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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3702-3706
The Incidence of Venous Thromboembolism in Asymptomatic Carriers of a
Deficiency of Antithrombin, Protein C, or Protein S: A Prospective
Cohort Study
By
Bernd-Jan Sanson,
Paolo Simioni,
Daniela Tormene,
Marco Moia,
Philip W. Friederich,
Menno V. Huisman,
Paolo Prandoni,
Alessandra Bura,
László Rejt ,
Philip Wells,
Pier M. Mannucci,
Antonio Girolami,
Harry R. Büller, and
Martin H. Prins
From the Departments of Vascular Medicine and Clinical Epidemiology
and Biostatistics, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands; the Institute of Medical Semeiotics,
University of Padova, Padova, Italy; the Hemophilia and Thrombosis
Center, IRCCS Maggiore Hospital, Milan, Italy; the Department of
General Internal Medicine, Leiden University Medical Center, Leiden,
The Netherlands; the Institute of Internal and Vascular Medicine,
University of Perugia, Perugia, Italy; the Second Department of
Medicine, University Hospital of Debrecen, Debrecen, Hungary; and the
Division of Hematology, Civic Parkdale Clinic, Ottawa, Ontario, Canada.
 |
ABSTRACT |
Deficiencies of antithrombin, protein C, and protein S are
associated with an increased risk of venous thromboembolism. The objective of this study was to prospectively assess the incidence of
venous thromboembolism in nontreated asymptomatic subjects with such a
deficiency. We conducted a prospective cohort study in asymptomatic
family members of unselected patients who presented with a venous
thromboembolic event and who were found to have a deficiency of
antithrombin, protein C, or protein S. No anticoagulant prophylaxis was
given to the study participants, except during risk periods for venous
thromboembolism. All venous thromboembolic events were diagnosed by
objective diagnostic tests. A total of 208 individuals with a mean age
of 37 years (range, 15 to 79) were included in the study. A total of
611 patient observation years was obtained. Nine venous thromboembolic
events occurred, resulting in an annual incidence of 1.5% (95%
confidence interval [CI], 0.7 to 2.8) for the 3 deficiencies
combined. Five of these events occurred spontaneously, resulting in an
annual incidence of spontaneous venous thromboembolism of 0.8% (95%
CI, 0.3 to 1.9). For antithrombin, protein C, and protein S
deficiencies separately, this figure was 1.6%, 1.0%, and 0.4%,
respectively. Thirty-four subjects experienced a total of 40 risk
periods during which 4 venous thromboembolic events occurred (10% per
risk period). We conclude that the use of continuous anticoagulant
prophylaxis seems not warranted in asymptomatic individuals with a
deficiency of antithrombin, protein C, or protein S. During risk
periods for venous thromboembolism, adequate anticoagulant prophylaxis is necessary.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THROMBOPHILIA is a term used to describe
an inherited tendency toward venous thromboembolism. Deficiency of the
anticoagulant antithrombin was the first inherited risk factor for
venous thromboembolism discovered in 1965.1 After this,
deficiencies of the naturally occurring anticoagulants protein C and
protein S were described as causes of inherited
thrombophilia.2,3 In recent years, several other
thrombophilic risk factors have been discovered, the most common of
which are the factor V Leiden and the prothrombin 20210A gene
mutations.4,5
There is ample evidence that deficiencies of antithrombin, protein C,
and protein S are associated with an increased risk of venous
thromboembolism.6,7 Over the years, many family studies
have reported on the risk of venous thromboembolism in such subjects.
However, the reported incidences in these studies are considered to be
overestimations of the true incidence due to the fact that they may
have been prone to selection and publication bias. A further
disadvantage of previous studies is that the diagnosis of venous
thromboembolic events was made primarily on clinical grounds, which is
known to be highly unspecific,8 thus adding to the
overreporting of venous thromboembolism.
