Risk Factors For Venous and Arterial Thrombosis

REVIEW
Risk factors for venous and arterial thrombosis
Emanuele Previtali, Paolo Bucciarelli, Serena M. Passamonti, Ida Martinelli
A. Bianchi Bonomi Haemophilia and Thrombosis Centre, Department of Internal Medicine and Medical
Specialties, IRCSS General Hospital, Policlinico , Mangiagalli and Regina Elena Foundation, Milan, Italy
Introduction thrombosis. Pathophysiological and epidemiological

Thrombophilia is considered as a condition findings have enabled the definition of the main risk
predisposing to the development of thrombosis. factors for atherothrombosis and VTE, listed in Tables
Arterial thrombosis usually occurs after the erosion I and II. This review summarises the recent
or rupture of an atherosclerotic plaque and, through epidemiological data on the main risk factors for
platelet-mediated thrombi, can cause ischaemic venous and arterial thrombosis, and considers the
injuries especially in tissues with a terminal vascular mechanisms by which they mediate the disease.
bed. Indeed, cardiac ischaemia and stroke are the most
severe clinical manifestations of atherothrombosis. Table I - Classical risk factors for cardiovascular
Ischaemia can arise slowly from the progression of disease35.
atherosclerotic disease (stable angina, claudication)
or acutely in the case of vascular (atherosclerotic Risk factor OR (99%CI)
plaque rupture) or intracardiac (atrial fibrillation, Hyperlipidaemia 3.25 (2.81-3.76)

mechanical valve prostheses) thromboembolisation. Smoking 2.87 (2.58-3.19)
Venous thromboembolism (VTE) is the most Diabetes 2.37 (2.07-2.71)
common vascular disease after acute myocardial Hypertension 1.91 (1.74-2.10)
infarction and stroke. It is represented by two main Abdominal obesity 1.62 (1.45-1.80)
clinical events: deep venous thrombosis (DVT) and OR: odds ratio; CI: confidence intervals.
pulmonary embolism (PE), which often constitute an
unique clinical picture in which PE follows DVT. Table II - Classical risk factors for venous
Although VTE is a common disease, the underlying thromboembolism.
pathogenic mechanisms are only partially known,
particularly in comparison to those of Strong risk factors (odds ratio >10)
atherothrombosis. During the past decades, progress trauma or fractures

major orthopaedic surgery
has been made in the identification and
oncological surgery
characterisation of the cellular and molecular
mechanisms that interdependently influence Moderate risk factors (odds ratio 2-9)
Virchow's triad. It is now accepted that the non-oncological surgery
combination of stasis and hypercoagulability, much oral contraceptives and hormone replacement therapy
more than endothelial damage, is crucial for the pregnancy and puerperium
hypercoagulability
occurrence of VTE; venous thrombi are mainly
previous venous thromboembolism
constituted by fibrin and red blood cells, and less by
platelets. In contrast, platelets are essential for primary Weak risk factors (odds ratio <2)
haemostasis, repair of damaged endothelium and play age
a pivotal role in the development of atherosclerosis. bed rest (> 3 days)
Inflammation, lipids and the immune system, through prolonged travel
a complex interplay, are also important determinants metabolic syndrome

air pollution
of arterial and, albeit to a lesser extent, of venous
Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

SIMTI Servizi Srl
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Risk factors for thrombosis
Age increase of 10 mg/dL for each decade of age. High

