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Protocol for Investigations Different guidelines have been recommended by different groups
and individuals for approaching the nal diagnosis of IDDVT.
ACCP guidelines [
score and normal value of D-dimer are present,
no further investigation should be done for conrmation of DVT and alternative diagnosis
should be looked for. With Wells score and higher
than normal D-dimer value both suggesting DVT,
CUS of proximal veins should be performed
immediately. If this is negative, the patient should
be evaluated with whole-leg CUS within 48–72h,
or the patient should be called back after 1week
for proximal vein CUS to detect proximal extension of probable calf vein thrombosis. Prospective
controlled studies with application of these
guidelines are yet awaited [
NICE guidelines [17] from UK also suggest
evaluating Wells score for estimating the probability of DVT to begin with. NICE guidelines categorise Wells score in only two groups—high
and low. The low-risk group undergoes D-dimer
estimation. If it is normal, no further investigation is performed.
In high-risk group, CUS of proximal veins is
performed, and if found positive, anticoagulant
therapy is started. But if CUS is negative, now
D-dimer is estimated. If it is normal, no further
investigation for DVT is done. If D-dimer is high,
CUS is repeated after 1week again for proximal
veins. If this is also negative, no further work-up
for DVT is done. But, NICE guidelines don’t
seem to consider existence of IDDVT in any limb
of the guidelines.
Neither ACCP nor NICE guidelines recommend use of bridging anticoagulation during the
waiting period for high-risk patients. If whole-leg
CUS is performed, the incidence of thromboembolic event is 0.5–0.3%. Righini also reported
that distal DVT was detected in 50% patient with
DVT in such studies, thus increasing the number
of patients receiving anticoagulation [
getting CUS done twice is very expensive and
difcult.
Considering common Indian patient population and their reluctance to travel for investiga-
15] suggest that if Wells
16].
18]. But
tions repeatedly along with their compromised
nancial status, both of these guidelines are not
suitable for them. Limited availability of operators who are appropriately trained for performing CUS is another limiting factor. So in author’s
opinion, the visits to medical facility before
reaching the treatment decision need to be as
few as possible. Or the patient with IDDVT may
be lost for follow-up and then may suddenly
present with extension of thrombus or PE.So
the author prefers to proceed for whole-leg CUS
in patients with high or moderate risk for DVT
based on Wells score and D-dimer levels. The
patients with unlikely probability and low
D-dimer levels are not subjected to any further
investigation for DVT, and alternative diagnosis
is considered.
Above approach may lead to over use of anticoagulant therapy, but I think it is worth it as the
possibility of life-threatening PE and development of troublesome PTS is certainly not desirable particularly in the absence of any long-term
studies related to Indian population.
11.8 Management andOutcome
Management of IDDVT is the most debated
aspect of this condition. There are two main
groups—one that doubts the need for anticoagulation in patients with IDDVT, mainly out of concern regarding haemorrhagic complications of
the therapy. This group recommends anticoagulation only if proximal extension is detected or the
patient belongs to high-risk category. This needs
repeated CUS of whole leg. The second group
believes in proceeding with anticoagulation once
the diagnosis of IDDVT is conrmed without
waiting for proximal extension.
If we consider the guidelines, NICE guidelines don’t seem to consider IDDVT as an entity,
and the investigation protocol does not address
this at all. So the question of treating IDDVT
does not arise as it is not diagnosed unless it leads
to proximal extension [17]. ACCP guidelines recommend anticoagulation of all diagnosed IDDVT
patients with initial parenteral agent like unfractionated or low molecular weight heparin or
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fondaparinux (Grade IA) followed by oral anticoagulation for 3months [15].
It is not surprising that with completely divergent guidelines and confusing, unclear natural
history, different workers in this eld are following and recommending different management
protocols based on presence of symptoms, location and length or diameter of thrombus and presence or absence of risk factors. This has further
added to unclear outcomes and natural history of
IDDVT.
