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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3678-3682
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
High levels of factor IX increase the risk of venous thrombosis
Astrid van Hylckama Vlieg,
Irma K. van der Linden,
Rogier M. Bertina, and
Frits R. Rosendaal
From the Department of Clinical Epidemiology and Hemostasis and
Thrombosis Research Center, Leiden University Medical Center,
Leiden, The Netherlands.
 |
Abstract |
Elevated plasma levels of factor VIII (> 150 IU/dL) are an
important risk factor for deep vein thrombosis (DVT). Factor VIII is
the cofactor of factor IXa in the activation of factor X. The risk of
thrombosis in individuals with an elevated factor IX level is unknown.
This study investigated the role of elevated factor IX levels in the
development of DVT. We compared 426 patients with a first objectively
diagnosed episode of DVT with 473 population controls. This study was
part of a large population-based case-control study on risk factors for
venous thrombosis, the Leiden Thrombophilia Study (LETS).
Using the 90th percentile measured in control subjects (P90 = 129 U/dL) as a cutoff point for factor IX
levels, we found a 2- to 3-fold increased risk for individuals who have
factor IX levels above 129 U/dL compared with individuals having factor IX levels below this cutoff point. This risk was not affected by
adjustment for possible confounders (age, sex, oral contraceptive use,
and high levels of factor VIII, XI, and vitamin K-dependent proteins).
After exclusion of individuals with known genetic disorders, we
still found an odds ratio (OR) of 2.5 (95% confidence interval [CI]:
1.6-3.9). The risk was higher in women (OR: 2.6, CI: 1.6-4.3) than in
men (OR: 1.9, CI: 1.0-3.6) and appeared highest in the group of
premenopausal women not using oral contraceptives (OR: 12.4, CI:
3.3-47.2). These results show that an elevated level of factor IX is a
common risk factor for DVT.
(Blood. 2000;95:3678-3682)
© 2000 by The American Society of Hematology.
| |
Introduction |
The incidence of deep vein thrombosis (DVT) in the
general population is about 1 in 1000 people per year.1,2
The pathogenesis of DVT is complex. In theory, hyperactive coagulation
pathways, hypoactive anticoagulant mechanisms, or hypoactive
fibrinolysis may cause the development of DVT.3
Risk factors can be classified into acquired and genetic
factors.4 DVT is a multicausal disease; that is, more than
a single risk factor needs to be present simultaneously to cause
thrombosis.5,6 Known acquired risk factors include
immobilization, surgery, trauma, pregnancy, puerperium, lupus
anticoagulant, malignant disease, and female hormones.5,7
Genetic risk factors causing a tendency to DVT are antithrombin
deficiency,8 protein C deficiency,9 protein S
deficiency,10 the factor V Leiden mutation,11
and the prothrombin 20210 A allele.12 However, in about
30% of patients with a family history of DVT, no underlying genetic
defect will be found. 13
Other risk factors that are frequently reported among patients with DVT
are elevated factor VIII levels14 and
hyperhomocysteinemia.15,16 We recently found that
elevated levels of factor XI17 and factor X in women who do
not use oral contraceptives18 are also associated with the
risk of thrombosis. The molecular basis of these abnormalities is still
unknown. Because factor VIII is the cofactor of factor IXa in the
activation of factor X, it seemed plausible that elevated levels of
factor IX could also be a risk factor for DVT.
Factor IX plays a key role in hemostasis; it is a vitamin K-dependent
glycoprotein, which is activated through the intrinsic pathway as well
as the extrinsic pathway.19 Factor IX, when activated by
factor XIa or factor VIIa-tissue factor, converts factor X into Xa and
this eventually leads to the formation of a fibrin clot. This
conversion is accelerated by the presence of the nonenzymatic cofactor
factor VIIIa, calcium ions, and a phospholipid membrane.20
In healthy individuals, factor IX activity and antigen levels vary
between 50% and 150% of that in pooled normal plasma.21
Several studies have reported that factor IX levels increase with
age22-24 as well as with oral contraceptive use.23,25 Deficiencies of factor VIII (hemophilia A) and
factor IX (hemophilia B) lead to clinically identical bleeding
tendencies. Analogy suggests similar effects of high levels of both
clotting factors on thrombotic risk.