There is an exponential increase in the risk of both plasma levels of fibrinogen may play a causative role
arterial and venous thrombotic events with age1,2, and in the high incidence of cardiovascular events
the increase in life expectancy in the second half of observed in elderly people, perhaps by enhancing the
the 20 th century is a major cause of the current bridging of platelets via their glycoprotein IIb-IIIa
epidemic of both arterial and venous thrombosis1,3. receptor, by serving as a direct substrate of the clot
Possible mechanisms include cumulative effects of and/or by increasing blood viscosity10. Alternatively,
risk factors on the arterial wall, decreased regular high fibrinogen levels may simply be a marker of the
exercise, increasing immobility resulting in venous chronic inflammatory state typical of aging, without
stasis, and increasing systemic activation of blood directly contributing to the risk10. A similar trend was
coagulation 4,5. Plasma concentrations of some shown for another acute phase protein, coagulation
coagulation factors (factors V, VII, VIII, and IX, factor VIII, which increases progressively with age,
fibrinogen) increase progressively with age6,7. The up to more than 200 U/dL in the seventh decade of
same is true for von Willebrand factor (vWF), a key life4. Coagulation factor VII, both as a zymogen and
protein in platelet-vessel wall interactions 8. For as the activated protease, also increases with age11.
instance, the Framingham study showed that plasma The role of tissue factor (TF) and factor VII as key
levels of fibrinogen increased from a mean value of components of blood coagulation and thrombus
280 mg/dL in individuals aged 47-54 years to more formation is well established (Figure 1). TF, a protein
than 300 mg/dL in those aged 65-79 years9, with an localised in the membrane of vascular cells,
Figure 1 - Role of tissue factor (TF) and coagulation factor VII in the activation of the coagulation
cascade leading to thrombin formation.
TAFI = thrombin activatable fibrinolysis inhibitor; "a" = "activated".
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Previtali E et al.
monocytes and circulating microparticles, is glycosaminoglycan content of the vessel wall, which
considered a key initiator of blood coagulation. When enhances the progression of atherosclerosis and
it is exposed in its active form at the vessel wall (e.g. indirectly contributes to atherothrombosis20. In
after endothelial activation or during chronic conclusion, there are several alterations of the
inflammation, both conditions typical of aging), TF haemostatic system in the elderly. A causal association
activates factor VII. This complex produces small between these alterations and thrombosis is likely but
amounts of thrombin and promotes thrombus has not been formally proven, because of the lack of
formation through the activation of coagulation prospective studies demonstrating the development
reactions on the membrane surfaces of activated of clinical manifestations of thrombosis in comparison
platelets and microparticles 12. During aging, an with aged healthy individuals.
increasing number of individuals develop a laboratory
picture of enhanced activity of coagulation enzymes, Thrombophilia abnormalities
expressed by high levels of the activation peptides Normally, the coagulation process is under the
that are cleaved from prothrombin, factor IX, factor control of several inhibitors that limit clot formation
X and fibrinogen [prothrombin fragment 1+2 (F1+2), near the damaged vessel wall, thus avoiding thrombus
thrombin-antithrombin complex (TAT), factor IX propagation (Figure 2). This delicate balance can be
activation peptide, factor X activation peptide, interrupted whenever the procoagulant activity of one
fibrinopeptide A] when these zymogens are converted of the coagulation factors is increased or the activity
into their corresponding active enzymes 13,14. An of one of the naturally occurring inhibitors decreases,
impairment of fibrinolytic activity also occurs with leading to thrombus formation. This occurs with
aging. There is an increase of plasminogen activator inherited deficiencies of natural inhibitors, as well as
inhibitor type 1 (PAI-1), the major inhibitor of with inherited gain-of-function mutations of some
fibrinolysis15, and a corresponding age-dependent coagulation factors 21 (Table III). Inherited
decrease in fibrinolytic activity16. An increase in antithrombin, protein C and protein S deficiencies are
platelet reactivity with aging has also been rare but strong risk factors for venous thrombosis; they
demonstrated, and activated platelets greatly have little or no effect on arterial thrombosis.
accelerate thrombin generation. Platelets of 60-year- Antithrombin directly inhibits several activated
old or older individuals aggregate more in response coagulation factors, particularly thrombin and
to adenosine diphosphate (ADP) and collagen than activated factor X, and the inhibitory effect is
platelets from younger individuals17. Furthermore, a amplified by its binding to glycosaminoglycans of the
positive correlation has been observed between age endothelial surface which carry heparin-like activity.
and markers of platelet activation such as plasma - Antithrombin deficiency results in significantly
thromboglobulin (a protein stored in the granules reduced inhibition of thrombin and activated factor
of platelets) and platelet membrane phospholipids18. X and an increased tendency to clot formation,
Because the vascular endothelium plays an important particularly in the venous system where the
role in the normal process of haemostasis, any coagulation pathway (as distinct from platelets) plays
structural or functional change in the vascular wall a major role in thrombus formation21. The protein C
(involving the extracellular matrix, vascular smooth anticoagulant pathway, localised on the surface of the
muscle or endothelium) that occurs during aging may endothelium, is essential in the down-regulation of
contribute to the increased risk of thrombosis in the thrombin generation. Thrombin activates protein C;
elderly, particularly atherothrombosis. Advanced age the presence of thrombomodulin, together with
is characterised by stiffness and dilation of the arteries, endothelial protein C receptor (EPCR), accelerates the
due to degeneration of elastic fibres and an increase catalytic efficiency of this activation. Activated protein
in collagen and calcium content, and by a decrease in C proteolytically inactivates factor Va and factor VIIIa,
prostacyclin and nitric oxide with a related reduction the two most important activated co-factors of the
in endothelium-dependent dilation19. There is also coagulation cascade, dramatically slowing the rate of
increased binding of platelet-derived growth factor thrombin and fibrin formation. The inhibitory effect
to arteries, caused by changes in the of activated protein C is accelerated by its main co-
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Figure 2 - Anticoagulant mechanisms of blood coagulation. Antithrombin (AT) inhibits mainly activated factors II (IIa)
and X (Xa) through its binding to glycosaminoglycans (GAG); protein C (PC), with its co-factor protein S
(PS), is activated by thrombomodulin (TM) and inhibits activated factors V (Va) and VIII (VIIIa) through its
binding to endothelial protein C receptor (EPCR).
TFPI = tissue factor pathway inhibitor; "a" = "activated".
Table III - Inherited, acquired and mixed coagulation or metabolic risk factors for thrombosis.
Inherited Acquired Mixed
Antithrombin deficiency Antiphospholipid syndrome Hyperhomocysteinaemia
Protein C deficiency Increased fibrinogen levels
Protein S deficiency Increased factor VIII levels
Factor V Leiden Increased factor IX levels
Prothrombin G20210A Increased factor XI levels
factor, protein S22. The inherited deficiency of one of V Leiden) and the G20210A mutation in the
these inhibitors leads to a critical reduction of the prothrombin gene. The factor V Leiden gain-of-
natural anticoagulant system and enhances thrombin function mutation consists of the substitution of an
generation, increasing susceptibility to VTE21. arginine by glutamine at position 506 of coagulation
The two most common genetic risk factors for VTE factor V (R506Q), which is the cleavage site for
are the G1691A mutation in the factor V gene (factor activated protein C in the factor V molecule23. Mutant
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factor V is partially resistant to inactivation by the complement system), leading to the activation of
activated protein C, leading to a hypercoagulable state. platelet and coagulation pathways 27. Recent
Factor V Leiden explains more than 90% of cases of observations show that antiphospholipid antibodies
activated protein C resistance 24. The G20210A interact directly with vessel wall and cause alterations
mutation in the prothrombin gene is a G to A transition of plasma lipoprotein [i.e. high density lipoprotein
at nucleotide position 20210 in the 3'-untranslated (HDL)] function leading to increased
region of the coagulation factor II (prothrombin) gene, atherothrombotic risk28.
which increases plasma prothrombin levels25. These Hyperhomocysteinaemia is a mild risk factor for
two mutations also increase the risk of thrombosis due to an impairment of the metabolic
atherothrombosis, but to a lesser extent 26. The pathway that transforms the amino acid methionine
prevalences of inherited thrombophilia in the general into cysteine, leading to an abnormal elevation of
population and in patients with VTE are shown in plasma concentrations of homocysteine, an
Table IV. intermediate product of this pathway. Genetic factors
The antiphospholipid antibody syndrome is one (e.g., gene mutations in methylenetetrahydrofolate
of the most important acquired risk factors for reductase and cystathionine -synthase) and acquired
thrombosis. Characterised by the presence of factors (e.g., deficiencies of folate, vitamin B12 or
circulating antiphospholipid antibodies in plasma, it vitamin B6, advanced age, chronic renal failure, and
is associated with arterial or venous thrombosis the use of anti-folic drugs) interact to determine
and/or pregnancy complications, including foetal loss. plasma homocysteine concentrations, so that
The clinically relevant antiphospolipid antibodies hyperhomocysteinaemia is a "mixed" (i.e., genetic
include lupus anticoagulant, anticardiolipin and and/or acquired) risk factor for both arterial and
anti- 2 -glycoprotein I antibodies. The term venous thrombosis29. The possible mechanisms by
"antiphospolipid antibodies" is widely used even if it which hyperhomocysteinaemia contributes to
is not correct, because antibodies are not directed thrombosis are multiple and still under study; they
against phospholipids per se, but against a wide variety include a toxic effect on endothelial cells, smooth-
of protein co-factors acting on phospholipid muscle-cell proliferation and intimal thickening,
membrane surfaces (2-glycoprotein I, prothrombin, impaired generation of nitric oxide and prostacyclin,
protein C, protein S, annexin V, coagulation factor increased platelet adhesion, activation of factor V,
XII and others). The resulting complexes interact with interference with protein C activation and
several cell types, including endothelial cells, thrombomodulin expression, induction of tissue factor
monocytes and platelets, all of which play important activity and inhibition of tissue plasminogen activator
roles in haemostasis and thrombogenesis. The indirect (t-PA)30.
activation of these cells results in the release of An association between increased plasma levels
prothrombotic and pro-inflammatory mediators (e.g. of some coagulation factors (VIII, IX, XI, and
TF-bearing microparticles, interleukin-6, proteins of fibrinogen) and an increased risk of VTE has been
Table IV - Prevalence (%) of inherited risk factors for VTE in the general population and in patients.
Abnormality General population Patients with VTE Patients with recurrent VTE
or age < 45 years
Antithrombin deficiency 0.02 - 0.17 1.1 0.5 - 4.9
Protein C deficiency 0.14 - 0.5 3.2 1.4 - 8.6
Protein S deficiency ? 2.2 1.4 - 7.5
Heterozygous factor V Leiden 3.6 - 6.0 21.0 10 - 64
Heterozygous prothrombin G20210A 1.7 - 3.0 6.2 18
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demonstrated 31. The plasma levels of these factors modifications, is evident from the results of recent
are influenced by age and inflammation, but are also clinical practice registries, which justifies the need
under genetic control. The mechanisms by which for adding pharmacotherapy.
increased coagulation factors plasma levels enhance From a biological point of view, the metabolic
the risk of thrombosis are unknown, but a shift in the syndrome is frequently accompanied by a
balance of the coagulation process towards a prothrombotic state. This includes elevated plasma
procoagulant state is plausible. High levels of levels of PAI-1, thrombin-activatable fibrinolysis
fibrinogen are associated with an increased risk of inhibitor (TAFI), vWF, coagulation factors VIII, VII,
atherothrombosis, while the effect of factor VIII is and XIII and fibrinogen, TF, increased release of
dependent on vWF, which plays the most important endothelial cell microparticles and decreased protein
role in the increased risk of thrombosis associated with C levels. Moreover, patients with the metabolic
the factor VIII/vWF complex. syndrome exhibit endothelial dysfunction (mainly
decreased production of nitric oxide and prostacyclin)
Metabolic syndrome and smoking and heightened platelet reactivity33. The activation of
One of the most widely used definitions of the the haemostatic system related to the metabolic
metabolic syndrome was proposed in 2001 by the syndrome has been mainly attributed to the action of
National Cholesterol Education Program Adult pro-inflammatory and pro-atherogenic mediators (e.g.
Treatment Panel III (NCEP ATP III) and is based on leptin, tumour necrosis factor-, interleukin-6)
the presence of at least three of the following released by adipose cells33, to a triggering effect of
diagnostic criteria: elevated waist circumference very low density lipoproteins (VLDL) and remnant
(abdominal obesity), elevated triglycerides, reduced lipoproteins on platelet activation and PAI-1 gene
HDL cholesterol, elevated blood pressure and elevated expression 41, to the adverse effects of chronic
fasting glucose32. There is increasing evidence for an hyperglycaemia on fibrin structure and function
association between atherothrombosis and the (generating a clot more resistant to fibrinolysis)42 and
metabolic syndrome32-34. The INTERHEART study to increased circulating microparticles that sustain
identified nine risk factors that collectively accounted blood coagulation by exposure of anionic
for more than 90% of the risk of acute myocardial phospholipids and TF 43.
infarction. Risk predictors included life-style factors This inflammatory and hypercoagulable state may
such as smoking, co-morbidities (hypertension, explain the biological role of the major cardiovascular
diabetes, abdominal obesity, abnormal lipid profiles), risk factors and could also be involved in VTE.
as well as psychosocial factors35. Meta-analyses of Patients with idiopathic VTE have a higher prevalence
randomised controlled trials on blood pressure36 and of atherosclerosis than patients with VTE secondary
cholesterol reduction37, and observational studies on to known risk factors and control subjects34. In
smoking cessation38 confirmed that these three risk addition, the long-term incidence of cardiovascular
factors play causative roles in arterial disease, partly disease is higher in patients with idiopathic VTE than
through atherogenesis and partly through a systemic in those with secondary VTE 44,45. These studies
activation of blood coagulation and inflammation39. support the hypothesis of VTE as the first symptomatic
Available evidence from multiple randomised trials cardiovascular event. Several epidemiological studies
supports life-styles that promote weight reduction, showed associations between obesity, metabolic
cigarette smoking cessation and regular moderate syndrome or type 2 diabetes and VTE46-50. A meta-
exercise in order to reduce platelet reactivity and analysis50 of 63,552 patients showed that the relative
coagulability, and to promote fibrinolysis. The overall risk of VTE was 2.33 (95% CI 1.68-3.24) for obesity,
effects can be expected to translate into an improved 1.42 (95% CI 1.12-1.77) for diabetes and 1.51 (95%
cardiovascular prognosis or other beneficial clinical CI 1.23-1.85) for hypertension (Table V). Obesity may
outcomes in healthy individuals and those with confer an increased risk of VTE independently of the
cardiovascular risk factors or established coronary metabolic syndrome, because a high body weight can
heart disease40. Nevertheless, a high residual risk for cause mechanical impairment of the valve system in
secondary ischemic events, despite life-style the deep veins of the lower limbs, favouring venous

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Table V - Associations between classic cardiovascular progression of atherosclerosis showed inconsistent

