DEEP VEIN THROMBOSIS (DVT)

Introduction
Deep-vein thrombosis (DVT) is a blood clot that
forms within the deep veins, usually of the leg, but
can occur in the arms and the mesenteric and
cerebral veins. Deep-vein thrombosis is a common
and important disease. It is part of the venous
thromboembolism disorders, representing the third
most common cause of death from cardiovascular
disease after heart attacks and stroke. Even in
patients who do not get pulmonary emboli,
recurrent thrombosis and "post-thrombotic
syndrome" are major causes of morbidity. Deep-
vein thrombosis is a major medical problem
accounting for most cases of pulmonary embolism.
Only through early diagnosis and treatment can
the morbidity be
Etiology
Risk Factors
Following are the risk factors that are considered
causes of deep venous thrombosis:
 Reduced blood flow: Immobility (bed rest,
general anesthesia, operations, stroke, long
flights)
 Increased venous pressure: Mechanical
compression or functional impairment leading
to reduced flow in the veins (neoplasm,
pregnancy, stenosis, or congenital anomaly
which increases outflow resistance)
 Mechanical injury to the vein: Trauma, surgery,
peripherally inserted venous catheters,
previous DVT, intravenous drug abuse
 Increased blood viscosity: Polycythaemia rubra
vera, thrombocytosis, dehydration
 Anatomic variations in venous anatomy can
contribute to thrombosis
 Increased Risk of Coagulation
[Link] deficiencies: Anticoagulation proteins
C and S, antithrombin III deficiency, factor V
Leiden mutation
[Link]: Cancer, sepsis, myocardial infarction,
heart failure, vasculitis, systemic lupus
erythematosus and lupus anticoagulant,
inflammatory bowel disease, nephrotic
syndrome, burns, oral estrogens, smoking,
hypertension, diabetes
Constitutional Factors
Obesity, pregnancy, the advanced age of older
than 60, surgery, critical care admission,
dehydration, and cancer are the established
causalities of DVT and VTE. Obesity is associated
with a hypercoagulability status via two
mechanisms, 1. Increased fibrinogen levels that
may even surpass twofold the normal value, and 2.
Slower venous circulation flow in the infra
diaphragmatic and especially in the lower limbs.
Both factors, associated with disorders in several
coagulation factors, favor the appearance of
venous thrombosis, thrombophlebitis, and
thromboembolic events, and mostly fatal
pulmonary thromboembolisms (PE), which are the
primary cause of mortality in obese patients.
Potential risk factors of deep vein thrombosis might
be categorized according to the transient,
persistent, or unprovoked criteria. Accordingly,
transient risk factors are as follows:
[Link] with general anesthetics,
[Link]
3. Cesarean section
4.. Hormone replacement therapy
[Link] and peripartum period
6.. Lower extremity injury with limited mobility
for more than 72 hours.
It should be noted that general anesthesia for
longer than 30 minutes and hospitalization for
longer than 72 hours are considered the transient
risk factors of DVT. However, active cancers and
specific medical conditions that increase the risk of
venous thromboembolism are categorized as
persistent risk factors. Systemic lupus
erythematosus and inflammatory bowel disease
are among the predisposing medical conditions.
Any further etiological risk factors not categorized
among either transient or persistent subgroups
should be labeled as unprovoked VTE. For instance,
a recent cohort study, including 500 participants
evaluating the association of blood lipid levels and
lower extremity DVT (LEDVT), demonstrated that
higher total cholesterol levels, high-density
lipoprotein (HDL-C), and apolipoprotein A1 (ApoA1)
were associated with a decreased risk of lower
extremity DVT (LEDVT). However, higher
triglyceride levels (TG) were associated with a
greater risk of LEDVT.
Epidemiology
Incidence and prevalence: Deep-vein thrombosis
and pulmonary emboli are common and often
“silent” and thus go undiagnosed or are only
picked up at autopsy. Therefore, the incidence and
prevalence are often underestimated. It is thought
the annual incidence of DVT is 80 cases per
100,000, with a prevalence of lower limb DVT of 1
case per 1000 [Link] in the United
States, more than 200,000 people develop venous
thrombosis; of those, 50,000 cases are complicated
by pulmonary embolism.