Singh et al. report that asymptomatic ICVT
should not be anticoagulated but observed. But
the study also observed higher possibility of
proximal extension in association with malignancy, orthopaedic surgeries and immobility
[19]. As these are the situations that are more
likely to be associated with asymptomatic
IDDVT due to immobility, withholding anticoagulation is difcult to accept.
In 1992, Solis etal. had reported that anticoagulation did not change the incidence of proximal extension of IDDVT after arthroplasty. So
they suggested that postoperative IDDVT need
not be treated. Repeated CUS was recommended
to detect proximal extension, and then anticoagulation was suggested. This appears inconvenient
from many angles [20] including cost and
availability.
A review article by Giannoukas etal. quoted
signicant increase in incidence of proximal
extension and recurrence of asymptomatic and
hence untreated IDDVT as compared to symptomatic and treated IDDVT [4]. This article
quoted incidence of proximal extension to be
32% and that of PE as 5% as suggested by ventilation perfusion scan. With risk of bleeding being
4–10% with anticoagulation, it was recommended that all patients detected to have IDDVT
should be anticoagulated for 3months. Only the
patients with high risk of haemorrhagic complications were followed with repeat CUS. In the
end this article states that in the absence of properly controlled prospective randomised trials, no
conclusion about treatment recommendation
could be reached [4].
In 2012 Singh etal. report that asymptomatic
ICVT should not be anticoagulated but observed.
But the study also observed higher possibility of
proximal extension in association with malignancy, orthopaedic surgeries and immobility [19]
as these are the situations that are more likely to
be associated with asymptomatic IDDVT due to
immobility, withholding anticoagulation is difcult to accept.
MCVT tends to be more often symptomatic
compared to ICVT, but the outcome on follow-up
as regard to death, recurrence and bleeding is the
same as reported by Galanaud etal. So the author
sees no reason to apply different treatment protocol to each of these entities [2].
Cohen and his group base the treatment decision on length and location of IDDVT. Hence
patients with IDDVT which is close to the venous
conuence, thrombus longer than 10cm in those
with no symptoms and asymptomatic thrombus
with length between 5 and 10cm, but associated
with higher risk for propagation (immobility,
malignancy) are all anticoagulated [7]. This
group does not recommend anticoagulation for
MCVT or small ICVT, instead suggest close
observation of these patients and repeated
CUS. These patients also receive thromboprophylaxis for variable time period. This protocol
obviously involves much more effort and expertise on the part of clinician and more expenses for
the patients. All patients whether symptomatic or
asymptomatic receive graduated compression
stockings and are ambulated as early as possible.
This is very acceptable and applicable for all
patients.
In 2007 Righini detected the incidence of
IDDVT to be 50% of all DVTs when whole-leg
CUS of both legs was performed. But he commented that though the advantages of performing
calf CUS are very valid, diagnosing these
IDDVTs would increase the number of patients
receiving anticoagulation and hence the possibility of overtreatment. So we need randomised
controlled trials [18]. After 10 years in 2017,
Righini and Ebadi reviewed some randomised
trials and observed increased risk of haemorrhagic
complications in symptomatic IDDVT patients
who received anticoagulation. This approach did
not prove to be superior in decreasing the incidence of venous thromboembolism (VTE) when
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compared to group treated with placebo [14]. So
the recommendation of this study was to conduct
more randomised controlled trials to identify the
optimal therapy particularly for high-risk
patients.
Actually this means that treatment concepts
about IDDVT are in the same confused state
today as they were in 1995!
In 2012, Masuda et al. recommended an
ambiguous approach [9]. They suggested acceptance of all reported methods of management of
IDDVT as there is no study providing strong evidence to recommend either repeated CUS or
anticoagulation.
While deciding the agent for anticoagulation,
ACCP guidelines support use of unfractionated
(UFH) or low molecular weight heparin (LMWH)
or fondaparinux either throughout the treatment
period or followed by oral anticoagulants (vit K
antagonist, VKA). A study using nadroparin did
not reveal superiority over placebo in symptomatic low-risk patients. It did not decrease the incidence of proximal extension or VTE. But it
increased the risk of haemorrhage. So the study
concluded that avoiding systemic anticoagulation
would have important effect on patient and would
also reduce the cost of treatment benetting the
public health expenditure [21].