risk factors and VTE. results59-64. Response variability to antiplatelet therapy
may contribute to the residual risk of thrombotic
Risk factor OR (95% CI)
events. Sufficient evidence supports the hypothesis
Obesity (BMI) 2.33 (1.68-3.24)50 that a persistent enhanced platelet reactivity despite
the use of aspirin65 and/or clopidogrel66 is associated
Diabetes 1.42 (1.12-1.77)50
with adverse clinical outcomes. A number of factors
Hypertension 1.51 (1.23-1.85)50 may influence response to antiplatelet therapy,
including drug dose and absorption, patient's
Smoking 1.42 (1.28-1.58)51
compliance and genetic polymorphisms66. Novel
BMI = body mass index; OR = odds ratio; CI = confidence intervals. approaches to limit platelet-mediated thrombosis, such
as prasugrel, ticagrelor and cangrelor, appear
stasis. In the same meta-analysis a non-significant promising. Nevertheless, current antiplatelet agents
increased risk for smoking was found50, while in a and those still in development, inhibit the
large population-based case-control study [Multiple thromboxane A2 or ADP platelet activation pathways
Environmental and Genetic Assessment (MEGA) but do not interfere with a number of other platelet
study], the relative risk of VTE was 1.42 (95% CI activation pathways that may contribute to thrombotic
1.28-1.58) in current smokers and 1.23 (95% CI 1.10- events. In addition, dual antiplatelet therapy is
1.37) in past smokers, compared to the risk in associated with increased bleeding. These
individuals who had never smoked51. considerations underline the urgent need for novel
Finally, also dyslipidaemia may exert a mild therapies that provide more complete platelet
influence on the risk of VTE52,53, as determined by a inhibition and, therefore, greater protection against
recent meta-analysis in which patients with VTE had thrombotic events, possibly without increasing the
high triglyceride and low HDL cholesterol levels, bleeding risk.
while no effect of total cholesterolaemia on VTE was The presence of a residual thrombus after a first
seen50. Moreover, preliminary evidence shows that episode of DVT is an independent risk factor for
statins may be protective against VTE54,55, supporting recurrence67. After a first episode of VTE, patients
the hypothesis of dyslipidaemia influencing the risk are 40 times more likely to develop a recurrent event
of VTE. compared to previously unaffected individuals68.
In conclusion, despite the discrepancy between the Previous VTE represents the most important risk
estimated relative risks of VTE and atherothrombosis factor for recurrence of DVT or PE (OR 15.5; 95%
associated with cardiovascular risk factors, the latter CI 6.77-35.99) and the risk is higher in individuals
may represent a link between two clinical entities with previous idiopathic VTE than in those with
which have classically been considered distinct. secondary VTE69. The risk of recurrence varies over
time, being higher during the first 6-12 months after
Previous thrombosis the index event70. In a study involving 355 patients,
Despite the unambiguous benefit achieved with the incidence of recurrent VTE was 8.6% at 6 months
life-style modification, blood pressure control and the and 17.5% after 2 years71. After 8 years, the rate of
use of statins, angiotensin II-active and antiplatelet recurrence was as high as 30.3% 71. Moreover,
agents, the residual risk of recurrent acute events in recurrent DVT or PE is associated with an increased
patients with established atherothrombotic disease risk of post-thrombotic syndrome and chronic
remains substantial56,57. The residual risk is likely thromboembolic pulmonary hypertension 72.
related to progression of atherosclerosis despite the Secondary prevention of VTE is, therefore, crucial to
use of statins and angiotensin II-active agents, to reduce the burden of these diseases significantly and
insufficient inhibition of platelet activation by aspirin to date the most effective strategy is represented by
and thienopyridines, and to other factors not yet anticoagulant therapy.
identified58. Studies that investigated the effect of A potential mechanism by which the residual
novel approaches with or beyond statins on thrombus increases the risk of recurrence is impaired
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venous outflow, resulting in blood stasis and clot conditions lead to VTE is a combination of stasis and
formation. However, because some patients develop local accumulation of TF (i.e., hypercoagulability).
recurrent thrombosis in the initially unaffected leg and Blood flow is relatively static in the pockets of venous
others develop isolated PE, other mechanisms must valves, particularly those of the lower limbs. This
be implicated. Residual thrombosis is perhaps a effect is accentuated by immobilization. Stasis locally
marker for a more generalized procoagulant diathesis. concentrates haemostasis activation factors (cytokines
Indeed, elevated plasma D-dimer levels after and other mediators of inflammation), favours cellular
withdrawal of oral anticoagulation (a marker of margination and interaction of circulating blood cells
hypercoagulability) are an independent risk factor for with endothelium, and is responsible for local hypoxia
recurrent venous thrombosis73,74. which is one of the principal mechanisms of
endothelial activation84. Studies in animals have
Trauma, surgery and immobilisation shown that stasis alone does not provoke thrombosis85.
These transient conditions are associated with an TF is expressed by cells in the subendothelial
increased risk of venous thrombosis. The incidence compartment. Thus, physical disruption of the
of DVT associated with major trauma is up to 58%, endothelium, as occurs in trauma or surgery, may lead
PE occurs in 2% of these individuals and is the third to exposure of blood to extravascular TF. However,
cause of death among patients who survive the first the vast majority of venous thrombi occur in the
24 hours after trauma75,76. Considering minor trauma, context of an intact endothelium. In these cases, TF
the incidence of DVT is 28% when lower limbs are may be expressed on the surface of activated
involved and the risk is higher in proximal than in endothelial cells and/or mononuclear cells which have
distal fractures77. In a large, population-based, case- been stimulated by any number of inflammatory
control study the relative risk of VTE associated with mediators including cytokines, chemokines
previous minor injury was 3.1 (95% CI 2.5-3.8)78. (interleukins 1, 6 and 8, tumour necrosis factor-,
Minor injuries in a leg were strongly associated with monocyte chemoattractant protein-1), vascular
VTE (OR 5.1; 95% CI 3.9-6.7), whereas minor endothelial growth factor, factors derived by
injuries in other parts of the body were not78. The complement activation (C5a and complex of
presence of factor V Leiden in patients with a leg membrane attachment), immunocomplexes and
injury increased the risk up to 50-fold78. The risk of antibodies, P-selectin, haemodynamic stress, hypoxia,
thrombosis associated with surgery varies from 15% and cell-cell interactions84,86. In addition to expressing
to 60% in the case of a laparotomic approach79, while TF on their cell surface, activated cells (e.g.,
the risk associated with laparoscopic and arthroscopic endothelial cells, monocytes, leucocytes and platelets)
surgery is less defined. Major orthopaedic surgery may release TF- and phospholipid-rich microparticles
involving the lower extremity is a major risk factor that circulate in the bloodstream87. Microparticles can
for VTE. Rates of DVT without prophylaxis range interact with other cells through the action of adhesive
from 40% to 60% in the 2 weeks after major proteins. For example, P-selectin glycoprotein ligand
orthopaedic surgery80. Patients undergoing total hip 1 facilitates the transfer of P-selectin from platelets
arthroplasty are in the highest risk category for or endothelial cells to microparticles of monocyte
developing post-operative VTE. Evaluation of the origin88. These properties may facilitate thrombus
natural history of this population of patients reveals propagation and activate coagulation in various sites.
that the incidence of DVT without appropriate Finally, leucocytes and platelets can further enhance
prophylaxis is as high as 32% to 60%, and that of PE thrombosis through their expression of TF under
is as high as 16%, with a 0.3% to 3.4% occurrence of inflammatory stimuli (C5a, bacterial formylated
fatal PE81. Current data suggest an overall DVT rate peptides, Pselectin) and platelet agonists (ADP,
of 9.9% and a proximal DVT rate of 2.1% after knee collagen, thrombin), respectively89.
arthroscopy without thromboprophylaxis82. Even with Although VTE is the most frequent thrombotic
appropriate thromboprophylaxis, total hip or knee complication of surgery, surgical iatrogenic injuries
replacement will lead to symptomatic VTE in 1% to can also lead to arterial occlusion. Moreover, arterial
3% of patients83. The mechanism by which these thrombosis secondary to surgery can represent the first

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manifestation of heparin-induced thrombocytopenia, expression as a host response in endothelial cells and

