Academic Center for Hemostasis and Thrombosis

Last updated: 365 days ago.

To provide excellent multidisciplinary care for patients with inherited bleeding disorders, including hemophilia and allied disorders in both adults and children. Comprehensive academic care is provided by dedicated hematologists, pediatric hematologists, specialized nurses and physical therapists, in close collaboration with clinical geneticists, obstetricians and gynecologists, orthopedic surgeons, liver specialists and specialists in rehabilitation medicine, as well as hospital pharmacists. We are a national NFU acknowledged Expert Center for patients with hemophilia and allied bleeding disorders and recently also as European Comprehensive care center.

It is also accredited as a hemophilia treatment center (one of the seven centers in the Netherlands) by Det Norske Veritas (DNV), according to HKZ criteria, and therefore are the only hospital in our region able to provide care for this patient group. In addition, multicenter (inter)national studies have been and are currently initiated from our center that will innovate patient care and insight into hemostatic mechanisms in the near future (To WiN study, OPTI-CLOT studies, DAVID studies, fibrinogen research). To provide academic, state of the art care for patients with venous and arterial thrombotic disorders, while embodying our role as regional Expert Center for anticoagulant treatment, as recently initiated by the Ministry of Health (“ Landelijke Standaard Ketenzorg Antistolling”).

Comprehensive care is provided by hematologists, pediatric hematologists, and a specialized nurse in collaboration with cardiologists, hospitalpharmacists, neurologists, intensive care specialists and pulmonologists. In addition, multicenter studies are initiated to study preventive and treatment strategies in pediatric thrombosis. (NEOCLOT, TropicALL) To continue the multidisciplinary care for patients with hemodynamic disorders of the venous system, including deep vein thrombosis, in collaboration with the vascular surgeons and intervention radiologists coordinated in the weekly vascular meeting.

The department of dermatology has been acknowledged as ‘NFU expert center for phlebology’ including post thrombotic syndrome. In addition, our hemostasis and thrombosis laboratory within the Department of hematology is staffed 24/7 and has as main aim to provides a variety of laboratory tests and molecular analysis necessary for diagnosis and treatment of (academic) patients and serves as a regional laboratory for complex hemostatic assays.

Academic Center of Excellence

Research Activities

Within the field of hemostasis the following translational- and clinical, but also fundamental and epidemiological research projects are currently ongoing: Aim: To optimize diagnosis and treatment for patients with inherited bleeding disorders. (Leebeek, Cnossen, Kruip) We have initiated and are expanding several large (inter-)national studies on von Willebrand disease (VWD) and Hemophilia. The Willebrand in the Netherlands study (WiN study; PI Leebeek) is the largest study on this most common inherited bleeding disorder in the world.

In this study we collaborate with all hemophilia treatment centers in the Netherlands. This study focusses on genetic variability (using NGS and WES) and phenotypic variation of VWD. In addition within the ACE H&T (inter)national multicenter pharmacokinetic studies are initiated by the ErasmusMC to optimize treatment of hemophilia and von Willebrand disease (OPTICLOT studies, To WiN, DAVID; PI Cnossen, Kruip)

We are in the lead in an innovative European Gene Therapy study for severe hemophilia B patients. Three of a total of 10 patients in Europe have been included at the ErasmusMC, with great therapeutic success. Prof Leebeek will also be principal investigator in a next phase III study that is planned to start in 2017 in collaboration with UniQure (the Netherlands/USA). Aim: To investigate the role of hemostatic abnormalities in the pathogenesis of arterial and venous thrombosis in both adults and children with the objective to improve patient care and long term outcome. (Leebeek, de Maat, Rijken, van Ommen, Dippel, Ikram, Roeters van Lennep).

The main focus in this research program within the ACE H&T is the role of von Willebrand factor, ADAMTS13 and the fibrinolytic system in the pathogenesis and outcome of stroke (in collaboration with Dippel, neurology and M.A. Ikram, epidemiology). Within the ACE H&T have collaborated in epidemiological studies (COCOS, ATTAC study, Rotterdam study).