In this study, we investigated the role of elevated coagulation factor
IX levels in the development of a first DVT. The study was part of a
large population-based case-control study on risk factors of venous
thrombosis, the Leiden Thrombophilia Study (LETS).
| |
Patients, materials, and methods |
Study design
The design of this study has been described in detail
previously.26,27 In short, we included 474 consecutive
patients younger than 70 years with an objectively confirmed first
episode of DVT that occurred in the period between January 1988 and
December 1992, who were selected from the files of the anticoagulation clinics in Leiden, Amsterdam, and Rotterdam. These clinics monitor outpatient anticoagulant treatment in well-defined geographical areas.
Patients with known malignant disorders were excluded. Each thrombosis
patient was asked to find his or her own control subject with the same
sex and approximately the same age (within 5 years). Partners of
patients were also asked if they were willing to participate in this
study as a control subject; if a patient was unable to find a control
subject, the first individual on the list of partners matching for sex
and age was asked to join the study; 474 control subjects were
included. Blood was collected from the antecubital vein into Starstedt
Monovette tubes, in 0.1 volume 0.106 mol/L trisodium
citrate. Plasma was prepared by centrifugation for 10 minutes at
2000g at room temperature and stored at  70°C, until
used. Patients and controls were seen concurrently and all samples were
analyzed with the same batch of reagents, using the same pooled normal
plasma within a 6-week period.
Forty-eight of the patients and 1 of the control subjects were on
long-term oral anticoagulant therapy and, because this results in
reduced levels of the vitamin K-dependent proteins, they were excluded
from the analysis. For the current analysis, we therefore studied 426 patients and 473 control subjects. The median time between thrombosis
and venipuncture for this study was 18 months (range, 6-56 months).
Measurement of factor IX
The levels of factor IX were determined by enzyme-linked
immunosorbent assay (ELISA). This ELISA is highly specific for factor IX and results are not affected by the levels of the other vitamin K-dependent proteins. PVC-microtiter plates (ICN Biomedicals BV, Zoetermeer, The Netherlands) were coated with rabbit antifactor IX
antibodies as capture antibodies (DAKO A/S, Glostrup, Denmark; 3 µg/mL, 100 µL/well). Bound factor IX was detected with
non-Ca++-dependent antifactor IX IgG28
conjugated to horseradish peroxidase (HRP). HRP activity was measured
with o-phenylenediamine. The color reaction was stopped after
15 minutes using H2SO4 and read spectrophotometrically at 492 nm. The assay was calibrated with dilutions of pooled normal plasma (1:25-1:1600). Plasmas were diluted
in washing buffer (50 mmol/L triethanolamine, pH 7.5, 100 mmol/L NaCl,
10 mmol/L EDTA, 0.1% Tween). The factor IX content of a plasma sample
was calculated as the mean result of single determinations of 3 different dilutions (1:100, 1:200, and 1:400). Results were accepted
when the coefficient of variation (CV) was less than 10%. Under these
conditions, the intra-assay and interassay CV was 7% (n = 9) and
7.2% (n = 41), respectively, at a factor IX antigen level of about
100 U/dL. Results are expressed in units per deciliter, where 1 U is
the amount of factor IX present in 1 mL pooled normal plasma.
Because of the presence of EDTA in the buffer, only antibodies against
the non-Ca++-dependent conformation of factor IX are used.
Therefore results will not be influenced by variations in the degree of
 -carboxylation of factor IX and represent truly factor IX protein
concentrations in plasma. Identical results can be obtained by using
commercial antifactor IX-HRP (Enzyme Research Laboratories, South Bend,
IN) or commercial factor IX ELISA, provided that EDTA
is present in or added to the buffer system.