an autoimmune disease triggered by exposure to the monocyte-macrophages 100. Data from several
heparin that is commonly given as antithrombotic epidemiological investigations demonstrated
prophylaxis of post-operative VTE. The clinical significant heterogeneity in the risk of VTE according
picture is characterised by transient thrombocytopenia to the different cancer histology. Pancreatic cancer,
(in more than 90% of cases the platelet count is lymphoma, and brain cancer have a relative risk for
>15,000/L) and both arterial and venous thromboses, VTE greater than 25, whereas the VTE risk associated
especially of the lower limbs, are described in surgical with cancer of the ovary, stomach, kidney, colon,
patients90. rectum, and lung is lower (> 17), compared with that
of individuals without cancer101. In the MEGA study,
Cancer patients with haematological malignancies had the
Cancer is one of the most important acquired risk highest risk of VTE (OR 28.0; 95% CI 4.0-199.7),
factors for VTE91. Some authors estimate an annual followed by that in patients with lung cancer and
incidence of VTE of 1 in 200 patients with cancer92, gastrointestinal cancer95.
and 20% of VTE cases occur in patients with cancer93. Considering the therapeutic factors that influence
Conversely, of all patients with cancer, 15% will the cancer-related risk of VTE, it has been shown that
develop symptomatic VTE93, 50% asymptomatic patients with cancer face double the risk of developing
VTE 94 , and 50% will have VTE diagnosed at VTE because of oncological surgery, compared with
autopsy91. The risk of VTE is higher at diagnosis (OR the risk in patients without cancer undergoing similar
53.5; 95% CI 8.6-334.3) and in patients with distant surgery 91. Chemotherapy increases the risk of
metastases (OR 19.8; 95% CI 2.6-149.1)95. If a patient thrombosis 6.5-fold102. The proposed mechanisms for
with cancer survives an initial VTE event, he or she chemotherapy-related risk of VTE probably include
has an increased risk of recurrence (OR 1.72; 95% CI both direct drug-induced damage of the endothelium
1.31-2.25) compared with that in a patient without and an increased expression of TF procoagulant
cancer. The cancer patient with VTE also has a activity by macrophages and monocytes, thus
significantly increased risk of death (OR 8.1; 95% CI inducing a procoagulant response by host cells103.
3.6-18.1), which persists for as long as the malignancy Another prothrombotic mechanism of antitumour
persists71. In addition, VTE is the second leading cause therapy is likely related to the direct hepatotoxicity
of death in hospitalised patients with cancer, after of radio- and chemo-therapy, which can cause a
infections96. reduction in the plasma levels of natural anticoagulant
The pathophysiology of VTE in patients with proteins (antithrombin, protein C and protein S)100.
cancer is even more complex than that in patients Women who are treated with tamoxifen for breast
without. Three sets of factors have been linked to the cancer have a 2- to 5-fold increased risk of VTE, and
increased risk of VTE in these patients: those related the risk is even higher after menopause and when
to the tumour, those related to the host, and those to tamoxifen is associated with chemotherapy104,105.
the therapies the patient is receiving97. Tumour mass Cancer patients with a central venous catheter or
may create stasis by compression and invasion of transvenous pacemaker have a 6-fold increase in
vessels. Tumour cells may promote the release of TF upper-extremity DVT106. Finally, the presence of
from the affected organs during expansion and the factor V Leiden in cancer patients increases the risk
metastatic processes. Importantly, cancer cells of VTE nearly 12-fold compared to those individuals
themselves may release TF-rich microparticles. These without cancer and who have the wild-type factor V
microparticles can then adhere to (and be incorporated Leiden; similar results have been observed in cancer
into) monocytes and other cells, in particular those patients carrying the prothrombin G20210A variant95.
activated by hypoxia, and promote fibrin
formation 98,99 . Finally, tumour cell-derived Oral contraceptives and hormone therapy
inflammatory and pro-angiogenic cytokines (e.g., Various clinical studies have investigated the risk
tumour necrosis factor-, interleukin 1 and mostly of thrombosis with hormone-based oral
vascular endothelial growth factor) may induce TF contraceptives. However, due to the variety of
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preparations and the heterogeneity of study are also a few reports of increased venous distensibility
populations, these studies showed different or even and reduced blood flow in women taking oral
contradictory results. Evidence on oral contraceptive- contraceptives117. A possible explanation might be an
related risk of VTE has mostly been derived from case- oestrogen-induced dose-dependent increase in the
control and nested case-control studies, attributing a expression of matrix metalloproteinases that cleave
relative risk of VTE to oral contraceptive use collagen and elastin in the vascular intima. The loss
(compared with non-use) ranging from 1.12 (95% CI of venous tone, with the accompanying tendency to
0.4-2.9) to 22.1 (95% CI 5.9-84.2)107. Overall, a 2- to venous stasis, increases the risk of venous thrombosis.
6-fold increased relative risk of VTE is observed in Oral contraceptives may increase the risk of arterial
oral contraceptive users compared with non-users, for thrombosis by promoting endothelial dysfunction.
an absolute risk of 1 to 3 cases of VTE per 10,000 However, this is a poorly investigated area and it has
women-years107 . An increased risk of VTE was not been established how much these changes matter
reported among women using third-generation oral in the pathophysiology of thrombosis in oral
contraceptives, i.e., those containing desogestrel or contraceptive users118. Another mechanism increasing
gestodene, compared to those using second-generation the risk of thrombosis, particularly that of
products containing levonorgestrel108-111. A meta- atherothrombosis in women taking oral
analysis confirmed that third-generation oral contraceptives, is linked to changes in lipids and
contraceptives were associated with a significantly lipoprotein metabolism. Oral contraceptives increase
increased risk of VTE (RR 1.9; 95% CI 1.5-2.2) total cholesterol, mainly by increasing LDL
compared with that associated with second-generation cholesterol. In addition, oestrogens decrease HDL
oral contraceptives 112. Another meta-analysis cholesterol and increase triglyceride levels, affect
confirmed an overall adjusted odds ratio for third- lipoprotein metabolism by increasing the hepatic
versus second-generation oral contraceptives of 1.7 synthesis of apolipoproteins, and may induce changes
(95% CI 1.4-2.0)113. Moreover, the odds ratios for in hormones affecting lipoprotein metabolism such
short-term users compared with those of longer term as cortisol, thyroxine or growth hormone 119,120.
users were 2.5 (95% CI 1.6-4.1) and 2.0 (95% CI 1.4- Progestogen-only oral contraceptives have generally
2.7), respectively 113. However, some authors no or little effect on plasma lipoprotein levels.
emphasised that the difference in VTE risk according Oral contraceptives modify the plasma levels of
to whether second- or third-generation oral several coagulation factors (Table VI). However, these
contraceptives are used is minimal, and probably changes are often modest and concentrations of
related to underlying congenital or acquired coagulation factors usually remain within the normal
thrombophilic states114. Second- and third-generation range. Oral contraceptive-mediated alterations in
oral contraceptives (as well as pregnancy/post-partum) coagulation factor levels may result in synergistic or
increase the risk of VTE in carriers of factor V Leiden opposing effects on the risk of venous thrombosis.
by 3.3- fold and 4.2-fold, respectively, whereas other Levels of the anticoagulant proteins antithrombin and
risk factors have a minor effect115. protein S decrease during oral contraceptive use,
An unequivocal mechanism for explaining the whereas protein C levels may increase121,122. The
thrombogenicity of oral contraceptives (especially greatest effects are seen with preparations containing
oestrogen compounds) has not been identified, as the highest oestrogen doses. Important effects of oral
several metabolic abnormalities might be triggered contraceptives on blood coagulation are an acquired
to induce a mild prothrombotic state. Mechanisms resistance to activated protein C and the reduction of
include a direct effect of oestrogens on the vascular protein S plasma levels123. These and other changes
wall, changes in factors that promote endothelial in coagulation factors appear to be more pronounced
dysfunction, and changes in coagulation factors. in women using third-generation compounds than in
Studies in animals suggest a loss of the normal elastic those using second-generation compounds124,125,
configuration of the aorta, significant intimal although the difference is debated 126 . Oral
thickening and an increase in endothelial permeability contraceptives also affect the fibrinolytic system by
after administration of oral contraceptives116. There reducing t-PA levels and increasing levels of TAFI,

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Previtali E et al.
Table VI - Haemostatic changes during oral contraceptive (OC) use and pregnancy.
Change during OC use Change during pregnancy
Procoagulant factors
fibrinogen, V, VII, VIII, IX, X, XII
XI = or
von Willebrand factor =
Anticoagulant proteins
antithrombin =
protein C = or = or
protein S
resistance to activated protein C (ratio)
Markers of thrombin formation
F1+2, TAT complexes, fibrinopeptide A
D-dimer
Fibrinolytic factors
TAFI, PAI 1 and 2
t-PA
increase, decrease, = no change, compared to non-use of oral contraceptives and to the non-pregnant state.
PAI-1 and D-dimer. An overall increase in thrombin during the first 3 months after delivery130. A 14-fold
generation in women on oral contraceptives has increased risk of DVT of the legs and a 6-fold
recently been demonstrated by means of the increased risk of PE were reported, with this risk being
endogenous thrombin potential test, i.e., the area under higher in the third trimester (OR 3.3; 95% CI
the thrombin generation curve, which is able to 2.2-5.0) and during puerperium (OR 11.0; 95% CI
identify a global hypercoagulable state and has been 8.1-15.1), and highest in the 2 days before and the
found to be higher in oral contraceptive users than in day after delivery (OR 77.6; 95% CI 52.4-114.8)131.
non-users118,121,122,127. The major risk factors for VTE during pregnancy
include the presence of thrombophilic abnormalities,
Pregnancy Caesarean section, advanced maternal age, obesity and
VTE remains the major cause of maternal mortality pre-eclampsia, which are identified in nearly 70% of
world-wide (the rate of maternal deaths from VTE is women with pregnancy- or puerperium-related VTE.
0.12 per 10,000 live births and stillbirths)128. Results It has been reported that the risk of pregnancy-related
from studies in which either all or most pregnant VTE might be 11- to 52-fold increased in factor V
women underwent accurate diagnostic testing for VTE Leiden carriers, 3- to 31-fold in carriers of the
report an incidence of VTE ranging from 0.6 to 1.3 prothrombin G20210A mutation, and more than 10-
events per 1,000 deliveries, confirming a 5- to 10- fold in those with deficiencies of antithrombin (7-fold
fold increased risk in pregnant women compared to for mild deficiency and 64-fold for severe deficiency),
that in non-pregnant women of comparable age129. The protein C (3.6-fold for mild deficiency and 7.2 fold
MEGA study showed that the risk of VTE is nearly for severe deficiency), or protein S (5-fold for mild
5-fold increased during pregnancy and up to 60-fold deficiency) compared to non-pregnant women without
130
thrombophilia 130,133-135. An association between monoxide (CO), nitrogen dioxide (NO2), sulphur
thrombophilia and adverse obstetric outcomes such dioxide (SO2) and ozone (O3). The latter include
as recurrent miscarriage, pre-eclampsia, placental particulate matter (PM) with a cut-off of less than 10
abruption, foetal growth retardation, stillbirth and m in aerodynamic diameter (PM10), fine particles of
foetal death has been observed136-138, although it is not less than 2.5 m (PM2.5) and ultrafine particles of less
certain139. than 0.1 m (PM0.1)147. As compared with PM10 and
From a biological point of view, normal pregnancy PM2.5, ultrafine particles have a larger total surface
is characterised by a hypercoagulable state. Pregnancy area and hence a greater potential for carrying toxic
is associated with haemostatic changes that include substances, including metals, elemental and organic
increased concentrations of most procoagulant factors, carbon and others. Because of their small size,
decreased concentrations of some of the natural ultrafine particles are deposited deep in the lung
anticoagulants and reduced fibrinolytic activity (Table alveoli and can reach the blood stream. Particulate
VI). These changes help to maintain placental function matter is the type of air pollutant that causes the most
during pregnancy and minimise blood loss at delivery. numerous and serious effects on human health,
However, they may also predispose to maternal because of the broad range of different toxic
thrombosis and placental vascular complications. substances that it contains148,149. Over the last decade,
Plasma concentrations of coagulation factors V, VII, a growing body of epidemiological and clinical
VIII, IX, X, and XII, fibrinogen and vWF rise evidence has led to a heightened concern about the
significantly during pregnancy, while factor XI levels deleterious effects of air pollution on the
tend to decrease. Total and free protein S decrease, cardiovascular system150-152. Observations from studies
whereas protein C and antithrombin remain across North America and Europe have shown higher
substantially unchanged140-141. Activated protein C rates of hospital admissions for all cardiovascular
resistance, likely caused by increasing factors V and causes, and a direct association was also identified
VIII and decreasing protein S, is frequently observed with the incidence of ischaemic heart disease and
in pregnancy142. The activation of coagulation is failure153. The correlation between PM2.5 levels and
demonstrated by increasing levels of F1+2, TAT onset of symptoms in 772 patients with myocardial
complexes, fibrinopeptide A and D-dimer141,142. These infarction was studied in a case-crossover study:
changes occur during the whole gestational period but elevated odds ratios were associated with an increase
are more pronounced in the third trimester. The of 25 g/m3 PM2.5 during a 2-h period before the event
fibrinolytic system is also impaired during pregnancy, (OR 1.48; 95% CI 1.09-2.02) and an increase of 20
as shown by increased plasma levels of TAFI, PAI-1 g/m3 PM2.5 was observed in the 24-h period before
and -2 (the latter of placental origin) and decreased t- the event (OR 1.69; 95% CI 1.13-2.34)154. In a study
PA activity142,143. TF is largely expressed in the placenta on air pollution and emergency admissions, an
and is markedly increased in the amniotic fluid but association was found between NO2 (12.7% increase),
not in plasma143, and, together with thrombomodulin, PM2.5 (8.6% increase) and the risk of hospitalisation
is involved not only in haemostasis, but also in the for myocardial infarction155. In another crossover
differentiation of placental blood vessels144. Placental study, an increase in ambient particulates of 10 g/m3
detachment at delivery with the ensuing release of was associated with a 4.5% increased risk of acute
trophoblastic substances at the site of separation is coronary syndromes (unstable angina and myocardial
responsible, together with post-partum infarction)156. The association between traffic-related
haemoconcentration, for the particularly high risk of air pollutants and acute myocardial infarction is also
VTE in the post-partum period145. Three weeks after supported by the results of the European HEAPSS
delivery, blood coagulation and fibrinolysis have (Health Effects of Air Pollution among Susceptible
generally returned to normal146. Subpopulations) study157.
Potential mechanisms leading to cardiovascular
Air pollution disease include autonomic dysfunction, systemic and
Air pollution consists of gaseous and particulate- local inflammation, endothelial injury, and alterations
matter pollutants. The former include carbon in the coagulation cascade150,151. Changes in heart rate

