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100 Acute and chronic venous thrombosis
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while forming a microbial containment barrier,
116,117
and
it has also been reported in the vasculature during sepsis and in inammatory non-infectious disease states,
such as small-vessel vasculitis.
118,119
It has recently been
shown that extracellular DNA contributes to thrombosis in experimental animal models.
120
In addition to their
phagocytic and bactericidal functions, neutrophils and
other leukocytes are known to release DNA bers to form
extracellular traps,
121–124
and neutrophils are one of the
main inammatory cells that participate in acute VT.20
In thrombi obtained from experimental VT in baboons
and mice,
of the thrombi, and co-localize with VWF.
126,127
extracellular traps are a structural part
120
Based on
125
these studies, extracellular DNA has recently been studied as a potential biomarker of VT. e results of this
study showed a signicant increase in circulating extracellular DNA in VT-positive patients compared to healthy
and VT-negative controls.
128
Extracellular DNA linked to
VT is one of the most promising discoveries in thrombogenesis, and we believe this will lead to a new era in VT
research.
8.6.2.1 GALECTINS AND VT
Galectin 3 (gal3) and gal3 binding protein (gal3 bp) play
important roles in a number of pathologies, such as cancer,
infections, diabetes, atherosclerosis, wound healing, and in
inammatory disorders such as asthma and rheumatoid
arthritis, but their role in VT has not been dened.
129 –137
gal3 bp was found to be upregulated in microparticles collected from human patients diagnosed with deep VT.
138
gal3 bp is a member of the lectin family and is associated
with integrin-mediated cell adhesion.
139
Recently, a detailed
review of galectins and their potential role in venous thrombogenesis, inammation, and brosis was published.78 e
results of these studies provide evidence that microparticles
are associated with VT; however, their role in thrombogenesis and also their potential role as biomarkers of VT were
recently studied.
140
Our laboratory recently discovered that
gal3 and gal3 bp are associated with murine thrombogenesis and co-localization, and that thrombogenesis is in part
gal3 dependent. We also showed that gal3 could be a potential biomarker in patients with acute VT.
140
gal3 bp and gal3
were found in all tissue and blood elements pertinent to
the thrombi that were examined (microparticles, red blood
cells, platelets, vein wall, and thrombus), with the exception
of leukocytes. In addition, increased levels of gal3 bp and
gal3 were observed during VT conditions in both mice and
humans in our recent work, showing parallelism between
these two species. However, despite the fact that the concentration levels of gal3 bp exceeded gal3 levels, our data
showed that the increased levels of gal3 were higher in VT
compared to the non-VT condition. Biomarkers of VT are
being intensively explored due to the absence of any that are
capable at present of ruling in VT, and herein we present
two clear biomarker candidates to be evaluated in future
studies.
140
8.7 CONCLUSION
It is an exciting time to study venous thrombogenesis and
the pathophysiology of the resulting vein wall damage,
in part because it has been relatively neglected compared
with arterial disease. Fortunately, the National Institutes of
Health has put forth two requests for funding applications
in the last several years to better study the clinical and basic
pathobiology of venous disease, and the Surgeon General
has approved a call to action against VTE. Adjuncts to or
replacement therapies for anticoagulants hold tremendous
promise, and will hopefully decrease the early risk of PE and
the late complications of PTS for the benet of the patient.
Guidelines 1.7.0 of the American Venous Forum on Acute and Chronic Venous Thrombosis: Pathogenesis and New Insights
No. Guideline
1.7.1 Acute venous thrombosis causes an acute to chronic inflammatory
responsein both the vein wall and the thrombus. This leads to thrombus
amplification, organization, and recanalization and damage to the vein
wall and the valves
1.7.2 D-dimer, endothelium, platelet derived microparticles and soluble P-selectin
are markers of thrombosis and they are increased in patients with acute
venous thromboembolism.
