INTRODUCTION

Venous thromboembolism (VTE) is a multicausal disease that manifests in the form of deep
vein thrombosis (DVT) and pulmonary embolism. The basic principle of VTE is that a blood
clot has formed in the veins.
1.0

Etiology of VTE
1.1

Age
The risk of VTE increases with age. Age can also be a precursor to
other predisposing factors such as decreased mobility, increased occurrence of
risk-enhancing diseases, decreased muscular tone and the acquisition of other
risk factors.1

1.2

Underlying medical conditions

Immobilisation that causes lack of movement or stasis in the limbs can
increase the risk of VTE occurrence because stasis leads to reduced blood
circulation. Pregnancy increases the risk of VTE events as well. Risk for VTE
is highest during the third trimester. Most thrombotic events take place in the
left leg. This is related to the gravid uterus pressing against the common iliac
vein. Venous thrombosis due to pregnancy is rare, however in approximately
half of the thrombotic events concerning women are related to pregnancy. Risk
of thrombosis during pregnancy is affected by the abnormalities in
prothrombin and increases during the absence of antithrombin.1

1.3

Surgery and trauma

In the absence of antithrombotic prophylaxis, the risk for VTE postsurgery is 50% higher. Surgery alone significantly increases the risk of
thrombotic events. Even with anticoagulants as prophylaxis, the risk of VTE
after surgery remains high. Arthroscopic knee surgery is a surgical procedure
that is most often associated with VTE.2

1.4

Cancer
Cancer increases risk for thrombotic events through several
mechanisms. Production of tissue factors by malignant cells sets precedence
for procoagulant state due to humoral factor. Besides, large tumours may
become a mechanical factor in venous thrombosis because they can cause
venous compression and venous obstruction. Other determinants in the risk for
VTE in cancer patients are the stage and type of the tumour, anticancer
therapy (chemotherapy, hormonal therapy, angiogenesis inhibitors, and
supportive therapy), surgery, and prothrombotic abnormalities.3

The mode of treatment also influences the risk of cancer in causing

VTE. Central venous catheters are identified as the most significant cause of
symptomatic thrombosis in the arm.
1.5

Antiphospholipid antibodies
The presence of antiphospholipid antibodies, whether in patients with
or without systemic lupus erythematodes, increases the risk of VTE.

1.6

Medication and lifestyle habits

1.6.1

Long-distance travel
Air travel has been known to present a high risk for pulmonary
embolism. However other methods of travel also can result in
thrombosis. The risk of pulmonary embolism increases with the
increase in flight duration. Not only the duration of travel but the
conditions in air travel, such as hyperbaric hypoxia, results in
hypercoagulation. This was observed in a minority of individuals and
the risk is doubled in those with prothrombotic risk factors. Other
variables that should be taken into account are presence of
prothrombotic genetic variants, usage of oral contraceptives, weight
(there is higher risk in the obese) and height.1

1.6.2

Lifestyle
The risk for venous thrombosis is decreased in those who
practice physical exercise, regardless of frequency and intensity of the
exercise.1 Risk for VTE is increased in prolonged periods of
immobilisation.2 Other lifestyle factors include obesity, smoking, and
use of oral contraceptives, all of which increase the risk for thrombotic
events if present. However, it is worth noting that alcohol consumption
appears to possess a protective effect. Regular alcohol consumption
has some protective effect but this effect is most pronounced in those
who consume two to four glasses of alcohol per day.1

1.6.3

Oral contraceptives
Oral contraceptives that contain oestrogen have several effects
on the coagulation system, increasing levels of procoagulant factors
and reducing levels of natural anticoagulants, hence increasing the risk
of a thrombotic event. Those that contain third-generation
progestrogens present a higher prothrombotic effect than those
containing second-generation progestrogens.1

1.7

Genetics

Deficiencies of natural coagulation inhibitors such as antithrombin,

protein C, and its cofactor S causes hypercoagulation and leads eventually to
thrombosis. These deficiencies are rare but considered as strong genetic risk
factors. Factor V Leiden is a mutation of the gene that is found in 20% of
patients with venous thrombosis. The mutation is located in a part of the gene
that encodes for one of the cleavage sites of factor V, where activated protein C
(APC) inactivates factor Va. The mutation causes a resistance to APC.
Mutation of the untranslated part of the prothrombin 20210A gene causes
increased prothrombin levels that is related to the increased risk of venous
thrombosis. Both factor V Leiden and prothrombin 20210A is not an
uncommon mutation and can occur together as compound heterozygotes, thus
increasing the risk for venous thrombosis twentyfold compared to individuals
without both mutation.4

1.8

Other abnormalities in the plasma

1.8.1

Hyperhomocysteinaemia
There is a connection between elevated homocysteine levels in
the plasma and venous thrombosis. The higher the level of
homocysteine in the plasma, the higher the risk for venous
thrombosis.1

1.8.2

High level of clotting factors

Excess of clotting factors responsible for coagulation, notably
factors VIII, IX and XI as well as prothrombin and fibrinogen, are
responsible for elevated risk for venous thrombosis. High levels of
factor VIII are related to the ABO blood type.1

1.8.3. Fibrinolytic factors

Risk for venous thrombosis is increased with high levels of
thrombin activatable fibrinolysis inhibitor (TAFI).1