 Age: Deep-vein thrombosis is rare in children,

and the risk increases with age, most occurring
in the over-40 age group.
  Gender: There is no consensus about whether
there is a sex bias in the incidence of DVT.
 Ethnicity: There is evidence from the United
States that there is an increased incidence of
DVT and an increased risk of complications in
African Americans and white people compared
to Hispanic and Asian populations.
 Associated diseases: In the hospital, the most
commonly associated conditions are
malignancy, congestive heart failure,
obstructive airway disease, and patients
undergoing surgery.
Pathophysiology
According to the Virchow triad, the following are
the main pathophysiological mechanisms involved
in DVT:

[Link] to the vessel wall

[Link] flow turbulence
[Link]
Thrombosis is a protective mechanism that
prevents the loss of blood and seals off damaged
blood vessels. Fibrinolysis counteracts or stabilizes
thrombosis. The triggers of venous thrombosis are
frequently multifactorial, with the different parts of
the triad of Virchow contributing in varying degrees
in each patient, but all result in early thrombus
interaction with the endothelium. This stimulates
local cytokine production and causes leukocyte
adhesion to the endothelium, promoting venous
thrombosis. Depending on the relative balance
between the coagulation and thrombolytic
pathways, thrombus propagation occurs. DVT is
commonest in the lower limb below the knee and
starts at low-flow sites, such as the soleal sinuses,
behind venous valve pockets.A potential
correlation between DVT and atherosclerosis (AS)
has been proposed. The endothelial dysfunction
involved in the pathophysiological mechanism of
DVT would potentially result in AS. Accordingly, a
greater risk of subsequent AS in patients with DVT
is predicted.
Histopathology
In the venous system following acute thrombosis
formation, an extensive remodeling process occurs.
Neutrophils and macrophages infiltrate the fibrin
clot from within the lumen of the vessel over weeks
leading to cytokine release and, eventually,
fibroblast and collagen replacement of fibrin. This
remodeling and fibrosis can result in diminished
blood flow long after the acute thrombosis
resolves.
History and Physical
The clinical presentation of acute lower extremity
DVT varies with the anatomic distribution, extent,
and degree of
occlusion of the thrombus. Symptoms may range
from absence to massive swelling and cyanosis
with impending venous gangrene. Three patterns
of thrombosis are usually recognized: isolated calf
vein (distal), femoropopliteal, and iliofemoral
thrombosis, and symptoms tend to be more severe
as thrombosis extends more proximally. However,
up to 50% of patients with acute DVT may lack
specific signs or symptoms. Postoperative patients
are, in particular, more likely to have small,
asymptomatic, distal, non-occlusive thrombi. When
present, signs and symptoms of acute lower
extremity DVT may include pain, edema, erythema,
tenderness, fever, prominent superficial veins, pain
with passive dorsiflexion of the foot (Homan’s
sign), and peripheral cyanosis. Phlegmasia cerulea
dolens, characterized by the triad of massive
swelling, cyanosis, and pain, is the most severe
form of acute lower extremity DVT and results from
complete thrombosis of an extremity’s venous
outflow. In advanced cases, it is marked by severe
venous hypertension with collateral and
microvascular thrombosis, leading to venous
gangrene. Venous gangrene is particularly
associated with warfarin-mediated protein C
depletion in patients with cancer or heparin-
induced thrombocytopenia.
Obtaining the diagnosis of DVT only based on clinical signs and
symptoms is notoriously inaccurate. The signs and symptoms of
DVT are generally non-specific. They may be associated and
misdiagnosed with other lower extremity disorders.
Accordingly, lymphedema, superficial venous thrombosis, and
cellulitis should be excluded. However, the most common
presenting symptoms with inconsistent sensitivity and
specificity are calf pain and swelling. The former index has a
sensitivity of 75% to 91% and a specificity of 3% to 87%, and
the latter might have a sensitivity of up to 97% and a specificity
of up to 88%. None of the signs or symptoms is sufficiently
sensitive or specific, either alone or in combination, to
accurately diagnose or exclude thrombosis.
History
 Pain (50% of patients)
 Redness
 Swelling (70% of patients)
Physical Examination
 Limb edema (may be unilateral or bilateral if the thrombus
extends to pelvic veins)
 Red and hot skin with dilated veins
 Tenderness
The Wells Score is widely used to estimate the
probability of DVT
Wells Criteria
 Active cancer – 1
 Paralysis, paresis, or recent plaster cast – 1
 Recently bedridden >3 days or major surgery
within 12 weeks – 1
 Localized tenderness along deep veins – 1
  Entire leg swollen – 1
 Calf swelling >3 cm compared to other leg – 1
 Pitting edema limited to symptomatic leg – 1
 Collateral superficial veins – 1
 Previous DVT – 1
 Alternative diagnosis more likely – –2
Interpretation
0 or less = Low probability
1–2 = Moderate probability
3 or more = High probability
DIAGNOSIS
[Link] Tests

