INHERITED THROMBOPHILIA
Virchow is frequently credited with having first postulated hypercoagulability. However,
when the German scientist originally theorized his triad, very little was known about
the mechanisms involved in triggering and sustaining blood coagulation, and the proposed
“abnormal blood constituents” were only later associated with thrombophilia, a condition
that is also referred to as “prothrombotic state” or “hypercoagulable syndromes.”[4]
[7] When Mammen drafted his seminal review in 1992, patients with any one of the abnormalities
he listed (decreased protein C, protein S, antithrombin III, plasminogen, tissue plasminogen
activator, or increased plasminogen activator inhibitor-1) were supposed to have an
increased risk of VTE. He also emphasized, however, that the presence of a single
congenital abnormality was not sufficient to “cause” a thrombosis, a standpoint consistent
with the previously mentioned hypothesis of the multifactorial origin of VTE. Over
the past 20 years, several other gene variants have been identified as risk factors
for VTE (including factor V Leiden and prothrombin G20210A polymorphism).
Antithrombin Deficiency
Antithrombin is a single-chain glycoprotein belonging to the serine protease inhibitor
(serpin) superfamily[8] and which functions as a natural anticoagulant by binding to, and inactivating,
thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa.[9] The result of this activity is a reduction in both the generation and the half-life
of thrombin. In addition to the active site responsible for coagulation factor inactivation,
the antithrombin molecule contains a heparin-binding site. When exogenous heparin
or endogenous heparan sulfate binds to this site, the ability of antithrombin to inactivate
the above-mentioned factors is greatly enhanced. As expected, any type of mutation
that leads to a reduction of antithrombin levels or to a decreased ability to interact
with either the activated factors or to heparin will result in an increased risk of
thrombosis.[10] Antithrombin deficiency is mainly transmitted as an autosomal dominant trait, and
patients usually present with recurrent VTE episodes during the second to third decade
of life. The penetrance of this disease is very high, as most affected family members
experience a thrombotic event by the age of 45 years. Antithrombin deficiency is probably
the most severe of the inherited thrombophilias, causing upwards of a 20-fold increased
risk for thrombosis compared with that of individuals not carrying this mutation.[11] However, the prevalence of this mutation in the general population is extremely
low, being only 0.02%. Its prevalence among unselected patients with VTE is estimated
at 1 to 3%.[12] Two major groups of antithrombin deficiencies can be distinguished by laboratory
phenotype: in type I deficiency, both antithrombin activity and antigen are reduced
to the same extent, whereas in type II deficiency, patients usually exhibit higher
antithrombin antigen than activity levels, which is indicative of a functional defect
of the antithrombin molecule.[13] Patients homozygous for type I deficiency have not been described, suggesting that
a complete deficiency of antithrombin is incompatible with survival.
Protein C Deficiency
Eberhard Mammen was recruited from the University of Marburg/Lahn to Wayne State in
the late 1950s to work as a research associate in the laboratory of Dr. Walter Seegers.
At that time, this laboratory was one of only a few investigating coagulation from
a biochemical standpoint. Indeed, Dr. Seegers was also the first to isolate clotting
factors from plasma, prove their existence, and characterize them. In collaboration,
Mammen and Seegers first described protein C, an inhibitor now recognized as one of
the major blood clotting inhibitors.[14] Protein C is a vitamin K–dependent glycoprotein normally synthesized in the liver.
Under physiologic conditions, once activated by the thrombin-thrombomodulin complex,
protein C acts as an anticoagulant by proteolytic degradation of activated coagulant
factors Va and VIIIa. As for other physiologic inhibitors of coagulations, any mutation
leading to a reduction of protein C activity increases the risk of thrombosis.[15] Inherited protein C deficiency is transmitted as a dominant autosomal trait.[16] Patients experience recurrent episodes of VTE, often before the age of 45 years.
Homozygous individuals have a more severe clinical picture, not infrequently leading
to neonatal purpura fulminans, a potentially fatal condition characterized by multiple
thrombosis in small vessels leading to skin necrosis.[17] The penetrance of the disease is less than that seen in antithrombin deficiency:
thus, heterozygous individuals have around a 10-fold increased risk for thrombosis
compared with that of the general population.[18] However, the disorder is quite rare with a prevalence in the population of only
0.2 to 0.4% and within 3 to 5% in patients selected for venous thrombosis. Two types
of protein C deficiency can be recognized. Type I deficiency, which is most common,
is characterized by concomitant reduction of protein C functional and antigen levels
due to a reduced synthesis of normal protein C molecules. In type II deficiency, the
functional protein C level is reduced but the antigen level is normal (typically due
to the synthesis of a normal amount of protein C variant molecules presenting with
reduced activity).[13]
Protein S Deficiency
Protein S is a vitamin K–dependent protein produced mainly by hepatocytes but also
by endothelial cells and megakaryocytes.[15] It functions as a cofactor of activated protein C for the degradation of activated
factors Va and VIIIa. Moreover, it is able to directly inactivate factors Va and Xa.
