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Saskia Middeldorp

Publications and source records attributed to Saskia Middeldorp.

16 recordsLinked to original sources
PubMed2006

A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation.

The prothrombin 20210A mutation has been associated with an increased risk for venous thromboembolism (VTE) and arterial cardiovascular disease. The risks for asymptomatic carriers of this mutation have thus far been studied only in case-control and retrospective cohort studies. Here we present the results of the first prospective observational study in asymptomatic first-degree family members of patients with either VTE or premature atherosclerosis and the prothrombin 20210A mutation. We included 464 individuals (236 carriers) with a total follow-up duration of 1816 years (943 years for the carriers). The annual incidence of a first VTE was 0.37% (95% CI, 0.08-1.08) for carriers and 0.12% (95% CI, 0.00-0.69) for noncarriers (HR, 3.1; 95% CI, 0.3-29.6). The annual incidence of a first arterial cardiovascular event was 0.56% (95% CI, 0.18-1.31) for carriers and 0.73% (95% CI, 0.27-1.58) for noncarriers (adjusted HR, 0.7; 95% CI, 0.2-2.5). We conclude that the absolute incidence of a first VTE or arterial cardiovascular event is low; therefore, the clinical implications of carriership of the prothrombin 20210A mutation are limited, and routinely testing all first-degree relatives of probands with this mutation does not appear to be justified.

Adolescent↗
PubMed2006

Inherited thrombophilias.

Many inherited thrombophilias have been detected and the pathophysiologic insight has increased tremendously during the last decades. Despite, however, the overwhelming observational evidence on the association between inherited thrombophilia and several women's health issues, including VTE, thus far the implications for clinical practice are uncertain. Although there is firm epidemiologic evidence that is helpful in counseling women who have inherited thrombophilia to prevent a first or recurrent VTE, the uncertainty is particularly present for women who have other pregnancy complications, such as recurrent pregnancy loss and pre-eclampsia. For this group, well-designed placebo-controlled trials to assess the harm-benefit ratio are urgently needed.

Abortion, Habitual↗
PubMed2005

Oral contraceptives and the risk of venous thromboembolism.

BACKGROUND: Oral contraceptives were introduced in the late 1950s, and their use has altered society and has led to radical changes. Combined oral contraceptives are considered the most acceptable, effective, and most easily reversible method of contraception. In the early 1960s, an association between venous thrombosis and pulmonary emboli and oral contraceptive use was identified. In response, the amount of estrogen used in these contraceptives was decreased. Later, the concept that reducing the dose of estrogen would eliminate the risk of venous thrombosis was strongly challenged. OBJECTIVE: The available epidemiologic data and the mechanisms that underly the risk of venous thromboembolism as a side effect of oral contraceptive use will be described. Clinical implications based on both the relative and absolute risks in the general population and in women with a known tendency for venous thromboembolism will be discussed. METHODS: A literature search of MEDLINE was conducted for the years 1995 through 2005, using search word combinations including oral contraceptive, estrogen, progestin, venous thrombosis, venous thromboembolism, pulmonary emboli, and pulmonary embolism. Relevant articles relating to the topic of oral contraceptives and the risk of venous thromboembolism were studied and summarized for inclusion in this review article. RESULTS: Certain third-generation progestins in low-estrogen preparations were found to increase the risk of venous thrombosis and pulmonary embolism. Also, the realization that genetic factors play a role in the degree of thrombosis risk led to insights into the hemostatic changes that occur during oral contraceptive use and that predispose women to thrombosis. Known risk factors for venous thromboembolism-inherited thrombophilia, a personal history of venous thromboembolism, and obesity-pose varying degrees of concern for both women and their physicians regarding the safety of oral contraceptives. CONCLUSION: In order to prevent venous thromboembolism, prudence is required when prescribing oral contraceptives to women who have an increased risk of that condition. Furthermore, having a risk factor may not be an absolute contraindication to the use of oral contraceptives, but it offers the opportunity for women to make informed decisions about their use. In the future, researchers should focus on developing effective oral contraceptives that are even safer than those that are available today.

Cardiovascular Diseases↗
PubMed2005

Protein S type III deficiency is no risk factor for venous and arterial thromboembolism in 168 thrombophilic families: a retrospective study.

