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Dive into the research topics where F. W. G. Leebeek is active.

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Featured researches published by F. W. G. Leebeek.


Thrombosis and Haemostasis | 2010

Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma

Johannes J.A. Auwerda; Y. Yuana; S. Osanto; M.P.M. de Maat; Pieter Sonneveld; R. M. Bertina; F. W. G. Leebeek

Multiple myeloma (MM) is associated with an increased risk of venous thromboembolic (VTE) complications. Aim of this study was to measure microparticle-associated tissue factor (MP-TF) activity in patients with newly diagnosed MM before and after chemotherapy and to investigate whether MP-TF activity is associated with VTE. MP-TF activity was assessed in 122 newly diagnosed MM patients who were eligible for combination chemotherapy. MP-TF activity levels (17.6 fM Xa/min [8.6-33.2] (median [IQR]) were higher in untreated MM patients compared to normal healthy volunteers (4.1 fM Xa/min [2.3-6.6], p <0.001). MP-TF activity prior to the start of treatment was not different between patients who developed a VTE during follow-up (n=15) and those who did not (n=107). In 75 patients in whom plasma was obtained before and after chemotherapy, MP-TF activity decreased significantly (from 17.4 [10.2-32.8] to 12.0 [7.0-18.5] fM Xa/min, P=0.006). MP-TF activity remained, however, elevated in patients who developed VTE (15.1 [10.3-25.2]), in contrast to patients not developing VTE (11.4 [7.0-25.2], P<0.001). In conclusion, MP-TF activity is increased in patients with MM. Whether MP-TF activity has a pathogenetic role in VTE in MM patients remains to be established in future studies.


The Journal of Clinical Endocrinology and Metabolism | 2012

The hypercoagulable state in Cushing's disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy.

R. van der Pas; C. de Bruin; F. W. G. Leebeek; M.P.M. de Maat; D. Rijken; Alberto M. Pereira; Johannes A. Romijn; Romana T. Netea-Maier; A.R.M.M. Hermus; Pierre Zelissen; F.H. de Jong; A. J. van der Lely; W. W. de Herder; S. W. J. Lamberts; L. J. Hofland; R. A. Feelders

CONTEXT Cushings disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.


Journal of Thrombosis and Haemostasis | 2011

Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review

M. C. Van Schie; J. E. van Loon; M.P.M. de Maat; F. W. G. Leebeek

Summary.  It is well established that high plasma von Willebrand factor (VWF) levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and ischemic stroke. As plasma VWF levels are, to a large extent, genetically determined, numerous association studies have been performed to assess the effect of genetic variability in the VWF gene (VWF) on VWF antigen and activity levels, and on the risk of arterial thrombosis. Genetic variations in other regulators of VWF, including the ABO blood group, ADAMTS‐13, thrombospondin‐1 and the recently identified SNARE protein genes, have also been investigated. In this article, we review the current literature as exploring the associations between genetic variations and the risk of arterial thrombosis may help elucidate the role of VWF in the pathogenesis of arterial thrombosis. However, as studies frequently differ in design, population and endpoint, and are often underpowered, it remains unclear whether VWF is causally related to the occurrence of arterial thrombosis or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent arterial thrombosis. Nevertheless, current studies provide interesting results that do not exclude the possibility of VWF as causal mediator and justify further research into the relationship between VWF and arterial thrombosis. Large prospective studies are required to further establish the role of VWF in the occurrence of arterial thrombosis.


Journal of Thrombosis and Haemostasis | 2013

Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: Effect on new thrombotic events and gastrointestinal bleeding

Manon Spaander; Jildou Hoekstra; Bettina E. Hansen; H.R. van Buuren; F. W. G. Leebeek; Hla Janssen

It remains unclear when anticoagulant therapy should be given in patients with non‐cirrhotic portal vein thrombosis (PVT). The aim of this study was to assess the effect of anticoagulation on recurrent thrombotic events and gastrointestinal bleeding in non‐cirrhotic PVT patients.


Thrombosis and Haemostasis | 2012

Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease.

E. M. De Wee; Y.V. Sanders; E. P. Mauser-Bunschoten; J. G. van der Bom; M. Degenaar-Dujardin; Jeroen Eikenboom; A. De Goede-Bolder; B. A. P. Laros-van Gorkom; Karina Meijer; Karly Hamulyak; Marten Nijziel; Karin Fijnvandraat; F. W. G. Leebeek

We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.


Journal of Thrombosis and Haemostasis | 2012

von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population

J. E. van Loon; Maryam Kavousi; F. W. G. Leebeek; J. F. Felix; A. Hofman; J. C. M. Witteman; M.P.M. de Maat

Summary.  Background:  High von Willebrand factor (VWF) levels are associated with an increased risk of coronary heart disease (CHD). However, it remains unclear whether VWF is causally related to the occurrence of CHD or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent CHD.