Furthermore the findings of these studies are related to more fundamental studies in the hemostasis research laboratory (Dr Rijken, Dr UittedeWillige) Other ongoing research projects with the H&T ACE:

  • optimization of anticoagulant treatment in collaboration with the Erasmus Anticoagulation Team (antistollingscommissie) and the regional thrombosis service (STAR, Rotterdam) (Kruip, Dubois, van den Bemt, van den Toorn, Klein Nagelvoort).
  • multicenter studies on prevention and treatment strategies in pediatric thrombosis (NEOCLOT, TropicALL: van Ommen) and ECMO associated thrombotic events (van Ommen, Wildschut).
  • Optimization of massive blood transfusion protocols (Leebeek, te Boekhorst, de Rijke)
  • Treatment of acute deep vein thrombosis: investigate the recent developments in the management of post thrombotic syndrome such as venous stenting and/or thrombolysis (in collaboration with de Maeseneer (expertise center on phlebology, Rood).
  • More fundamental research focusses on the influence of fibrin structure on thrombotic risk (de Maat, Leebeek) and wound healing (de Maat, van Neck)

Type of

Collaborations

We have initiated and are expanding several large (inter-)national studies on von Willebrand disease (VWD) and Hemophilia. The Willebrand in the Netherlands study. In this study we collaborate with all hemophilia treatment centers in the Netherlands. In addition within the ACE H&T (inter)national multicenter pharmacokinetic studies are initiated by the ErasmusMC to optimize treatment of hemophilia and von Willebrand disease (OPTICLOT studies, To WiN, DAVID; PI Cnossen, Kruip)We are in the lead in an innovative European Gene Therapy study for severe hemophilia B patients. Three of a total of 10 patients in Europe have been included at the ErasmusMC, with great therapeutic success. Prof Leebeek will also be principal investigator in a next phase III study that is planned to start in 2017 in collaboration with UniQure (the Netherlands/USA).

Educational

Contributions

Contribution of the ACE H&T to: Bachelor (Medicine, clinical technology; university college, zorgacademie);Master Phase; PhD courses; Resident (AIOS) level; post-graduate courses. Objectives:

  • To provide high quality interactive education in hemostasis and thrombosis for medical students (1st, 2nd and 4th year), clinical technology students (1st year), University College students and nurses in the general curriculum and elective courses. We provide a one-month elective course on blood coagulation for second year medical students. Feedback from evaluations by students over the last 10 years are excellent (grade every year >8.0). Many students participate in research programs during their 20-weeks elective research period of the master phase of study.
  • To teach MDs or PhD students the clinical and biochemical aspects of hemostasis and thrombosis by providing post-doctoral education during their residency training, and in various PhD courses, within the COEUR (vascular medicine), and for AIOS in cardiology, anesthesiology, emergency/ internal medicine.
  • To provide post-doctoral education in hemostasis and thrombosis for medical specialists (nascholing hematology; PhD course Dutch Heart Foundation, Dutch Society of Hematology) We currently have no international students. 10 residents/ fellows who specifically take care (and are trainedi) of patients with bleeding disorders and thrombosis (vascular medicine and (pediatric) hematology), 16 PhD students in the ACE H&T, who are supervised by staff from ACE H&T.

Patient

Care Activities

Regarding the patients with Hemophilia and allied bleeding disorders: A total of 900 patients (children and adults) are treated in the ErasmusMC, of whom 334 with Hemophilia A or B, nearly 500 with Von Willebrand disease and 80 with other rare bleeding disorders. This is around 20% of all patients in the Netherlands. In the "Beleidsvisie" of the Ministry of Health for hemophilia care it is stated that this care should take place in certified hemophilia treatment centers (HTC), with expertise on these disorders.

Patients within the ACE H&T require multidisciplinary care, for which a team of expert specialists is collaborating in the multidisciplinary team of the HTC. All patients are treated according to individual treatment plans that are at least yearly updated. Both the children and adult hemophilia treatment centers of the ErasmusMC are NFU accredited centers of excellence.

We have also obtained the DNV GL business assurance process certificate in 2014, 2015 and 2016 as treatment center for haemophilia according to the guidelines of HKZ and the Dutch Hemophilia Treaters Society (NVHB). We have also been certified as European Hemophilia Comprehensive Care Center in 2016 by the EAHAD. We have been designated with a "golden Pin" based on the high quality of our center. We have recently also been registered as European Reference Network center for Rare Hematological disorders: EuroBloodNet.

We have initiated a plan to study value based health care for patients with hemophilia in collaboration with Prof Hazelzet, and will expand this in the Haemophilia in the Netherlands study (HIN-6), carried out in all HTCs in the Netherlands. As mentioned earlier we have several studies ongoing on innovative treatment strategies in hemophilia care, such as gene therapy for Hemophilia B (3 patients in our center have already been treated), participation in studies on long-acting and newly developed recombinant coagulation factor concentrates, which will become standard of care in the near future.