Free protein S rather than total protein S levels are currently measured to detect inherited protein S deficiency. Because type III (free protein S) deficiency is still not established as risk factor for thrombosis, we assessed the absolute risk of venous and arterial thromboembolism in a family cohort study. Annual incidences in first-degree relatives with and without protein S deficiency type III were compared. Probands had experienced thrombosis and had either the prothrombin G20210A mutation, increased factor VIII:C levels or hyperhomocysteinemia. Relatives were tested for these thrombophilic disorders and factor V Leiden. Levels of antithrombin, protein C, total and free protein S, and factor XI:C were additionally measured. Of 500 relatives enrolled, 105 were excluded from analysis because they could not be classified, due to acquired conditions. Protein S deficiency type III was demonstrated in 60/395 remaining relatives (15%). Other thrombophilic defects were equally distributed among deficient and non-deficient relatives. Annual incidences of venous thromboembolism were 0.28 per 100 person-years [95% confidence interval (CI), 0.09-0.66] in deficient relatives versus 0.20 per 100 person-years (95% CI, 0.12-0.30) in non-deficient relatives [hazard ratio, 1.4 (95% CI, 0.4-4.0)]. For arterial thromboembolism these values were 0.16 per 100 person-years (95% CI, 0.03-0.46) versus 0.10 per 100 person-years (95% CI, 0.05-0.19) [hazard ratio, 1.5 (95% CI, 0.3-6.0)]. These results suggest that protein S deficiency type III is not associated with an increased risk of either venous or arterial thromboembolism.

Adolescent↗
PubMed2005

Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review.

BACKGROUND AND OBJECTIVES: The aim of this systematic review was to summarize the evidence from randomized controlled trials (RCT) concerning the efficacy and safety of medical or surgical treatments of superficial vein thrombosis (SVT) for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE). DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE and the Cochrane (CENTRAL) database to identify all randomized trials that evaluated the effect of surgical or medical treatment in the prevention of venous thromboembolism (VTE) in patients with SVT of the legs. RESULTS: Five studies were included. Pooling of the data was not possible due to the heterogeneity among the studies. Moreover, three studies had major methodological drawbacks limiting the clinical applicability of the results. One of the remaining (pilot) studies showed a non-significant trend in favor of high- compared to low-dose unfractionated heparin for the prevention of VTE. The last remaining study showed a non-significant trend in favor of short-term treatment with low-molecular-weight heparin (LMWH) or a non-steroidal anti-inflammatory drug (NSAID) as compared to placebo shortly after treatment with respect to VTE, but the apparent benefit disappeared after three months of follow-up. Active treatment of SVT reduced the incidences of SVT extension or recurrence. INTERPRETATION AND CONCLUSIONS: Treatment with a therapeutic or prophylactic dose of LMWH or a NSAID reduces the incidence of SVT extension or recurrence, but not VTE. More RCT are needed before any evidence-based recommendations on the treatment of SVT for the prevention of VTE can be given. With the present lack of solid evidence we would suggest treating patients with at least intermediate doses of LMWH.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study.

BACKGROUND: The prothrombin 20210A mutation has been associated with an increased risk of venous thromboembolism (VTE). Its relationship with arterial disease and pregnancy-related complications is, however, still uncertain. The aim of this study was to estimate the incidences of first venous and arterial thrombotic events and pregnancy-related complications in relatives of patients with the mutation. METHODS: After clinical classification, the presence of the mutation was determined in first-degree relatives of consecutive patients with the mutation and a history of VTE or premature atherosclerosis. Relatives with and without the mutation were compared. RESULTS: Of all relatives, 204 (50%) were heterozygous, 5 were homozygous, and 198 had a normal genotype. The annual incidence of a first episode of VTE was 0.35% and 0.18% in carriers and noncarriers, respectively (odds ratio [OR], 1.9; 95% confidence interval [CI], 0.9-4.1); the annual incidence of a first arterial thrombosis was 0.22% and 0.15% in carriers and noncarriers, respectively (OR, 2.3; 95% CI, 0.8-6.3). The annual incidence of a first myocardial infarction was 0.14% (95% CI, 0.05%-0.23%) and 0.05% (0.01%-0.14%) in carriers and noncarriers, respectively (OR, 4.7; 95% CI, 1.0-22.5; P =.06). In particular, homozygous carriers were at increased risk of VTE (OR, 6.0; 95% CI, 1.3-27.2), whereas a history of VTE in the proband influenced the risk of VTE in the relatives. Women with the mutation did not experience significantly more pregnancy-related complications than their relatives with a normal genotype. CONCLUSIONS: The prothrombin mutation is a mild risk factor for VTE within families of carriers but does not seem to play an important role in arterial thrombotic disease, with the exception of myocardial infarction, or in pregnancy-related complications.

Adolescent↗
PubMed2004

Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice.

To explore social aspects of asymptomatic carriership of factor V Leiden mutation (FVL) and how carriers have experienced procedure of screening for FVL, we have performed a qualitative study using semi-structured interviews. Seventeen carriers of FVL without history of venous thromboembolism (VTE) were interviewed. Carriership of FVL has the potential to influence daily life by inducing concerns, stigmatisation and problems with insurances. Furthermore, proper procedure of screening is important because carriers have many questions concerning progeny, risk factors for VTE and preventive measures. Both health worker and the individual to be screened for FVL need to be fully aware of the possible consequences of screening and the fact that proper screening comprises more than only the collection of a blood sample or explaining the amount of risk for VTE induced by a genetic defect. Any guideline to be developed for the screening for FVL should take this into account too.