131
Previtali E et al.
and heart-rate variability, arrhythmias, increase in increased risk of VTE167. The absolute risk of a
markers of inflammation and tissue damage such as symptomatic event within 4 weeks of flights longer
C-reactive protein, cytokines, interleukins and serum than 4 hours was 1 in 4600 flights, whereas the risk
lipids are conditions induced by air pollution that of acute PE increased with duration of travel, being
affect the cardiovascular system151. Experimental and up to 4.8 per million in flights longer than 12 hours167.
epidemiological studies evaluating plasma Taken together, these data are consistent with the
concentrations of coagulation factors in association hypothesis that medium- to long-distance travellers
with air pollution exposure have produced different have a 2- to 4-fold increased relative risk of VTE
results. While some studies found increased levels of compared to non-travellers. Among the several
factor VII, fibrinogen and vWF158-161, others showed plausible explanations for this increased risk are
decreased levels or no change162. More recently, a immobilisation and a sitting position. Tall individuals
novel association between air pollution and are particularly vulnerable because of cramped
hypercoagulability was observed both in healthy seating, and short individuals because their feet do
individuals and in patients with DVT163,164. Air not touch the floor and they, therefore, undergo extra
pollution is associated with a shortened prothrombin compression of the popliteal veins168. Thrombin
time in healthy subjects162 and increased total plasma generation among travellers has been evaluated in
homocysteine levels in smokers163. A large case- several studies through measurements of F1+2 and
control study164 showed that high mean PM10 levels its inhibitor complex TAT. Several studies
in the year before venous thrombosis were associated investigating the effect of prolonged immobilisation
with a significantly shortened prothrombin time, and on thrombin generation and on the fibrinolytic system
that each increase of 10 g/m3 in PM10 was associated have yielded conflicting results167 and the vast majority
with a 70% increase in risk of VTE. This effect was of these reports lacked a control group. The only
absent in women who used oral contraceptives. As controlled study published to date169 failed to find a
the aforementioned coagulation changes induced by difference in F1+2, TAT and D-dimer between
air pollution are similar in characteristics and degree travellers and non travellers. The effect of hypoxia
to those observed in oral contraceptive users, it may (due to decreased cabin pressure) on coagulation has
be that coagulation is already activated by oral been investigated in both hypobaric and normobaric
contraceptives so that no further enhancing effect is conditions. The results during hypobaric, but not
observed after exposure to PM10. normobaric, hypoxia support activation of the
coagulation and fibrinolytic systems, reflected in a
Travel shortened activated partial thromboplastin time,
Over the past decades, several studies have decreased levels of fibrinogen and factor VIII170, factor
investigated the relationship between thrombosis and VII antigen and TF pathway inhibitor (TFPI)171,
travel, but whether or not long-distance travel and increased levels of D-dimer170, F1+2, TAT and factor
symptomatic VTE are truly associated is still debated, VIIa-TF complex171,172. However, two other studies
as most travellers who develop DVT or PE also have found no difference in markers of thrombin generation
one or more other predisposing risk factors 165. during hypobaric or normobaric hypoxia 173,174.
Considering an analysis of three large case-control Fibrinolysis was more activated during air travel than
studies on patients with clinically suspected DVT and during immobilisation or deambulation, as shown in
PE, the resulting pooled odds ratio for the association a crossover study175.
between a median travel time of 7 hours and
symptomatic VTE was negligible (OR 0.9; 95% CI Conclusions
0.6-1.4)166. However, a further analysis of the duration A large body of evidence over the past 20 years
of travel yielded an increased odds ratio of 2.5 (95% has improved our understanding of the biochemical
CI 1.0-6.2) in the category of 10 to 15 hours of mechanisms involved in the pathogenesis of thrombus
travel166. A more recent review that summarised formation, in arteries as well as in veins. We begin to
available data on this topic concluded that long- understand that changes in blood coagulation,
distance travel is associated with an up to 4-fold inflammation, and immune response are intricately
132
linked and interdependent. Heightened generation of Willebrand factor in Italian centenarians.

thrombin, the ultimate enzyme involved in Haematologica 2003; 88: 39-43.
9) Kannell WB, Wolf PA, Castelli WP, et al. Fibrinogen
coagulation, platelet activation and also cell-signalling and risk of cardiovascular disease. The Framingham
effector molecules, is crucial not only in the Study. JAMA 1987; 258: 1183-6.
development of VTE, but also of atherothrombosis. 10) Tracy RP. Hemostatic and inflammatory markers as
On the other hand, traditional cardiovascular risk risk factors for coronary disease in the elderly. Am J
Geriatr Cardiol 2002; 11: 93-100.
factors may also play a role in VTE. Thus, 11) Ofosu FA, Craven S, Dewar L, et al. Age-related
pathogenesis of thrombosis has to be considered changes in factor VII proteolysis in vivo. Br J
within a multifaceted perspective, as confirmed by Haematol 1996; 94: 407-12.
the amount of epidemiological data on both genetic 12) Furie B, Furie BC. Mechanisms of thrombus
formation. N Engl J Med 2008; 359: 938-49.
and environmental thrombotic risk factors. 13) Bauer KA, Weiss LM, Sparrow D, et al. Aging-
Nevertheless, a significant proportion of arterial and associated changes in indices of thrombin generation
venous thrombotic episodes, especially among young and protein C activations in humans. Normative Aging
individuals, occur without a plausible explanation. Study. J Clin Invest 1987; 80: 1527-34.
14) Mari D, Mannucci PM, Coppola R, et al.
Further basic and clinical research is needed to reach Hypercoagulability in centenarians: the paradox of
a correct identification of new factors associated with successful aging. Blood 1995; 85: 3144-9.
VTE and/or arterial thrombosis, in order to assess the 15) Wilkerson WR, Sane DC. Aging and thrombosis. Sem
individual risk of thrombosis and promote more Thromb Hemost 2002; 28: 555-67.
16) Gleerup G, Winther K. The effect of ageing on platelet
targeted prophylactic and therapeutic options. function and fibrinolytic activity. Angiology 1995; 46:
715-8.
Acknowledgements 17) Kasjanovova D, Balaz V. Age-related changes in
We thank Dr. Mario Colucci for his help in human platelet function in vitro. Mech Ageing Dev
1986; 37: 175-82.
designing the figures. 18) Bastyr EJ 3rd, Kadrofske MM, Vinik AI. Platelet
activity and phosphoinositide turnover increase with
Keywords: Venous thrombosis, arterial advancing age. Am J Med 1990; 88: 601-6.
thrombosis, risk factors, coagulation, pathogenesis. 19) Taddei S, Virdis A, Ghiadoni L, et al. Age-related
reduction of NO availability and oxidative stress in
humans. Hypertension 2001; 38: 274-9.
References 20) Feyzi E, Saldeen T, Larsson E, et al. Age-dependent
1) Hume M, Sevitt S, Thomas DP. Venous Thrombosis modulation of heparan sulfate structure and function.
and Pulmonary Embolism. Harvard University Press, J Biol Chem 1998; 273: 13395-8.
Cambridge, MA; 1970. 21) Seligsohn U, Lubetsky A. Genetic susceptibility to
2) Gordon T, Kannel WB. Predisposition to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
atherosclerosis in the head, heart and legs. The 22) Lane DA, Philippou H, Huntington JA. Directing
Framingham Study. J Am Med Ass 1972; 221: 661. thrombin. Blood 2005; 106: 2605-12.
3) Nieto FJ. Cardiovascular disease and risk factor 23) Bertina RM, Koeleman BP, Koster T, et al. Mutation
epidemiology: a look back at the epidemic of the 20th in blood coagulation factor V associated with
century. Am J Pub Health 1999; 89: 292-94. resistance to activated protein C. Nature 1994; 369:
4) Lowe GDO, Rumley A, Woodward M, et al. 64-7.
Epidemiology of coagulation factors, inhibitors and 24) Dahlbck B, Carlsson M, Svensson PJ. Familial
activation markers: the Third Glasgow MONICA thrombophilia due to a previously unrecognized
Survey I. Illustrative reference ranges by age, sex and mechanism characterized by poor anticoagulant
hormone use. Br J Haematol 1997; 97: 775-84. response to activated protein C: prediction of a
5) Rumley A, Emberson JR, Wannamethee SG, et al. cofactor to activated protein C. Proc Natl Acad Sci
Effects of older age on fibrin D-dimer, C-reactive USA 1993; 90: 1004-8.
protein and other hemostatic and inflammatory 25) Poort SR, Rosendaal FR, Reitsma PH, et al. A
variables in men aged 60-79 years. J Thromb Haemost common genetic variation in the 3'-untranslated region
2006; 4: 982-7. of the prothrombin gene is associated with elevated
6) Abbate R, Prisco D, Rostagno C, et al. Age-related plasma prothrombin levels and an increase in venous
changes in the hemostatic system. Int J Clin Lab Res thrombosis. Blood 1996; 88: 3698-703.
1993; 23: 1-3. 26) Ye Z, Liu EH, Higgings JP, et al. Seven hemostatic
7) Franchini M. Hemostasis and aging. Crit Rev Oncol gene polymorphisms in coronary disease: meta-
Hematol 2006; 60: 144-151. analysis of 66,155 cases and 91,307 controls. Lancet
8) Coppola R, Mari D, Lattuada A, Franceschi C. von 2006; 367: 1729-30.