Factor VII and VIII were measured by 1-stage coagulation
assays.14,29 Prothrombin levels were measured by a
chromogenic assay using Echis carinatus venom as
activator.12 Factor X antigen was measured by a sandwich
ELISA using commercial polyclonal antibodies (DAKO A/S)18
and factor XI antigen by an ELISA using a monoclonal antifactor XI
antibody as catching antibody and polyclonal antifactor XI as tagging
antibody.17
The technician was blinded concerning the origin of the sample, that
is, whether it was from a patient or from a control subject.
Statistical analysis
The study was divided into 2 parts. First we investigated possible
determinants of factor IX levels, looking only at the control subjects
as reflecting the general population. The determinants were established
mainly by comparing means and using linear regression. To assess the
relationship between factor IX levels and oral contraceptive use, an
extra selection was made in the study population, as described earlier.30,31 We selected nonmenopausal women between 15 and 49 years of age. Women who were at the index date (similar date as
time of thrombosis for patients) pregnant (n = 10), within 30 days
postpartum (n = 14), who had a recent miscarriage (n = 2), or had
used only depot contraceptives (n = 3) were excluded. A total of 153 control subjects were left for this specific analysis.
Secondly, we investigated whether a high level of factor IX is a risk
factor for DVT by calculating the adds ratio (OR) and the 95%
confidence interval (CI). As a cutoff point we used the 90th percentile
of factor IX levels measured in the control subjects. The factor IX
levels were also divided in strata to assess a relationship between
factor IX levels and the thrombosis risk (dose response).
To adjust for possible confounders, for example, age, sex, oral
contraceptive use at the time of thrombosis as well as at the time of
venipuncture, and high levels of factor VIII, XI, and the vitamin
K-dependent clotting factors (all dichotomized at the 90th
percentile), we used a logistic regression model. In case of sparse
data (ie, known genetic risk factors for thrombosis, oral contraceptive
use), we also used restriction, that is, analysis only of those without
thrombophilic risk factors, only of men, or only of women
(premenopausal and postmenopausal) who did not change their oral
contraceptive use since their thrombosis (and who were not pregnant,
not within 30 days postpartum, did not have a recent miscarriage, nor
used only depot oral contraceptives). The thrombophilic risk factors
used in the restriction were protein C deficiency (< 0.67 U/mL),
protein S deficiency (< 0.67 U/mL), antithrombin deficiency
(< 0.80 U/mL), the factor V Leiden mutation, and the prothrombin
20210 A allele.32
Because factor VIII is the cofactor of factor IX and itself a
risk factor for thrombosis,14 we assessed the effect on the thrombotic risk of elevated factor IX levels alone and of elevated factor IX levels in combination with elevated factor VIII levels.
| |
Results |
The mean age of patients and controls at the time of the thrombosis
was 45 years (range, patients 15-69; controls, 15-72). Among cases and
controls alike, 59% were women.
Determinants of factor IX levels
The mean (range) of factor IX levels was 103 (52-188) U/dL. As shown
in Table 1, factor IX levels increased with
age, only after the age of 55; factor IX levels were almost equal in
men and in women (mean difference: 3.4 U/dL, CI: 0.4 to 7.2). No difference was found in factor IX levels between blood groups. Factor
IX levels were weakly associated with factor VIII and factor XI levels
(regression coefficient with factor IX level as dependent variable,
factor VIII: 0.18, CI: 0.12-0.24 and factor XI 0.23, CI: 0.14-0.33).
Among 153 healthy premenopausal women, factor IX levels were
substantially higher among women who used oral contraceptives compared
with women who did not (mean difference: 22.7 U/dL, CI: 15.8-29.5, after age adjustment: 25.6 U/dL, CI: 18.0-33.2).
The time between thrombosis and the venipuncture did not influence the
levels of factor IX in the patients. After dividing the intervening
time into 4 periods, the factor IX levels remained approximately the
same, ranging from 113 U/dL in individuals with a venipuncture within 1 year after the thrombosis (n = 108) to 111 U/dL in individuals with a
venipuncture more than 3 years after their thrombosis (n = 35).