Adult↗
PubMed2004

Treatment of venous thromboembolism with vitamin K antagonists: patients' health state valuations and treatment preferences.

Determining the optimal duration of vitamin K antagonist (VKA) therapy for patients with venous thromboembolism (VTE) requires a weighting of the benefits and risks of treatment. The objectives of our study were to investigate patient variability in health state valuations associated with VKA therapy and treatment preferences, and to investigate the extent to which valuations and treatment preferences are associated with prior experience with these health states and other patient characteristics. Valuations of outcomes after VTE scaled from 0 (tantamount to death) to 1 (tantamount to perfect health) were elicited from 53 patients who had experienced VTE, 23 patients who had experienced major bleeding during treatment, and 48 patients with the post-thrombotic syndrome. In addition, patients' treatment preferences were evaluated using treatment trade-off questions. Median health state valuations ranged from 0.33 for 'non-fatal haemorrhagic stroke' to 0.96 for 'no VKA treatment'. Variability between patients was substantial. Patients' treatment preferences also varied: 25% of patients chose cessation of treatment, regardless of the probability of recurrent VTE presented, whereas 23% of patients were never willing to choose cessation of treatment. Differences in valuations and treatment preferences were not associated with type of event experienced. Due to the substantial and unpredictable variability in valuations and treatment preferences, recommendations regarding treatment duration should be tailored to patients' specific values and concerns.

Adult↗
PubMed2004

Unselected women with elevated levels of factor VIII:C or homocysteine are not at increased risk for obstetric complications.

Acquired and hereditary thrombophilias are associated with obstetric complications such as (pre-)eclampsia, HELLP syndrome and fetal loss. Our objective was to assess the risk of obstetric complications in women with elevated levels of FVIII:C or hyperhomocysteinemia, as compared with their relatives who had normal FVIII:C or homocysteine levels. From a large family study of patients with venous thromboembolism or premature atherosclerosis and elevated levels of FVIII:C or hyperhomocysteinemia (propositi), the obstetric histories of female first degree relatives, who had been pregnant at least once, were studied. Levels of FVIII:C and homocysteine (both fasting and post-methionine loading) were determined. The number of obstetric complications was calculated and compared in women with normal and elevated levels of FVIII:C, and normal and elevated levels of homocysteine. Women with elevated levels of FVIII:C had a 15.4% risk for toxicosis, preeclampsia, or HELLP syndrome and a 23.9% for fetal loss. This was not statistically different from women with normal levels of FVIII:C. Women with hyperhomocysteinemia tended to have a lower risk for toxicosis, pre-eclampsia, or HELLP syndrome (8.0%, RR 0.6, 95% CI 0.2-1.7) and fetal loss (22.0%, RR 0.8, 95% CI 0.5-1.5) as compared to relatives with normal levels, although these differences did not reach statistical significance. If the analysis was limited to comparing extremes, the results did not materially differ. Unselected women with elevated plasma levels of FVIII:C or hyperhomocysteinemia are not at increased risk for obstetric complications as compared to their relatives with normal levels.

Adolescent↗
PubMed2004

Thrombophilia and new anticoagulant drugs.

Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is the result of an imbalance among procoagulant, anticoagulant and profibrinolytic processes. This imbalance reflects a complex interplay between genetic and environmental or acquired risk factors. Genetic thrombophilic defects influence the risk of a first episode of thrombosis. How these defects influence the risk of recurrence in patients whose first episode of venous thromboembolism was unprovoked is less certain. Thus, when anticoagulants are stopped, patients with unprovoked venous thromboembolism have a risk of recurrence of at least 7% to 10% per year, even in the absence of an underlying thrombophilic defect. Consequently, there is a trend toward longer durations of anticoagulation therapy for these patients, which is problematic given the limitation of existing anticoagulants. This chapter provides an overview of the thrombophilic defects and how they influence the risk of venous thromboembolism. The chapter also details advances in anticoagulant therapy, focusing on new inhibitors of factor Xa and thrombin. In Section I, Dr. Saskia Middeldorp describes the various thrombophilic defects and reviews their relative importance in the pathogenesis of a first episode of venous thromboembolism. She then discusses the influence of these defects on the risk of recurrent thrombotic events in patients with unprovoked venous thromboembolism and in those whose thrombosis occurred in association with a known risk factor, such as surgery. In Section II, Dr. William Geerts reviews the pharmacology of new parenteral and oral factor Xa inhibitors and describes the results of the Phase II and III clinical trials with these agents. He then provides perspective on the potential advantages and drawbacks of these drugs for the prevention and treatment of venous thromboembolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mechanism of action and compares and contrasts their pharmacological profiles prior to describing the results of Phase II and III clinical trials. Dr. Heit then provides perspective on the potential advantages and limitations of these drugs relative to existing anticoagulants.

