Reappraising the role of von Willebrand factor in therapeutic concentrates for the treatment of haemophilia A

Eva Stokhuijzen, the PhD student from our group working on this project developed the methods to analyze the glycan profile of von Willebrand Factor by proteomics under supervision of Sander Meijer. Her PhD thesis is a combined result of experimental work at Sanquin and clinical studies in the department of pediatric hematology at the AMC, and will expectedly be defended at the end of 2018.  

The experimental studies address the cord blood platelet proteome and the glycan profile of ADAMTS13 that influences von Willebrand cleavage. The clinical studies analyze the role of von Willlebrand Factor in acquiring tolerance in hemophilia patients that have developed antibodies towards FVIII after treatment with FVIII concentrates. Further clinical studies address the diagnostic potential of bleeding questionnaires in children that present to the clinic with hemorrhagic symptoms.

Matisse: MAnaging Trombocyte transfusion In a Special Subgroup: nEonates

Each year about 5000 newborn babies are admitted to a Neonatal Intensive Care Unit (NICU) in the Netherlands and 1500- 2000 of them are very premature, born before the 32nd week of pregnancy. These very premature newborns frequently develop thrombocytopenia, with platelet counts below 50 x 10⁹/l. As low platelet counts impair blood coagulation this may increase the risk of haemorrhage. It is common practice to keep platelet counts above certain thresholds. The national Dutch (CBO consensus) guideline  states that platelets should be kept above 20 x 10⁹/l in stable neonates and above 50 x 10⁹/l in clinically ‘ill’ patients. This requires frequent prophylactic transfusions of platelets.

These platelet thresholds are based on expert opinion as there is hardly any evidence available on the effect of different platelet triggers and the association between platelet counts and major bleeding. Rational use of platelet concentrates is mandatory in this intensively transfused patient group, since platelet transfusions carry risks of complications such as bacterial infection. We have performed a randomized clinical trial in collaboration with Prof Simon Stanworth of the NHS Blood Transfusion Service in the UK, studying two different platelet thresholds: 25 and 50 x 10⁹/l. The trial included its 660th and last premature participant in August 2017 and the exciting first analyses of the results are expected in 2018.

STARRING

Red blood cell alloimmunization is a major complication of transfusion therapy in sickle cell disease (SCD), challenging donor matching and risking transfusion reactions. Once alloantibodies are formed, the search for compatible donor units places the transfusion service for logistic challenges and, as compatible units become scarce, transfusion options for these patients become increasingly restricted. Therefore, reducing alloimmunization is of major importance to improve both patient care, efficacy and safety of transfusion therapy and to relieve the blood supply system from a significant logistic burden. This research line contributes to the medical needs of transfusion dependent SCD patients by identifying patients at increased risk of alloimmunization. This will make it possible to direct preventive strategies specifically towards this high risk group. Moreover, we also aim to increase our understanding of the immunological mechanisms underlying alloantibody production, in collaboration with Prof. S. Zeerleder and Prof E. van der Schoot. These insights may identify potential new therapeutic targets for preventive or therapeutic intervention. The results of this program may also impact the wider field of transfusion in other patient groups than SCD, as risk factors and biomarkers recognizing recipients at high risk of alloimmunization identified within this cohort of SCD patients may be relevant for other transfusion recipients as well. In 2017 the first patients were recruited for the study.

Key pulications

• Loomans, J. I.; van Velzen, A. S.; Eckhardt, C. L.; Peters, M.; Mäkipernaa, A.; Holmstrom, M.; Brons, P. P.; Dors, N.; Haya, S.; Voorberg, J.; van der Bom, J. G.; Fijnvandraat, K.  Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.  J Thromb Haemost, Vol. 15, No. 2, 2017, p. 246-254.
• Loomans, J. I.; Eckhardt, C. L.; Reitter-Pfoertner, S. E.; Holmström, M.; van Gorkom, B. Laros; Leebeek, F. W. G.; Santoro, C.; Haya, S.; Meijer, K.; Nijziel, M. R.; van der Bom, J. G.; Fijnvandraat, K.  Mortality caused by intracranial bleeding in non-severe hemophilia A patients. J Thromb Haemost. Vol. 15, No. 6, 2017, p. 1115-1122.
• Sins, J. W. R.; Schimmel, M.; Luken, B. M.; Nur, E.; Zeerleder, S. S.; van Tuijn, C. F. J.; Brandjes, D. P. M.; Kopatz, W. F.; Urbanus, R. T.; Meijers, J. C. M.; Biemond, B. J.; Fijnvandraat, K. Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state.  J Thromb Haemost. Vol. 15, No. 7, 2017, p. 1392-1402.
• Stokhuijzen, Eva; Koornneef, Johanna Maria; Nota, Benjamin; van den Eshof, Bart Laurens; van Alphen, Floris Pieter Joachim; van den Biggelaar, Maartje; van der Zwaan, Carmen; Kuijk, Carlijn; Mertens, Koen; Fijnvandraat, Karin; Meijer, Alexander Benjamin / Differences between Platelets Derived from Neonatal Cord Blood and Adult Peripheral Blood Assessed by Mass Spectrometry. J Proteome Research Vol. 16, No. 10, 2017, p. 3567-3575.
• Sins, J.W.,  Biemond, BJ van den Bersselaar SM, Heijboer H, Rijneveld AW, Cnossen MH,  Kerkhoffs JH, van Meurs AH, von Ronnen FB,  Zalpuri, S de Rijke YB, van der Schoot CE, de Haas M, van der Bom JG, Fijnvandraat K. Early occurrence of red blood cell alloimmunization in patients with sickle cell disease. Am J Hematol 2016 Aug;91(8):763-9.