Protein S circulates in plasma in equilibrium between an inactive form, bound to a
carrier called C4b-binding protein (C4BP), and a free, functionally active form, which
accounts for ~40% of the total plasma protein S. The bioavailability of protein S
is closely linked to the concentration of C4BP, which acts as an important regulatory
protein. Thus, all conditions (i.e., pregnancy, oral contraceptive use, acute thrombosis,
inflammatory states) associated with increased C4BP levels also cause an increase
in bound protein S and a reduction of the unbound free form.[19] Transmitted as an autosomal dominant trait, familial protein S deficiency has a
clinical presentation very similar to that observed in protein C deficiency.[20] Thus, heterozygous individuals experience early recurrent VTE episodes and sometimes
warfarin-induced skin necrosis, and rare homozygotes exhibit a very severe clinical
picture with neonatal purpura fulminans. The penetrance of the disease is also similar
to that seen in protein C deficiency, causing a nearly 10-fold increased risk of venous
thrombosis in affected individuals compared with that of the normal population. The
prevalence of protein S deficiency in the general population is estimated at 0.03
to 0.1%, and it occurs in 1 to 3% of patients with venous thrombosis.[19] Three types of protein S deficiency have been defined: type I deficiency is characterized
by low total and free protein S antigen and activity, type II deficiency (dysfunctional
protein S) is characterized by normal total and free protein S antigen but reduced
protein S activity, and type III deficiency is characterized by low free protein S
antigen and activity in the presence of normal or subnormal total protein S antigen
level.[21]
Activated Protein C Resistance (Factor V Leiden)
This concept of resistance to activated protein C (APC) was first described in 1994
by Dahlback and Hildebrand,[22] who observed that plasma from many patients with venous thrombosis was resistant
to the normal anticoagulant effect of APC. In fact, the activated partial thromboplastin
time (APTT) of these patients was not prolonged after the addition of APC to their
plasma. Successive studies have demonstrated that the great majority of these patients
had a mutation in the factor V gene consisting of a single amino acid change (Arg506 to Gln) at one of the APC cleavage sites.[23] This substitution makes factor V resistant to inactivation by APC. The original
mutation identified was called factor V Leiden, as it was initially characterized
in Leiden in The Netherlands. Subsequently, other point mutations (Arg306 to Thr and Arg306 to Gly) and polymorphisms of factor V (HR2 haplotype) have been identified, although
these are much rarer than factor V Leiden and are without a clear clinical significance.[24]
[25]
[26] Factor V Leiden is a relatively common mutation, being present in ~5% of the normal
population of northern European origin and in 10 to 50% of patients presenting with
a first episode of VTE.[12]
[27] According to the Longitudinal Investigation of Thromboembolism Etiology (LITE) study
and the Leiden Thrombophilia (LET) study, patients heterozygous for factor V Leiden
have a relatively low risk for thrombosis, from 3.5 to 8.1 times greater than that
of the general population. In contrast, and consistent with the multifactorial view
of thrombosis, homozygotes exhibit a very high risk for venous thrombosis, ~24 to
80 times the normal risk.[28]
[29]
Prothrombin 20210A
This polymorphism was first described in 1996 by Poort and colleagues,[30] who showed that a G to A transition at nucleotide 20210 of the prothrombin gene
within the 3′ untranslated region caused increased basal levels of functionally normal
prothrombin, thereby conferring to heterozygous carriers an increased risk (approximately
two- to four-fold) for developing venous thrombosis. Thus, these individuals exhibit
a relatively low thrombotic risk, and most of them will not have had a thrombotic
episode by age 50 years. In contrast, homozygosity for prothrombin gene mutation is
much rarer and causes a higher thrombotic risk. Like factor V Leiden, the prothrombin
G20210A polymorphism is quite common, being found in ~2% of the general population
and in 5 to 10% of selected patients with VTE.[31] According to the LITE study and the LET study, patients heterozygous for G20210A
polymorphism have a relatively low relative risk for thrombosis (1.9 to 2.8 times
greater).[28]
[29] Remarkably, Margaglione et al hypothesized that the prothrombin G20210A polymorphism
might be associated with DVT in the lower extremities alone or when complicated by
PE, but not with isolated PE.[32]
Sticky Platelet Syndrome
The sticky platelet syndrome (SPS) is an autosomal dominant platelet disorder associated
with arterial and venous thromboembolic events, characterized by hyperaggregability
of platelets in platelet-rich plasma with adenosine diphosphate (ADP) and epinephrine
(type I), epinephrine alone (type II), or ADP alone (type III). Clinically, patients
may present with angina pectoris, acute myocardial infarction (MI), transient cerebral
ischemic attacks, stroke, retinal thrombosis, peripheral arterial thrombosis, and
venous thrombosis, frequently recurrent under oral anticoagulant therapy.[33] Although the role of platelet hyperaggregability as a possible risk factor for VTE
is not well defined and this syndrome appears to be prominent especially in patients
with unexplained arterial vascular occlusions, combinations of SPS with either congenital
thrombophilic defects or acquired disease entities have been described,[34] and both platelet hyperaggregability and SPS may represent independent risk factors
in patients with otherwise unexplained VTE.[35]
ACQUIRED THROMBOPHILIA
At the time of the seminal review by Mammen in 1992, most acquired risk factors for
VTE were already known: surgery and other traumas, previous VTE, prolonged immobility
and paralysis, malignancy, congestive heart failure, obesity, advanced age, pregnancy
and puerperium, varicose veins, and oral contraceptives (OCs).[7] Nevertheless, several studies (especially reviews and meta-analyses) contributed
over time to further expand the known components of acquired thrombophilia and to
elucidate the relative contribution of each single risk factor in the pathogenesis
of VTE.