Until recently, perhaps the most reliable figures on the in- cidence
of venous thromboembolism in subjects with a deficiency of either
antithrombin, protein C, or protein S were those reported in a review
analysis of the available literature, which reported an incidence of a
first thromboembolic event in asymptomatic subjects of approximately
3% per year for these 3 thrombophilic defects combined.9
An earlier smaller prospective study in 44 asymptomatic individuals
with a deficiency of protein C or protein S reported an incidence of
spontaneous venous thromboembolism of 1.4% per year.10 In
a recent retrospective study in 181 previously asymptomatic deficient
subjects, an incidence of spontaneous venous thromboembolism of only
0.4% per year was found.11 In that study, the incidence of
a first venous thromboembolic event related to surgery, trauma, or
immobilization was 8.1% per risk period, and the incidence during
pregnancy and the postpartum period was 4.1% per
pregnancy.12
The screening of patients with a venous thromboembolic event for
thrombophilic factors, and subsequently their family members, has led
to the recognition of an increasing number of asymptomatic individuals
with a thrombophilic defect. However, it has remained unclear what the
appropriate clinical approach should be in these individuals. For
clinical decisions regarding the use of anticoagulant prophylaxis in
these asymptomatic individuals with antithrombin, protein C, or protein
S deficiency, reliable incidence figures of venous thromboembolism in
the various clinical situations are needed. The decision whether these
individuals should receive anticoagulant prophylaxis must be made by
balancing the risk of developing a venous thromboembolic complication,
either spontaneously or risk period-related, against the risk and
severity of bleeding complications associated with the use of
anticoagulant prophylaxis. This clinical dilemma has led to the design
of the present study of which the objective was to prospectively assess
the incidence of venous thromboembolism (both spontaneous and risk
period-related) in nontreated asymptomatic subjects with a deficiency
of antithrombin, protein C, or protein S.
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MATERIALS AND METHODS |
Study subjects.
All patients presenting to the participating centers with a documented
period of venous thromboembolism were screened for deficiencies of
antithrombin, protein C, and protein S. The presence of a deficiency
was confirmed by testing on two separate occasions. Patients with a
deficiency of antithrombin (excluding heparin binding defect cases),
protein C, or protein S served as index patients for the study. The
patients were not tested for other prothrombotic states such as the
factor V Leiden mutation, the prothrombin mutation, or
hyperhomocysteinemia, as these were not known at the time of the start
of the study. All participating centers are referral hospitals for the
local community for the diagnostics of venous thromboembolism. The
patient populations seen in the centers are therefore representative of
typical patients with venous thromboembolism.
Family members of the index patients above the age of 15 years were
contacted and were asked to participate. In first instance, only
first-degree relatives were contacted. If these were not available,
second-degree relatives were asked to participate. A detailed medical
history was obtained from these family members with specific attention
being paid to the occurrence of prior venous thromboembolic events.
Hereafter, the deficiency status of these family members was
determined. Those subjects who were found to be deficient on 2 consecutive determinations with a minimum interval of 1 month and who
reported no prior venous thromboembolism in their medical history were
eligible for inclusion in the study. A prior venous thromboembolic
event was considered to have occurred if it had been confirmed by
objective diagnostic methods or if anticoagulant therapy had been
instituted for a minimum of 3 months after a clinical diagnosis.
Exclusion criteria were the presence of a combined inhibitor deficiency
and the known presence of an active malignancy. Informed consent was
obtained from all study participants. Inclusion for the study was
performed between April 1993 and July 1997; follow-up was completed in
October 1997.
Study design.
In this prospective cohort study, no continuous anticoagulant
prophylaxis was given to the included subjects. During a risk period
for the occurrence of venous thromboembolism, the use of anticoagulant
prophylaxis was encouraged; however, the decision to do so and the
regimen used was left to the discretion of the treating physician. The
definition of a risk period was surgery, trauma, prolonged
immobilization (>7 days), pregnancy, and the postpartum period. The
use of oral contraceptives was discouraged, but not prohibited. Its use
was recorded. Follow-up was performed every 6 months, either by a visit
to the study center or by telephone contact. At this time, attention
was paid to the occurrence of signs or symptoms possibly indicating the
presence of a venous thromboembolic event. The occurrence of risk
periods in the past period was also recorded.
