROPHYLAXIS

Susilo Chandra MD
INCIDENCE
Pulmonary embolism is responsible for
approximately 150,000 to
200,000 deaths per year in the
United States. No Indonesian
data are available. Despite
significant advances in the
prevention and treatment of
venous
thromboembolism
(venous
thrombosis
and
pulmonary
embolism),
pulmonary embolism remains
the most common preventable
cause of hospital death.
Venous
thromboembolism
usually
occurs
as
a
complication in patients who
are sick and hospitalized, but
it may also affect ambulant
and
otherwise
healthy
individuals. Many patients
who die from pulmonary
embolism succumb suddenly
or within 2 hours after the
acute event (i.e., before
therapy can be initiated or take
effect). Therefore, prevention
is the key to reducing death
and morbidity from venous
thromboembolism. Effective
and
safe
prophylactic
measures
against
venous
thromboembolism are now
available for most high-risk
patients.
PATHOGENESIS
Deep venous thrombosis most commonly
arises in the deep veins of the
calf
muscles
or,
less

commonly, in the proximal deep veins

of the leg. Deep venous thrombosis
confined to the calf veins is associated
with a low risk of clinically important
pulmonary
embolism.
Without
treatment, however, approximately
20% of calf vein thrombi extend into
the proximal venous system, where
they are a serious and potentially lifethreatening
disorder.
Untreated
proximal venous thrombosis is
associated with a 10% risk of fatal
pulmonary embolism and at least a
50% risk of pulmonary embolism or
recurrent
venous
thrombosis.
Furthermore,
the
postphlebitic
syndrome is associated with extensive
proximal venous thrombosis and
carries its own long-term morbidity.
It is now well established that clinically important
pulmonary emboli arise from thrombi
in the proximal deep veins of the legs.
Other less common sources of
pulmonary embolism include the deep
pelvic veins, renal veins, inferior vena
cava, right side of the heart, and
occasionally axillary veins. The
clinical significance of pulmonary
embolism depends on the size of the
embolus and the cardiorespiratory
reserve of the patient.
RISK FACTORS
Without prophylaxis, the frequency of fatal
pulmonary embolism ranges from
0.1% to 0.8% in patients undergoing
elective general surgery, [52] [53] [87] [91]
2% to 3% in patients undergoing
elective hip replacement, [18] and 4% to
7% in patients undergoing surgery for
a fractured hip

Day 2, 19 February 2005, Special Lecture 4 (14.00-15.15) Mutiara 2 Gran Melia Jakarta
2nd Annual Meeting of Indonesian Society of Obstetric Anesthesia
and Indonesian Society of Regional Anesthesia and Pain Medicine
in conjunction with Recent Advances in Anesthesia Symposia

FACTORS PREDISPOSING TO THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM

Clinical risk factors

Inherited or acquired abnormalities

Surgical and nonsurgical trauma

Activated protein C resistance

Previous venous thromboembolism

Protein C deficiency

Immobilization

Protein S deficiency

Malignant disease

Antithrombin III deficiency

Heart disease

Anticardiolipin syndrome

Leg paralysis

Heparin-induced thrombocytopenia

Age (>40)
Obesity
Estrogens
Parturition

PREVENTION
OF
VENOUS
THROMBOEMBOLISM
Thromboprophylaxis can be directed toward
three components of Virchow's
triad: blood flow, factors within
the blood itself, and the
vascular endothelium. Some
methods act on all three,
resulting in a reduction of
venous stasis, prevention of the
hypercoagulable state induced
by tissue trauma and other
factors, and protection of the
endothelium.
Whichever
method
is
used,
thromboprophylaxis
should
probably be initiated before
induction of anesthesia because
it has been demonstrated that
the thrombotic process begins
intraoperatively.
The ideal thromboprophylactic agent would
prevent all deep venous
thromboses, be free from side
effects, be simple to apply or

administer
(e.g.,
oral
administration),
need
no
laboratory monitoring, and be
cost-effective. None of the
available approaches meets all
of these criteria. The selection
of
a
particular
thromboprophylactic method
therefore depends on the type
of surgery, the overall risk
category into which the patient
falls, and the preference of the
responsible
clinician.
For
example, it may not be
appropriate to treat with
anticoagulants patients at high
risk of bleeding or at risk of

complications secondary to bleeding or to

use mechanical devices on
patients who have peripheral
ischemia.
There are two approaches to the prevention
of fatal pulmonary embolism:
(1) Primary prophylaxis is