General Surgery
During extensive tissue damage, the balance between thrombosis and fibrinolysis is
altered. Accordingly, Mammen associated three leading thrombogenic factors with surgery
and trauma: (1) release of procoagulant material during surgery; (2) preoperative,
perioperative, and postoperative immobility; and (3) reduced postoperative fibrinolytic
activity (fibrinolytic shutdown).[7] Before the introduction of routine thromboprophylaxis with heparins, more than 20
years ago, the rates of DVT and fatal PE in both moderate- and high-risk general surgery
patients were respectively between 15% and 30% and between 0.2% and 0.9%.[36] However, the risk of VTE in contemporary general surgery is uncertain, because studies
without thromboprophylaxis are no longer performed. Generally, the risk of VTE varies
widely depending on the type of surgery (site, duration, type of anesthesia) and the
clinical characteristics of the patients (increasing age, cancer, prior VTE, obesity,
comorbidities). Data from the LET study indicate an odds ratio of 5.9 for general
surgery.[37] The risk of DVT in patients undergoing major abdominal surgery, gynecologic surgery,
and urologic surgery (in particular open prostatectomy) without thromboprophylaxis
is 15 to 30%.[37] Colorectal surgery, in particular, carries a specific high risk for postoperative
thromboembolic complications compared with that of other types of general surgery,
resulting from the frequent presence of several concomitant conditions, including
advanced age, pelvic dissection, perioperative positioning of the patients, and presence
of cancer or inflammatory bowel disease.[38] It is also worth mentioning that in the Leiden region, where extended anticoagulant
prophylaxis is routinely prescribed for most surgical interventions, 18% of patients
with thrombosis have had a previous surgical intervention, which increased the risk
of venous thrombosis sixfold.[37] Data from other types of surgery are highly heterogeneous.
Since the early 1990s, the demand for cosmetic surgery has grown dramatically in many
Western countries, apparently fueled by societal perceptions of the ideal body image.
Besides costs, important health care consequences are the potential complications,
including thromboembolic disorders, carried by this (mostly unnecessary) type of surgery.
In 2001, the American Society of Plastic Surgeons (ASPS) extrapolated existing data
to estimate that more than 18,000 cases of DVT may occur in plastic surgery patients
each year. Of all common plastic surgery procedures, abdominoplasty has the highest
rate of thromboembolic complications, with estimates as high as a 1.2% incidence for
DVT and an 0.8% incidence for PE.[39] Despite this, more than half of the surgeons responding to an ASPS questionnaire
indicated that they currently used no form of thromboprophylaxis.[40] When liposuction is combined with other procedures, the mortality rate increases
from 1 per 47,415 surgeries to 1 per 7314.[41] Besides surgery and anesthesia, several additional risk factors have been identified
in these patients, including smoking, obesity, advanced age, use of hormone replacement
or OCs, congestive heart failure, immobilization (bed rests, casts), malignancy, history
of previous VTE, and inherited hypercoagulable states, which may act synergistically
to increase the individual risk.[39]
Orthopedic Surgery and Trauma
Major orthopedic surgery involving the lower extremity is a prominent risk factor
for VTE, and even with appropriate thromboprophylaxis, total hip or knee replacement
will lead to symptomatic VTE in 1 to 3% of patients.[37] Globally, the rate of postoperative DVT in patients who do not receive effective
prophylaxis is 70% after nonelective hip surgery and 48% after elective orthopedic
surgery. In a recent analysis of more than 4000 patients, Bannink et al still reported
a fourfold increased risk of symptomatic thrombosis after orthopedic surgery.[42] Perioperative factors affecting risk include venous stasis, direct injury to the
veins during surgery, postoperative immobilization, and need for transfusion. Patient-related,
or predisposing, risk factors include inherited thrombophilia, advanced age, obesity,
varicose veins, and current use of estrogen-containing medications (such as OCs and
hormone replacement therapy). Rates of DVT without prophylaxis range from 40 to 60%
seven to fourteen days after major orthopedic surgery; routine ventilation-perfusion
scans in patients after hip or knee arthroplasty revealed pulmonary emboli in 3 to
28% of patients.[43]
Patients who undergo total hip arthroplasty are in the highest risk category for developing
postoperative VTE. Evaluation of the natural history of this patient population reveals
that the incidence of DVT without appropriate prophylaxis is as high as 32 to 60%,
and the incidence of PE is as high as 16%, with an 0.3 to 3.4% occurrence of fatal
PE.[44] Patients with hip fractures and without appropriate prophylaxis have a DVT rate
of 30 to 60%, with a proximal DVT rate of up to 36% and a risk of fatal PE from 0.4
to 13%. DVT after knee arthroscopy is a consistent finding in studies of nonprophylaxed
patients when routine screening using ultrasound or contrast venography is used. Current
data suggest an overall DVT rate of 9.9% and a proximal DVT rate of 2.1% after knee
arthroscopy without thromboprophylaxis.[45]
Minor injuries of the leg are also associated with greater risk for VTE, as shown
in a large, population-based, case-control study. After adjustment for sex and age,
VTE was associated with previous minor injury (adjusted odds ratio = 3.1). The association
was strongest for injuries during the 4-week period preceding thrombosis, and no association
was evident before 10 weeks. Nevertheless, minor injuries in the leg were more strongly
associated with thrombosis (adjusted odds ratio = 5.1), whereas minor injuries affecting
other body parts were not associated with thrombosis. The presence of factor V Leiden
in patients with a leg injury increase the risk up to 50-fold.[46]
Cancer
In the challenging cancer biology, transforming genes often act in concert with numerous