At the start of the study, all subjects were instructed to present with
any symptoms, which could indicate the presence of a venous
thromboembolism (eg, swelling, pain, or redness of the leg; acute
shortness of breath, chest pain, hemoptysis). In such a
condition, a clinical assessment was made and diagnostic tests were
performed when deemed appropriate. Both the study subjects and their
general practitioners received written information concerning the
implications of the observed deficiency and the advice to strongly
consider anticoagulant prophylaxis during a risk period. The study
protocol was approved by the medical ethical committees in the
participating centers.
Laboratory assays.
Blood samples were collected into plastic syringes containing 3.8%
(wt/vol) sodium citrate in a ratio of 0.1:0.9 (vol/vol) anticoagulant
to blood. Platelet poor plasma was obtained by centrifugation at
2,000g for 20 minutes and stored at  80°C until it
was analyzed.
The same materials and methods for the diagnosis of antithrombin,
protein C, and protein S defects were used in all centers. Antithrombin
antigen concentrations were measured using the Asseraplate Antithrombin
III Kit (Boehringer Mannheim, Mannheim, Germany), and antithrombin
activity was measured using Berichrom ATIII (Behringwerke, Marburg,
Germany). Protein C antigen concentrations were measured with
enzyme-linked immunosorbent assays (ELISA) using rabbit antiprotein C
polyclonal antibody (DAKO, Glostrup, Denmark) as catching antibody. Rabbit antiprotein C polyclonal horseradish peroxidase (HRP)-conjugated antibody (DAKO) was used as the second antibody diluted 1:1,000 in the
ELISA buffer. Protein C activity was measured using the Protein C
Reagent Kit (Behringwerke). Concentrations of total and free protein S
were measured by ELISA using rabbit antiprotein S polyclonal antibody
(DAKO) and the 15C4 antiprotein S monoclonal antibody (Serbio,
Gennevilliers, France) as catching antibodies, respectively. Rabbit
antiprotein S polyclonal HRP-conjugated antibody (DAKO), diluted
1:1,000, was used as the second antibody. The 15C4 antiprotein S
monoclonal antibody recognized only free protein S antigen, whereas
PS-C4bp complexes were not detected. A calibration curve for free
protein S antigen was obtained by dilution of pooled normal plasma,
which contained by definition 100% of free protein S antigen.
Therefore, the level of free protein S antigen in patients' plasma was
expressed as the percentage of the free instead of the total protein S
antigen present in pooled normal plasma. Protein S activity was
measured using the Protein S IL-Kit (Instrumentation Laboratories,
Milan, Italy).
The following reference values were used: antithrombin antigen
concentration, 80% to 120%; antithrombin activity 80% to 120%; protein C antigen concentration, 70% to 130%; protein C activity, 70% to 130%; total protein S concentration, 70% to 120%; free protein S concentration, 70% to 120%; and protein S activity, 70% to
130%. The criteria used for the classification of antithrombin, protein C, and protein S defects were in accordance with those reported
in the current literature.13
DNA analysis for the factor V Leiden mutation and the 20210A
prothrombin variant were performed in those patients who became symptomatic during follow-up using previously described
methods.14,15 In the same group of patients, levels of
homocysteine, as well as the presence of antiphospholipid antibodies,
were determined according to previously reported
methods.16,17
Outcomes.
The primary outcome was the occurrence of an objectively documented
venous thromboembolic event. This was defined as any of the following:
(1) deep vein thrombosis of the leg or of the arm, documented by either
contrast venography or compression ultrasonography; (2) pulmonary
embolism documented either by a high-probability ventilation-perfusion
scan or by pulmonary angiography; and (3) objectively documented
thrombosis of deep veins elsewhere in the body. A venous thromboembolic
event was categorized as being either spontaneous or secondary to a
risk period. A spontaneous venous thromboembolism was defined as a
thrombotic event occurring without a predisposing risk period. A
secondary venous thromboembolism was defined as an event occurring
during or within a 3-month period after a risk period.