The studies on pharmacokinetic driven treatment of patients with hemophilia and Willebrand disease, that are initiated in our treatment center and performed in collaboration with all HTC in the Netherlands, will have direct impact on care and will lead to a more effective and efficient application of this extremely costly treatment (120 million per year in the Netherlands) . With regard to patients with thrombosis: Children with thrombosis need to be treated in academic centers due to the rare nature and difficulties of treatment.

For adults, mainly patients with thrombosis at unusual sites are diagnosed and treated in an academic center, including splanchnic vein thrombosis, cerebral vein thrombosis and patients with rare inherited thrombophilic conditions, making them more prone for recurrent events. The specialized hemostasis laboratory of our department serves as a regional referral center, and many patients are seen for second opinions regarding thrombotic disorders in the outpatient department of (pediatric) hematology.

We also have an important regional role in treatment of patients with anticoagulants. This is initiated based on the "Landelijke Standaard Ketenzorg Antistolling", to improve care for these patients within the hospital and region. Within the ErasmusMC an "anticoagulation team" with specialists from various disciplines is active in making protocols, implementing current national guidelines. We collaborate closely with the regional Thrombosis service to improve quality of care.

Societal Relevance to Research, Education and Patient Care

With regard to hemophilia and allied bleeding disorders: The results of our studies on pharmacokinetic dosing and the data obtained will be available to other treatment centers worldwide. We are currently exploiting the possibility to valorize this by patents. Regarding education: One of the nurse practitioners has developed an E-learning tool for patients on intravenous home treatment with coagulation factor concentrates. This tool is now widely used in other centers to instruct the patients how to infuse themselves with coagulation factors, and has led to an improved knowledge on the disease and its complications. The innovational contribution of the ACE regarding research is exemplified by three large-nationwide studies that are ongoing (WiN study, OptiClot studies and DAVID studies), that are initiated from our ACE within the ErasmusMC. Many members of the ACE H&T have been or are participating in writing national and international guidelines (e.g. Dutch guideline for Hemophilia care, CBO 2009 Leebeek et al, eds) which is currently updated (Leebeek, Kruip, Cnossen, NVHB 2016). Also the Dutch guidelines for antithrombotic treatment has recently been published with the participation of many members of our ACE (Dubois cardiology, van Ommen pediatric hematology, Leebeek and Kruip, hematology). Leebeek participated in the writing of guidelines for treatment of Vascular Diseases of the liver (including abdominal vein thrombosis) in the BAVENO guidelines, and the European EASL guidelines. The ACE contributed to education of patients by writing patient books and leaflets and developing E-based information material (www.cyberpoli.nl), trombose en kanker (stichting September), leaflets of the Dutch patient society for Hemophilia, Hematologie actueel, For educational purposes we have written chapters for many books regarding hemostasis and thrombosis (werkboek pediatrie , Cnossen van Ommen; Williams Textbook of Hematology, Leebeek; Leerboek hematologie, editor and contributor Leebeek) Leerboek Vasculaire Geneeskunde (leebeek, Kruip), leerboek spoedeisende geneeskunde voor verpleegkundigen (Kruip)

Viability of Research, Education and Patient Care

In the ACE H&T we collaborate on diagnosis and treatment of venous and thrombotic disorders with many clinical disciplines. Patient care and research is carried out by the department of (pediatric) hematology in close collaboration with the departments of neurology (Dippel, Koudstaal; Mr Clean study); cardiology (Dubois, anticoagulant treatment for atrial fibrillation and other cardiac disorders; pulmonology and internal medicine (van den Toorn, Klein Nagelvoort, Rood; pulmonary embolism, YEARS study) ; gender specific thrombotic disorders (vascular medicine, Roeters van Lennep), pharmacy (van den Bemt, optimizing anticoagulant treatment), treatment of post-thrombotic syndrome (Dermatology, de Messenaer).

