Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT).

Abstract

Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies.
In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin-, protein C- or protein S deficiency, or factor V Leiden).
The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death).
Twenty-six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow-up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5-1.2) in the carriers compared with 0.1% per year (95% CI 0.0-0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden.
The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long-term anticoagulant treatment in the literature (1-3%).

Full text

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IN FOCUS
Risk of a first venous thrombotic event in carriers of a familial
thrombophilic defect. The European Prospective Cohort on
Thrombophilia (EPCOT)
C. Y. VOSSEN,* J. CONARD,? J. FONTCUBERTA,? M. MAKRIS,§ F. J. M. VAN DER MEER,–
I. PABINGER,** G. PALARETI,?? F. E. PRESTON,§ I. SCHARRER,?? J. C. SOUTO,? P. SVENSSON,§§
I. D. WALKER–– and F. R. ROSENDAAL*–
*Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; ?Department of Biological Haematology,
Ho ˆtel-Dieu Hospital, Paris, France; ?Department of Haematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; §Department of
Haematology, Royal Hallamshire Hospital, Sheffield, UK; –Department of Haematology, Leiden University Medical Center, Leiden, the
Netherlands; **Department of Haematology and Haemostaseology, University Hospital Vienna, Vienna, Austria; ??Department of Angiology and
Blood Coagulation, University Hospital S. Orsola, Bologna, Italy; ??Department of Internal Medicine, University Hospital, Frankfurt/Main,
Germany; §§Department for Coagulation Disorders, University Hospital, Malmo ¨, Sweden; and ––Department of Haematology, Glasgow Royal
Infirmary, Glasgow, UK
To cite this article: Vossen CY, Conard J, Fontcuberta J, Makris M, van der Meer FJM, Pabinger I, Palareti G, Preston FE, Scharrer I, Souto JC,
Svensson P, Walker ID, Rosendaal FR. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European
Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3: 459–64.
See also Spencer FA, Goldberg RJ. Asymptomatic thrombophilia—a family affair. This issue, pp 457–8.
Summary. Background: Reliable risk estimates for venous
thrombosis in families with inherited thrombophilia are scarce
but necessary for determining optimal screening and treatment
policies. Objectives: In the present analysis, we determined the
risk of a first venous thrombotic event in carriers of a
thrombophilic defect (i.e. antithrombin-, protein C- or protein
S deficiency, or factor V Leiden). Patients and methods: The
asymptomaticcarriershadbeentestedpriortothisstudyinnine
European thrombosis centers because of a symptomatic carrier
in the family, and were followed prospectively for 5.7 years on
averagebetweenMarch1994andJanuary2001.Annually,data
were recorded on the occurrence of risk situations for venous
thrombosisandevents(e.g.venousthrombosis,death).Results:
Twenty-six of the 575 asymptomatic carriers (4.5%) and seven
of the 1118 controls (0.6%) experienced a first deep venous
thrombosisorpulmonaryembolism duringfollow-up.Ofthese
events, 58% occurred spontaneously in the carriers compared
with43%inthecontrols.Theincidenceoffirsteventswas0.8%
per year (95% CI 0.5–1.2) in the carriers compared with 0.1%
peryear(95%CI0.0–0.2)inthecontrols.Thehighestincidence
was associated with antithrombin deficiency or combined
defects, and the lowest incidence with factor V Leiden.
Conclusions: The incidence of venous events in asymptomatic
individualsfromthrombophilicfamiliesdoesnotexceedtherisk
of bleeding associated with long-term anticoagulant treatment
in the literature (1–3%).
Keywords: asymptomatic, inherited thrombophilia, venous
thrombosis.