1.7.3 Resolution of the thrombus is modulated by natural anticoagulants such as
antithrombin III, protein C and S, and thrombin.
1.7.4 Polymorphonuclear cells promote both fibrinolysis and collagenolysis and
they play key role in thrombus resolution. Monocytes are essential in late
thrombus resolution.
Grade of evidence
(A: high quality;
B:moderate quality;
C:low or very low quality)
A
A
B
A
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120. Fuchs TA, Brill A, and Wagner DD. Neutrophil
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121. Brinkmann V, Reichard U, Goosmann C etal.
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Epidemiology and risk factors of acute
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venousthrombosis
MARK H. MEISSNER
9
9.1 Introduction 107
9.2 The epidemiology of lower extremity DVT 107
9.3 Risk factors for DVT 109
9.1 INTRODUCTION
Deep venous thrombosis (DVT) and pulmonary embolism (PE) share many risk factors and pathophysiological
features and are usually considered manifestations of the
same disease: venous thromboembolism (VTE). A total of
25%–40% of patients with DVT have asymptomatic PE.
VTE is the third most common cardiovascular disorder in
Western populations, following only myocardial infarction
and stroke.
e incidence of DVT is approximately twice that of
PE,2 so that among patients presenting with VTE, approximately a third manifest PE while two-thirds manifest DVT.
e deep veins of the lower extremity are most commonly
involved, although with more frequent instrumentation and
improved diagnostic tests, thrombosis of the upper extremity veins is increasingly being recognized. rombosis only
rarely involves unusual sites such as the cerebral sinuses,
retina, and mesenteric veins. e prevention and management of VTE requires some understanding of its epidemiology and associated risk factors, particularly in recognizing
populations warranting prophylaxis, counseling patients
regarding high-risk situations such as pregnancy, contraception, and hormone-replacement therapy, and determining the duration of anticoagulation required to minimize
recurrent thrombosis.
3
1,2
9.2 THE EPIDEMIOLOGY OF LOWER
EXTREMITY DVT
e incidence of lower extremity DVT is highly dependent on the population studied, their underlying risk factors, and the means by which DVT is documented. Autopsy
studies are biased by the inclusion of the very sick and very
9.4 Conclusions 115
References 115
old, while clinical trials are oen directed towards specic inpatient groups, such as post-operative patients. True
estimates of the incidence of DVT are limited by the few
population-based studies, the clinically silent nature of
most thromboses, and the need for objective documentation of the diagnosis. Even the interpretation of methodologically sound studies is complicated by the inconsistent
inclusion of DVT and/or PE, diering exclusion or inclusion of recurrent DVT, and variable age ranges. It is generally believed that incidence rates from autopsy studies are
overestimates, while those from epidemiological studies are
underestimates.
Although likely an underestimate due to the outpatient
treatment of VTE, recent estimates suggest an average of
547,596 hospitalizations with a diagnosis of VTE per year in
the United States.5 A systematic review of nine methodologically sound epidemiological studies suggests a weighted
mean age-adjusted incidence of a rst episode of DVT alone
of 50.4 per 100,000 person-years.6 Considering both DVT
and PE, the age- and sex-adjusted incidence of rst-time
symptomatic VTE (DVT + PE) in the United States is esti-
mated to be between 71 and 117 cases per 100,000 population.4 A substantial increase in the incidence of VTE has
been noted since 2001, largely due to an increased incidence
of PE but not DVT.7 Among people of European descent,
more recent reviews report an incidence of 104–183 per
100,000 for VTE, 45–117 per 100,000 for isolated DVT, and
29–78 per 100,000 for PE alone.7 It has been suggested that
the rising incidence of PE is related to the increased availability and diagnostic accuracy of computed tomography
pulmonary angiography and magnetic resonance imaging.
Despite this observation, the age-adjusted PE mortality rate
in France has been noted to decline by 3% per year between
2000 and 2010.