Factor IX as a risk factor for DVT
Ten percent of the healthy control subjects had factor IX
levels above 129 U/dL (90th percentile = 129 U/dL). More than 20% of
the patients had factor IX levels exceeding this cutoff point, which
implies that individuals with a factor IX level higher than 129 U/dL
had a more than 2-fold increased risk to develop DVT when compared with
individuals having factor IX levels below this cutoff value (Table
2). After adjustment for age, sex, and oral contraceptive use, the OR was 2.8 (CI: 1.9-4.3). When adjustment included factor VIII, XI, and vitamin K-dependent clotting factor levels (all dichotomized at the 90th percentile), the OR was 2.0 (CI:
1.3-3.2). When adjustment only included the vitamin K-dependent clotting factors (factor II, VII, and X), the risk associated with
factor IX levels exceeding the 90th percentile remained increased 2-fold (OR: 2.0; CI: 1.3- 3.0). Additional adjustment for C-reactive protein did not affect the risk estimates.
A total of 130 patients and 51 control subjects had a known
genetic risk factor for thrombosis. Exclusion of these individuals only
marginally affected the risk estimates (crude OR: 2.5, CI: 1.6-3.9;
after adjustment for age, sex, and oral contraceptive use: OR: 3.0, CI:
1.9-4.7; when adjustment included factor VIII, XI, and vitamin
K-dependent clotting factor levels: OR: 2.2, CI: 1.3-3.6).
We used the 90th percentile as a cutoff point for the levels
of factor IX. When the 95th percentile (P95 = 142 U/dL)
was used, the crude OR was slightly higher, at 2.5 (CI: 1.5-4.3). Table 3 shows the risk of thrombosis for strata
of factor IX levels. Table 3 shows that there is a relationship between
thrombosis and factor IX levels (dose response), with a 3.2-fold
increased risk for individuals with factor IX levels over 150 U/dL
compared with those having levels below 100 U/dL.
Comparing younger and older subgroups (with the median age as a
division), the odds ratios were equal: a 2.5-fold increased risk for
high factor IX levels in the individuals aged under 45 and a 2.3-fold
increased risk for the older people (Table 2).
When the risk of developing DVT is assessed for men and women
separately, as shown in Table 2, we found a slightly higher relative
risk in women than in men. Restricting the female population to
premenopausal women who did not use oral contraception at the time of
thrombosis (or similar date for the controls) nor at the time of
venipuncture, the relative risk increased to 12.4. For women using oral
contraceptives both at the thrombotic event and at the time of
venipuncture, the relative risk was 1.5, whereas for postmenopausal
women the relative risk was 6.2.
For the analysis of the effect on the thrombotic risk of combinations
of factor VIII and factor IX levels, we used the 90th percentile (of
the controls) as cutoff points for both (151 IU/dL for factor VIII and
129 U/dL for factor IX) (Table 4). Although a high level of factor VIII and a high level of factor IX each contribute to the risk of developing DVT, the risk is highest when both
clotting factor levels are above the 90th percentile (8 times higher
than when both clotting factor levels are below the 90th percentile,
CI: 3.6-18.4).
| |
Discussion |
Individuals who have high levels of factor IX (> 129 U/dL) have a
more than 2-fold increased risk of developing a first DVT compared with
individuals having low levels of factor IX. The risk of thrombosis
increased with increasing plasma levels of factor IX (dose response).
At factor IX levels more than 125 U/dL, an increase of the risk can
already be observed compared with the reference category (factor IX
levels  100 U/dL). Individuals with a factor IX level over 150 U/dL
have a more than 3-fold increase in the risk of thrombosis when
compared with the reference category.
