Platform 5

Advanced Diagnostics

Platform project

A. Adenäuer, Prof Barco, Prof Lämmle and Prof Rossmann have initiated an international registry with a biobank for congenital defects of the kallikrein kininogen system (see fig) funded by the ISTH and DGKL in 2024, for which they are seeking further cooperation partners. It serves the systematic recording and diagnosis of cases with hereditary prekallikrein (PK) deficiency or deficiency of high molecular weight kininogen (HK). Due to the lack of obvious symptoms and the previously erroneously assumed rarity of these protein deficiencies, a comprehensive and well-structured international cohort study has been lacking so far. The cohort study initiated here aims to provide important insights into the physiological and pathophysiological significance of PK and HK, which will help to improve the care of patients with these deficits and advance the development of PK and HK-based therapy options. As part of the study, we offer free functional and molecular genetic PK and HK analysis to participating centres.

Further projects using the platform's expertise

• Prof. Danckwardt: Genomics in Thrombosis and Hemostasis (GinTH) ISTH SSC
• Prof Pierre Morange, Prof. David Alexandre Trégouët, Prof. Danckwardt: non-coding determinants in T&H
• A. Adenäuer, Prof. Schmaier (Case Western Reserve University and UH Cleveland Medical Center), Prof. Lämmle, Prof. Rossmann: Molecular characterisation of historical samples with defects in the kallikrein kininogen system
• Dr. Häuser, Dr. Falter, Dr. Mittler, Dr. Radsak, Dr. Sasca, Prof. Rossmann: Development of ddPCR-based methods for the sensitive quantification of chimerism after bone marrow transplantation and solid organ transplantation from gDNA or cfDNA
• Dr. Häuser, A. Adenäuer, Prof. Rossmann: Characterisation of splice variants to complement modern molecular genetic diagnostics
• Dr. Häuser, A. Adenäuer, PD Dr. O. Beck, Prof. Rossmann, Prof. Lämmle: Importance of molecular genetic tests in the diagnosis of spherocytosis
• S. Popp, Dr. Nitsche, Prof. Rossmann: Integration of functional and molecular genetic diagnostics in primary ciliary dyskinesia (PCD)
• Prof. Vanhoorelbeke (Universität Leuven, Belgien), Prof. Lämmle, Dr. Falter, Prof. Rossmann: Significance of the ADAMTS13 conformation for the pathogenesis of TTP
• Prof. Jurk, A. Adenäuer, Prof. Rossmann: Genetic causes of platelet dysfunction and thrombocythaemia
• Prof. Jurk, Prof. Faber, Prof. Russo, Prof. Rossmann: Patient registry for congenital platelet disorders
• Prof. Lämmle, Dr. v. Auer, Dr. Falter, Prof. Rossmann: Genetic causes and modifiers of TTP (thrombotic thrombocytopenic purpura)
• Prof. Danckwardt, A. Adenäuer, Dr. Häuser, Prof. Rossmann: VWD (von Willebrand disease): Genotype/phenotype ratio
• Dr. Sibbing, Prof. Gori, Prof. Danckwardt, Dr. Wenzel: TROPICAL-ACS (Testing RespOnsiveness To Platelet Inhibition On Chronic AntiplateLet treatment For Acute Coronary Syndromes); contribution of polymorphisms to vascular and platelet function
• Prof. Gori, Prof. Danckwardt: Prevention of in-stent thrombosis
• Dr. Schmidgen, Prof. Gori, Prof. Ruf, Prof. Steinbrink, Prof. Danckwardt: Significance of signalling pathways in cutaneous inflammation
• Dr. Kleis-Fischer, Prof. Grabbe, Prof. Danckwardt: Influence of genetics on wound healing
• This platform is part of the 'Shared Expertise' of the DZHK ('Plattformlobor CTH' - shared expertise SE076)

Particular attention is paid to the molecular analysis of genes that are important for thrombosis and haemostasis. The core of the platform is the sequencing of selected genes using next-generation sequencing (NGS). This gene panel comprises 92 genes with known diagnostic relevance for thrombosis and haemostasis as well as around 300 other genes that are associated with these processes and are of scientific interest to the members of the CTH. The NGS panel is flexible and modular, so that it can be expanded with additional modules if required. This enables customisation to the specific requirements of future cooperation partners, which can be supplemented by additional methods such as whole exome sequencing, Sanger sequencing, pyrosequencing, MLPA (detection of large deletions and insertions), fragment analysis using capillary electrophoresis (for repeat or homopolymer regions), ddPCR (for sensitive allele quantification or quantitative expression analysis) and splice investigations (with and without NMD inhibition; readout: ddPCR, nanopore sequencing).

A further focus of this platform is the analysis of alterations in non-coding sequence regions that predispose to the occurrence of thrombosis or bleeding. This is of particular interest because a significant proportion of thrombosis and hemostasis disorders do not show significant changes in coding regions. In particular, we investigate the dysregulation of hemostatic components by non-coding RNAs (such as miRNAs, lncRNAs) or RNA-binding proteins. For analysis, we develop and use high-throughput interactome analyzes (miTRAP, (crosslinking) immunoprecipitation (CLIP)) and high-resolution transcriptome analyzes (TRENDseq). With these activities, the platform is internationally anchored in the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis.

To initiate a cooperative project please contact Prof. Heidi Rossmann (Tel. 17-7297), A. Adenäuer (Tel. 17-6904) or Prof. Danckwardt (Tel. 17-6041 or 17-2632)

Scientific Platform Coordiantors

• Kontakt

MD Heidi Rossmann

Platform-Coordinator and senior physician at the Institute of Clinical Chemistry and Laboratory Medicine

06131 17-7297

References

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