Statistical analysis.
The annual incidence of spontaneous venous thromboembolism and its 95%
confidence interval (CI) were calculated for the total study population
and for the individual deficiencies separately. The incidence of risk
period-related venous thromboembolism and its 95% CI were calculated.
The occurrence of risk period-related venous thromboembolism was
related to the type of risk period and whether anticoagulant
prophylaxis had been used.
| |
RESULTS |
Subjects.
Ninety-four unrelated patients with an objectively documented venous
thromboembolism and a deficiency of antithrombin (n = 24), protein C (n = 30), or protein S (n = 40) served as index patients in this study.
From these 94 families, 841 family members were identified as
potentially eligible for participation in the study. In total, 106 subjects were not interviewed or tested for their deficiency status due
to refusal in 49 cases and nonavailability of the subject in 57 cases
(eg, living abroad, contact not able to be established). The remaining
735 subjects (mean, 8 per index patient; range, 0 to 18) were
interviewed and their blood was tested for the presence of the relevant
thrombophilic defect. Eighty-seven (11.8%; mean, 1 per index patient;
range, 0 to 3) of these subjects reported a prior episode of venous
thromboembolism and were excluded from the study. Twenty of these
subjects came from families with an antithrombin deficiency, 27 from
families with a protein C deficiency, and 40 from families with a
protein S deficiency. Of the remaining 648 subjects, 208 were found to be deficient and were included in the study. Forty-five subjects had an
antithrombin deficiency (type I or II), 93 a protein C deficiency (type
I or II), and 70 a protein S deficiency (type I or III). None exhibited
protein S variants (type II defects). Ninety-five of these subjects
were male and 113 were female. The mean age of the subjects at the time
of their inclusion in the study was 37 (range, 15 to 79) years
(Table 1).
Observation years.
A total of 611 patient observation years were obtained, 125 years in
the antithrombin-deficient group, 204 years in the protein C-deficient
group, and 282 years in the protein S-deficient group. The average
duration of observation per subject was 3 years (range, 0.3 to 4.5 years). Nine venous thromboembolic events occurred during the course of
the study, 5 in the antithrombin-deficient group and 2 in both the
protein C- and protein S-deficient groups. The overall annual
incidence of venous thromboembolism was 1.5% (95% CI, 0.7 to 2.8).
Spontaneous events.
A total of 5 spontaneous venous thromboembolic events occurred. This
results in an annual incidence of 0.8% per year (95% CI, 0.3 to 1.9)
when the 3 deficiency groups are combined. Two of these events occurred
in the antithrombin-deficient group (1.6% per year; 95% CI, 0.2 to
5.8); 2 in the protein C-deficient group (1.0% per year; 95% CI, 0.1 to 3.5); and 1 in the protein S-deficient group (0.4% per year; 95%
CI, 0.3 to 1.9). All of these patients were female, none of whom were
taking oral contraceptives or hormone replacement therapy at the time
of their thrombosis. The average age of the subjects at the time of the
thromboembolic event was 60 years (range, 42 to 69 years). Four
patients had proximal deep vein thrombosis, while the fifth presented
with a nonfatal pulmonary embolism (Table
2). Two patients presented with minimal complaints during a routine
follow-up visit and were found to have deep vein thrombosis on
ultrasonography.
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Table 2.
Characteristics of the Subjects With a Venous
Thromboembolic Event During the Study, the Relation to a Risk Period,
the Location, and the Diagnostic Method
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Risk period-related events.
Thirty-four of the 208 subjects experienced a total of 40 risk periods.