Journal of Thrombosis and Haemostasis | 2005

Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians

T.N. Bongers; M.P.M. de Maat; Diederik W.J. Dippel; A.G. Uitterlinden; F. W. G. Leebeek

A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS-13) is a recently characterized metalloprotease that cleaves Ultra Large Von Willebrand Factor (ULVWF) [1]. A deficiency of ADAMTS-13 results in an accumulation of ULVWF, and leads to microangiopathic thrombosis, which is characteristic of thrombotic thrombocytopenic purpura (TTP) [2]. The microangiopathic arterial thrombotic complications of TTP occur predominantly in the brain. It is hypothesized that lowADAMTS-13 levels may be a risk factor for arterial thrombosis, because less ULVWF cleavage may result in an excess of high VWF multimers, resulting in more adhesion and aggregation of platelets [3]. Recently, the proline (Pro) to serine (Ser) polymorphism in codon 475 of the ADAMTS-13 gene has been identified. This Pro475Ser polymorphism, caused by a base substitution of C1423 to T in exon 12, is reported to impair the activity of ADAMTS-13. In a Japanese study the frequency of the rare 475Ser allele of this single nucleotide polymorphism (SNP) was 5.1% in 364 healthy controls and it has been suggested that the 475Ser allele may increase the risk of arterial thrombosis because of the reduced activity of ADAMTS-13 [3,4]. To study whether this ADAMTS-13 polymorphism contributes to arterial thrombosis in Caucasians, we investigated the distribution of the Pro475Ser polymorphism in a Caucasian population of 125 patients suffering from ischemic stroke and 125 ageand gender-matched healthy controls. The genotype was determined by polymerase chain reaction, digestion with RsaI and separation on a 2% agarose gel. We found that none of the 250 individuals carried the rare 475Ser allele. We also investigated the Pro475Ser polymorphism in other populations, including 110 Chinese (HD02 and HD100 of the Human Variation Panel, Coriell Institute for Medical Research, Camden, NJ, USA) where we found one heterozygous subject, giving a frequency for the 475Ser allele of 0.5% [95% confidence interval (CI) 0–2.9]. This confirms the results of Ruan et al. who reported a frequency of 1.7% (95% CI 0.6–4.2) in healthy Chinese and 1.9% (95%CI 0.2–3.8) in Chinese patients who had had amyocardial infarction [5]. Also in Afro-Americans (HD50), the 475Ser allele was not present. Since no 475Ser carrier for the polymorphism was identified in our study (95%CI 0–1.5%) we conclude that the Pro475Ser polymorphism, which is associated with a reduced ADAMTS13 activity, is not an important contributor to the risk of ischemic stroke in Caucasians. Our data suggest that outside the Japanese population, the 475Ser allele is very rare.


Thrombosis and Haemostasis | 2011

Gynaecological and obstetric bleeding in moderate and severe Von Willebrand Disease

E. M. De Wee; H. M. Knol; E. P. Mauser-Bunschoten; J. G. van der Bom; M. Degenaar-Dujardin; Jeroen Eikenboom; Karin Fijnvandraat; A. De Goede-Bolder; B. A. P. Laros-van Gorkom; Paula F. Ypma; Sonja Zweegman; Karina Meijer; F. W. G. Leebeek

A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged ≥16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of ≥2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD.


Haemophilia | 2015

Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey.

S.C.M. Stoof; H.W. van Steenbergen; A. Zwagemaker; Y.V. Sanders; Suzanne C. Cannegieter; J.J. Duvekot; F. W. G. Leebeek; M. Peters; M. J. H. A. Kruip; Jeroen Eikenboom

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL−1, prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002–2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss ≥500 mL within 24 h postpartum and severe PPH as blood loss ≥1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL−1 cut‐off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2–6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population.


Haemophilia | 2002

Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors

E. P. Mauser-Bunschoten; Mmw Koopman; Arja de Goede-Bolder; F. W. G. Leebeek; J.W.M. van der Meer; G. M. Van Marwijk Kooij; P. W. G. Van Der Linden

Summary.  We have prospectively monitored treatment of haemophilia patients with inhibitors by recombinant factor VIIa (rFVIIa) administered by continuous infusion to obtain more insight in the underlying factors of the clinical efficacy of this administration method. At present, 43 treatment episodes of 14 different Dutch haemophilia inhibitor patients are included in the database. Analysis of the data showed a discrepancy between the efficacy of rFVIIa continuous infusion treatment of acute and surgical bleeds in the oral cavity [one (14%) effective, two (29%) partially effective, four (57%) not effective] and other parts of the body [29 (80%) effective, four (11%) partially effective, two (6%) not effective, one (3%) impossible to classify]. Patients who had acute or surgical oral cavity bleeds, uncontrolled by rFVIIa continuous infusion, reacted favourably to rFVIIa continuous infusion in other locations of the body. Acute bleeding episodes in the oral cavity, which could not be controlled by rFVIIa continuous infusion, stopped when the treatment regimen was switched to rFVIIa bolus injections. Finally, haemostatic control during dental extractions was excellent after the initial rFVIIa bolus injection preceding the continuous infusion, but rebleeds occurred in all patients within 48 h under rFVIIa continuous infusion coverage. These observations suggest that the efficacy of rFVIIa continuous infusion depends, at least in part, on the location of the body in which the bleeding occurs and that rFVIIa bolus injections are more effective than rFVIIa continuous infusion in the oral cavity. We hypothesize that the inability of rFVIIa continuous infusion treatment to sufficiently inhibit fibrinolysis is the underlying cause of the decreased efficacy of rFVIIa continuous infusion treatment in the oral cavity.

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M.P.M. de Maat

Erasmus University Rotterdam

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Karina Meijer

University Medical Center Groningen

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Marjon H. Cnossen

Erasmus University Medical Center

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Jeroen Eikenboom

Leiden University Medical Center

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M. J. H. A. Kruip

Erasmus University Rotterdam

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Y.V. Sanders

Erasmus University Rotterdam

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J. G. van der Bom

Leiden University Medical Center

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