A. D-Dimer Test
Measures fibrin degradation products.
Very sensitive but not specific.
A negative D-dimer in a patient with low or
moderate Wells score strongly rules out DVT.
False positives occur in:
 Pregnancy
 Cancer
 Post-surgery
 Elderly
 Infections
Therefore, a positive D-dimer does NOT confirm
DVT — it simply means imaging is required.
[Link] Studies (Definitive Diagnosis)
[Link] Ultrasonography (CUS) – First-
line test
 Most commonly used.
 Looks for incompressible veins, which indicates
a thrombus.
 High sensitivity for proximal DVT, slightly lower
for distal DVT.
 Duplex ultrasound includes:
 B-mode imaging
 Doppler flow analysis
B. Whole-leg ultrasound
Evaluates both proximal and distal veins in one
test.
C. CT Venography
Used when ultrasound is inconclusive or pelvic DVT
is suspected.
 D. MR Venography
Highly sensitive but expensive; used selectively.
[Link] Venography (rarely used)
 Gold standard historically
 Invasive, requires contrast
 Now replaced by ultrasound
Diagnostic Pathway
 Step 1: Assess symptoms + Wells score
Low Wells score → do D-dimer
High Wells score → skip D-dimer, go directly to
ultrasound
 Step 2: D-dimer
Negative + low risk → DVT excluded
Positive → ultrasound required
 Step 3: Compression Ultrasound
Positive → DVT confirmed → start anticoagulation
Negative + high Wells → repeat ultrasound in 5–7
days
Negative + low Wells → DVT excluded
Treatment / Management
Treatment of DVT aims to prevent pulmonary
embolism, reduce morbidity, and prevent or
minimize the risk of developing post-thrombotic
syndrome. The cornerstone of treatment is
anticoagulation. NICE guidelines only recommend
treating proximal DVT (not distal) and those with
pulmonary emboli. In each patient, the risks of
anticoagulation need to be weighed against the
benefits. Treatment for DVT should be addressed
mainly according to the underlying causality of DVT
as follows:

The preferred anticoagulant to address DVT in

cancer-associated thromboembolism is low
molecular weight heparin and factor Xa inhibitors,
including rivaroxaban. However, in the following
circumstances, the higher levels of anticoagulation
should be considered:
1. recently diagnosed cancer,
2. extensive VTE circumstances, and
3. cancer treatment-related adverse effects,
including vomiting.

In circumstances where once-daily oral therapy is

the preferred management, the following options
are viable;
1. rivaroxaban,
2. edoxaban, and
3. vitamin-K antagonist (VKA)

In the context of liver disease, DVT should be

managed with low-molecular-weight [Link]
oral anticoagulants (DOACs) are contraindicated in
raised INR levels.
In patients with renal disease suppressed
creatinine clearance to less than 30 ml/min, VKAs
are recommended. DOACs and LMWH should be
avoided in patients with end-stage renal disease.
In patients with a remarkable past medical history
of coronary artery disease, the following
alternatives are recommended: 1. VKA,
2. rivaroxaban,
3. apixaban, and
4. edoxaban.
In patients with remarkable dyspepsia or any past
medical history suggestive of gastrointestinal
bleeding, VKA, and apixaban are the preferred
treatments. It should be noted that DOCAs, eg,
dabigatran, factor Xa inhibitors, eg, rivaroxaban,
and selective factor Xa inhibitors, eg, edoxaban,
might be associated with higher rates of
gastrointestinal bleeding.
In the group of patients with a history compatible
with poor compliance, VKA is preferred. However, it
should be noted that some patients might still be
highly compliant with other alternatives, including
DOACs.
If thrombolytic therapy is indicated, unfractionated
heparin is indicated.
In patients who might later be subjected to
reversal of thrombolytic therapy, it should be noted
that reversal agents for DOACs are not universally
available.
Since most anticoagulants have the potential to
cross the placenta, the preferred anticoagulation
therapy during pregnancy is LMWH.
Moreover, the following guidelines address the
required duration of treatment.