Introduction
Venous thrombosis has an overall incidence of about 1–2 per
1000 individuals per year and is a serious disorder with
potential major complications such as death from pulmonary
embolism,recurrencesandthedevelopmentofadisablingpost-
thrombotic syndrome [1–3]. It has been postulated that not a
single risk factor, but interaction between multiple genetic and
environmental risk factors is a prerequisite for venous throm-
bosistodevelop[4–6].Currently,severalgeneticriskfactorsare
knowntoincreasetheriskofvenousthrombosis:deficienciesin
the anticoagulation factors protein C, protein S and anti-
thrombin, and the factor V Leiden and prothrombin G20210A
mutations [7–11]. In accordance with the multicausal nature of
thrombosis, it was found that the presence of a family history
of venous thrombosis increases the thrombotic risk in individ-
uals with protein C deficiency or factor V Leiden, due most
probably to the concomitant presence of other genetic or
environmental risk factors within the family [6,12,13].
Correspondence: Professor F. R. Rosendaal MD, Department of
Clinical Epidemiology, Leiden University Medical Center, PO Box
9600, 2300 RC Leiden, the Netherlands.
Tel.: +31 71 5264037; fax: +31 5266994; e-mail: F.R.Rosendaal@
lumc.nl
Received 12 August 2004, accepted 18 November 2004
Journal of Thrombosis and Haemostasis, 3: 459–464
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A prerequisite to determining the optimal clinical approach,
e.g. with regard to screening or (long-term) prophylactic
anticoagulant treatment in families with inherited thrombo-
philia is to define the absolute risk of venous thrombosis, and
to weigh this risk against the risk of bleeding complications
associated with prophylactic treatment. To obtain valid risk
estimates of the absolute risk of venous thrombosis in families
with inherited thrombophilia, we started the European Pros-
pective Cohort on Thrombophilia (EPCOT) study. The
EPCOT study, by combining data from nine centers, is the
largest prospective cohort of individuals with deficiencies of
protein C, protein S and antithrombin and factor V Leiden. In
this paper, we present data on the risk of a first venous
thromboemboliceventassociatedwithinheritedthrombophilia
in relatives of probands from thrombophilic families who were
asymptomatic at the time of inclusion in the study.
Methods
Participants
The design of the study has been described in detail previously
[14]. In short, inclusion of the participants took place between
March 1994 and September 1997 with prospective follow-up
until January 2001. Nine centers from eight countries (Austria,
France, Germany, Italy, Spain, Sweden, the Netherlands and
the United Kingdom) participated. Each center enrolled all
registered probands (first of a family in whom thrombophilia
was detected) with a deficiency of protein C, protein S or
antithrombin or factor V Leiden, and their registered relatives
with one of these defects. Healthy partners or, if there were
none,friendsoracquaintances of participatingindividualswith
inherited thrombophilia were included as controls. Controls
were excluded if they were known to have heritable thrombo-
philia, or if they were related to a participant with an inherited
thrombotic defect. Controls were, however, not tested for any
of the defects under study after study entry. All participants
gave informed consent. Data were collected at baseline, and
annually during follow-up. At study entry data were collected
on subjects’ general demographics, hereditary defect [type,
subtype(ifavailable),levels(ifavailable),informationonDNA
testing], current medication and current risk factors for
thrombosis, history of thrombosis, obstetric history and family
history of thrombosis.The data recordedat follow-up included
the occurrence of risk situations [surgery, hospital admission,
plaster casts, prolonged bed rest (> 2 weeks), traveling
(> 8 h), details on pregnancies, medication)] and on outcome
events (e.g. venous thrombosis, hemorrhage, death). Comple-
ted forms were sent to the coordinating center with only the
patient identifier’s code to protect patient confidentiality.
From a total of 1626 individuals with thrombophilic defects
and 1212 control subjects, this paper includes only relatives of
probands who had not previously experienced any venous
thrombotic event [deep venous thrombosis (DVT), pulmonary
embolism (PE), or superficial thrombophlebitis (STP)] before
inclusion in the study, and who did not receive long-term
prophylactic oral anticoagulant treatment during prospective
follow-up (defined as treatment for at least 1 year without
interruptions). Twenty thrombophilic individuals received
long-term prophylactic oral anticoagulant treatment: 10 for
prevention of venous thrombosis and 10 for a personal history
of arterial disease. Eight controls received long-term anticoag-
ulation treatment for an arterial indication. In addition, we
only included relatives of probands tested because of venous
thrombosis or a positive family history. Families in which
thrombophilia was detected because of screening before
hormone prescription or research purposes were not included,
in an effort to stay as close as possible to the real-life situation
of an individual from a symptomatic thrombophilia family
asking a physician for advice.