One aspect of management of IDDVT that is
uniformly agreed upon is use of graduated pressure elastic compression stockings (Class II
below knee). This helps in relieving the edema
and pain particularly during initial period.
Available evidence does not support continued
long-term use of compression stockings after
IDDVT [1, 14].
Addressing the duration of anticoagulant therapy, Sule etal. have quoted an open labelled, randomised trial that concluded that anticoagulation
for 6weeks is adequate in patients with IDDVT
[10]. The outcome would certainly guide the
management protocol. Sule et al. have quoted
that 5% of patients presenting with PE were associated with IDDVT.So though the possibility of
PE is more with proximal DVT, it is not negligible with IDDVT. This study also mentions the
incidence of major bleeding following anticoagulation to be 1–7%. The independent factors
responsible for higher likelihood of bleeding
were past history of stroke or gastrointestinal
bleeding, age more than 65years and presence of
one or more comorbid conditions. The incidence
of major bleeding at 48months varied from 3%
to 53% depending on number of risk factors
detected in the patient. After evaluating the low
incidence of proximal extension of IDDVT and
the signicant risk of bleeding after anticoagulation, Sule et al. recommended observation and
follow-up CUS in patients with IDDVT. The
CUS should be done at 2 weeks, 1 month and
3months. Any evidence of extension of thrombus
or augmentation of symptoms should prompt
anticoagulation [10].
After study of all available data about management of IDDVT, conclusion drawn by Ebadi
and Righini seems logical. They suggest that
symptomatic, low-risk patients with IDDVT
should receive compression stockings and follow- up CUS to detect proximal extension and no
anticoagulation. Though the available evidence is
inadequate, symptomatic, high-risk patients with
previous VTE, malignancy and unprovoked DVT
as well as patients with low risk of haemorrhage
should receive anticoagulation in therapeutic
dose [14].
So the pendulum swings from no anticoagulation even after diagnosis of IDDVT to anticoagulation of all patients conrmed to have IDDVT!
Palareti accepts the fact that optimal management
of IDDVT is still a debated topic and probably
same protocol cannot be applied to all patients.
Though CALTHRO study has shown that use of
Class II compression stockings alone has shown
very low incidence of VTE, the therapeutic and
prophylactic utility of this modality has not been
studied yet [3]. The need to diagnose and treat
each patient with IDDVT and the agent and duration of anticoagulation has not yet been established. So we have two options—one is to detect
and treat only proximal DVT or the second being
to perform whole-leg CUS in all suspected cases
and treat all IDDVTs that are detected. If rst
CUS is negative, second CUS after 1week would
be needed in 80–90% of patients, and it’s difcult
to obtain this compliance. But if only the patients
with high D-dimer are called back then, the num-
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ber reduces to 30% [3], and better compliance
may be achieved with appropriate counselling.
The management protocol used by Palareti
seems practical and more suitable for Indian scenario [1]. He opposes the ACCP guidelines that
recommend serial CUS after diagnosis of
IDDVT to detect proximal extension (Grade
2C). His patients as well as mine would want
treatment of their diagnosed, symptomatic
IDDVT, and it has to be in appropriate dose
using appropriate medication. Palareti also
reports low diagnostic accuracy of Wells score
for IDDVT and good negative predictive value
of D-dimer assay. He recommends that all
patients conrmed to have IDDVT should be
evaluated for any contraindications for anticoagulation, and if none are detected, the patient
should be anticoagulated initially with UFH or
LMWH or fondaparinux followed by VKA in
titrated dose for period of 1–3 months. In
selected high-risk cases like presence of malignancy and pregnancy, the parenteral therapy is
continued throughout the treatment period and
even later in prophylactic dose [1]. He recommends reduction in the dose of parenteral anticoagulant to 50% after 2 months in high-risk
patients and after 10 days in transient-risk
patients. The author does not perceive the need
to do this dose modication. All patients are
instructed to use Class II below knee compression stockings. CUS is performed on completion
of anticoagulation period to evaluate the effect
of therapy and status of thrombosed veins.