133
Previtali E et al.
27) Urbanus RT, Derksen RHMW, de Groot PG. Current 44) Becattini C, Agnelli G, Prandoni P, et al. A prospective
insight into diagnostics and pathophysiology of the study on cardiovascular events after acute pulmonary
antiphospholipid syndrome. Blood Rev 2008; embolism. Eur Heart J 2005; 26: 77-83.
22: 93-105. 45) Prandoni P, Ghirarduzzi A, Prins MH, et al. Venous
28) Charakida M, Besler C, Batuca JR, et al. Vascular thromboembolism and the risk of subsequent
abnormalities, paraoxonase activity, and dysfunctional symptomatic atherosclerosis. J Thromb Haemost
HDL in primary antiphospholipid syndrome. JAMA 2006; 4: 1891-6.
2009; 302: 1210-7. 46) Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A
29) Cattaneo M. Hyperhomocysteinemia, atherosclerosis prospective study of risk factors for pulmonary
and thrombosis. Thromb Haemost 1999; 81: 165-76. embolism in women. J Am Med Ass 1997;
30) D'Angelo A, Selhub J. Homocysteine and thrombotic 277: 642-5.
disease. Blood 1997; 90: 1-11. 47) Hansson PO, Eriksson H, Welin L, et al. Smoking
31) Franco RF, Reitsma PH. Genetic risk factors of venous and abdominal obesity. Risk factors for VTE among
thrombosis. Hum Genet 2001; 109: 369-84. middle-aged men. "The study of men born in 1913''.
32) Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis Arch Int Med 1999; 159: 1886-90.
and management of the metabolic syndrome: an 48) Tsai A, Cushman M, Rosamond W, et al.
American Heart Association/National Heart, Lung and Cardiovascular risk factors and VTE incidence. Arch
Blood Institute Scientific Statement. Circulation 2005; Int Med 2002; 162: 1182-9.
112: 2735-52. 49) Ageno W, Prandoni P, Romauldi E, et al. The
33) Franchini M, Targher G, Montagnana M, et al. The metabolic syndrome and the risk of venous
metabolic syndrome and the risk of arterial and venous thrombosis: a case-control study. J Thromb Haemost
thrombosis. Thromb Res 2008; 122: 727-35. 2006; 4: 1914-8.
34) Prandoni P, Bilora F, Marchioli A, et al. An association 50) Ageno W, Becattini C, Brighton T, et al.
between atherosclerosis and venous thrombosis. N Cardiovascular risk factors and venous
Engl J Med 2003; 348: 1435-41. thromboembolism: a meta-analysis. Circulation 2008;
35) Yusuf S, Hawken S, Ounpuu S, et al. Effect of 117: 93-102.
potentially modifiable risk factors associated with 51) Pomp ER, Rosendaal FR, Doggen CJ. Smoking
myocardial infarction in 52 countries (the increases the risk of venous thrombosis and acts
INTERHEART study): case control study. Lancet synergistically with oral contraceptive use. Am J
2004; 364: 937-52. Hematol 2008; 83: 97-102.
36) Turnbull F. Blood Pressure Lowering Treatment 52) Vaya A, Mira Y, Ferrando F, et al. Hyperlipidemia
Trialists' Collaboration. Effects of different blood- and venous thromboembolism in patients lacking
pressure-lowering regimens on major cardiovascular thrombophilic risk factors. Br J Haematol 2002;
events: results of prospectively-designed overviews 118: 255-9.
of randomised trials. Lancet 2003; 362: 1527-35. 53) Deguchi H, Pecheniuk NM, Elias DJ, et al. High-
37) Baigent C, Keech A, Kearney PM, et al. Efficacy and density lipoprotein deficiency and dyslipoproteinemia
safety of cholesterol-lowering treatment: prospective associated with venous thrombosis in men. Circulation
meta-analysis of data from 90,056 participants in 14 2005; 112: 893-9.
randomised trials of statins. Lancet 2005; 54) Ray J. Dyslipidemia, statins and venous
366: 1267-78. thromboembolism: a potential risk factor and a
38) Doll R, Peto R, Boreham J, Sutherland I. Mortality in potential treatment. Curr Opin Pulm Med 2003;
relation to smoking: 50 years' observations on male 9: 378-84.
British doctors. BMJ 2004; 328: 1519. 55) Glynn RJ, Danielson E, Fonseca FA, et al. A
39) Wannamethee SG, Lowe GD, Shaper AG, et al. The randomized trial of rosuvastatin in the prevention of
metabolic syndrome and insulin resistance: venous thromboembolism. N Engl J Med 2009;
relationship to haemostatic and inflammatory markers 360: 1851-61.
in older non-diabetic men. Atherosclerosis 2005; 56) Antithrombotic Trialists' Collaboration. Collaborative
181: 101-8. meta-analysis of randomised trials of antiplatelet
40) Lee KW, Lip GY. Effects of lifestyle on hemostasis, therapy for prevention of death, myocardial infarction,
fibrinolysis, and platelet reactivity: a systematic and stroke in high risk patients. BMJ 2002;
review. Arch Intern Med 2003; 163: 2368-92. 324: 71-86.
41) Olufadi R, Byrne CD. Effects of VLDL and remnant 57) Cannon CP, Steinberg BA, Murphy SA, et al. Meta-
particles on platelets. Pathophysiol Haemost Thromb analysis of cardiovascular outcomes trials comparing
2006; 35: 281-91. intensive versus moderate statin therapy. J Am Coll
42) Grant PJ. Diabetes mellitus as a prothrombotic Cardiol 2006; 48: 438-45.
condition. J Intern Med 2007; 262: 157-72. 58) Pepine CJ. Residual risk for secondary ischemic
43) Arteaga RB, Chirinos JA, Soriano AO, et al. events in patients with atherothrombotic disease:
Endothelial microparticles and platelet and leukocyte opportunity for future improvements in patient care.
activation in patients with the metabolic syndrome. Ann Med 2010; 42: 19-35.
Am J Cardiol 2006; 98: 70-4. 59) Kastelein JJ, van Leuven SI, Burgess L, et al. Effect
134
of torcetrapib on carotid atherosclerosis in familial 76) Rocha AT, Tapson VF. Venous thromboembolism in
hypercholesterolemia. N Engl J Med 2007; intensive care patient. Clinical Chest Med 2003;
356: 1620-30. 24: 103-22.
60) Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of 77) Abelseth G, Buckley RE, Pineo GE, et al. Incidence
torcetrapib on the progression of coronary of DVT in patients with fractures of the lower
atherosclerosis. N Engl J Med 2007; 356: 1304-16. extremity distal to the hip. J Orthop Trauma 1996;
61) Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin 10: 230-5.
with or without ezetimibe in familial 78) van Stralen KJ, Rosendaal FR, Doggen CJ. Minor
hypercholesterolemia. N Engl J Med 2008; injuries as a risk factor for venous thrombosis. Arch
358: 1431-43. Intern Med 2008; 168: 21-6.
62) Crouse J 3rd, Raichlen JS, Riley WA, et al. Effect of 79) Geerts WH, Pineo GP, Heit JA, et al. Prevention of
rosuvastatin on progression of carotid intima-media venous thromboembolism: the Seventh ACCP
thickness in low-risk individuals with subclinical Conference on Antithrombotic and Thrombolytic
atherosclerosis: the METEOR Trial. JAMA 2007; Therapy. Chest 2004; 126: 338-400S.
297: 1344-53. 80) White RH, Zhou H, Romano PS. Incidence of
63) Smilde TJ, van Wissen S, Wollersheim H, et al. Effect symptomatic venous thromboembolism after different
of aggressive versus conventional lipid lowering on elective or urgent surgical procedures. Thromb
atherosclerosis progression in familial Haemost 2003; 90: 446-55.
hypercholesterolaemia (ASAP): a prospective, 81) Pineo GF, Hull RD. Prophylaxis of venous
randomised, double-blind trial. Lancet 2001; thromboembolism following orthopaedic surgery:
357: 577-81. mechanical and pharmacological approaches and the
64) Barter PJ, Caulfield M, Eriksson M, et al. Effects of need for extended prophylaxis. Thromb Haemost
torcetrapib in patients at high risk for coronary events. 1999; 82: 918-24.
N Engl J Med 2007; 357: 2109-22. 82) Ilahi OA, Reddy J, Ahmad I. Deep venous thrombosis
65) Krasopoulos G, Brister SJ, Beattie WS, et al. Aspirin after knee arthroscopy: a meta-analysis. Arthroscopy
'resistance' and risk of cardiovascular morbidity: 2005; 21: 727-30.
systematic review and meta-analysis. BMJ 2008; 83) Rosendaal FR. Venous thrombosis: the role of genes,
336: 195-8. environment, and behavior. Hematology (Am Soc
66) Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Hematol Educ Program) 2005:1-12.
Variability in individual responsiveness to clopidogrel: 84) Arnout J, De Gaetano G, Hoylaerts M, et al.
clinical implications, management, and future Thrombosis. Fundamental and Clinical Aspects.
perspectives. J Am Coll Cardiol 2007; 49: 1505-16. Leuven, Leuven University Press; 2003.
67) Prandoni P, Lensing AWA, Prins MH, et al. Residual 85) Day SM, Reeve JL, Pedersen B, et al. Macrovascular
venous thrombosis as a predictive factor of recurrent thrombosis is driven by tissue factor derived primarily
venous thromboembolism. Ann Intern Med 2002; 137: from the blood vessel wall. Blood 2005; 105: 192-8.
955-60. 86) Mackman N. Role of tissue factor in hemostasis,
68) Kearon C. Natural history of venous thrombosis, and vascular development. Arterioscl
thromboembolism. Circulation 2003; 107: 122-30. Thromb Vasc Biol 2004; 24: 1015-22.
69) Samama MM. An epidemiologic study of risk factors 87) Lynch SF, Ludlam CA. Plasma microparticles and
for deep vein thrombosis in medical outpatients: the vascular disorders. Br J Haematol 2007; 137: 36-48.
Sirius study. Arch Intern Med 2000; 160: 3415-20. 88) Chirinos JA, Heresi GA, Velasquez H, et al. Elevation
70) Fowkes FJ, Price JF, Fowkes FG. Incidence of of endothelial microparticles, platelets and leukocyte
diagnosed deep vein thrombosis in the general activation in patients with venous thromboembolism.
population: systematic review. Eur J Vasc Endovasc J Am Coll Cardiol 2005; 45: 1467-71.
Surg 2003; 25: 1-5. 89) Maugeri N, Brambilla M, Camera M, et al. Human
71) Prandoni P, Lensing AW, Cogo A, et al. The long- polymorphonuclear leukocytes produce and express
term clinical course of acute deep venous thrombosis. functional tissue factor upon stimulation. J Thromb
Ann Intern Med 1996; 125: 1-7. Haemost 2006; 4: 1323-1330.
72) Baglin T. What happens after venous 90) Greinacher A. Heparin-induced thrombocytopenia. J
thromboembolism? J Thromb Haemost 2009; Thromb Haemost 2009; 7: 9-12.
7: 287-90. 91) Falanga A, Zacharski L. Deep vein thrombosis in
73) Eichinger S, Minar E, Bialonczyk C, et al. D-dimer cancer: the scale of the problem and approaches to
levels and risk of recurrent venous thromboembolism. management. Ann Oncol 2005; 16: 696-701.
JAMA 2003; 290: 1071-4. 92) Lee AY, Levine MN. Venous thromboembolism and
74) Palareti G, Cosmi B, Legnani C, et al, for the cancer: risks and outcomes. Circulation 2003; 107:
PROLONG Investigators. D-dimer testing to I17-I21.
determine the duration of anticoagulation therapy. N 93) Caine GJ, Stonelake PS, Lip GY, et al. The
Engl J Med 2006; 355: 1780-9. hypercoagulable state of malignancy: pathogenesis
75) Rogers FB. Venous thromboembolism in trauma and current debate. Neoplasia 2002; 4: 465-73.
patients: a review. Surgery 2001; 130: 1-12. 94) Johnson MJ, Walker ID, Sproule MW, et al. Abnormal