Recruitment was before description of the G20210A muta-
tion intheprothrombin gene,but during prospectivefollow-up
we gathered informationonthepresenceof thismutationas an
additional defect.
Quality assessment thrombophilia testing and verification
of events
The participating centers performed the various assays accord-
ing to their local protocol and participated in an external
quality assessment scheme for thrombophilia testing. For the
first2yearsthiswasthequalityassuranceschemedevelopedfor
the European Concerted Action on Thrombosis (ECAT/
EQAS)(Leiden)andforthesubsequentyearstheUKNational
External Quality Assessment Service (NEQAS) (Sheffield,
UK).
Per center, a local investigator verified all events in
prospective follow-up. In case of death the autopsy data were
collected, if available. An adjudication committee scored all
reported events independently after receiving all the relevant
medical information from each center, but in case of doubt or
when no consensus was reached at first, further information
was asked for (e.g. actual test results). Committee members
were not blinded for whether a person was a thrombophilia
carrier or control, but were unaware of the type of defect of the
carriers. Venous thromboses were classified as definite venous
events when they were objectively confirmed, i.e. for DVT by
ultrasound (duplex, Doppler), impedance plethysmography,
venography or leg symptoms plus definite PE, and for PE by
angiography,high probability
spiral computerized tomography or autopsy. STPs were
considered definite events when diagnosed by a physician.
Fortheanalysisreportedhere,weincludedonlydefinitevenous
events.Consensusontheclassificationofthevenousevents,i.e.
that a majority of the steering committee members agreed, was
reached in 67 of the 72 (93%) reported events during
prospective follow-up (47 DVTs or PEs, 21 STPs, four major
hemorrhages). Of the remaining five events which were
classified as definite DVT or PE (n ¼ 4) or no PE (n ¼ 1),
consensus was reached after additional information was
provided (n ¼ 4) or after reconsideration (n ¼ 1). For con-
trols, immediate consensus was reached in 88% of the reported
ventilation-perfusion-scan,
460 C. Y. Vossen et al
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events (15 of 17) and in thrombophilic subjects in 95% of the
reported events (52 of 55).
Analysis and statistics
We calculated the annual absolute risk (incidence) and relative
risk of a first DVT or PE for various groups in the cohort. The
incidence of venous thrombotic events was calculated by
dividing the number of events by the total of observation-years
(follow-up time). Follow-up time was the time between
inclusion and the event of interest, death or the last date of
follow-up (the end of the study or last date before loss to
follow-up), whichever occurred first. A DVT or PE was
consideredfirsteventonlywhennotprecededbyaSTP.IfaPE
followeda DVTwithin3 months,these events were considered
a single event. The 95% confidence intervals (95% CI) were
calculated according to a Poisson distribution for the number
of events [15]. Hazard ratios as estimation of the relative risk of
venous thrombosis were calculated by Cox-regression with
venous thrombosis as the dependent variable and presence or
absence of thrombophilia as independent variable. Center, age
(as stratum: age < 45 or ‡ 45) and sex were entered in the
Cox-regression model to adjust for center, age and sex effects.
Results
We collected prospective data on 575 relatives with a throm-
bophilicdefectand1118controls(825partners,293friends),all
without a thrombotic event prior to inclusion and not on long-
term oral anticoagulant treatment. The total follow-up time
was 3283 years in the individuals with thrombophilia (mean
5.7; range 0.2–7.3) and 6289 years in the controls (mean 5.6;
range 0.7–7.2). During follow-up, 20 thrombophilic subjects
and 64 controls were lost to follow-up (complete follow-up in
95%), and eight thrombophilic individuals and 12 controls
died. The causes of death in the carriers were heart disease
(n ¼ 3), suspected pulmonary embolism (n ¼ 1) and other
causes (n ¼ 4). Causes of death in controls were not related to
venous thrombosis (cancer (n ¼ 4), myocardial infarction
(n ¼ 4), accidents in traffic or at work (n ¼ 3) or surgery
(n ¼ 1)). The main characteristics at inclusion are shown in
Table 1. A preponderance of the thrombophilic individuals
was female (62%), whereas sex was distributed more equally
among the controls.