11.9 The Author’s Approach
Prophylaxis All methods of mechanical and
pharmacological prophylaxis are strictly followed according to risk stratication. Adequate
hydration, early ambulation, calf and ankle exercises in bed and appropriate use of calf pump if
needed are strictly observed. Pharmacoprophylaxis using LMWH is administered in
appropriate dose to all moderate-, high- and very
high-risk patients unless contraindicated. The
time of administration and withdrawal of neuraxial blockade access is adjusted suitably.
Diagnosis of IDDVT
In-hospital or outpatients
with suspicion of IDDVT undergo calculation of
Wells score and evaluation of D-dimer levels.
D-dimer levels may not be dependable particularly in postoperative or trauma patients. Wholeleg CUS is performed in all the suspected patients
based on Wells score and D-dimer. Main problem
is experienced in patients who can’t sit and those
with cast on leg due to orthopaedic surgery or
trauma. Radiologists or technicians well versed
with correct method of performing whole leg
CUS are very few even in metropolis like
Mumbai. It is necessary to encourage them to
learn the methodology, and a document describing the method is provided to them. Even then it
is difcult and repeated serial evaluation is almost
impossible. It is also expensive, and outpatients
particularly from out of Mumbai nd it very difcult to comply with follow-up. Occasionally the
author is forced to ask for MR venography
(though it’s expensive) as application of CUS
technology is difcult due to patient’s condition.
Such a situation may force dependence on proximal CUS and repeat CUS at 1week interval if the
rst evaluation is negative for DVT.
Our Treatment Protocol
All ambulatory
patients are provided with Class II below knee
compression stockings with complete explanation about its use and care.
In all patients with diagnosed IDDVT, anticoagulation is initiated (unless contraindicated)
using LMWH and rarely UFH with dose calculation according to the molecule and weight of
patient. Patients with malignancy and pregnancy
are continued on LMWH.Others start receiving
VKA from day 1, and the overlap continues for at
least 5–6days till the INR reaches 2 on three consecutive evaluations done daily. The INR is maintained in the therapeutic range between 2.5 and 3
by dose titration if needed. INR is evaluated
every 15days after therapeutic range is achieved
and stabilised. This is continued for 3 months,
and CUS is obtained to conrm satisfactory
response before withdrawal of anticoagulation.
Patient and family are educated about the anticoagulant medication, its effects and possible
haemorrhagic complications, need for regular
11 Isolated Infrapopliteal Deep Venous Thrombosis
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monitoring and precautions to be taken. A contact phone number is provided for emergency
contact. Instructions about follow-up schedule
are explained. All these instructions are also provided on a sheet written or printed in the language that the patient or the family can read and
understand. I have observed that patient education is the most important aspect of improving
patient compliance.
Newer oral anticoagulants available in India are
rivaroxaban, apixaban and dabigatran. The availability is rather restricted, and cost is high. But
xed dose, no requirement for repeated dose titration and no need to monitor the therapeutic effect
make these agents easy to use if patients can afford
the cost and ensure availability. The author uses
these agents particularly factor Xa inhibitors (as
direct thrombin inhibitors have really limited
availability) whenever the patient can afford it.
Patient education is certainly desirable.
Conclusion
Due to wide variation in the treatment proto-
col, the outcomes reported vary over a wide
range. The fear of haemorrhagic complica-
tions seems to have overwhelming effect on
the treatment and actually overlooks the pos-
sibility of proximal extension of thrombus,
possibility of PE, development of PTS and
recurrent VTE. All these outcomes, though
less than proximal DVT, are not nonexistent.
It appears that over the last several years,
very little progress has been made regarding
our understanding of natural history, appropriate treatment and optimal dosage of anticoagulants as well as the outcome of IDDVT. So
each one still is forced to follow his or her own
protocol.