Deep vein thrombosis is more often seen in women than in
men.33 Blood groups other than O, as well as increasing
age, increase the risk of developing DVT, which was reviewed in several
studies.14,26,33 Our observations that factor IX levels
increase with age and with oral contraceptive use are in accordance
with earlier studies.23-25 However, the OR for high levels
of factor IX adjusted for these factors did not differ from the crude
OR, which means that the risk associated with high levels of factor IX
is not explained by these other factors nor by other thrombophilic
abnormalities, as shown by restriction to individuals without these abnormalities.
It is not likely that the factor IX levels changed as a consequence of
the thrombosis because factor IX is not an acute-phase reactant;
venipuncture was at least 6 months after the event, and no effect of
the time elapsed between thrombosis and venipuncture on factor IX
levels was observed; also, adjustment for C-reactive protein did not
affect the results.
Age had no effect on the relative risk of DVT caused by elevated levels
of factor IX, which implies a larger absolute effect in older age
groups where thrombosis is more common than among younger individuals.
The relative risk appeared highest in postmenopausal women (6-fold
increased risk) and premenopausal women who did not use oral
contraceptives (12-fold increased risk). This high relative risk in
women not using oral contraceptives contrasts to previous findings on
other abnormalities of the clotting system, where the risk was highest
in women who used oral contraceptives.30 For example, the
factor V Leiden mutation causes a 7- to 8-fold increase of the risk
among both nonusers of oral contraceptives and women who do use oral
contraceptives. Because use of oral contraceptives increases the risk
4-fold, the risk in carriers of factor V Leiden mutation who used
oral contraceptives was about 30 times higher than the risk in a
nonuser who did not carry the mutation.30
In this study we found, however, that the risk associated with elevated
factor IX levels was highest in women who did not use oral
contraceptives. An explanation for this finding could be a ceiling
value for the factor IX levels; that is, in women who have a tendency
to increased factor IX levels, oral contraceptives do not cause
additional increases. This is explained in Figure 1. Comparing the healthy premenopausal
control women in Figure 1 (groups 2 and 4), one can see that oral
contraceptive use causes the factor IX levels to rise. Figure 1 also
shows that the factor IX levels in premenopausal patients (groups 1 and
3) are about equal, regardless of their oral contraceptive use. In
female patients the factor IX levels, therefore, do not seem to
increase when they use oral contraceptives, whereas they do increase in
healthy female controls. In the group of women who use oral
contraceptives (groups 1 and 2), the factor IX levels of patients and
controls are therefore closer together, which decreases the estimated
relative risk.
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| Fig 1.
Comparison of the factor IX levels in premenopausal and
postmenopausal women.
Factor IX antigen levels are shown (median, interquartile range, and
range); OC+ refers to oral contraceptive use both at the time of
thrombosis and at the time of venipuncture; OC refers to
nonusers of oral contraceptives (both at the time of thrombosis and at
the time of the venipuncture); premenop and postmenop refer to
premenopausal and postmenopausal, respectively. Group 1: premenopausal
patients using oral contraceptives (n = 30; median = 116 U/dL);
group 2: premenopausal healthy controls using oral contraceptives
(n = 47; median = 112 U/dL); group 3: premenopausal patients not
using oral contraceptives (n = 40; median = 110 U/dL); group 4:
premenopausal healthy controls not using oral contraceptives (n = 90;
median = 91 U/dL); group 5: postmenopausal patients not using oral
contraceptives (n = 60; median = 119 U/dL); group 6: postmenopausal
controls not using oral contraceptives (n = 88; median = 105
U/dL).
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This does not mean that oral contraceptives act protectively against
the risk of DVT due to elevated levels of factor IX. It may be,
however, that in women who already have elevated levels of factor IX,
the use of oral contraceptives does not contribute further to the risk
of DVT associated with increased levels of factor IX. Another
explanation is chance. Compared with women who did not use oral
contraceptives and had low factor IX levels, those who had high factor
IX levels and did not use oral contraceptives had a 12-fold increased
risk after age adjustment (CI: 3.1-45.5), whereas those who used oral
contraceptives and had high factor IX levels had a 3.3-fold increased
risk (CI: 1.2-8.9). The confidence intervals of those estimates show a
fairly large overlap.