Risk of a first event
Of the 575 thrombophilic individuals, 26 thrombophilic
subjects experienced a first DVT or PE during follow-up
(4.5%) (one relative had a mesenteric vein thrombosis)
compared with seven of the 1118 controls (0.6%) (Table 2).
The events occurred spontaneously, i.e. did not occur after
exposure to a known acquired risk factor, in 15 thrombophilic
individuals (58%) and three controls (43%). The risk factors
present at the time of the event in the remaining 11 thrombo-
philic individuals were hospitalization (n ¼ 3), hormone
replacement therapy (n ¼ 2), infection (n ¼ 2), pregnancy
(n ¼ 2), cancer (n ¼ 1) and oral contraceptives (n ¼ 1), and in
the four remaining controls surgery (n ¼ 2), hospitalization
(n ¼ 1)and cancer (n ¼ 1).Theincidenceofa first DVTorPE
was higher in the thrombophilic individuals than in the
controls, respectively, 0.8% per year (95% CI 0.5–1.2) com-
pared with 0.1% per year (95% CI 0.0–0.2) (Table 2) with a
relative risk of 9.0 (95% CI 3.8–21.1), adjusted for sex, age at
entry and center effects (crude relative risk: 7.3; 95% CI 3.2–
16.8). The incidence of a STP as first event was 0.5% per year
(95% CI 0.3–0.8) in the thrombophilic subjects and 0.1% per
year (95% CI 0.0–0.2) in the controls (Table 2) with a relative
risk of 5.2 (95%CI 2.0–13.7), adjusted for sex, ageat entry and
center effects (crude relative risk: 5.3; 95% CI 2.1–13.5).
The annual incidence of a first DVT or PE was highest for
thrombophilic individuals with antithrombin deficiency (1.7%
year)1;95%CI0.8–3.3)orcombineddefects(1.6%year)1;95%
CI 0.5–3.7) and lowest in thrombophilic individuals with the
factor V Leiden mutation (0.1% year)1; 95% CI 0.0–0.6)
(Table 2). Unfortunately, the numbers per type of defect were
too small to estimate the risks by age and sex. Our database
contained subtype information (or sufficient level information
todeterminethesubtype)of120proteinCdeficientindividuals,
97 individuals with protein S deficiency and 76 individuals with
antithrombindeficiency.Whenweincludedintheanalysisonly
Table 1 General characteristics at inclusion
Thrombophilic
individualsControls
All (n)
Men (n)
Women (n)
OCC use, age 10–50 (n/total N)*
HRT use, age ‡ 50 (n/total N)
PC deficiency (n)
PS deficiency (n)
AT deficiency (n)
FVL (n)
Combined defects (n)
PC-PS (n)
FVL-PC (n)
FVL-PS (n)
FVL-AT (n)
FVL-PT20210A (n)
PT20210A-PC (n)
PT20210A-PS (n)
PT20210A-AT (n)
Mean age at inclusion (years (range))
Mean BMI (kgm)2(range))**
Cancer ever (n (%))
575
214
361
63/265
17/77
143
107
96
173a
56
1
11
15
6
8b
9
4c
2
35 (0–91)
23 (13–42)
8 (1)
1118
588
530
153/360
47/159
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
41 (3–87)
24 (13–39)
12 (1)
OCC ¼ oral contraceptives, HRT ¼ hormone replacement therapy,
PC ¼ protein C, PS ¼ protein S, AT ¼ antithrombin, FVL ¼ factor
V Leiden, PT20210A ¼ prothrombin G20210A, NA ¼ not applicable,
BMI ¼ body mass index.a10 were homozygous;bone was homozygous
for factor V Leiden;
G20210 A. *The oral contraceptives contained estrogen in 34/265
(13%) thrombophilic women and 139/360 (39%) of the control women.