The protocol has to depend on accrued
experience, availability and affordability of
investigative modalities and pharmacological
agents, nancial and educational status of
patient population and availability of trained
and interested medical personnel.
But we do need standard guidelines that
can be easily applied and are acceptable. For
this purpose appropriately designed, randomised, controlled trials enrolling large
patient population are desperately needed.
These should preferably be conducted in different countries with application of same
trial design and protocol. This would make it
possible to pool the results and may be prepare guidelines specic for each participating country. These guidelines based on the
conditions specic to that country could then
be recommended as the standard of care for
that country. That would be the ideal solution
to this condition which is in dilemma for
years!
References
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2. Galanaud J-P, Sevestre M-A, Genty C, Laroche J-P,
Zizka V, Quéré I, Bosson J-L, OPTIMEV SFMV
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Diamand JM, Quere I, Bosson JL, OPTIMEV-SFMV
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7. Cohen AT, Balaratnam S, Fassiadis N. Are
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8. Gillet J-L, Perrin MR, Allaert FA. Short-term and
mid-term outcome of isolated symptomatic muscular
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9. Masuda EM, Kistner RL, Musikasinthorn C, Liquido
F, Geling O, He Q.The controversy of managing calf
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10. Sule AA, Chin TJ, Handa P, Earnest A.Should symptomatic, isolated distal deep vein thrombosis be treated
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Novel Biomarkers inDeep Vein
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Thrombosis
AjayK.Khanna, ManbendraVaidya,
andSoumyaKhanna
12
Venous thromboembolic disease (VTE) remains
a signicant source of morbidity and mortality.
As non-specic subjective complaints and a paucity of objective clinical examination ndings
complicate the diagnosis of both deep venous
thrombosis (DVT) and pulmonary embolism
(PE), diagnostic modalities remain essential.
Symptoms suggestive of deep vein thrombosis
are extremely common in practice but unfortunately non-specic. The modied Wells score
remains the most supported clinical decision rule
for risk stratifying these concerns. Compression
ultrasound remains the gold standard for diagnosis of DVT.Reliable imaging is not always available, so making a serologic diagnosis, or
biomarker, is highly desirable. While D-dimer, a
highly sensitive biomarker, is useful for excluding acute VTE, it lacks the specicity necessary
for diagnostic conrmation. As such, ongoing
research efforts target and support the utility of
alternative plasma biomarkers to aid in the diagnosis of VTE including selectins, microparticles,
IL-10, and other inammatory markers. These
molecular markers may also predict recurrence
risk, guide length and modality of treatment, and
predict which thrombi will resolve spontaneously
A. K. Khanna (*)
Department of General Surgery, Institute of Medical
Sciences, Banaras Hindu University, Varanasi, India
M. Vaidya · S. Khanna
Institute of Medical Sciences,
Banaras Hindu University, Varanasi, India
or recanalize, thus potentially identifying patients
who would benet from more aggressive therapies than standard anticoagulation [1].
Currently, the only biomarker used in the diagnosis of deep vein thrombosis (DVT) is plasma
D-dimer. D-dimer, a product of brin degradation, is a sensitive biomarker that, when low or
absent, can be used to exclude or “rule out” the
diagnosis of DVT in patients with a low Wells
score. However, this biomarker is not specic for
DVT as it is frequently elevated in the setting of
non-specic inammation such as cancer, pregnancy, surgery, trauma, etc. Because of the low
specicity of D-dimer, elevated levels alone cannot be used to conrm the diagnosis of DVT, and
in such instances, an imaging study is needed for
denitive diagnosis. The current gold standard for
diagnosis of DVT is compression duplex ultrasound. However, the availability of this diagnostic
modality is limited at smaller medical centers,
outpatient settings, and on nights and weekends
and also person-to-person expertise. In these circumstances, a chemical or laboratory diagnosis to
“rule in” the diagnosis of DVT without having to
rely on duplex ultrasound would be helpful. Using
the biology of platelet and leukocyte activation,
inammation, and thrombosis, it has been identied that soluble P-selectin (sPsel) and microparticles (MP) are potential novel biomarkers to
make the diagnosis of DVT. Of these, sPsel has
shown the greatest promise. D-dimer, a brin degradation product, has been thoroughly investi-
© Springer Nature Singapore Pte Ltd. 2018
A. K. Khanna, R. Jindal (eds.), Venous Disorders, https://doi.org/10.1007/978-981-13-1108-6_12
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A. K. Khanna et al.