135
Previtali E et al.
coagulation and deep venous thrombosis in patients cardiovascular death and nonfatal venous
with advanced cancer. Clin Lab Haematol 1999; thromboembolism in women using oral contraceptives
21: 51-4. with differing progestagen components. Lancet 1995;
95) Blom JW, Doggen CJM, Osanto S, et al. Malignancies, 346: 1589-93.
prothrombotic mutations, and the risk of venous 110) Bloemenkamp KW, Rosendaal FR, Helmerhorst FM,
thrombosis. JAMA 2005; 293: 715-22. et al. Enhancement by factor V Leiden mutation of
96) Ambrus JL, Ambrus CM, Mink IB, et al. Causes of risk of deep-vein thrombosis associated with oral
death in cancer patients. J Med 1975; 6: 61-4. contraceptives containing a third-generation
97) Kessler CM. The link between cancer and venous progestagen. Lancet 1995; 346: 1593-6.
thromboembolism. Am J Clin Oncol 2009; 32: S3-S7. 111) Spitzer WO, Lewis MA, Heinemann LA, et al. Third
98) Prandoni P, Falanga A, Piccioli A. Cancer and venous generation oral contraceptives and risk of venous
thromboembolism. Lancet Oncol 2005; 6: 401-10. thromboembolic disorders: an international case-
99) Hron G, Kollars M, Weber H, et al. Tissue factor- control study. BMJ 1996; 312: 83-8.
positive microparticles: cellular origin and association 112) Farley TM, Meirik O, Collins J. Cardiovascular
with coagulation activation in patients with colorectal disease and combined oral contraceptives: reviewing
cancer. Thromb Haemost 2007; 97: 119-123. the evidence and balancing the risks. Hum Reprod
100) Key N, Makris M, O'Shaughnessy D, et al. Practical Update 1999; 5: 721-35.
Hemostasis and Thrombosis. 2nd ed. Oxford, UK: 113) Kemmeren JM, Algra A, Grobbee DE. Third
Wiley-Blackwell; 2009. generation oral contraceptives and risk of venous
101) Heit JA. Cancer and venous thromboembolism: scope thrombosis: meta-analysis. BMJ 2001; 323: 131-4.
of the problem. Cancer Control 2005; 12: 5-10. 114) Mammen EF. Oral contraceptive pills and hormonal
102) Lyman GH, Khorana AA, Falanga A, et al. American replacement therapy and thromboembolic disease.
Society of Clinical Oncology guideline: Hematol Oncol Clin North Am 2000; 14: 1045-59.
recommendations for venous thromboembolism 115) Simioni P, Sanson BJ, Prandoni P, et al. Incidence of
prophylaxis and treatment in patients with cancer. J venous thromboembolism in families with inherited
Clin Oncol 2007; 25: 5490-505. thrombophilia. Thromb Haemost 1999; 81: 198-202.
103) Palumbo A, Rajkumar SV, Dimopoulos MA, et al. 116) Almen T, Hrtel M, Nylander G, et al. The effect of
Prevention of thalidomide- and lenalinomide- estrogen on the vascular endothelium and its possible
associated thrombosis in myeloma. Leukemia 2008; relation to thrombosis. Surg Gynecol Obstet 1975;
22: 414-23. 140: 938-40.
104) Fisher B, Costantino J, Redmond C, et al. A 117) Fawer R, Dettling A, Weihs D, et al. Effect of the
randomized clinical trial evaluating tamoxifen in the menstrual cycle, oral contraception and pregnancy on
treatment of patients with node-negative breast cancer forearm blood flow, venous distensibility and clotting
who have estrogen receptor-positive tumors. N Engl factors. Eur J Clin Pharmacol 1978; 13: 251-7.
J Med 1989; 320: 479-84. 118) Godsland IF, Winkler U, Lidegaard , et al. Occlusive
105) Pritchard KI, Paterson AH, Paul NA, et al. Increased vascular diseases in oral contraceptive users.
thromboembolic complications with concurrent Epidemiology, pathology and mechanisms. Drugs
tamoxifen and chemotherapy in a randomized trial of 2000; 60: 721-869.
adjuvant therapy for women with breast cancer. 119) Wynn V, Doear J, Mills G, et al. Fasting serum
National Cancer Institute of Canada Clinical Trials triglyceride, cholesterol, and lipoprotein levels during
Group Breast Cancer Site Group. J Clin Oncol 1996; oral-contraceptive therapy. Lancet 1969; 2: 756-60.
14: 2731-7. 120) Wynn V, Doear J, Mills G, et al. Some effects of oral
106) Hutten BA, Prins MH, Gent M, et al. Incidence of contraceptives on serum-lipid and lipoprotein levels.
recurrent thromboembolic and bleeding complications Lancet 1966; 2: 720-3.
among patients with venous thromboembolism in 121) Kluft C, Lansink M. Effect of oral contraceptives on
relation to both malignancy and achieved international hemostasis variables. Thromb Haemost 1997; 78: 315-
normalized ratio: a retrospective analysis. J Clin Oncol 26.
2000; 18: 3078-83. 122) Winkler UH. Blood coagulation and oral
107) Gomes MP, Deitcher SR. Risk of venous contraceptives: a critical review. Contraception 1998;
thromboembolic disease associated with hormonal 57: 203-9.
contraceptives and hormone replacement therapy: a 123) van Vliet HA, Bertina RM, Dahm AE, et al. Different
clinical review. Arch Intern Med 2004; effects of oral contraceptives containing different
164: 1965-76. progestogens on protein S and tissue factor pathway
108) World Health Organization Collaborative Study of inhibitor. J Thromb Haemost 2008; 6: 346-51.
Cardiovascular Disease and Steroid Hormone 124) Rosing J, Middeldorp S, Curvers J, et al. Low-dose
Contraception. Venous thromboembolic disease and oral contraceptives and acquired resistance to activated
combined oral contraceptives: results of an protein C: a randomized cross-over study. Lancet
international multicentre case-control study. Lancet 1999; 354: 2036-40.
1995; 346: 1575-82. 125) Tans G, Curvers J, Middeldorp S, et al. A randomized
109) Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cross-over study in the effects of levonorgestrel- and
136
desogestrel-containing oral contraceptives on the pregnancy. Thromb Haemost 1998; 79: 1166-70.
anticoagulant pathways. Thromb Haemost 2000; 84: 143) Franchini M. Haemostasis and pregnancy. Thromb
15-21. Haemost 2006; 95: 401-13.
126) Winkler UH. Hemostatic effects of third- and second- 144) Lockwood CJ, Krikun G, Runic R, et al. Progestin
generation oral contraceptives: absence of a causal epidermal growth factor regulation of tissue factor
mechanism for a difference in risk of venous expression during decidualization of human
thromboembolism. Contraception 2000; 62: 11S-20S. endometrial stromal cells. J Clin Endocrinol Metab
127) Tchaikovski SN, van Vliet HA, Thomassen MC, et al. 2000; 85: 297-301.
Effect of oral contraceptives on thrombin generation 145) Lanir N, Aharon A, Brenner B. Hemostatic
measured via calibrated automated thrombography. mechanisms in human placenta. Best Pract Res Clin
Thromb Haemost. 2007; 98: 1350-6. Haematol 2003; 16: 183-95.
128) Tan JY. Thrombophilia in pregnancy. Ann Acad Med 146) Dalhamn T, Hellgren M, Blomback M. Changes in
Singapore 2002; 31: 328-34. blood coagulation and fibrinolysis in the normal
129) Bates SM, Greer IA, Pabinger I, et al. Venous puerperium. Gynecol Obstet Invest 1985; 20: 37-44.
thromboembolism, thrombophilia, antithrombotic 147) WHO Working Group. Health Aspects of Air Pollution
therapy, and pregnancy: American College of Chest with Particulate Matter, Ozone and Nitrogen Dioxide.
Physicians Evidence-Based Clinical Practice Accessed on 13/04/10 at http:/www.euro.who.int/air/
Guidelines. Chest 2008; 133: 844S-886S. activities/20050222_2).
130) Pomp ER, Lenselink AM, Rosendaal FR, et al. 148) Schwarze PE, Ovrevik J, Lag M, et al. Particulate
Pregnancy, the postpartum period and prothrombotic matter properties and health effects: consistency of
defects: risk of venous thrombosis in the MEGA study. epidemiological and toxicological studies. Hum Exp
J Thromb Haemost 2008; 6: 632-637. Toxicol 2006; 25: 559-79.
131) Ros HS, Lichtenstein P, Bellocco R, et al. Pulmonary 149) Bathnagar A. Environmental cardiology. Studying
embolism and stroke in relation to pregnancy: how mechanistic links between pollution and heart disease.
can high-risk women be identified? Am J Obstet Circ Res 2006; 99: 692-705.
Gynecol 2002; 186: 198-203. 150) Franchini M, Mannucci PM. Short-time effect of air
132) McColl MD, Ramsay JE, Tait RC, et al. Risk factors pollution on cardiovascular diseases outcomes and
for pregnancy associated venous thromboembolism. mechanisms. J Thromb Haemost 2007; 5: 2169-74.
Thromb Haemost 1997; 78: 1183-8. 151) Brook RD, Franklin B, Cascio W, et al. Air pollution
133) Martinelli I, De Stefano V, Taioli E, et al. Inherited and cardiovascular disease. A statement for health case
thrombophilia and first venous thromboembolism professionals from the expert panel on population and
during pregnancy and puerperium. Thromb Haemost prevention science of the American Heart Association.
2002; 87: 791-5. Circulation 2004; 109: 2655-71.
134) Gerhardt A, Scharf RE, Beckmann MW, et al. 152) Vermylen J, Nemmar A, Nemery B, et al. Ambient
Prothrombin and factor V mutations in women with a air pollution and acute myocardial infarction. J
history of thrombosis during pregnancy and the Thromb Haemost 2005;3:1955-1961.
puerperium. N Engl J Med 2000; 342: 374-80. 153) Hoek G, Brunekreef B, Fischer P, et al. The association
135) Gerhardt A, Scharf RE, Zotz RB. Effect of hemostatic between air pollution and heart failure, arrhythmia,
risk factors on the individual probability of thrombosis embolism, thrombosis, and other cardiovascular
during pregnancy and the puerperium. Thromb causes of death in a time series study. Epidemiology
Haemost 2003; 90: 77-85. 2001; 12: 355-7.
136) Gammaro L, Lippi G, Bottini E, et al. Severe 154) Peters A, Dockery DW, Muller JE, et al. Increased
preeclampsia in antithrombin III deficiency with no particulate air pollution and the triggering of myocardial
history of venous thromboembolism. J Nephrol 2001; infarction. Circulation 2001; 103: 2810-5.
14: 312-5. 155) Zanobetti A, Schwartz J. Air pollution and emergency
137) Brenner B. Thrombophilia and fetal loss. Semin admissions in Boston, MA. J Epidemiol Community
Thromb Hemost 2003; 29: 165-70. Health 2006; 60: 890-5.
138) Rodger MA, Paidas M. Do thrombophilias cause 156) Pope CA 3rd, Muhlestein JB, May HT, et al. Ischemic
placenta-mediated pregnancy complications? Semin heart disease events triggered by short-term exposure
Thromb Hemost 2007; 33: 597-603. to fine particulate air pollution. Circulation 2006; 114:
139) Rodger MA, Paidas M, McLintock C, et al. Inherited 2443-8.
thrombophilia and pregnancy complications revisited. 157) Lanki T, Pekkanen J, Aalto P, et al. Associations of
Obstet Gynecol 2008; 112: 320-4. traffic related air pollutants with hospitalisation for
140) Bloom AL, Forbes CD, Thomas DP, et al. Hemostasis first acute myocardial infarction: the HEAPSS study.
and Thrombosis. 3rd ed. Edinburgh, UK: Churchill Occup Environ Med 2006; 63: 844-51.
Livingstone; 1994. 158) Seaton A, Soutar A, Crawford V, et al. Particulate air
141) Brenner B. Hemostatic changes in pregnancy. Thromb pollution and the blood. Thorax 1999; 54: 1027-32.
Res 2004; 114: 409-14. 159) Liao D, Heiss G, Chinchilli VM, et al. Association of
142) Clark P, Brennard J, Conkie JA, et al. Activated protein C criteria pollutants with plasma hemostatic/
sensitivity, protein C, protein S and coagulation in normal inflammatory markers: a population-based study. J