The results of this study indicate that an elevated level of factor IX
is a common risk factor for DVT. The relative risk of thrombosis of 2.3 caused by high levels of factor IX (> 129 U/dL) is present in 10%
of the population. This implies that high levels of factor IX are
responsible for a considerable number of thromboses.
The development of DVT is the result of several interactions between
genetic and environmental components.5,6 The role of factor
VIII as a risk factor of DVT was described earlier.14 We
found that both factor VIII and factor IX levels contribute to the risk
of DVT. When both coagulation factors are elevated, however, the risk
of DVT is highest. At present, the molecular basis of elevated factor
IX levels is unknown (genetic, acquired, or a combination of both).
More studies need to be done to find out what causes factor IX levels
to be high or low.
| |
Acknowledgments |
We thank Dr F. J. M. van der Meer (Anticoagulation Clinic, Leiden), Dr
L. P. Colly (Anticoagulation Clinic, Amsterdam), and Dr P. H. Trienekens (Anticoagulation Clinic, Rotterdam) for their kind
cooperation and Dr T. Koster for collecting blood samples from patients
and control subjects.
| |
Footnotes |
Submitted August 16, 1999; accepted February 4, 2000.
Supported by the Netherlands Heart Foundation (number 89.063).
Correspondence: F. R. Rosendaal, Department of
Clinical Epidemiology, Leiden University Medical Center, C0-P46, PO Box 9600, NL-2300 RC, Leiden, The Netherlands; e-mail:
f.r.rosendaal{at}lumc.nl.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Nordström M, Lindblad B, Bergqvist D, Kjellstrom T.
A prospective study of the incidence of deep-vein thrombosis within a defined urban population.
J Intern Med.
1992;232:155-160[Medline]
[Order article via Infotrieve].
2.
Anderson FA, Wheeler HB, Goldberg RJ, et al.
A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.
Arch Intern Med.
1991;151:933-938[Abstract].
3.
Miletich JP, Prescott SM, White R, et al.
Inherited predisposition to thrombosis.
Cell.
1993;72:477-480[Medline]
[Order article via Infotrieve].
4.
Lane DA, Mannucci PM, Bauer KA, et al.
Inherited thrombophilia: part 1.
Thromb Haemost.
1996;76:651-662[Medline]
[Order article via Infotrieve].
5.
Rosendaal FR.
Venous thrombosis: a multicausal disease.
Lancet.
1999;353:1167-1173[Medline]
[Order article via Infotrieve].
6.
Seligsohn U, Zivelin A.
Thrombophilia as a multigenic disorder.
Thromb Haemost.
1997;78:297-301[Medline]
[Order article via Infotrieve].
7.
Carter CJ.
The natural history and epidemiology of venous thrombosis.
Prog Cardiovasc Dis.
1994;36:423-438[Medline]
[Order article via Infotrieve].
8.
Egeberg O.
Inherited antithrombin deficiency causing thrombophilia.
Thromb Diath Haemorrh.
1965;13:516-530[Medline]
[Order article via Infotrieve].
9.
Griffin JH, Evatt B, Zimmerman TS, et al.
Deficiency of protein C in congenital thrombotic disease.
J Clin Invest.
1981;68:1370-1373.
10.
Comp PC, Nixon RR, Cooper MR, Esmon CT.
Familial protein S deficiency is associated with recurrent thrombosis.
J Clin Invest.
1984;74:2082-2088.
11.
Bertina RM, Koeleman BP, Koster T, et al.
Mutation in blood coagulation factor V associated with resistance to activated protein C.
Nature.
1994;369:64-67[Medline]
[Order article via Infotrieve].
12.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM.
A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood.
1996;88:3698-3703[Abstract/Free Full Text].
13.
Bertina RM.
Factor V Leiden and other coagulation factor mutations affecting thrombotic risk.