We collaborate with other disciplines in defining protocols and research projects to improve patient care in clinical situations related to bleeding or thrombotic disorders (pediatric ICU Wildschut, ECMO and, clinical chemistry, de Rijke, massive transfusion protocols)

Most of the graduated PhD students were medical students and all of them have started an internship to become a medical specialist after completing their research project. The other PhD students have found another position as post-doc in Sweden (Talens) or USA (Cheung). In the last five years the ACE H&T the department of (pediatric-) hematology has published over 200 PubMed articles, of which 75% are in the TOP 25% of our research field. The other participants have also published several articles related to this topic, but bibliographic data are limited (see list of joint publications)

Key and relevant publications of the last five years

  • 1.     Rijken DC, Abdul S, Malfliet JJ, Leebeek FW, Uitte de Willige S. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII. J Thromb Haemost. 2016 May 5.
  • 2.     Biedermann JS, van Rein N, van den Besselaar AM, Buhre PN, de Maat MP, van der Meer FJ, Leebeek FW, Kruip MJ. Impact of point-of-care international normalized ratio monitoring on quality of treatment with vitamin K antagonists in non-self-monitoring patients: a cohort study. J Thromb Haemost. 2016 Apr;14(4):695-703
  • 3.     Hazendonk HC, Lock J, Mathôt RA, Meijer K, Peters M, Laros-van Gorkom BA, van der Meer FJ, Driessens MH, Leebeek FW, Fijnvandraat K, Cnossen MH. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications. J Thromb Haemost. 2016 Mar;14(3):468-78.
  • 4.     Abdul S, Leebeek FW, Rijken DC, Uitte de Willige S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood. 2016 Feb 4;127(5):538-45.
  • 5.     Sonneveld MA, de Maat MP, Portegies ML, Kavousi M, Hofman A, Turecek PL, Rottensteiner H, Scheiflinger F, Koudstaal PJ, Ikram MA, Leebeek FW. Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. Blood. 2015 Dec 17;126(25):2739-46.
  • 6.     Plompen EP, Darwish Murad S, Hansen BE, Loth DW, Schouten JN, Taimr P, Hofman A, Uitterlinden AG, Stricker BH, Janssen HL, Leebeek FW. Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study. J Hepatol. 2015 Dec;63(6):1459-65.
  • 7.     Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, Obermann-Slupetzky O, Chapman M, Fritsch S, Pavlova BG, Presch I, Ewenstein B. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015 Oct 22;126(17):2038-46.
  • 8.     de Vries PS, Boender J, Sonneveld MA, Rivadeneira F, Ikram MA, Rottensteiner H, Hofman A, Uitterlinden AG, Leebeek FW, Franco OH, Dehghan A, de Maat MP. Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. Blood. 2015 Jun 18;125(25):3949-55.
  • 9.     Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van der Bom JG, Coppens M, de Meris J, Laros-van Gorkom BA, Mauser-Bunschoten EP, Leebeek FW, Eikenboom J; WiN study group. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood. 2015 May 7;125(19):3006-13.
  • 10.  Cheung EY, Weijers EM, Tuk B, Scheffer R, Leebeek FW, van Neck JW, Koolwijk P, de Maat MP. Specific effects of fibrinogen and the γA and γ'-chain fibrinogen variants on angiogenesis and wound healing. Tissue Eng Part A. 2015 Jan;21(1-2):106-14.

PhD theses of the last five years

  • 1.     Dr. E.L.E. de Bruijne: Thrombin activatable fibrinolysis inhibitor and thrombosis (22 June 2011)
  • 2.     Dr. E. de Wee: von Willebrand disease in the Netherlands (26 October 2011)
  • 3.     Dr. J.H. Smalberg: Budd-Chiari Syndrome and portal vein thrombosis: Etiology and treatment (12 January 2012)
  • 4.     Dr. M. van Schie: The influence of genetic variation on von Willebrand factor levels and the risk of stroke (9 May 2012)
  • 5.     Dr. E. Cheung: The role of fibrinogen variants in cardiovascular diseases and wound healing (26 June 2012)
  • 6.     Dr. J. van Loon: Genetic determinants of von Willebrand factor and the risk of cardiovascular disease (9 November 2012)
  • 7.     Dr. S. Talens: Novel fibrin clot components Identification, characterization and function (15 March, 2013)
  • 8.     Dr. Y. Sanders: Willebrand disease: Genetic en phenotypic variability ( 11-11-2015)
  • 9.     Dr. S.C. Stoof: Optimizing treatment of Haemophilia (17-02-2016)
  • 10.  Dr. E.P.C. Plompen: Thrombophilia and genetics in vascular liver disease (18-02-2016)

Non-scientific publications related to the ACE

Principal coordinator(s)