** Information on BMI was available for 574 thrombophilic individ-
uals and 1117 controls.
cone was homozygous for prothrombin
Familial thrombophilia and first venous event 461
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individuals known to have subtype I (103 with protein C
deficiency, 68 with protein S deficiency and 59 with antithrom-
bindeficiency),theriskofamajoreventwassimilartotheriskin
Table 2.TheriskofthrombosisinthosewithatypeIIdefector
typeIIIproteinSdefect wasnot lower thanin thosewithtypeI
abnormalities,althoughthenumberofindividuals(n ¼63)with
type II or III defects was low (results not shown).
In men with thrombophilia, the annual incidence of a first
DVTorPEwashigher(1.4%year)1;95%CI0.8–2.2)compared
with thrombophilic women (0.5% year)1; 95% CI 0.2–0.9)
(Table 2). In controls, the incidences of a first DVT or PE did
notdifferbetweenthesexes(Table 2).Thepercentageofwomen
above the age of 50 using hormone replacement therapy was
slightly lower in thrombophilic women (22%) compared with
controls (30%), whereas a much lower percentage of women
with inherited thrombophilia used estrogen-containing oral
contraceptives (13%; age 10–50 years) compared with the
control women (39%; age10–50 years).The incidence of afirst
DVT or PE in thrombophilic women who did not use oral
contraceptives (age 10–50 years) was 0.4% year)1(95% CI
0.1–0.9)comparedwith0.5%year)1(95%CI0.0–2.9)inwomen
using estrogen-containing oral contraceptives.
The first DVT or PE occurred about 20 years earlier in the
thrombophilic individuals than in the controls (Table 2). The
mean age at onset was ?40 years for individuals with protein
C-, protein S- or antithrombin deficiency or combined defects
and 63 years for the subject with factor V Leiden, in
comparison to 63 years in the controls (Table 2).
The risk of a first DVT or PE was 1.0% per year (95% CI
0.6–1.6) among the 285 thrombophilic individuals who
encountered acquired risk factors during prospective follow-
up and who did not receive short-term anticoagulation during
these risk situations (i.e. surgery, hospitalization, bed rest for
more than 13 days, plaster cast, cancer, pregnancy or traveling
for more than 8 h). Table 3 shows the frequency of venous
events associated with the presence of acquired risk factors
during prospective follow-up for which no short-term pro-
phylactic anticoagulant treatment was provided. Cancer,
although the number of individuals was small, and pregnancy
appear to be the risk factors during which most secondary
venous events occurred in the thrombophilic individuals. The
incidence of a first DVT or PE in the 156 thrombophilic
individuals who did not encounter acquired risk factors for
which they could have received short-term anticoagulation
Table 2 Incidence (% year)1) and age at onset of a first venous thrombosis
Total subjects, n DVT/PE, n
Age onset,
years (range)Person-years, n
Incidence,
(95% CI)
Thrombophilic individuals
PC deficiency
PS deficiency
AT deficiency
FVL
Combined defects
Males
Females
Age at inclusion 18–45 years
Age at inclusion above 45 years
Controls
Males
Females
Age at inclusion 18–45 years
Age at inclusion above 45 years
575
143
107
96
173
56
214
361
339
146
1118
588
530
652
426
26
6
5
9
1*
5*
16
10
18
7
7
2
5
1
6
40 (20–65)
41 (22–65)
38 (28–63)
39 (21–58)
63
36 (20–62)
37 (20–65)
44 (21–65)
32 (21–47)
61 (51–65)
63 (38–84)
58 (57–59)
64 (38–84)
38
67 (57–84)
3194.4
833.2
619.1
520.6
902.1
319.4
1162.0
2032.4
1880.1
793.2
6269.6
3303.0
2966.6
3601.8
2445.7
0.8 (0.5–1.2)
0.7 (0.3–1.6)
0.8 (0.3–1.9)
1.7 (0.8–3.3)
0.1 (0.0–0.6)
1.6 (0.5–3.7)
1.4 (0.8–2.2)
0.5 (0.2–0.9)
1.0 (0.6–1.5)
0.9 (0.4–1.8)
0.1 (0.0–0.2)
0.1 (0.0–0.2)
0.2 (0.1–0.4)
0.0 (0.0–0.2)
0.2 (0.1–0.5)
DVT ¼ deep venous thrombosis, PE ¼ pulmonary embolism, CI ¼ confidence interval, PC ¼ protein C, PS ¼ protein S, AT ¼ antithrombin,
FVL ¼ factor V Leiden. *All were heterozygous.