[Link] low-molecular-weight heparin or

fondaparinux for 5 days or until the international
normalized ratio (INR) is greater than 2 for 24
hours (unfractionated heparin for patients with
renal failure and increased risk of bleeding).
[Link] with vitamin K antagonists for 3
months.
[Link] patients with cancer, consider anticoagulation
for 6 months with low-molecular-weight heparin.
[Link] patients with unprovoked DVT, consider
vitamin K antagonists beyond 3 months.
[Link] is an oral factor Xa inhibitor that has
recently been approved by the Food and Drug
Administration and NICE and is attractive because
there is no need for regular INR monitoring.
[Link] the platelet count drops to less than 75,000,
switch from heparin to fondaparinux, which is not
associated with heparin-induced
thrombocytopenia.
Thrombolysis: The indications for the use of
thrombolytics include:

Symptomatic iliofemoral DVT

Symptoms of less than 14 days duration
Good functional status
A life expectancy of 1 year or more
Low risk of bleeding
The use of thrombolytic therapy can result in an
intracranial bleed, and hence, careful patient
selection is vital. Recently endovascular
interventions like catheter-directed extraction,
stenting, or mechanical thrombectomy have been
tried with moderate success.

Compression hosiery: Below-knee graduated

compression stockings with an ankle pressure
greater than 23 mm Hg for 2 years if there are no
contraindications
Inferior vena cava filters: If anticoagulation is
contraindicated or if emboli are occurring despite
adequate anticoagulation

Newer Drugs:

Rivaroxaban, apixaban, dabigatran, edoxaban, and

betrixaban are relatively newer factor Xa inhibitors
approved for prophylaxis of deep vein thrombosis.
The duration of DVT treatment is 3 to 6 months,
but recurrent episodes may require at least 12
months of treatment. Patients with cancer need
long-term treatment. Inferior vena cava filters are
not recommended in acute DVT. There are both
permanent and temporary inferior vena cava filters
available. These devices may decrease the rate of
recurrent DVT but do not affect survival. Today,
only patients with contraindications to
anticoagulation with an increased risk of bleeding
should have these filters inserted
Differential Diagnosis
The following are differential diagnoses of deep
venous thrombosis:

 Cellulitis
 Post-thrombotic syndrome (especially venous
eczema and lipodermatosclerosis)
 Ruptured Baker cyst
 Trauma
 Superficial thrombophlebitis
 Peripheral edema, heart failure, cirrhosis,
nephrotic syndrome
 Venous or lymphatic obstruction
 Arteriovenous fistula and congenital vascular
abnormalities
 Vasculitis
Complication
The following are the 2 major complications of DVT:
 Pulmonary emboli (paradoxical emboli if an atrial-septal
defect is present)
 Post-thrombotic syndrome
 Bleeding from the use of anticoagulants
Prognosis
The prognosis for DVT includes the following:
 Many DVTs will resolve with no complications.
 Post-thrombotic syndrome occurs in 43% of patients 2
years post-DVT (30% mild, 10% moderate, and severe
3%).
 The risk of recurrence of DVT is high (up to 25%).
 Death occurs in approximately 6% of DVT cases and 12%
of pulmonary embolism cases within one month of
diagnosis.
 Early mortality after venous thromboembolism is strongly
associated with the presentation of pulmonary embolism,
advanced age, cancer, and underlying cardiovascular
disease.
Referrences
 1. Harrison’s Principles of Internal Medicine, 21st edition
Chapter on Venous Thromboembolism.
2. Tintinalli’s Emergency Medicine, 9th edition
Chapter: “Venous Thromboembolism: Diagnosis and
Management.”
3. Braunwald’s Heart Disease Textbook
Section: Thromboembolic Disease.
4. Oxford Handbook of Clinical Medicine
Section on DVT evaluation and diagnosis