epigenetic factors, including hypoxia, inflammation, contact between blood and cancer
cells, and emission of procoagulant vesicles from tumors, to determine a net imbalance
of the hemostatic potential, which is detectable by a variety of laboratory tests.[47]
[48] Procoagulant factors in particular are intimately involved in all aspects of hemostatic,
cell proliferation, and cellular signaling systems. However, the biggest as-yet unresolved
question is why cancer patients develop thrombosis? Because the thrombus itself does
not apparently contribute directly to the tumor biology, enhanced hemostasis activation
in cancer patients may be interpreted according to the most recent biological evidence.
In this perspective, thrombosis may be interpreted as a epiphenomenon of an intricate
and effective biological feedback to maintain or promote cancer progression.[48] In this section, we briefly analyze the pathogenesis and laboratory, clinical, and
therapeutic features of cancer and thrombosis.
Trousseau first identified a relationship between thrombosis and malignancy in 1865.[49] Since then, it has been widely acknowledged that cancer and its related treatments
greatly increase the risk of VTE.[50] Basically, hemostasis and cancer biology interact bidirectionally in a sort of “vicious
cycle,” where cancer cells are a mighty source of procoagulants (tissue factor, cancer
procoagulant, thrombin), which in turn act as strong promoters of cancer growth and
spread.[48] Hence, thromboembolic complications may be the first clinical presentation of cancer;
prospective cohort studies documented an increased incidence of cancer after an episode
of idiopathic VTE compared with the incidence in the general population.[51] Moreover, the onset of VTE in patients with cancer is associated with an increased
risk of death approximately twofold to eightfold depending on gender and presence
or absence of chemotherapy,[52]
[53] and patients with cancer who are treated for VTE have higher thrombosis recurrence
rates and more hemorrhagic complications compared with that of patients without cancer
who are treated for VTE.[54]
[55]
Overall, patients with cancer have a four- to seven-fold increased risk of thrombosis
compared with that of the general population.[56]
[57]
[58]
[59] Men are at a greater risk, showing an age-adjusted male-to-female ratio of 1.2:1.[53] However, data from several epidemiologic investigations demonstrated significant
heterogeneity in the risk of VTE according to the different histologic origin. Thodiyil
et al, analyzing data from the data set presented in the Medicare Provider Analysis
and Review Record (MEDPAR),[60] calculated the relative risk of VTE by site of malignancy compared with that of
subjects with nonmalignant disease and observed greater relative risk for cancer of
uterus (3.4), brain (2.4), ovary (2.2), pancreas (2.1), stomach (1.5), kidney (1.4),
colon (1.4), lung (1.1), rectum (1.1), and for blood cancers (leukemia 2.2, lymphoma
1.8). The relative risk of other forms of cancer was comparable (prostate, liver,
cervix) or even lower (esophagus, breast, bladder, head/neck) than that of patients
with various medical conditions who were assumed to have a relative risk of 1.0 for
VTE.[61] In a later article, Heit also estimated the relative risk of VTE for various types
of cancer, concluding that pancreatic cancer, lymphoma, and brain cancer have a relative
risk for VTE greater than 25, whereas the VTE risk associated with cancer of the ovary,
stomach, kidney, colon, rectum, and lung was much lower, albeit still increased (> 17)
compared with that of persons without cancer.[53] In the Multiple Environmental and Genetic Assessment (MEGA) study, patients with
hematologic malignancies had the highest risk of venous thrombosis (odds ratio = 28),
followed by lung cancer and gastrointestinal cancer. The risk of VTE was higher at
diagnosis (odds ratio = 54) and in patients with distant metastases (odds ratio = 20).[56]
Several treatments, including surgery, chemotherapy, and hormone therapy,[57] along with the placement of a central venous catheter,[62] also increase the risk of thrombosis. Patients receiving cytotoxic or immunosuppressive
chemotherapy have a nearly sixfold increased risk for VTE, probably due to vascular
damage induced by several chemotherapeutic agents and release of prothrombotic substances
after cell necrosis.[63] Women who are treated with tamoxifen for breast cancer have a two- to fivefold increased
risk of VTE, and the risk is even greater after menopause and when tamoxifen is associated
with chemotherapy.[64]
[65] Although recently published studies suggest that the incidence of symptomatic and
asymptomatic catheter-related thrombosis has decreased significantly in recent years,[66] cancer patients with a central venous catheter or transvenous pacemaker have a sixfold
increase in upper-extremity VTE (odds ratio = 6.5).[54] Finally, the presence of the factor V Leiden mutation in cancer patients determines
an increase of nearly 12-fold in the risk versus that of individuals without cancer
and factor V Leiden, similar results being observed in cancer patients carrying the
prothrombin 20210A variant.[56]
Hospital Care Setting
The rate of VTE, reportedly higher in the hospital than in the ambulatory setting,
occurs frequently during and after hospitalization for acute medical illness or surgery
due to the higher clot burden and lower rates of VTE prophylaxis. Hence, ~10% of all
deaths in-hospital are still related to PE. In his seminal review of the scientific
literature, Mammen provided clear evidence of a relationship between bedrest and venous
thrombosis, in that patients confined to bed for more than 1 week have a considerably
higher incidence than that of those bedridden for less than 1 week. He also highlighted
that preoperative immobility was associated with a higher postoperative incidence
of DVT, and postoperative patients remain at higher risk during the entire period
of immobility, especially if they remain immobile after discontinuation of thrombosis
