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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Gastroenterology and Hepatology,
Leiden University Medical Center; Department of Hepatogastroenterology,
Erasmus University Hospital, Rotterdam; Division of Haemostasis,
Thrombosis and Rheology, University Hospital, Groningen; Department of
Internal Medicine, University Hospital St. Radboud, Nijmegen;
Department of Gastroenterology and Hepatology, University Hospital,
Groningen; Haemostasis and Thrombosis Research Center Leiden, Leiden
University Medical Center; Department of Gastroenterology, University
Hospital, Utrecht; Department of Internal Medicine, Academic Medical
Center, Amsterdam; Department of Gastroenterology, University Hospital
Maastricht; and Department of Clinical Epidemiology, Leiden University
Medical Center, The Netherlands.
In a collaborative multicenter case-control study, we investigated
the effect of factor V Leiden mutation, prothrombin gene mutation, and
inherited deficiencies of protein C, protein S, and antithrombin on the
risk of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). We
compared 43 BCS patients and 92 PVT patients with 474 population-based
controls. The relative risk of BCS was 11.3 (95% CI 4.8-26.5) for
individuals with factor V Leiden mutation, 2.1(95% CI 0.4-9.6) for
those with prothrombin gene mutation, and 6.8 (95% CI 1.9-24.4) for
those with protein C deficiency. The relative risk of PVT was 2.7 (95%
CI 1.1-6.9) for individuals with factor V Leiden mutation, 1.4 (95% CI
0.4-5.2) for those with prothrombin gene mutation, and 4.6 (95% CI
1.5-14.1) for those with protein C deficiency. The relative risk of BCS or PVT was not increased in the presence of inherited protein S or
antithrombin deficiency. Concurrence of either acquired or inherited
thrombotic risk factors was observed in 26% of the BCS patients and
37% of the PVT patients. We conclude that factor V Leiden mutation and
hereditary protein C deficiency appear to be important risk factors for
BCS and PVT. Although the prevalence of the prothrombin gene mutation
was increased, it was not found to be a significant risk factor for BCS
and PVT. The coexistence of thrombogenic risk factors in many patients
indicates that BCS and PVT can be the result of a combined effect of
different pathogenetic mechanisms.
(Blood. 2000;96:2364-2368) Budd-Chiari syndrome (BCS) represents occlusion of
hepatic outflow either at the level of the hepatic veins or inferior
vena cava.1 Clinically, the disease is characterized by
hepatomegaly, manifestations of portal hypertension, and sometimes
rapidly deteriorating liver function.2 Portal vein
thrombosis (PVT) often occurs in conditions leading to decreased portal
flow and also becomes manifest by symptoms of portal
hypertension.3 Both BCS and PVT have been linked to
several hypercoagulable states, primarily myeloproliferative
disorders.4 However, most studies on the pathogenesis of
BCS and PVT contain few patients or are hampered by the lack of
complete testing for thrombophilia and absence of a well-documented
control group.
Resistance to activated protein C due to factor V Leiden mutation
is to date the most frequent cause of hereditary
thrombophilia.5,6 Its prevalence in the general white
population is approximately 5%, but the relative risk of BCS and PVT
for subjects carrying factor V Leiden mutation is uncertain. In a
recent study, factor V Leiden appeared to be present in about one
fourth of patients with BCS, whereas its occurrence in patients with
PVT was negligible.7
Carriers of the prothrombin gene mutation, which results from guanine
to adenine transition at nucleotide position 20210 in the 3'
untranslated region of the gene, exhibit increased plasma levels of
prothrombin and may therefore be at increased risk for venous
thromboembolisms.8 This mutation, also referred to as prothrombin 20210 A variant, has recently been recognized as a risk
factor for a selected group of patients with idiopathic
PVT.9 With regard to BCS, the impact of the prothrombin
gene mutation is uncertain.10 For both BCS and PVT, the
importance of several other hypercoagulable states, such as inherited
deficiencies of the coagulation inhibitors protein C, protein S, and
antithrombin, is also unknown because their association with BCS and
PVT is based solely on anecdotal reports.11,12
We initiated a large multicenter population-based case-control study to
establish the influence of factor V Leiden mutation, prothrombin gene
mutation, protein C deficiency, protein S deficiency, or antithrombin
deficiency on the risk of BCS and PVT.