4
8
107
108 Epidemiology and risk factors of acute venousthrombosis
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DVT is a multi-causal disease resulting from the interaction of genetic and environmental risk factors. rombosis
occurring in the absence of recognized thrombotic risk factors is designated primary, idiopathic, or unprovoked DVT,
while that developing in their presence is designated secondary or provoked DVT. e proportion of patients with
idiopathic DVT ranges between 26% and 49%.
1,3, 4,9,10
Risk
factors for secondary or provoked DVT may be either transient or permanent and may be either genetic or acquired
(environmental). Permanent risk factors may be considered
to be those that raise an individual’s baseline thrombotic
potential, while transient risk factors are oen those that
trigger an acute thrombotic event. Temporary, reversible
risk factors are present in 42.4% of patients, most commonly immobility (15%), surgery (14.4%), and severe medical illness (8.2%).
10
Most risk factors for DVT can be related to the components of Virchow’s triad—stasis, abnormalities of the vessel
wall, and abnormalities of blood—and many are associated
with some component of hypercoagulability on a genetic,
acquired, or situational basis (Table 9.1). Well-established
risk factors for thrombosis are shown in Table 9.2.
11–27
ere
are substantial dierences between the risk factors associated with inpatient and outpatient DVT. Although malignancy, surgery, and trauma within the previous 3 months
remain signicant risk factors for outpatient thrombosis, the frequencies of surgery and malignancy are higher
among inpatients with DVT.
28,29
Furthermore, although
usually considered to be manifestations of the same disease, some of these factors do appear to have a dierential eect on the risk of DVT and PE.2 Black ethnicity and
some inammatory pulmonary diseases (chronic obstructive pulmonary disease, sickle cell trait, and pneumonia)
appear to be stronger risk factors for PE, while minor leg
injuries, obesity, reproductive factors (oral contraceptives
[OCs] and pregnancy) and the factor V Leiden mutation are
stronger risk factors for DVT.2 Many of the risk factors more
strongly associated with DVT arise from activated protein
C resistance, and it has been postulated that this may be due
to associated impaired brinolysis and decreased embolic
risk in these patients.
e degree of risk associated with each of these factors
has been established to a variable extent (Table 9.2), but the
importance of any individual factor is a function of both
its relative risk in comparison to normal controls and its
prevalence in the population. For example, although deciencies of the natural anticoagulants (antithrombin, protein C, and protein S) are associated with an approximately
10-fold increased risk of thrombosis, they are rare defects.
In contrast, the factor V Leiden mutation is associated with
a much lower relative risk, but with a prevalence of 5% in
Caucasians, it is far more important from a populationbased perspective.
Perhaps most importantly, the development of clinically
manifest thrombosis usually occurs with the convergence of
multiple genetic and acquired risk factors. e simultaneous presence of multiple risk factors is in fact oen a prerequisite for thrombosis. In symptomatic outpatients, the odds
ratio for an objectively documented DVT increases from
1.26 for one risk factor to 3.88 for three or more risk factors.28 However, many gene–gene and gene–environment
interactions are synergistic, dramatically increasing risk
above the sum of individual risk factors.17 For example, air
travel in a patient with factor V Leiden and high factor VIII
levels increases thrombotic risk by approximately 50-fold.
30
Finally, it is clear that VTE is the acute manifestation
of a chronic disease. Approximately 30% of patients will
sustain a recurrent event within 10 years of a rst episode
of VTE.7 Although the 10-year risk of recurrence is as high
as 50% in patients with idiopathic DVT, even among those
with secondary VTE it may be as high as 22.5%.31 Risk
factors for recurrence include unprovoked DVT, thrombophilia, age, obesity, male gender, active cancer, and
neurological diseases associated with lower extremity pare-
7,3 1
sis.