prophylaxis.[7] Fifteen years later, Piazza et al strengthened these findings, concluding that hospitalized
medical patients had an ~43% higher relative frequency of PE compared with that of
nonmedical patients.[67] PE also accounts for up to 10% of deaths in hospitalized patients, making VTE the
most common preventable cause of in-hospital death.[68] The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous
Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study, a multinational
cross-sectional survey designed to assess the prevalence of VTE risk in the acute
hospital care setting, estimated that more than half of patients in the hospital care
setting (64.4% surgical and 41.5% medical) are at risk for VTE according to 2004 American
College of Chest Physicians evidence-based consensus guidelines.[68] Major independent risk factors for VTE in these patients are paresis, acute infectious
disease, congestive heart failure, malignancy, an indwelling central venous catheter,
varicose veins, and previous thrombosis. Therefore, although the risk varies widely
according to the reason for hospitalization and the presence of comorbidities, stroke
and infections leading to intensive care management represent conditions at greater
risk. In his studies on paralyzed patients after spinal cord injury, Mammen identified
a high risk for developing DVT associated with this condition, reporting an overall
incidence from 50 to 100%, depending on the methods used for determination, with little
relationship to other risk factors. He also reported that the paralyzed limbs in acute
stroke patients have a 63% rate of thrombosis compared with only 7% in the nonparalyzed.[7] High-risk patients also include those hospitalized for chronic inflammatory pathologies,
such as lupus erythematosus, Wegener granulomatosis, inflammatory bowel diseases,
and Behçet's disease.[69] A potential explanation for this finding was again provided by Mammen, who identified
abnormality of hemorheology, one of the components of Virchow's triad, as a potential
cause. Blood flow slows down as blood viscosity increases; the hyperviscosity syndrome,
sustained by dehydration, increased hematocrit values, and increased levels of acute-phase
proteins including fibrinogen, is commonplace in patients with inflammatory disorders
and in those with spinal cord injury and paralysis.[7] In patients hospitalized for chronic heart failure, raised venous pressure with
subsequent decreased blood flow could be the predisposing factor for the high incidence
of VTE.[7]
Immobilization of the Lower Extremities and Long-Distance Travel
Immobilization is traditionally assumed as a prominent risk factor for thrombosis
because it abolishes the essential function of the calf musculature in pumping the
blood upstream through the veins.[70] Mammen originally reported that patients with lower-limbs fractures are at high
risk of venous thrombosis, especially when limbs are immobilized by a plastic cast,
whereas prophylaxis by external compression modalities greatly reduces the risk, because
these devices not only prevent stasis but also apparently activate the fibrinolytic
system.[7] Accordingly, the mean rate of VTE in patients with immobilization of the lower extremities
before widespread use of thromboprophylaxis has been reported to be 17%, decreasing
to 9.6% with the use of low-molecular-weight heparin (LMWH).[71]
The association between VTE and air flight was first reported during World War II,
where a sixfold increased risk of PE was observed after air raids.[72] Just 15 years later, Homans designated long-distance travel as a clinical entity,[73] a condition further translated into the traditional denomination of “economy class
syndrome” (combination of immobility and relative dehydration).[74] Several studies have investigated the relationship between thrombosis and travel
over the past decades, but whether long-distance travel and symptomatic VTE are really
associated is still a matter of debate, as most travelers who develop DVT or PE also
have one or more other predisposing risk factors that include older age, obesity,
recent injury or surgery, previous thrombosis, venous insufficiency, malignancy, hormonal
therapies, pregnancy, and inherited thrombophilia (especially factor V Leiden and
the prothrombin gene mutation).[70] A recent review has synthesized available data on this topic, concluding that long-distance
travel is associated with an increased risk of VTE up to four-fold. The absolute risk
of a symptomatic event within 4 weeks of flights longer than 4 hours is 1 in 4600
flights, whereas the risk of acute PE increases with duration of travel, up to 4.8
per million in flights longer than 12 hours.[75] In a separate article, Ten Wolde et al estimated an accurate odds ratio for the
relationship between recent traveling and symptomatic VTE. The analysis consisted
of three large case-control studies on patients with clinically suspected DVT and
PE. The resulting pooled odds ratio for the association between any medial travel
time of 7 hours (quartile range, 4 to 10 hours) and symptomatic VTE was negligible
(0.9). When separate analyses were performed for transport by plane, car, bus, train,
or boat; no increased risk was identified (odds ratios = 1.2, 0.8, 0.8, 1.4, and 1.4,
respectively). However, a further analysis for duration of travel yielded to an increased
odds ratio of 2.5 in the category of 10 to 15 hours of travel. Remarkably, the odds
ratio decreased to 1.3 when journeys of more than 15 hours were considered. However,
this last finding is probably insignificant, as the study population in the longest
duration category was rather small (n = 11).[76] Taken together, these data are consistent with the hypothesis that medium- to long-distance
travelers have a two- to fourfold increase in relative thrombosis risk compared with
that of nontravelers, but the averaged absolute risk is small and there is no evidence
that thrombosis is more likely in economy class than in business- or first-class passengers.[70] Long-distance travelers (> 10 hours), conversely, may carry an increased risk of
VTE, regardless of the type of transportation.