2.0

Pathophysiology
The key to venous thromboembolism is haemostasis. Haemostasis occurs as a
result of the formation of an impermeable platelet and fibrin plug at a site of injury. It
also requires the procoagulant substances to not only be activated but also remain
localised at the site of injury. There are several key steps in the coagulation process.5
The initiation phase begins with the FVIIa/TF (tissue factor) complex
activating small amounts of factor IX and X. Factor Xa associates with factor FVa to
form prothrombinase complexes on the TF-bearing cells. Platelets become adherent to
collagen and other extracellular components at the site of injury, which causes the

activation of other platelets and promotes secretion of partially activated FV. Factor
Xa that dissociates from the cells that carry TF is rapidly inhibited in the fluid phase
by TF pathway inhibitors (TFPI) or antithrombin (AT). Usually FXa is protected from
inhibition by plasma protease inhibitors and this prevents formation of clots.
However, the presence of inhibitors of the plasma protease will cause the activity of
FXa to be localised to the surface on which it was formed. Under normal
circumstances, the TF pathway does not cause clot formation because the important
clotting factors, which are platelets and FVIII complexed with von Willebrand factor
(vWF) are sequestered.5
Thrombin generated by TF-bearing cells induces a higher level of
procoagulant activity by activating more platelets in the vicinity of the injury site.
Thrombin also activates factors V and VIII on the platelet surface as well as FXI. This
sets the stage for thrombin activation on a massive scale and constitutes the
amplification stage.5
The propagation phase consists of several key events. The first is the binding
of activated FIXa to FVIIIa on the surface of the platelet, the second is the supply of
additional FIXa by platelet-bound FXIa, and the third event is where FXa rapidly
associates with platelet surface FVa to mass-produce thrombin in a short time with
enough magnitude to cause fibrinogen to clot.5
The final step is the conversion of fibrinogen to fibrin that is mediated by
thrombin, forming fibrin strands. Factor XIIIa covalently seals the fibrin strands
together until they form a meshwork that surrounds and envelopes the aggregated
platelets to form a stabilised clot. The coagulation process does not immediately halt,
rather the site of initiation of the coagulation eventually gets paved over by platelets
and fibrin. The activating factors that come into initial contact with the platelets that
were attracted to the collagen are thus sequestered and does not allow for further
coagulation. Excess thrombin from the propagation phase has been proposed to
activate TAFI, which protects the clot from proteolysis.5
Fibrinolytic system is responsible for clot dissolution. Plasminogen is
converted to plasmin by tissue plasminogen activator and urokinase plasminogen
activator, which will dissolve the fibrin mesh by degrading it into soluble end
products known as fibrin split products or fibrin dissolution products. Plasminogen
activator inhibitor-1 inhibits plasminogen activators while antiplasmin inhibits
plasmin activity. Hypercoagulability and thus thrombotic events occur when the
fibrinolytic system fails to be activated.6

3.0

Clinical importance
VTE can be managed through several steps: conventional anticoagulants that
consist of unfractionated heparin, which has since been replaced by low molecular

weight heparin (LMWH) and vitamin K antagonists such as warfarin. Warfarin is the
most common oral anticoagulant used for the management of VTE. It possesses
several disadvantages: slow onset of action, narrow therapeutic window, food and
drug interaction, and wide interindividual dosing differences. Not only is extensive
monitoring required, but warfarin resistance and optimal warfarin initiation dose are
also a concern.7
However, LMWH also poses some disadvantages of its own. LMWH is costeffective compared to unfractionated heparin as initial therapy. However in the long
run, it will be too costly to maintain. Besides that, LMWH is not adequate for patients
with renal insufficiency as it is renally excreted. The anticoagulant effect of LMWH is
not as easily reversed as warfarin. The dosage for LMWH must be adjusted to suit the
body weight of patients as different weight constitutes different risk of bleeding from
LMWH against oral anticoagulants.8
As both LMWH and warfarin possess their own advantages and
disadvantages, there is need to review both treatment options for VTE.

METHODS
The articles used for this report are not older than the year 2005. They are sourced
online through various search engines and databases. The search engine that is used is
Google. The online scientific databases used to search and obtain the journals are
ScienceDirect and PubMed. The main search keywords used during the information sourcing
process are venous thromboembolism, venous thrombosis and VTE.
The articles that were used as reference for the report are not confined to a particular
type, but tertiary sources such as clinical practice guidelines and textbooks were not used in
the comparative review of LMWH and warfarin. However, tertiary source was used in the
introduction part of the article only. The articles used consist of journal articles, most
compared LMWH and warfarin. There were also randomised trials that were considered as
the best primary source that were used as reference for this report.

References:

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2. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation.
2003:107;I-9-I-6.
3. Buller HR, van Doormal FF, van Sluis GL, Kamphuisen PW. Cancer and thrombosis:
from molecular mechanisms to clinical presentations. J Thromb Haemost.
2007:5(1);246-54.
4. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost.
2009:7(1);301-4.
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Thromb Vasc Biol. 2006:26;41-8.
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system. J Thromb Haemost. 2009:7;4-13.
7. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term Lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with
cancer. Am J Med. 2006:119;1062-72.
8. Babu B, Carman TL. Cancer and clots: all cases of venous thromboembolism are not
treated the same. Cleveland Clin J Med. 2009:26(2);129-35.