Persistently elevated D-dimer levels, as an indicator
of ongoing activation of coagulation, are also predictive
Table 9.1 Congenital, acquired, and situational thrombophilias
Congenital Acquired Situational Congenital or acquired
Factor V Leiden Age Surgery Hyperhomocysteinemia
Prothrombin G20210A Malignancy Trauma Factor VIII, IX, and XI excess
AT deficiency Antiphospholipid antibodies Pregnancy
Protein C deficiency HIV infection Oral contraceptives
Protein S deficiency Polycythemia vera Hormone-replacement therapy
Elevated plasma factor VIII Paroxysmal nocturnal
Elevated plasma factor XI Heparin-induced
Non-type O blood Behcet disease
Note: AT, antithrombin.
hemoglobinuria
thrombocytopenia
Nephrotic syndrome
Inflammatory bowel disease
Hyperthyroidism
9.3 Risk factors for DVT 109
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Table 9.2 Thromboembolic risk factors
Risk factor Prevalence
Age 1.9× per 10-year increase 11
Surgery 18%–39% 4–5.9× (general surgery: 25%; retropubic
Trauma 3%–12% 20.5× 14
Malignancy 18%–51% Without chemotherapy: 4.4–6.9×
Hospital/nursing home 18.4× 14
History of venous thromboembolism 15.6× 16
Primary hypercoagulable states
AT, protein C&S deficiency 5.5%–9.5% 10×
Factor V Leiden 20%
Heterozygous 3–8× 2,13,15,17,18
Homozygous 50–80×
Prothrombin 20210A 4%–7% 2–4×
Increased factor VIII 25% 6×
Increased factor IX
Increased factor XI
Hyperhomocysteinemia
Non-O blood type
Family history 2.9× 19
Oral contraceptives 16%
Estrogen replacement 2–4× 21
Immobilization 10%–17% 2× (pre-operative) to 5.6× (medical patients) 16,22
Long-distance travel 13.3% 2.4–4× 13,16,23,24
Pregnancy and puerperium 25%–30%
Central venous catheter 11.8× 14
Antiphospholipid antibodies 3.1% Lupus anticoagulant: 6×
Inflammatory bowel disease 1.2%–7.1% 1.5–3.6× 2,27
Hyperthyroidism 2× 2
Obesity Variable
Varicose veins Variable
Myocardial Infarction/CHF 11% Variable
Note: AT, antithrombin; CHF, congestive heart failure.
a
Prevalence of risk factor among patients with deep venous thrombosis or venous thromboembolism (population-attributable risk).
b
Among women <45 years of age.
10% 2×
a
prostatectomy: 32%; gynecology (benign
disease): 14%; neurosurgery: 22%; hip/
knee arthroplasty: 51%/47%)
With chemotherapy: 6.5–9.9×
2.2×
2–3×
1.6–2.3×
b
b
2.9×
(30–50× with factor V Leiden)
4.3× 25
Anticardiolipin antibody: 2×
Risk References
12,13
14,15
20
26
of recurrence.32 ere is also a signicant relationship
between the incident event—whether DVT or PE—and the
type of recurrent event. ose with a PE as the index event
are more likely to present with recurrent PE than those
with primary DVT.
9.3 RISK FACTORS FOR DVT
9.3.1 Demographic risk factors
Age, gender, and race may inuence the incidence of DVT.
Among these, age has been most consistently associated
with an increased risk of DVT. e incidence of DVT
increases exponentially with age,
3
rising by a factor of 200
between 20 and 80 years of age, with a relative risk of 1.9
for each 10-year increment.11 Rosendaal33 similarly noted an
incidence of 0.006 per 1000 children under 14years of age
increasing to 0.7 among adults of 40–54 years of age, while
34
Hansson et al.
found the prevalence of objectively documented thromboembolic events among men to increase
from 0.5% at 50 years of age to 3.8% at 80 years of age.
Several age-associated factors, including decreased mobility, an increased number of major thrombotic risk factors,
age-related hypercoagulability, and changes in the venous
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