Clin Chem.
1997;43:1678-1683[Abstract/Free Full Text].
14.
Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR.
Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.
Lancet.
1995;345:152-155[Medline]
[Order article via Infotrieve].
15.
Falcon CR, Cattaneo M, Panzeri D, et al.
High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis.
Arterioscler Thromb.
1994;14:1080-1083[Abstract/Free Full Text].
16.
den Heijer M, Koster T, Blom HJ, et al.
Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
N Engl J Med.
1996;334:759-762[Abstract/Free Full Text].
17.
Meijers JCM, Tekelenburg WLH, Bouma BN, et al.
High levels of factor XI as a risk factor for venous thrombosis.
N Engl J Med.
2000;342:696-701[Abstract/Free Full Text].
18. de Visser MCH, Poort SR, Vos HL, et al. Factor X promoter
polymorphisms, factor X levels and the risk of venous thrombosis
[abstract]. Thomb Haemost. 1999(suppl):508.
19.
Furie B, Furie BC.
The molecular basis of blood coagulation.
Cell.
1988;53:505-518[Medline]
[Order article via Infotrieve].
20.
van Dieijen G, Tans G, Rosing J, Hemker C.
The role of phospholipid and factor VIIIa in the activation of bovine factor X.
J Biol Chem.
1981;256:3433-3442[Abstract/Free Full Text].
21.
Reiner AP, Davie EW.
The physiology and biochemistry of factor IX. In:
Bloom AL,Thomas DP, eds.
Haemostasis and Thrombosis. 3rd ed. Edinburgh: Churchill Livingstone.; 1994:309-324.
22.
Simpson NE, Biggs R.
The inheritance of Christmas factor.
Br J Haematol.
1962;8:191-203.
23.
Lowe GD, Rumley A, Woodward M, et al.
Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use.
Br J Haematol.
1997;97:775-784[Medline]
[Order article via Infotrieve].
24.
Sweeney JD, Hoernig LA.
Age-dependent effect on the level of factor IX.
Am J Clin Pathol.
1993;99:687-688[Medline]
[Order article via Infotrieve].
25.
Briët E, van Tilburg NH, Veltkamp JJ.
Oral contraception and the detection of carriers in haemophilia B.
Thromb Res.
1978;13:379-388[Medline]
[Order article via Infotrieve].
26.
van der Meer FJ, Koster T, Vandenbroucke JP, et al.
The Leiden Thrombophilia Study (LETS).
Thromb Haemost.
1997;78:631-635[Medline]
[Order article via Infotrieve].
27.
Koster T, Rosendaal FR, de Ronde H, et al.
Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.
Lancet.
1993;342:1503-1506[Medline]
[Order article via Infotrieve].
28.
Poort SR, van der Linden IK, Krommenhoek-van Es C, et al.
Rabbit polyclonal antibodies against the calcium-dependent conformation of factor IX and their application in solid phase immunoradiometric assays.
Thomb Haemost.
1986;55:122-128[Medline]
[Order article via Infotrieve].
29.
Koster T, Rosendaal FR, Reitsma PH, et al.
Factor VII and fibrinogen levels as risk factors for venous thrombosis.
Thromb Haemost.
1994;71:719-722[Medline]
[Order article via Infotrieve].
30.
Vandenbroucke JP, Koster T, Briët E, et al.
Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.
Lancet.
1994;344:1453-1457[Medline]
[Order article via Infotrieve].
31.
Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, et al.
Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives.
Thromb Haemost.
1998;80:382-387[Medline]
[Order article via Infotrieve].
32.
Koster T, Briët E, van der Meer FJ, et al.
Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study).
Blood.
1995;85:2756-2761[Abstract/Free Full Text].
33.
Rosendaal FR.
Thrombosis in the young: epidemiology and risk factors: a focus on venous thrombosis.
Thromb Haemost.
1997;78:1-6[Medline]
[Order article via Infotrieve].
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Abstract
Introduction