gated and performs well in select populations,
although it is best as a rule-out test because of its
generally low specicity. Soluble P-selectin, a
marker of endothelial activation, has shown good
diagnostic performance in several studies but has
not yet been adopted widely. Others, including
cellular adhesion molecules, tissue factor, circulating microparticles, and C-reactive protein, are
under investigation, with varying results in a few
studies [2].
12.1 D-Dimer
D-dimer is the most common and widely
accepted biomarker to rule out deep vein thrombosis. When assayed by a quantitative ELISA or
by some automated turbidimetric assays,
D-dimer is highly sensitive (more than 95%) in
excluding acute deep vein thrombosis or pulmonary embolism, usually below a threshold of
500 μg/L. Hence, a concentration lower than
this value rules out acute venous thromboembolism (VTE), at least in patients with low or
intermediate clinical probability [3]. ELISAbased tests can be of two types, whole-blood or
plasma latex agglutination tests. Sensitivity of
these tests ranges from 84 to 97%, but again,
specicity is low [4]. Recently D-dimer values
are being used as an indicator to determine the
duration for anticoagulation therapy in patients
with DVT or VTE.It has been still a matter of
debate because while extending oral anticoagulation therapy reduces the risk of recurrence by
90%, it is associated with an increased clinically
important risk of major bleeding. In 2005,
Cosmi etal. [5] investigated D-dimer levels in
combination with residual venous obstruction
and the risk of recurrence after anticoagulation
withdrawal for a rst idiopathic DVT.Authors
concluded that abnormal D-dimer levels at
1month after therapy withdrawal are an independent risk factor for recurrent VTE.They also
noted that residual venous obstruction on duplex
ultrasound at the time of oral anticoagulation
withdrawal, despite a normal or abnormal
D-dimer after 1 month, does not inuence the
rate of recurrence.
12.2 Soluble P-Selectin
Soluble P-selectin (sPsel), a member of the selectin family of cell adhesion receptors, has been
proposed as a key molecule in hemostasis and
thrombosis mediating platelet rolling, generating
procoagulant microparticles, and enhancing
brin deposition. Recently soluble P-selectin
(sPsel) has emerged to be a very promising biomarker in diagnosing DVT.P-selectin is an adhesion glycoprotein present in platelet α-granules
and endothelial cell Weibel-Palade bodies that is
responsible for the initiation of leukocyte rolling.
The sPsel has been proposed not only as a marker
of inammation or platelet activation but also as
a direct inducer of procoagulant activity associated with vascular and thrombotic diseases [6].
P-selectin is the major receptor supporting constitutive leukocyte rolling and promotes platelet
adhesion to stimulated vessel wall. It also
enhances brin formation thereby leading to formation of venous thrombosis. The sPsel, when
combined with the Wells score, may represent the
best combination for the diagnosis of VTE.With
a suspicion of DVT, a high Wells score (≥2) and
sPsel above 90ng/mL) may establish the diagnosis of DVT for the rst time, with a positive predictive value (PPV) of 100%. Furthermore, sPsel
has evidenced even a very high sensitivity (99%)
in some cases [7]. However, high sPsel concentrations have been observed in other diseases
including ischemic heart disease, atherosclerosis,
and acute ischemic stroke [8]. Furthermore, high
levels of sPsel were recently associated with an
increased risk for recurrence of DVT.