Eleven of these risk periods were surgery, 11 were a trauma, 4 were
immobilization, 9 were pregnancies, and 5 were other types of risk
periods. Anticoagulant prophylaxis was administered by the treating
physician during 22 of these risk periods. Fifteen subjects received
low-dose unfractionated heparin, 2 low-dose, and 3 high-dose
low-molecular-weight heparin, and 3 subjects received oral vitamin K
antagonists (international normalized ratio [INR], 2 to
3) as prophylaxis during the risk period. Eight women used oral
contraceptives for variable times during the study for a total duration
of 18 years. These women had chosen to continue the use of oral
contraceptives despite being informed of the potential risk of venous
thromboembolism. None of them developed a venous thromboembolism.
Four venous thromboembolic events occurred during or within 3 months of
a risk period (Table 3). This results in an
overall incidence of 10.0% per risk period (95% CI, 2.8% to 23.7%).
One event occurred in a protein S-deficient woman 1 day postpartum while receiving low-dose unfractionated heparin prophylaxis. The remaining 3 events occurred in antithrombin-deficient subjects who
received no anticoagulant prophylaxis for their risk period. During the
22 risk periods in which anticoagulant prophylaxis was administered 1 event occurred, resulting in an incidence of 4.5% per risk period,
while 3 events (16.7%) occurred during the 18 risk periods in which no
form of anticoagulant prophylaxis was given. The average age of the
subjects at the time of the risk period-related venous thromboembolic
event was 41 years (range, 24 to 66) (Table 2).
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Table 3.
The Number of Risk Periods and Whether Anticoagulant
Prophylaxis Was Used, the Number of Risk Period-Related Venous
Thromboembolic Events, and the Incidence per Risk Period
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All subjects who developed a venous thromboembolic event during the
study were evaluated for the presence of multiple genetic risk factors.
None were found to be carriers of the factor V Leiden mutation or the
prothrombin 20210A gene mutation, or have hyperhomocysteinemia, antiphospholipid antibodies, or dysfibrinogenemia.
| |
DISCUSSION |
This large prospective cohort study was designed to assess the
incidence of both spontaneous and risk period-related venous thromboembolism in asymptomatic deficient family members of patients who have presented with a venous thromboembolism and a deficiency of
antithrombin, protein C, or protein S. The observed incidence of
spontaneous venous thromboembolism in the total group was 0.8% per
year (95% CI, 0.3% to 1.9%). The incidence of spontaneous venous
thromboembolism in the 3 deficiency groups separately shows a
relatively large variation (antithrombin, 1.6% per year; protein C,
1.0% per year; and protein S, 0.4% per year). Therefore, it could be
questioned whether it is correct to group these 3 thrombophilic defects
into 1 category. It must be noted, however, that the incidence found in
all 3 groups falls within each other's 95% confidence limits and that
similar odds ratios for the occurrence of venous thromboembolism have
been reported for these 3 thrombophilic defects.9 This
study has been limited to the deficiencies of antithrombin, protein C,
and protein S, as these were the only known inherited risk factors at
the start of this study. Furthermore, these deficiencies carry a
significantly greater risk for venous thromboembolism than the factor V
Leiden mutation.9,18
The observed incidence of 0.8% per year of spontaneous venous
thromboembolism is lower than was calculated based on the published family studies. These earlier estimates of the incidence are likely to
be inflated because these family studies were prone to selection bias
and relied primarily on clinical diagnoses of venous thromboembolism. In this study, selection bias was prevented by including index patients
independent of their family history. Patients with a previous episode
of venous thromboembolism were excluded. However, a broad range of
subjects remained in the study with a relatively low average age. It
could be argued that exclusion of the 87 patients with a history of
thrombosis would bias the current analysis toward a lower incidence of
first thrombotic events. However, in the retrospective analysis of a
subset of the same families, in which these cases were the outcome
event, even a lower incidence was observed.11 The on
average relatively high age of the patients at the time of the
thrombotic events in this study, which is still lower than in large
prospective cohort studies of unselected patients with venous
thromboembolism,19-21 can be attributed to its prospective design. Retrospective studies, as previously performed, naturally tend
toward collection of many observation years and thus events in the
younger age groups. In this study, all venous thromboembolic events
were diagnosed by means of objective diagnostic methods. The
determination of deficiency status was performed, as in most laboratories, by measurement of functional plasma concentrations and
not by genetic determination.