Table 3 Number of first venous events per risk situation for which subjects did not receive short-term prophylactic anticoagulation
Thrombophilic individuals Controls
n Situations nDVT/PE, n (%)n Situations nDVT/PE, n (%)
Travel (> 8 h)
Surgery/immobilization**
Plaster cast
Cancer?
Pregnancies
260
143
27
10
24
504*
176
33
10
28
0 (0%)
3 (2%)
0 (0%)
1 (10%)
2 (7%)
567
290
59
17
61
1244*
407
71
17
75
0 (0%)
2 (0%)
0 (0%)
1 (6%)
0 (0%)
DVT ¼ deep venous thrombosis, PE ¼ pulmonary embolism. *The number of follow-up years in which individuals reported to have traveled at
least once for more than 8 hours. **Immobilization is defined as a hospital stay, or bed rest for at least 14 days at home. ?Defined as malignancy
still present or developed during prospective follow-up. Nine (four thrombophilic individuals, five controls) received anticoagulation during and
after surgery for cancer.
462 C. Y. Vossen et al
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during prospective follow-up was, however, similar: 0.8% per
year (95% CI 0.3–1.7).
A total of 134 thrombophilic individuals (23%) received
short-term prophylactic anticoagulation during one or more
risk situations: surgery (n ¼ 95), pregnancy (n ¼ 43; 13 during
puerperium only; range start treatment during pregnancy:
weeks 5–36), plaster cast (n ¼ 13), traveling (n ¼ 9) and after
twistingakneeoranankle(n ¼ 2).Novenouseventsoccurred
during any of these risk situations under short-term prophy-
lactic anticoagulant treatment. Of the controls, 115 (10%) also
received short-term anticoagulant treatment during risk situ-
ations: during surgery (n ¼ 107), pregnancy (n ¼ 4; 3 during
puerperium only), plaster cast (n ¼ 12), traveling (n ¼ 1) and
aftertwistingaknee(n ¼ 1)orduringchronicenteritis(n ¼ 1).
Discussion
We conducted a large prospective follow-up study in nine
centers in eight countries on 1626 probands and relatives, and
1212 controls to obtain valid estimates of the risk of venous
thrombosis in families with inherited thrombophilia. In the
present report, we describe the risk of a first venous throm-
boembolic event in 575 thrombophilic individuals and 1118
controlsubjectswhowerefollowed-upto7 years(meanfollow-
up 5.6 years) and who were asymptomatic and not on long-
term anticoagulant treatment at study inclusion.
Among the thrombophilic individuals, the annual risk of
a first DVT or PE was 0.8% per year. The incidence was
lowest for thrombophilic individuals with factor V Leiden
(0.1% year)1) and highest for thrombophilic subjects with
antithrombin deficiency (1.7% year)1), individuals with
combined defects (1.6% year)1) and men (1.4% year)1).
DVTs and PEs occurred spontaneously in 58% of the
thrombophilic individuals and 43% of the controls. The
annual risk was not increased in thrombophilic individuals
who encountered additional acquired risk situations (e.g.
surgery, immobilization, pregnancy, plaster cast) during
which no short-term anticoagulation treatment was pre-
scribed. As 134 thrombophilic individuals did receive short-
term anticoagulation during risk situations, mainly during
pregnancy and surgery, this finding could be the result of
the intention of doctors to treat those with a high risk of
venous thrombosis only in definite high-risk situations.