George etal. [9] studied 11 studies, comprising of 586 VTE patients, and 1843 controls were
deemed eligible. The sPsel was signicantly
increased after VTE (OR=2.89, 95%CI=2.31–
3.61, p < 0.001) or DVT only (OR = 2.64,
95%CI=1.95–3.56, p<0.001). Subgroup analysis evidenced that sPsel was also increased after
VTE when evaluating only studies with patients
that had no prior medical history (OR = 2.88,
95%CI = 1.98–4.19, p < 0.001). Exclusion of
studies including patients with solid organ tumor
and HIV or lupus anticoagulant-positive patients
did not alter the ndings. Pooled sensitivity and
12 Novel Biomarkers inDeep Vein Thrombosis
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131
specicity of sPsel were 0.57 (95%CI = 0.30–
082, p < 0.001) and 0.73 (95%CI = 0.51–0.90,
p < 0.001), respectively, and DOR was 4.31
(95%CI = 2.22–8.37, p < 0.01). SROC curve
yielded in signicant accuracy of sPsel performance (AUC= 0.74, p = 0.05). The sPsel was
signicantly elevated in patients with DVT, both
uncomplicated and complicated with PE, and
presented with high levels of diagnostic
performance.
Knut etal. [10] investigated the plasma levels
of the endothelium-specic biomarkers soluble
E-selectin and endocan in a consecutive and
unselected group of 120 patients admitted to the
hospital for suspected deep vein thrombosis.
DVT patients showed evidence for an acute phase
reaction with increased serum C-reactive protein
levels, but this was similar to many other patients
admitted with suspected but not veried thrombosis. Plasma endocan and E-selectin levels did
not differ between patients with thrombosis,
healthy controls, and the patients without veried
thrombosis (i.e., patients with other causes of
their symptoms, including various inammatory
and non-inammatory conditions). However, the
combined use of endothelial biomarkers,
C-reactive protein, and D-dimer could be used to
identify patient subsets with different frequencies
of venous thrombosis. Thus, analysis of plasma
biomarker proles including endothelial cell
markers may be helpful in the initial evaluation
of patients with deep vein thrombosis.
12.3 Homocysteine
Another biomarker which has shown its close
relation with DVT is homocysteine. More than
40 years ago, it has been reported that some
patients suffering from mental retardation had
homocystinuria and hyperhomocysteinemia.
This group of people also shared other specic
phenotypic characteristics, including skeletal and
ophthalmic abnormalities, as well as an increased
predisposition to thrombosis [11].
Homocysteine is a nonessential sulfated
amino acid that is not directly involved in protein
synthesis. It is ubiquitously produced by all cells
and has been preserved throughout the evolution.
Mild to moderate hyperhomocysteinemia may be
a result of acute occlusive events such as myocardial infarction and thromboembolic stroke [11].
Homocysteine leaks from damaged tissue, and it
also tends to accumulate during the repair process. The latter is possibly due to the essential
methylation reactions required to form new
DNA, RNA, and proteins. High homocysteine
levels are also present in malignancies, including
breast cancer, gliomas, and acute lymphoblastic
leukemia. Total homocysteine concentration in
plasma falls during uncomplicated pregnancy.
The physiology of this is unclear, but it may be
hormonally driven since a similar effect is
observed with combined oral contraceptive pill
use and hormone replacement therapy. A contributory factor could be the use of folate supplements to prevent neural tube defects.
Den etal. [12] studied 24 retrospective studies, which included a total of 3289 subjects with
hyperhomocysteinemia. There was signicant
heterogeneity between the reports, but overall
these studies have shown that each 5 μmol/L
increase in measured homocysteine is associated
with a 60% increased risk of venous thrombosis.
12.4 CRP (C-Reactive Protein)
In 1930 after the publication of the seminal article by Tillett etal. [13] which clearly suggested
that CRP was not really a pathogenic secretion of
bacteria but rather a non-specic physiochemical
reaction to bacterial infection, there have been a
lot of studies which have shown CRP as a predictor in arterial thrombotic events [14]. Clinical
data on the association between increased plasma
CRP concentrations and venous thrombosis are
conicting.