The observed incidence of spontaneous venous thromboembolism is also
slightly lower than that reported in a small prospective study of
asymptomatic protein C- and protein S-deficient subjects by Pabinger
et al10 (1.4% per year), but as mentioned, is slightly higher than that which we found in the previous retrospective study
(0.4% per year).11 A possible explanation for this
difference in the observed incidence is that because proper information
was provided systematically to (potential) participants, the subjects were made aware of the signs and symptoms of venous thromboembolism. Moreover, we performed objective diagnostic testing when complaints occurred. Therefore, it is possible that thrombotic events were diagnosed, which would otherwise have passed unnoticed. However, the
observed incidences in this study and our retrospective study fall
within each other's 95% confidence limits.
Clinical conditions such as surgery, immobilization, trauma, pregnancy,
and the postpartum period, as well as the use of oral contraceptives,
are well-recognized risk periods for the occurrence of venous
thromboembolism. Patients with a deficiency of antithrombin, protein C,
or protein S, and 1 of these clinical conditions are at an increased
risk in comparison to the normal population. In the present study, the
incidence of risk period-related venous thromboembolism in the
subjects who received anticoagulant prophylaxis was 4.5% as compared
with 16.7% in the group who did not receive prophylaxis. Limitations
in the observations concerning risk period-related venous
thromboembolism in this prospective study are the relatively small
number of risk periods during the observation period and the nonuniform
approach concerning anticoagulant prophylaxis. However, because it is
likely that anticoagulant prophylaxis was not given in the presumed
lower risk situations, the incidence of thrombosis without prophylaxis
is probably an underestimation of the true incidence and that likewise
the effect of prophylaxis is underestimated.
However, on the basis of the high incidence of venous thromboembolism
related to risk periods found in this study (10%), in which both
patients and physicians were aware of the implications of the presence
of a deficiency, it is warranted to stress the importance of
prophylactic strategies in asymptomatic-deficient individuals during
risk periods. It remains unknown whether during such risk periods
higher dosages of anticoagulation are required, whether the prophylaxis
should be continued for a longer period of time, and whether there
should be a lower threshold for the administration of anticoagulant
prophylaxis in comparison to patients without a thrombophilic defect.
What are the implications of this study for decisions concerning the
continuous use of anticoagulant prophylaxis in asymptomatic carriers of
a deficiency of antithrombin, protein C, or protein S? When considering
the use of long-term prophylactic anticoagulation, in particular
vitamin K antagonists, the benefits of the use of these agents must be
carefully weighed against the risk of bleeding complications associated
with their use. The annual incidence of serious bleeding during the use
of therapeutic dosages of vitamin K antagonists is approximately 2%,
while that of fatal bleeding complications is approximately 0.25% per
year.19,20 These incidences clearly increase with age. We
have found an annual incidence of a first spontaneous thrombotic event
in the 3 deficiencies combined of 0.8%. In this study, no fatal venous
thromboembolic events occurred; however, it has been estimated that 5%
of venous thromboembolic events may be fatal.21 Taking
these various factors into consideration, the annual incidence of
spontaneous fatal venous thromboembolism would be 0.04% in
asymptomatic-deficient individuals. If these assumptions are used on
the upper limit of the 95% confidence interval of the incidence
(1.9%), we find an annual incidence of spontaneous fatal venous
thromboembolic events of 0.10%. Based on these assumptions, the use of
continuous anticoagulant prophylaxis seems not warranted in
asymptomatic individuals with a deficiency of antithrombin, protein C,
or protein S.
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FOOTNOTES |
Submitted January 21, 1999; accepted July 26, 1999.
H.R.B. is an established investigator of the Dutch Heart Foundation.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Bernd-Jan Sanson, MD, Department of
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ
Amsterdam, The Netherlands; e-mail: b.j.sanson{at}amc.uva.nl.
| |
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