The strongest point of this study is its size: deficiencies of
natural anticoagulants are rare, and large prospective studies
are therefore scarce. We excluded events that were not
objectively confirmed; as these were few and equally distri-
buted over thrombophilic individuals and controls (of the
DVTs and PEs 12% were non-definite in the carriers
compared with 14% in the controls) this could not have
affected our results. The results of this study should not be
generalized to all individuals with thrombophilia, as we
focused on asymptomatic subjects with familial thrombo-
philia, to which patient group these results apply. We have
shown previously that the risk of thrombosis is higher in
selected individuals from families with a clear familial
thrombophilia than in unselected individuals without a strong
family history, regardless of the defect [12,13]. Other studies
on the risk of a first venous thrombotic event in carriers of a
hereditary defect [16–22] reported annual incidences of venous
thrombosis ranging from 0.4% to 2.5% for protein C
deficiency, 0.1% to 3.2% for protein S deficiency and 0.9%
to 2.9% for antithrombin deficiency. For factor V Leiden, the
reported incidences ranged from 0.1% to 0.7% per year
[17,19,23–25]. The risks found in the present study could have
been underestimated due to preventative measures taken by
the treating physicians, who were aware of the presence of a
thrombophilic defect, to reduce the risk of venous thrombosis.
However, the risk for individuals with single defects might
have been overestimated when they carried the prothrombin
G20210A mutation, but were not tested for this particular
mutation in our study. We were able to gather information on
the presence of this mutation as an additional defect for 360 of
the 575 thrombophilic individuals (63%).
Although the risk of a first DVT or PE was increased in
thrombophilic individuals, the risk was still low and did not
outweigh the reported risk of 1–3% of hemorrhagic compli-
cations in patients with prolonged anticoagulant therapy with
target INRs with a lower limit of 2.0 [26,27]. Therefore, long-
term prophylactic anticoagulant treatment does not seem
beneficial in asymptomatic relatives of symptomatic probands
with inherited thrombophilia, although future prophylactic
treatment options with a lower risk of bleeding might change
this. However, there might be a need for a more stringent
thromboprophylactic treatment policy during temporary
periods of increased thrombotic risk as no DVT or PE
occurred in thrombophilic individuals during risk situations
in which prophylactic anticoagulation was used. In the
thrombophilic individuals, 42% of all DVTs or PEs occurred
in the presence of a known risk situation and could therefore
have been prevented.
Whether screening or short-term prophylaxis would be
beneficial is difficult to conclude from our results, as the low
risk of thrombosis might be the result of screening and a policy
aimed at preventing thrombosis, as can be deduced from the
low number of women with estrogen-containing oral contra-
ceptives and the high number of women with prophylactic
anticoagulant therapy during pregnancy or puerperium.
Further studies should elucidate whether a more stringent
policy of thromboprophylaxis in risk situations could further
reduce the risk of thrombosis, which should in particular focus
on individuals with antithrombin deficiency and combined
defects, who had the highest risk of thrombosis.
Addendum
F. R. Rosendaal originatedandcoordinated the study together
with F. E. Preston, E. Brie ¨t, I. D. Walker and J. Fontcuberta
(the study steering committee). The first author, C. Y. Vossen,
performed the analyses and wrote the manuscript. All other
authors were involved in designing the study and involved in
collecting patient data and reviewing the manuscript.
Familial thrombophilia and first venous event 463
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Page 6

Acknowledgements
The study was supported by BIOMED II grant number
BMHI-CT94-1565 (coordinator F. R. Rosendaal). We thank
E. Brie ¨t, I. de Jonge, L. Velmans, W. Noteboom (Leiden),
P. Bayliss (Sheffield), M. J. Gallego (Barcelona), E. Aygo ¨ ren-
Pu ¨ rsu ¨ n, M. Krause (Frankfurt am Main), C. Legnani
(Bologna), E. Berntorp, V. Meha (Malmo ¨ ) and S. Koder
(Vienna) for their contributions to the study.
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