Patients were selected by means of a search in the computerized
hospital registration systems (ZIS) of 7 academic hospitals in The
Netherlands. The hospitals were located in Leiden, Groningen, Rotterdam, Utrecht, Nijmegen, Amsterdam, and Maastricht. All patients registered with the diagnosis of BCS or PVT between January 1984 and
July 1997 were identified. Diagnostic criteria for BCS and PVT were
partial or complete obstruction of hepatic outflow or the portal vein,
respectively, as documented by appropriate radiographic abdominal
imaging (ie, Doppler ultrasonography, computed tomography, magnetic
resonance imaging, venography) or laparotomy. We excluded patients with
veno-occlusive disease, patients with hepatic outflow obstruction
caused by congestive heart failure, and patients who were younger than
15 years of age in July 1997. For all identified patients (BCS,
n = 76; PVT, n = 214) a standardized questionnaire, asking for
specific clinical information to confirm the diagnosis of PVT and BCS,
was completed with data obtained from the medical charts by local
investigators under close supervision of one member of our team
(H.L.A.J.). Twenty-five patients with BCS and 100 with PVT had died
before July 1997. Patients alive were asked to visit the hospital in
which they were registered for blood sampling, at the same time
enabling investigators to complete the questionnaire with information
on previous thrombotic events, familial thrombosis, acquired risk
factors of thrombosis, and the use of anticoagulants at the time of
venipuncture. Eight patients could not be traced, 14 were unwilling to
participate, and 5 were registered in 2 hospitals; in 3 cases
insufficient material for DNA extraction was obtained. Forty-three
patients with BCS and 92 patients with PVT were enrolled in the study
and underwent a full screening for thrombogenic disorders. Five
patients had both BCS and PVT. These patients were included in the
analyses of both diseases. The population-based control group consisted of 474 healthy individuals who had no history of venous
thromboembolism, had not used coumarin derivatives for at least 3 months before blood sampling, and had no myeloproliferative or
malignant disease (LETS study control population6). Age,
sex, and ethnic descent of patients and the controls were similar. More
than 95% of patients and controls were of Caucasian origin. The study
was approved by the ethical committee of each participating hospital
and the participants gave their informed consent before entering the study.
Blood was collected in tubes containing 3.2% trisodium citrate. After
centrifugation for 10 minutes at 2000g, plasma and white blood cells were separated and stored at Characteristics of patients and controls are shown in Table
1. Myeloproliferative disease was present
in 12 (28%) BCS patients and 16 (17%) PVT patients. Thirty-two (74%)
BCS patients and 24 (26%) PVT patients were treated with coumarin
derivatives. This difference may be attributable not only to the lack
of evidence that anticoagulation is beneficial in PVT but also to the
predominance of variceal bleeding in PVT patients (36%) compared to
BCS patients (7%).
Among the 43 BCS patients factor V Leiden mutation (n = 11, 25.6%,
OR 11.3, 95% CI 4.8-26.5), hereditary protein C deficiency (n = 4,
9.3%, OR 6.8, 95% CI 1.9-24.4) and prothrombin gene mutation (n = 2, 4.7%, OR 2.1, 95% CI 0.4-9.6) were more prevalent than in
controls (Table 2). In particular, factor
V Leiden mutation and protein C deficiency were predominant risk
factors for BCS. One patient exhibited homozygous carriership for
factor V Leiden mutation; the combined presence of factor V Leiden
mutation and hereditary protein C deficiency was found in 2 patients.
Protein S deficiency and antithrombin deficiency could not be
demonstrated for any of the BCS patients. Among the 19 patients with
idiopathic BCS, factor V Leiden mutation was found in 7 (36.8%, OR
19.1, 95% CI 6.5-56.0) protein C deficiency in 2 (10.5%, OR 7.8, 95% CI 1.5-40.6), and prothrombin gene mutation in none.
Among the 92 PVT patients, factor V Leiden mutation was observed in 7 patients (7.6%, OR 2.7, 95% CI 1.1-6.9), hereditary protein C
deficiency in 6 patients (6.5%, OR 4.6, 95% CI 1.5-14.1), and
prothrombin gene mutation in 3 patients (3.2%, OR 1.4, 95% CI
0.4-5.2) (Table 3). Although less
pronounced than in the BCS group, the relative risk of PVT was
increased in the presence of these thrombogenic factors. In one patient
with primary biliary cirrhosis factor V Leiden mutation and protein C
deficiency were present simultaneously. The prevalence of both protein
S deficiency (2.2%, OR 0.9, 95% CI 0.2-4.3) and antithrombin
deficiency (1.1%, OR 0.6, 95% CI 0.1-4.5) was low, being comparable
to that found for controls. In the group of 21 patients with idiopathic
PVT factor V Leiden mutation was observed in 3 (14.2%, OR 5.5, 95% CI
1.4-20.7), prothrombin gene mutation in 1 (4.8%, OR 2.1, 95% CI
0.3-17.1), and protein C deficiency in none.
