Dr R.A. Middelburg (Rutger)

Assistant professor


  • Bleeding
  • Platelet transfusions
  • Methodology


Rutger Middelburg obtained a PhD in clinical epidemiology in January 2011. He now works at Sanquin Research (Center for Clinical Transfusion Research), as an Assistant professor at the Leiden University Medical Center (Department of Clinical Epidemiology ), and as a methodological member of the METCZWH (Medical ethical committee South West Holland ). His research focusses on methodology of etiologic clinical transfusion research. In particular personalisation of transfusion medicine, the effect of blood transfusions on bleeding complications in hemato-oncology patients, and the effect of donor pregnancies on mortality of transfusion recipients.

Main Research Themes

1.         Donor pregnancies and recipient mortality

In 2011 we were the first to find an indication for an association of transfusions of red blood cells from female donors with increased mortality in male recipients under 50 years of age. Recently, in an independent dataset, this association of red blood cell transfusions from female donors with decreased survival of male recipients was confirmed. We furthermore showed this association to be limited to female donors with a history of pregnancy and estimated that this association could be responsible for 1 potentially preventable death per day in the Netherlands.

Understanding of the underlying biological mechanisms will enable optimized changes to blood transfusion practice. Where a general sex-matched transfusion policy might be one possible strategy, identification of the responsible mediators of the observed effects will allow more efficient selection of blood products. Additionally, important mediators in donor blood might be intervened upon ex vivo. This will ensure precision transfusion medicine with at the same time a blood inventory that is as flexible and broad as possible.

2.         Bleeding in hemato-oncology patients

Hemato-oncology patients often become thrombocytopenic and dependent on platelet transfusions for the prevention of spontaneous bleeding. Under the current platelet transfusion policy half the transfused patients still experiences bleeding of which 10-20% is considered serious to life threatening (i.e. WHO grades 3 and 4; resulting in mortality or lasting morbidity, or requiring medical intervention). Conversely, some studies also suggest that for certain patient groups it might be safe to switch to a therapeutic, instead of a prophylactic, transfusion strategy. In conclusion, current policy is both ineffective and inefficient.

The key to resolving these issues lies in identifying the few patients who need (highly intensive) platelet transfusions and distinguishing them from the many who need less or no platelet transfusions. To be able to specifically identify these patients, who are at increased risk of bleeding, risk factors for bleeding need to be identified and the interaction of platelet counts with other risk factors for bleeding needs to be quantified. Quantification of interaction of risk factors with platelet counts better reflects the multi-causal nature of bleeding complications and therefore offers more options for personalised preventive intervention.

3.         Methodology of personalisation of clinical transfusion medicine

All diseases and secondary disease outcomes, which most transfusions aim to prevent, are caused by the joint action of multiple distinct causes. In one patient one set of causes might be operating while in another patient it could be a (partially or completely) different set of causes. A transfusion aimed at eliminating a cause which is not present in an individual patient will obviously not be effective in that patient. The transfusion will be equally ineffective in a patient with this cause present but unnecessary for the outcome (e.g. due to the simultaneous presence of many other causes). The transfusion will be wholly unnecessary, and therefore also technically ineffective, in a patient who a priori lacks a sufficient set of causes for the outcome to occur. It will only be effective in a patient in whom this particular cause constitutes “the last straw”.

This is the phenomenon of effect modification and it is a direct result of the multi-causal nature of all diseases. The effect of a treatment on one particular patient is always modified by (i.e. interacts with) other contributory causes present in that patient.

We incorporate this fundamental concept of multi-causality into all clinical transfusion research we perform at the Center for Clinical Transfusion Research. Further, we also develop new methodological concepts and perform simulation studies and proof of principle studies incorporating new insights about multi-causality to enhance the personalisation of clinical transfusion medicine.