137
Previtali E et al.
Expo Anal Environ Epidemiol 2004; 15: 319-28. 170) Colucci G, Stricker H, Roggiani W, at al. Venous stasis
160) Pekkanen J, Brunner EJ, Anderson HR, et al. Daily and thrombin generation. J Thromb Haemost 2004;
concentrations of air pollution and plasma fibrinogen 2: 1008-9.
in London. Occup Environ Med 2000; 57: 818-22. 171) Simons R, Krol J. Jet leg, pulmonary embolism, and
161) Ruckerl R, Ibald-Mulli A, Koenig W, et al. Air hypoxia. Lancet 1996; 348: 416.
pollution and markers of inflammation and 172) Hodkinson PD, Hunt BJ, Parmar K, et al. Is mild
coagulation in patients with coronary heart disease. normobaric hypoxia a risk factor for venous
Am J Respir Crit Care Med 2006; 173: 432-41. thromboembolism? J Thromb Haemost 2003;
162) Baccarelli A, Zanobetti A, Martinelli I, et al. Effects 1: 2131-3.
of exposure to air pollution on blood coagulation. J 173) Toff WD, Jones CI, Ford I, et al. Effect of hypobaric
Thromb Haemost 2007;5:252-260. hypoxia, simulating conditions during long-haul air
163) Baccarelli A, Zanobetti A, Martinelli I, et al. Air travel, on coagulation, fibrinolysis, platelet function,
pollution, smoking and plasma homocysteine. Environ and endothelial activation. JAMA 2006;
Health Perspect 2007; 115: 176-81. 295: 2251-61.
164) Baccarelli A, Martinelli I, Zanobetti A, et al. Exposure 174) Schobersberger W, Schobersberger B, Mittermayr M,
to particulate air pollution and risk of deep vein et al. Air travel, hypobaric hypoxia, and prothrombotic
thrombosis. Arch Int Med 2008; 168: 920-7. changes. JAMA 2006; 296: 2313-4.
165) Gallus AS. Travel, venous thromboembolism, and 175) Schreijer AJM, Cannegieter SC, Meijers JCM, et al.
thrombophilia. Semin Thromb Hemost 2005; 31: 90-6. Activation of coagulation system during air travel: a
166) Ten Wolde M, Kraaijenhagen RA, Schiereck J, et al. crossover study. Lancet 2006; 367: 832-8.
Travel and the risk of symptomatic venous
thromboembolism. Thromb Haemost 2003;
89: 499-505.
167) Kuipers S, Schreijer AJM, Cannegieter SC, et al.
Travel and venous thrombosis: a systematic review. J
Intern Med 2007; 262: 615-34.
168) Cannegieter SC, Doggen CJM, van Houwelingen HC,
et al. Travel-related venous thrombosis: results from
a large population-based case control study (MEGA Received: 4 August 2010 - Accepted: 31 August 2010
Correspondence: Ida Martinelli
study). PLoS Med 2006; 3: 1258-65. Haemophilia and Thrombosis Centre
169) Tardy B, Tardy-Poncet B, Bara L, et al. Effect of long IRCCS Ca' Granda - Ospedale Maggiore Policlinico
travels in sitting position in elderly volunteers on Via Pace, 9
20122 Milano, Italy
biological markers of coagulation activation and e-mail: martin@policlinico.mi.it
fibrinolysis. Thromb Res 1996; 83: 153-60.

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Risk Factors For Venous and Arterial Thrombosis

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REVIEW

Risk factors for venous and arterial thrombosis

Emanuele Previtali, Paolo Bucciarelli, Serena M. Passamonti, Ida Martinelli

Introduction thrombosis. Pathophysiological and epidemiological

plaque rupture) or intracardiac (atrial fibrillation, Hyperlipidaemia 3.25 (2.81-3.76)

atherothrombosis. During the past decades, progress trauma or fractures

a complex interplay, are also important determinants metabolic syndrome

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Age increase of 10 mg/dL for each decade of age. High

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Inherited Acquired Mixed

Antithrombin deficiency Antiphospholipid syndrome Hyperhomocysteinaemia

Protein C deficiency Increased fibrinogen levels

Protein S deficiency Increased factor VIII levels

Factor V Leiden Increased factor IX levels

Prothrombin G20210A Increased factor XI levels

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Antithrombin deficiency 0.02 - 0.17 1.1 0.5 - 4.9

Protein C deficiency 0.14 - 0.5 3.2 1.4 - 8.6

Protein S deficiency ? 2.2 1.4 - 7.5

Heterozygous factor V Leiden 3.6 - 6.0 21.0 10 - 64

Heterozygous prothrombin G20210A 1.7 - 3.0 6.2 18

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Table V - Associations between classic cardiovascular progression of atherosclerosis showed inconsistent

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

manifestation of heparin-induced thrombocytopenia, expression as a host response in endothelial cells and

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Change during OC use Change during pregnancy

fibrinogen, V, VII, VIII, IX, X, XII

von Willebrand factor =

resistance to activated protein C (ratio)

Markers of thrombin formation

F1+2, TAT complexes, fibrinopeptide A

TAFI, PAI 1 and 2

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

linked and interdependent. Heightened generation of Willebrand factor in Italian centenarians.

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10

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