Anticoagulants↗
PubMed2002

The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders.

The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence. Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case--control analysis in 105 matched pairs of carriers either with or without recurrence. The overall annual recurrence rate was 2.3 per 100 patient-years. The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9.1 (1.3-62.8) for the FII mutation; 1.0 (0.2-4.9) for homozygosity for FV Leiden; 1.5 (0.2-9.5) for inherited deficiencies of protein C or S; 1.8 (0.7-4.9) for FVIII coagulant activity (FVIII:C) levels >122%; 5.4 (1.6-18.6) for fasting homocysteine levels >15.2 micromol/l; and 4.4 (1.0-18.7) for loading homocysteine levels >45.8 micromol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0.45 per 100 patient--years after a secondary first event in the absence of concomitant disorders to 4.8 per 100 patient-years when a spontaneous first event was combined with concomitant disorders. Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders, in addition to whether the first thrombotic event occurred spontaneously.

Adolescent↗
PubMed2002

Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism.

BACKGROUND AND OBJECTIVES: The clinical expression of factor V Leiden varies widely within and between families and only a minority of carriers will ever develop venous thromboembolism. Co-segregation of thrombophilic disorders is a possible explanation. Our aim was to assess the contributions of high levels of factor VIII:C, factor XI:C, thrombin activatable fibrinolysis inhibitor (TAFI) and lipoprotein (a) (Lp(a)) to the risk of venous thromboembolism in factor V Leiden carriers. DESIGN AND METHODS: Levels of the four proteins were measured, in addition to tests of deficiencies for antithrombin, protein C and protein S, and the prothrombin G20210A mutation, in 153 factor V Leiden carriers, derived from a family cohort study. The (adjusted) relative risk and absolute risk of venous thromboembolism for high levels of each protein were calculated. RESULTS: Of carriers, 60% had one or more concomitant thrombophilic disorders. Crude odds ratios (95% CI) of venous thromboembolism for high protein levels were: 3.2 (1.1-9.3) (factor VIII:C); 1.7 (0.6-4.9) (factor XI:C); 3.0 (1.1-8.2) (TAFI); and 1.9 (0.7-5.7) (Lp(a)). Adjusted for age, sex, other concomitant thrombophilic disorders and exogenous risk factors, the odds ratio for venous thromboembolism were 2.7 (0.8-8.7) for high factor VIII:C levels and 1.8 (0.6-5.3) for high TAFI levels. Annual incidences in subgroups of carriers were 0.35% (0.09-0.89), 0.44% (0.05-1.57) and 0.94% (0.35-2.05) for concomitance of high levels of factor VIII:C, TAFI and both, respectively, as compared to 0.09% (0.00-0.48) in single factor V Leiden carriers and 1.11% (0.30-2.82) for other concomitant disorders. INTERPRETATION AND CONCLUSIONS: High levels of factor VIII:C and TAFI, in contrast with factor XI:C and Lp(a), are mild risk factors for venous thromboembolism, and substantially contribute to the risk of venous thromboembolism in factor V Leiden carriers. Our data support the hypothesis that the clinical expression of factor V Leiden depends on co-segregation of thrombophilic disorders.

Adult↗
PubMedDate not supplied

Acquired and inherited thrombophilic factors and the risk for residual venous thrombosis.

Acquired and inherited thrombophilic factors increase the risk for (recurrent) venous thrombotic disease. However, little is known about the pathophysiological mechanisms causing these recurrences, or the persistence of thrombosis despite adequate treatment. Because residual thrombosis has been associated with a worse prognostic outcome, we performed an explorative study in order to investigate the prevalence of residual thrombotic lesions after anticoagulant treatment in patients with deep venous thrombosis. Thrombotic parameters as assessed by ultrasonography after a 12-week course of anticoagulants were used. Both thrombophilia in general and acquired thrombophilia in particular were found to be associated with the extent of residual thrombosis. Of the individual thrombophilic factors, protein C deficiency, prothrombin 20210A mutation, active malignant disease and lupus anticoagulant were associated with an increased risk of residual thrombotic mass. Patients with inherited thrombophilia did not differ from patients without any thrombophilic abnormality with regard to residual thrombotic mass [relative risk (RR) 1.3, 95% confidence interval (CI) 0.9-1.8], while acquired thrombophilic disorders increased the risk for residual thrombotic mass as compared to patients without any defect (RR 1.7, 95% CI 1.2-2.2). Although these results should be confirmed in a larger study, they might help us form hypotheses concerning why patients with thrombophilia are more prone to recurrent venous thromboembolic disease.

Anticoagulants↗