Key Publications

1.         Donor pregnancies and recipient mortality

  • Caram-Deelder C, Kreuger AL, Evers D, de Vooght KMK, van de Kerkhof D, Visser O, Péquériaux NCV, Hudig F, Zwaginga JJ, van der Bom JG, Rutger A. Middelburg. Association of Blood Transfusion From Female Donors With and Without a History of Pregnancy With Mortality Among Male and Female Transfusion Recipients. JAMA. 2017 Oct 17;318(15):1471-1478.
  • Rutger A. Middelburg, Ernest Briët, Johanna G. van der Bom. Mortality after transfusions, relation to donor sex. Vox Sang. 2011 Oct;101(3):221-9.


2.         Bleeding in hemato-oncology patients

  • Caram-Deelder C, van der Bom JG, Putter H, Leyte A, Kerkhof DV, Evers D, Beckers EA, Weerkamp F, Hudig F, Zwaginga JJ, Rondeel JMM, de Vooght KMK, Péquériaux NCV, Visser O, Wallis JP, Rutger A. Middelburg. Age of platelet concentrates and time to the next transfusion. Transfusion. 2018 Jan;58(1):121-131.
  • Kreuger AL, Caram-Deelder C, Jacobse J, Kerkhoffs JL, van der Bom JG, Rutger A. Middelburg. Effect of storage time of platelet products on clinical outcomes after transfusion: a systematic review and meta-analyses. Vox Sang. 2017 May;112(4):291-300.
  • Caram-Deelder C, Kreuger AL, Jacobse J, van der Bom JG, Rutger A. Middelburg. Effect of platelet storage time on platelet measurements: a systematic review and meta-analyses. Vox Sang. 2016 Nov;111(4):374-382.
  • Rutger A. Middelburg, Paula F. Ypma, Pieter F. van der Meer, Rinie J. van Wordragen-Vlaswinkel, Okke Eissen, Jean-Louis H. Kerkhoffs. Measuring clinical bleeding using a standardized daily report form and a computer algorithm for adjudication of WHO bleeding grades. Vox Sang. 2013 Aug;105(2):144-9.
  • Rutger A. Middelburg, Mark Roest, Jannemieke Ham, Miriam Coccoris, Jaap Jan Zwaginga, Pieter F. van der Meer. Flow cytometric assessment of agonist-induced P-selectin expression as a measure of platelet quality in stored platelet concentrates. Transfusion. 2013 Aug;53(8):1780-7.


3.         Methodology of personalisation of clinical transfusion medicine

  • Rutger A. Middelburg, van der Bom JG. Transfusion-related acute lung injury not a two-hit, but a multicausal model. Transfusion. 2015 May;55(5):953-60.
  • Rutger A. Middelburg, Johanna C. Wiersum-Osselton, Leo M.G. van de Watering, Johanna G. van der Bom. Observational etiologic research: Part 4 - Matching in case control studies; almost always a bad idea. Transfusion. 2014 Feb;54(2):267-70.
  • Rutger A. Middelburg, Johanna C. Wiersum-Osselton, Leo M.G. van de Watering, Johanna G. van der Bom. Observational etiologic research: Part 3 - Case control studies; it’s all about the source population. Transfusion . 2014 Jan;54(1):12-6.
  • Rutger A. Middelburg, Johanna C. Wiersum-Osselton, Leo M.G. van de Watering, Johanna G. van der Bom. Observational etiologic research: Part 2 - Effect measures in etiologic research. Transfusion. 2013 Dec;53(12):3048-51.
  • Rutger A. Middelburg, Johanna C. Wiersum-Osselton, Leo M.G. van de Watering, Johanna G. van der Bom. Observational etiologic research: Part 1 - The etiologic research question; it requires DATA. Transfusion. 2013 Nov;53(11):2606-8.
  • Rutger A. Middelburg, Leo M.G. van de Watering, Johanna G. van der Bom. Blood transfusions: good or bad? Confounding by indication, an underestimated problem in clinical transfusion research. Transfusion 2010 Jun;50(6):1181-3.

Publicaties op PubMed van R.A. Middelburg


E-mail: R.A.Middelburg@lumc.nl