Day 2, 19 February 2005, Special Lecture 4 (14.00-15.15) Mutiara 2 Gran Melia Jakarta
2nd Annual Meeting of Indonesian Society of Obstetric Anesthesia
and Indonesian Society of Regional Anesthesia and Pain Medicine
in conjunction with Recent Advances in Anesthesia Symposia

carried out using drugs,

physical
methods,
or
a
combination of both methods
that are effective for preventing
deep venous thrombosis, and
(2)
secondary
prevention
involves the early detection and
treatment of subclinical venous
thrombosis
by
screening
postoperative patients with
objective tests that are sensitive
for venous thrombosis. Primary
prophylaxis is preferred in
most clinical circumstances.
Furthermore, prevention of
deep venous thrombosis and
pulmonary embolism is more
cost-effective than treatment of
the complications when they
occur. Secondary prevention by
case-finding studies should
never
replace
primary
prophylaxis. It should be
reserved for patients in whom
primary prophylaxis is either
contraindicated or relatively
ineffective.

THROMBOPROPHYLAXIS

The prophylactic measures most commonly

used are low-dose or adjusted
dose unfractionated heparin,
low-molecular-weight heparin
(LMWH), oral anticoagulants
(International
Normalized
Ratio [INR] of 2 to 3),
intermittent
pneumatic leg compression, and graduated
compression stockings. More
recently, studies on the prevention of venous
thrombosis
have
been
performed with

Fondaparinux. Other less common measures

include the use of aspirin and
intravenous dextran.
Fondaparinux versus
weight heparins

lowmolecular-

Fondaparinux is the first of a new class of

antithrombotic agents. Like the originally
investigated heparin pentasaccharide, this
synthetic, selective factor Xa (FXa) inhibitor
mimics the site of heparin that binds to AT
III. However, there are several minor
structural differences between these two
agents. Fondaparinux has several potentially
important
advantages
over
other
antithrombotic agents:

It is synthetic.
It has no viral or other animal contaminants.
It has a well-defined, pure, homogenous molecular structure.
It has a relatively long half-life.
It has superior bioavailability.
It has a predictable dose effect.
It does not interact with PF4.
It does not cross-react with heparin antibody.

It has been shown to be an effective

antithrombotic through numerous animal
model investigations, and it has been
confirmed through four phase 3 clinical trials

in orthopedic surgery. The FDA has approved

fondaparinux for the prevention of venous
thromboembolic events after orthopedic
surgery. Although a 55% relative risk
reduction of venous thrombosis was found in

Day 2, 19 February 2005, Special Lecture 4 (14.00-15.15) Mutiara 2 Gran Melia Jakarta
2nd Annual Meeting of Indonesian Society of Obstetric Anesthesia
and Indonesian Society of Regional Anesthesia and Pain Medicine
in conjunction with Recent Advances in Anesthesia Symposia

clinical trials, the bleeding risk with

fondaparinux was not reduced compared with
that for LMWHs.

Pentasaccharide exhibits markedly different

properties than these drugs. It has a
homogenous molecular weight distribution,
exhibits high anti-Xa activity, low USP
activity, and strong antithrombotic and
bleeding actions. The relative release of TFPI
is much lower with pentasaccharide. The
reported incidence of heparin-induced
thrombocytopenia is surprisingly high, as
depicted in.

A comparison of the original heparin

pentasaccharide and various LMWHs is given
in table below. As can be seen, the LMWHs
vary widely in their physicochemical,
biochemical, and pharmacologic actions.

Comparison of fondaparinux with various lowmolecular-weight heparins

Agent

MW<2500, MW>7500, AXa

%
%
(U/mg)

USP
(U/kg)

AT
activity

Bleeding
index IV

Bleeding
index SC

TFPI
realease

Fragmin

25

148

75

14

0.3

45

110

Lovenox

15

37

98

53

0.5

68

120

Normiflo

35

60

70

0.9

35

130

Innohep

31

89

60

14

0.8

71

168

650

<5

0.3

27

24

Pentasaccharide 100

Thrombocytopenia and heparin-induced thrombocytopenia with LMWH

1. Unfractionated heparin (ACCP metaanalysis) 1%

2. Dalteparin (Metaanalysis)

0.3%

3. Enoxaparin (Aventis documents)

1.9%

4. Tinzaparin (Hull, personal communication)

1%

5. Pentasaccharide

3.9%