Third party funded individual grant
Acronym: TR-Platelet Hemostasis
Start date : 01.05.2022
End date : 30.04.2023
Immune checkpoint inhibitors (ICIs) have revolutionized classical approaches to the treatment of various cancer entities, but are also associated with a number of side effects. One of these may be life-threatening clotting disorders with risk of thrombotic or hemorrhagic complications, the mechanisms of which are still poorly understood. In the present study, we analyze the direct effects of pembrolizumab, nivolumab and ipilimumab on platelet aggregation as well as plasma coagulation followed by fibrinolysis in an ex vivo model.
Thrombocytes represent the smallest cellular
components of peripheral blood and play a key role in the regulation of
physiological and pathophysiological processes within blood. Acting as
essential regulators of hemostasis and thrombosis, platelets are responsible
for delicate balance of coagulation and fibrinolysis pathways through the
generation of thrombin, fibrin formation and the entire evolution of blood clot
formation; from generation to termination. In addition, recent studies led to a
paradigm shift in the view of platelets as mere mediators of hemostasis but to
also encompass regulatory functions within innate immunity, including pathogen
defense mechanisms and immunological leukocyte:platelet cross talk.
Critical aspects of platelet biology, however, are still poorly understood and
require further studies in order to gain insight into the delicate mechanism of
platelet-mediated coagulation and thrombosis within the steady state as well as
in the context of treatment-associated side effects. The project therefore aims
to investigate if and how ICI-treatment affects fibrin polymerization and
fibrinolysis.
The project will therefore evaluate the kinetics of thrombin generation in ICI-treated (pembrolizumab, nivolumab and ipilimumab) fresh platelet apheresis samples, turbidity analysis and aggregometry in order to identify potential variances in clotting behavior of treated platelets. Secondly, the structure of fibrin clots formed by exogenic thrombin generated by ICI-pretreated platelets will be visualized using confocal microscopy. This will allow an assessment of potential morphological changes of ICI-pretreated samples and in concert with aggregometry data provide an insight into potential impacts on platelet-mediated clot formation, maturation and subsequent degradation. Lastly, the potential impact of ICI on the biased signaling induced by thrombin, APC, and plasmin through PAR receptors on platelets will be characterized by measuring the level of secreted PAI-1.
Potentially identified ICI-specific effects may contribute to our understanding of the mechanisms by which ICI affects platelets and suggest how, in a clinical setting, to reduce coagulation disorders during ICI-treatment in the future.