Use of oral contraceptives was an important acquired risk factor for
BCS and PVT. Among women in the age group of 15 to 49 years, oral
contraceptives had been used at the time of diagnosis in 12 of 20 patients (60.0%, OR 2.4, 95% CI 0.9-6.2) with BCS and in 12 of 25 patients (48.0%, OR 1.5, 95% C 0.6-3.4) with PVT compared to 65 of
169 (38%) controls. Concurrence of inherited thrombogenic factors (ie,
factor V Leiden mutation, prothrombin gene mutation, protein C
deficiency, protein S deficiency, and antithrombin deficiency) and
acquired prothrombotic states for BCS and PVT is shown in Table
4. For 11 of the 43 BCS patients (26%)
and 15 of the 92 PVT patients (16%) no risk factors for thrombosis
could be demonstrated. At least one of the inherited prothrombotic risk
factors was present in 14 patients with BCS (32.5%, OR 3.9, 95% CI
1.9-7.9) and 17 patients with PVT (18.5%, OR 1.8, 95% CI 1.0-3.3).
Coexistence of acquired and inherited risk factors was found for 6 (14%) of those with BCS and 13 (14%) with PVT. Analysis of all
thrombogenic risk factors, irrespective of whether they were acquired
or inherited, revealed 11 (26%) patients with BCS and 34 (37%)
patients with PVT who had more than one risk factor (Table
5). Three BCS patients and 12 PVT patients exhibited 3 or more factors considered to be a risk for development of thrombosis in hepatic and portal veins, respectively.
This study shows a high prevalence of factor V Leiden mutation and hereditary protein C deficiency in patients with BCS and PVT, indicating that individuals with these thrombogenic conditions have an increased relative risk for both manifestations of thrombosis. The prevalence of the prothrombin gene mutation was less than 5% for BCS and PVT, and individuals with this mutation only had an increased relative risk for BCS and PVT, which was not significant. In general, the prevalence of the investigated hereditary risk factors for thrombosis was especially high among patients with idiopathic BCS and PVT. Mahmoud and associates, who investigated 30 BCS patients and 32 PVT patients, reported that factor V Leiden mutation was an important factor in the pathogenesis of BCS but not of PVT.7 The present study, which included 92 PVT patients and therefore had more statistical power, demonstrates that factor V Leiden mutation is also a risk factor for PVT. Chamouard and colleagues recently found the prothrombin gene mutation in 4 of 10 patients with PVT.9 Although they investigated a subgroup of patients with idiopathic PVT, the importance of the prothrombin gene mutation in the etiology of PVT could well be overestimated in that study due to the limited number of patients included. Large studies on venous thromboembolisms did not show a mutation frequency of more than 6.2%, and on pathophysiologic grounds there is no reason to believe patients with the prothrombin gene mutation would exhibit an additional risk for PVT.8 As previously documented for patients with deep venous thrombosis,13 the prevalences of hereditary protein S deficiency and antithrombin deficiency were low in both BCS and PVT patients, and no differences with controls were observed. In view of the low prevalences of these thrombogenic states as well as the investigated diseases, we cannot exclude the association of protein S or antithrombin deficiency with BCS and PVT, as was suggested in several case reports.12,16,17 Although the higher prevalence of protein S deficiency in our control group as compared to other estimates would not suggest so, the use of total protein S values instead of free protein S could have led to an underestimation of the prevalence of inherited protein S deficiency in our study.13,18 In any case, our results indicate that inherited defects of both protein S and antithrombin are probably not major predisposing factors in the pathogenesis of BCS and PVT. At least one of the inherited prothrombotic risk factors investigated (factor V Leiden mutation, prothrombin gene mutation, and protein C, protein S, or antithrombin deficiency) was present in approximately one third of the BCS population and in one fifth of the PVT population. The fact that the significance of these prothrombotic abnormalities was more pronounced in BCS than in PVT can be explained by the heterogeneous etiology of PVT in which many focal factors, such as abdominal surgery, pancreatitis, and preexistent cirrhosis, appear to be of importance. The diagnosis of inherited deficiencies in protein C, protein S, and antithrombin in patients with BCS and PVT is difficult and should be interpreted as estimates primarily because acquired deficiencies can develop in the event of liver failure, acute thrombosis, and anticoagulant