Translational integratomics of the hemostatic triad
Hemostasis is maintained by the delicate triadic interplay between blood vessel wall, circulating platelets and coagulation factors. Defects in any of these components can result in extended and spontaneous bleeding and other poorly understood clinical manifestations. The mission of the Medical Priority Bleeding & Hemostasis is to improve preventive measures, diagnosis, and treatment of patients with congenital and/or acquired hemostatic disorders. This is done by: i) generating fundamental and translational knowledge to directly support clinical and blood bank decision making aimed at prevention of undesirable side-effects of currently available transfusion-based therapies ii) increasing understanding of the pathogenic mechanisms underlying hemostatic disorders using system-wide -omics technologies and iii) invigorating the development of innovative treatment-options for patients suffering from hemostatic abnormalities. The Medical Priority Bleeding & Hemostasis is composed of a multidisciplinary team of experts that allows for conducting fundamental, translational as well as epidemiological studies to address unmet medical needs in bleeding and hemostasis.
Coordinators: Rick Kapur MD PhD, Prof Jan Voorberg PhD
Improving clinical efficacy of blood products.
Randomized controlled trials supported by Sanquin (PATCH, PlaNeT2 MATISSE) have convincingly demonstrated that administration of platelet concentrates may present unexpected side-effects, especially in neonates. These clinical studies have resulted in worldwide adaptations of clinical practice. However, the mechanisms that underlie the observed side-effects of platelet transfusion remain unknown. Current efforts are aimed to develop tailored personalized platelet transfusion treatment for patients at risk for bleeding by A) optimizing platelet transfusion strategies by means of comparative studies in patients with various medical conditions, including hemato-oncological treatment, trauma, surgery and premature birth B) investigating the molecular and cellular mechanisms of adverse effects of platelet transfusions and C) performing mechanistic and clinical studies to optimize safety, functionality, storage conditions, and clinical efficacy of platelet concentrates.
System-wide and individualized dissection of aberrant hemostatic networks.
Innovative technologies are important to advance the field of hemostasis. We focus on the development of novel mass spectrometry-based tools to (A) improve diagnosis of bleeding disorders, by dissecting key players in both primary - (von Willebrand factor, blood platelets, vessel wall) as well as secondary hemostasis (coagulation proteins) (B) gain fundamental insight in the structure-function relationship of hemostatic proteins and in hemostatic cell signaling networks in platelets and vascular endothelial cells (C) improve prediction of individual bleeding risks by defining plasma protein-based signatures associated with endothelial cell damage and platelet dysfunction to tailor timely platelet transfusion and (D) assess functional relationships between hemostasis and the immune system focused on immunogenicity of therapeutic coagulation proteins by immunopeptidomics, and autoantibody-mediated destruction of platelets. We expect that integrated multi-omic approaches will drastically change the diagnostic landscape of rare (bleeding) disorders and will provide a strong fundament for personalized therapeutic treatment strategies.
Innovative treatment of hemostatic abnormalities
To further reduce current side-effects of platelet transfusions and tackle the challenge of generating donor-independent ‘personalized’ or ‘universal’ platelet concentrates for clinical use, we develop robust protocols for the generation of non-immunogenic megakaryocytes from induced pluripotent stem cells (iPSC). To develop new treatments for bleeding in patients using anticoagulation we focus on A) the generation of an improved prothrombin complex concentrate B) the development of cyclodextrin-based small molecules that promote hemostasis and C) the development of innovative, affordable gene therapy and gene correction approaches for patients with bleeding disorders.