Oral Contraceptives
VTE is rare among young women but increases with age. In healthy young women, the
estimated incidence of VTE is 1 per 10,000 woman-years of follow-up. Recent estimates
by the World Health Organization (WHO) show that more than 100 million women are currently
using some form of hormonal contraception worldwide.[77] The association between female sex hormone–containing preparations and thrombosis
has been documented since the 1960s.[78] First-generation OCs containing estrogens and high doses of ethinyl estradiol combined
with derivatives of norethindrone acetate or nethisterone are no longer available
on the market.[78] Over the past decades, type and dosage of estrogens and progestogens components
have been profoundly modified, so that the UK Royal College of Obstetricians and Gynaecologists
defines a second-generation combined OC as a preparation containing 20 to 35 μg ethinyl
estradiol, with a progestogen (generally norethisterone and levonorgestrel).[79] The most used third-generation progestogens are gestodene and desogestrel.[78]
A variety of clinical investigations have assessed the risks of thrombosis associated
with hormone-based contraceptives. However, due to the variety of preparations and
the heterogeneity of the study populations, these studies showed different or even
contradictory outcomes. Evidence on OC risk of VTE is mostly derived from case-control
and nested case-control studies, attributing to OC use a cumulative risk for thrombosis
from 0.89 to 22.1.[80] OCs use was also associated with 1 to 3 VTE cases per 10,000 woman-years, translating
to a two- to sixfold increased relative risk of VTE.[80] Although third-generation OCs have been reported to increase the risk of VTE compared
with that of second-generation OCs, this view is still controversial due to the presence
of several confounding variables and study biases. An increased risk of VTE was first
reported in the mid-1990s among women using third-generation OCs compared with that
of second-generation products, with odds ratios ranging from 1.5 to 2.2.[81]
[82]
[83]
[84] In a meta-analysis published in the 1999 by Farley et al, third-generation OC use
was associated with a significantly increased risk (odds ratio = 1.9) of VTE compared
with that of second-generation OCs.[85] The most recent meta-analysis of Kemmeren et al supported this hypothesis, showing
an overall adjusted odds ratio for third- versus second-generation of 1.7. Similar
risk was found when OCs containing desogestrel or gestodene were compared with those
containing levonorgestrel, in both younger and older women. Moreover, the odds ratios
for short-term users compared with that of longer-term users were 2.5 and 2.0, respectively.[86]
Although Gomes and Deitcher implicitly confirmed that third-generation OCs might be
more thrombogenic, they also concluded that current evidence does not support a recommendation
that women already using third-generation OCs stop taking them, given the low absolute
risk associated with the use of third-generation OCs for the individual patient.[80] Overall, this is consistent with an earlier hypothesis by Mammen, who emphasized
that there is no convincing evidence that the balance between clotting and fibrinolysis
is disturbed in OC users. Accordingly, the risk of thromboembolic complications with
use of second- and third-generation OCs is minimal and probably related to underlying
congenital or acquired thrombophilic states.[87] It is worth mentioning, however, that OC use (and pregnancy/postpartum period) increases
the risk of thrombosis in carriers of factor V Leiden to 3.3-fold and 4.2-fold, respectively,
whereas other risk factors have a minor effect.[88] An unequivocal mechanism for explaining the thrombogenicity of OCs (especially estrogen
compounds) has not been identified, as several metabolic abnormalities might be triggered
to induce a mild prothrombotic state, including increased resistance to APC, increased
levels of procoagulant factors VII, IX, X, XII, and XIII, and reduced concentrations
of the anticoagulant factors protein S and antithrombin.[37]
[89]
Because of the significant risk of VTE in OC users, the 2004 guideline “Venous Thromboembolism
and Hormonal Contraception” issued by the UK Royal College of Obstetricians and Gynaecologists
recommends that women with current VTE should not use hormonal contraception, whereas
women with a personal history of VTE should not use combined oral contraception but
may use progestogen-only methods. It is also recommended that combined OC should be
discontinued at least 4 weeks before major surgery where immobilization is expected
but that progestogen-only methods need not be discontinued prior to surgery even when
immobilization is expected and hormonal methods do not need to be discontinued before
minor surgery without immobilization. However, it is also suggested that routine thrombophilia
screening prior to hormonal contraceptive use is not recommended but may be considered