Vormittag etal. [15] studied two case-control
studies and reported a positive univariate association between CRP and VTE, but not after multivariable adjustment. Similarly, Tsai et al. [16]
studied two other cohort studies, with limited
numbers of VTE events, and reported no association between CRP and VTE.However, a subsequent analysis of the prospective population-based
132
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A. K. Khanna et al.
ARIC study which included a larger number of
VTE cases and longer follow-up found that
increased CRP concentrations were independently associated with an increased risk of VTE
[17]. In a recently published case-control study,
Luxembourg etal. [18] showed that markers of
inammation, including brinogen, factor VIII,
and CRP, were at higher concentrations in patients
with idiopathic compared to secondary VTE, supporting the hypothesis that idiopathic VTE and
arterial thromboembolism share common risk
factors. Finally, the prospective Copenhagen City
Heart Study (CCHS) and the cross-sectional
Copenhagen General Population Study (CGPS)
by Zacho etal. [19] observed that nongenetically
increased CRP concentrations were robustly associated with increased risk of VTE.
Although still a matter of debate, the potential
role of CRP in the pathogenesis of cardiovascular
disorders is currently considered plausible,
because inammation represents one of the
underlying mechanisms leading to the formation
of human atheroma, favoring both the destabilization of vulnerable plaques and formation of
occlusive thrombi. Although it has been hypothesized that VTE and arterial thromboembolism
share common risk factors, there is scarce and
mostly conjectural evidence supporting the contribution of increased CRP to the development of
venous thrombosis. Therefore, for cardiovascular
disorders, the crucial and unresolved question is
whether CRP represents an independent risk factor for VTE and may therefore play a causal role
or rather does it reect mutual associations with
established VTE risk factors.
tion between elevated plasma FVIII levels and
VTE was rst described in the Leiden
Thrombophilia Study (LETS). Cumulatively,
studies have clearly demonstrated that high FVIII
levels constitute a prevalent, dose-dependent risk
factor for VTE.Furthermore, more recent studies
have shown that the risk of recurrent venous
thrombosis is also signicantly increased in
patients with high FVIII levels.
In a retrospective study, Kraaijenhagen et al.
[20] studied 60 patients with recurrent VTE, 65
patients with a single episode of thrombosis, and
60 age- and sex-matched controls. The authors
calculated that for each 10 iu/dL increment in
plasma FVIII level, the risk for a single and recurrent episode of VTE increased by 10% and 24%,
respectively. Furthermore, for patients with FVIII
levels above 200iu/dL, the odds ratio for a recurrent thrombotic episode was markedly elevated at
45. Kyrle etal. [21] studied 360 patients with a
rst episode of objectively conrmed VTE.Plasma
FVIII levels were signicantly increased in the
cohort of patients who developed recurrent
VTE.However the relationship between increased
FVIII levels and risk of recurrent thrombosis was
nonlinear. Consequently, patients with plasma
FVIII levels above the 90th percentile (>234iu/
dL) were at particular high risk for developing
recurrent VTE.Cristina etal. [22] in his prospective cohort study also observed that the risk of
recurrent venous thrombosis was signicantly
increased in patients with elevated FVIII.
12.6 Microparticles (MPs)
12.5 Factor VIII
Modern thrombophilia testing fails to identify
any underlying prothrombotic tendency in a signicant number of patients presenting with
objectively conrmed VTE.This observation has
led to a search for other novel inherited or
acquired human thrombophilia markers. An
increasing body of work supports the hypothesis
that increased plasma factor VIII (FVIII) levels
may be important in relation to DVT.An associa-
Microparticles (MPs) are small (0.1–1.0 μm)
membrane vesicles constitutively released from
the surface of cells after activation and apoptosis.
The clinical research on MPs is hampered by the
limitations of the currently available detection
methods. A correlation between MPs and venous
thromboembolism (VTE) has been observed.
The effects of MPs on thrombogenesis involve
the exposure of phosphatidylserine, the vehiculation of tissue factor, and MP-induced intercellular cross talk between inammation and
coagulation [23].
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