therapy. To minimize the number of incorrectly diagnosed inherited deficiencies we decided to (1) evaluate the levels of protein C, protein S, and antithrombin in relation to the levels of factor II and factor X, which are also liver- and vitamin K-dependent factors, and (2) subject all patients with an imbalance of these factors to review by a blinded expert panel. Furthermore, as in many previous studies of BCS and PVT patients, one might question whether selection is introduced by the inclusion of only patients who were alive. Patients with fulminant disease who died early in the course of their illness could bias the results. Nevertheless, a bias would only be present if one assumes that the investigated thrombogenic risk factors are directly related to mortality in BCS and PVT. This is unlikely, but has never been well investigated. For the present study, separate analysis of thrombophilia screening, as performed by local hematologists, indicated that 76% of the 25 registered patients with fatal BCS did not reveal a major difference in the prevalence of the investigated thrombogenic states. Most of the PVT patients who died were incompletely tested for thrombophilia because they either had abdominal malignancies or end-stage liver failure. A remarkable finding of the present study is the coexistence of several thrombophilic states in about one fourth of patients with BCS and more than one third of those with PVT (Table 5). Several patients even had 4 thrombotic risk factors of either acquired or inherited origin. It is plausible that prothrombotic mutations in one or more genes create an inherited predisposition for BCS and PVT. Subsequent clinical thrombosis might then manifest in the presence of thrombotic stimuli such as use of oral contraceptives, pregnancy, myeloproliferative disease, and abdominal surgery.19 Hence, for appropriate risk assessment even in the presence of an overt thrombotic risk factor, physicians should request complete thrombophilia screening for patients with life-threatening thrombotic manifestations such as BCS and PVT. With the continuing search for genetic molecular defects, the number of thrombogenic disorders will probably grow and we therefore might enter an era in which true idiopathic thrombotic disease will become uncommon.
We are indebted to Mrs T. Visser for laboratory assistance and to Prof Dr S. W. Schalm (Department of Hepatogastroenterology, Erasmus University Hospital Dijkzigt-Rotterdam) for his helpful advice. In addition to the authors, the following investigators cooperated in the study: M. P. R. Cooreman (University Hospital St. Radboud-Nijmegen); C. B. H. W. Lamers, P. J. Kingma (Leiden University Medical Center); P. L. M. Jansen (University Hospital Groningen); H. R. van Buuren, H. W. Tilanus (University Hospital Dijkzigt-Rotterdam).
Submitted February 16, 2000; accepted May 31, 2000.
Supported by a grant from the Netherlands Digestive Diseases Foundation.
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.
Reprints: Bart van Hoek, Department of Gastroenterology and Hepatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
1. Ludwig J, Hashimoto E, McGill DB, van Heerden JA. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd-Chiari syndrome. Mayo Clin Proc. 1990;65:51-55[Medline] [Order article via Infotrieve]. 2. Dilawari JB, Bambery P, Chawla Y, et al. Hepatic outflow obstruction (Budd-Chiari syndrome): experience with 177 patients and a review of the literature. Medicine (Baltimore) 1994;73:21-36[Medline] [Order article via Infotrieve]. 3. Cohen J, Edelman RP, Chopra S. Portal vein thrombosis: a review. Am J Med. 1992;92:173-182[Medline] [Order article via Infotrieve]. 4. Valla D, Casadevall N, Lacombe C, et al. Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med. 1985;103:329-334. 5. Bertina RM, Koeleman BPC, 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]. 6. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993;342:1503-1506[Medline] [Order article via Infotrieve].
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A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis.
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© 2000 by The American Society of Hematology.
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Top
Abstract
Introduction
20°C until analysis. Material was collected and transported to Leiden by the study coordinators. All laboratory assessments were performed at the Haemostasis and Thrombosis Research Centre of the Academic Hospital Leiden. High molecular weight DNA was isolated from the white blood
cell fraction by standard methods. The presence of mutations in the
factor V gene (1691, G
A) and the prothrombin gene
(20 210, G