in a woman with a history of VTE in a first-degree relative under the age of 45 years
who, after counseling, still wishes to use combined OC.[79]
Pregnancy and Postpartum
VTE remains a major cause of maternal mortality worldwide, in some geographic areas
being ranked as the second most common cause of maternal deaths (rate of maternal
deaths from thromboembolism, 0.12 per 10,000 live births and stillbirths).[90] In an early study of more than 72,000 deliveries in Scotland, the incidence of DVT
was 0.71 per 1000 deliveries with 0.50 occurring in the antenatal period and 0.21
in the puerperium. The incidence of PE was 0.15 per 1000 deliveries, 0.07 antenatal
and 0.08 in the puerperium.[91] Such a risk of nearly 1 venous thrombotic event per 1000 deliveries is at least
a 10-fold increased risk compared with that of nonpregnant women.[37] Overall, results from studies in which either all or most patients underwent accurate
diagnostic testing for VTE report that the incidence of VTE ranges from 0.6 to 1.3
episodes per 1000 deliveries, confirming a 5-fold to 10-fold increase in risk compared
with that of nonpregnant women of comparable age.[92] In the most recent MEGA study, however, it has been estimated that the risk of VTE
might be nearly 5-fold increased during pregnancy and up to 60-fold during the first
3 months after delivery.[93] A 14-fold increased risk of deep venous thrombosis of the leg was also observed
compared with a 6-fold increased risk of PE, such risk being highest in the third
trimester of pregnancy (odds ratio = 8.8) and during the first 6 weeks after delivery
(odds ratio = 84). Finally, the adjusted relative risk of PE associated with cesarean
section compared with that associated with vaginal delivery is 6.7.[94]
The major risk factors for thrombosis during pregnancy include thrombophilia, operative
delivery, advanced maternal age, obesity, and preeclampsia; these can be identified
in ~70% of women who develop complications during pregnancy and the puerperium. Thrombophilic
abnormalities further affect the risk of thrombosis during pregnancy, particularly
antithrombin, factor V Leiden, and prothrombin gene G20210A.[90]
[91] Remarkably, it has been reported that the risk of pregnancy-associated VTE might
be 11- to 52-fold increased in factor V Leiden carriers, 3- to 31-fold increased in
carriers of the prothrombin 20210A mutation, and more than 10-fold in those with abnormalities
of antithrombin (7-fold for mild deficiency and 64-fold for severe deficiency), protein
C (3.6-fold for mild deficiency and 7.2-fold for severe deficiency), or protein S
(5-fold for mild deficiency) compared with that of nonpregnant women without these
abnormalities.[93]
[95]
[96]
[97] Recent studies have also shown an association between thrombophilia and adverse
obstetric outcomes such as recurrent miscarriage, preeclampsia, placental abruption,
fetal growth retardation, stillbirth, and fetal death.[98]
[99]
[100]
Postpartum DVT is believed related to increased activation of the hemostasis system
at the time of delivery. Gerbasi, Mammen, and coauthors investigated 11 hemostatic
indices simultaneously in 70 healthy pregnant women, observing a significant increase
in fibrinopeptide A, β-thromboglobulin, and platelet factor 4, suggesting maximum
platelet activation and fibrin formation at the time of delivery. In addition to continued
clotting activity at 3 hours postpartum, increased D-dimer, fibrin-fibrinogen degradation
products, and decreased α2-antiplasmin levels suggest maximum fibrinolysis. These
changes reflected a peak in hemostatic activity at delivery and in the immediate postpartum
period that may predispose the development of DVT.[101]
Hormone Replacement Therapy
Hormone replacement therapy (HRT) is based on administration of sex steroid hormones,
primarily estrogens, with or without progesterone. This therapy is widely used for
the treatment of menopausal symptoms, to prevent onset of osteoporosis (especially
fracture risk), and to lower the burden of cardiovascular events (especially stroke
and coronary heart disease).[102] HRT might also be prescribed to women with premature ovarian failure, which is defined
by the occurrence of amenorrhea, hypergonadotropinemia, and estrogen deficiency at
a young age (< 40 years), and has a prevalence of 0.9 to 1.2% under the age of 40
years.[103]
Because the dose of estrogens in HRT is much lower than that in OCs, it has been assumed
for years that HRT regimens are safer than OCs with respect to the risk of VTE, and
the global benefits advocated to HRT in postmenopausal women far outweigh the potential
risks.[87] However, recent evidence attests that HRT is instead associated with an increased
risk of stroke, stroke severity, and VTE but not of cardiovascular events. In a recent
meta-analysis, including 31 trials (44,113 subjects), HRT was associated with increases
in VTE (odds ratio = 2.1), which is comparable with that previously observed for OCs
in premenopausal women. Although trials reporting PE by vital status are too scarce
to draw definitive conclusions, ordinal analysis revealed that HRT might more than
double the severity of PE. Age has little influence on the risk, whereas the addition
of progesterone to estrogens apparently doubles the risk.[104] Therapy with raloxifene, a selective estrogen receptor modulator indicated for the
prevention of osteoporosis in postmenopausal women, is associated with a 62% increase
in odds of either DVT or PE (odds ratio = 1.62), 54% increase in odds of DVT (odds
ratio = 1.54), and 91% increase in odds of PE alone (odds ratio = 1.91).[105] Based on available evidence, Gomes and Deitcher concluded that the increased relative
risk of VTE among oral HRT users translates into an absolute risk of 2.3 cases per
1000 woman-years, with a two- to fourfold increased relative risk of VTE among oral
HRT users compared with that of nonusers.[80] The most recent meta-analysis of Canonico et al identified a 2.1- to 2.5-fold increased
risk for first-time VTE in current users of oral estrogen.[106] Past users of oral estrogen had a similar risk of VTE to never-users. The risk of
VTE in women using oral estrogen was also higher in the first year of treatment (relative
risk = 4.0) compared with that of treatment for more than 1 year (relative risk = 2.1).
Obesity
The association between obesity and thrombotic disorders (especially cardiovascular)
is of pivotal importance because obesity is increasing dramatically worldwide. The
body mass index (BMI) and the waist-to-hip ratio (WHR) have been considered as risk
factors for DVT or correlates of coagulation factors concentrations. Samama reported
a twofold increased risk of DVT among outpatients with BMI greater than 30 kg/m2.[107] Such findings were confirmed in a further investigation by White et al, who also
observed a relative risk of 2.5 for VTE among patients with a BMI greater than 25
kg/m2 after hip arthroplasty.[108] According to a report on 454 consecutive patients with a first episode of objectively
diagnosed thrombosis from three anticoagulation clinics in The Netherlands,[109] obesity (BMI ≥ 30 kg/m2) increased the risk of thrombosis twofold, adjusted for age and sex. The combined
effect of obesity and OCs further increased the risk of thrombosis up to a 10-fold
increased risk among younger women (15 to 45 years old) with a BMI greater than 25
kg/m2. Finally, in a recent meta-analysis of 21 case-control and cohort studies with a
total of 63,552 patients, the relative risk of obesity for VTE was 2.3.[110]
Antiphospholipid Antibodies
Antiphospholipid antibodies, such as anticardiolipin antibodies (aCL), are associated
with thrombosis and appear to be the most common of the acquired blood protein defects.[111] Patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies
are at a greater risk for VTE than are SLE patients without these antibodies. In a
meta-analysis of seven observational studies of risk for antiphospholipid-associated
VTE, excluding SLE patients, the overall odds ratio for lupus anticoagulant (LA)-associated
VTE was 11. Moreover, the overall odds ratio for aCL-associated VTE was 3.2.[112] In a systematic review of published articles, Galli and Barbui concluded that LA
are a clear risk factor for thrombosis (odds ratio ranging from 4.1 to 16.2), irrespective
of the site and type of thrombosis, the presence of SLE, and the methods used to detect
them. The aCL and anti-β2-glycoprotein I antibodies were also possible risk factors
of thrombosis, at least in some selected situations, showing odds ratios from 1.0
to 2.5 and 1.0 to 19.0, respectively.[113]
Other Risk Factors
In a recent meta-analysis of 21 case-control and cohort studies with a total of 63,552
patients, the risk of VTE was 1.51 for hypertension, 1.42 for diabetes mellitus, 1.18
for smoking, and 1.16 for hypercholesterolemia, a finding consistent with the hypothesis
that cardiovascular risk factors might be associated with VTE, and this association
might deserve further scrutiny with respect to individual screening, risk-factor modification,
and primary and secondary prevention of VTE.[110] In a meta-analysis including six case-control studies, incorporating 1826 cases
of VTE and 1074 controls, a statistically significant association between lipoprotein(a)
levels > 300 mg/L and VTE (odds ratio = 1.87) was identified. A random-effects model,
which accounts for the interstudy variation, yielded a similar estimate of increased
risk (odds ratio = 1.77).[114] There is still debate on hyperhomocysteinemia as a risk factor for VTE. A meta-analysis
of 10 eligible case-control studies found a pooled estimate of the odds ratio of 2.5
for a fasting plasma homocysteine concentration above the 95th percentile. For the
post-methionine increase in homocysteine concentration, a pooled estimate of 2.6 was
found, supporting hyperhomocysteinemia as a mild risk factor for VTE.[115] More recently, Cattaneo reported that the odds ratio of hyperhomocysteinemia for
VTE, as deducted from several prospective studies, might range from 1.2 to 3.4.[116]
