Research areas

It is a privilege to conduct research with excellent colleagues and to produce qualitative knowledge in different areas of hemostasis. In the following paragraphs, we will briefly summarize the current laboratory projects and collaborations. 

At sites of vascular injury, platelets become exposed to collagen and thrombin, the strongest physiologic platelet agonists. We have described and characterized a fraction of platelets that, upon combined activation by collagen and thrombin, become highly efficient in sustaining thrombin generation (Blood 2000;95:1694). These procoagulant collagen-and-thrombin (COAT) activated platelets express negatively charged aminophospholipids, loose their aggregating properties, and retain a coat of procoagulant and prohemostatic α-granules proteins on their surface, in a serotonin- and transglutaminase-dependent manner (Nature 2002;415:175). This novel concept of procoagulant platelets representing a critical aspect of platelet response is nowadays accepted (Arterioscler Thromb Vasc Biol. 2013;33:1747; J Thromb Haemost. 2013;11:2). Recent work of our group has shown that:

1. The decreased ability to generate procoagulant COAT platelets is a significant cause of bleeding, which is missed by standard investigations (Cytometry B Clin Cytom 2014;86:397).

2. The in vivo administration of DDAVP (desmopressin, Octostim^®) selectively enhances procoagulant COAT platelet generation (Blood 2014;123:1905). This is a novel mechanism explaining the beneficial hemostatic action of DDAVP in platelet disorders.

3. The subpopulation of procoagulant COAT platelets derives from aggregating platelets by a peculiar dichotomous intracellular signaling starting about two minutes after platelet activation by collagen and thrombin (Thromb Haemost 2017;117:1101; Thromb Haemost 2020, doi: 10.1055/s-0040-171670).

Our current interests are:

• To further dissect signaling mechanisms underlying and modulating procoagulant COAT platelet generation such as dichotomous ion fluxes (Cytometry A 2020;97:933) and protein phosphorylation.
• To investigate real-time platelet activation under shear stress in a flow chamber assay coupled to fluorescence microscopy for live-cell imaging.
• To study the role and clinical impact of procoagulant COAT platelets in patients with bleeding diathesis (Int J Mol Sci. 2020; 21: 9515) or hematological diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), myeloproliferative neoplasms (MPN), and heparin-induced thrombocytopenia (HIT).
• To study the role of procoagulant COAT platelets in transfusion medicine (Transfusion 2018;58:2395). This work is performed in collaboration with the “Laboratoire de Recherche sur les Produits Sanguins” of the “Transfusion Interrégionale Croix Rouge Suisse SA” in Epalinges.

This is an ambitious collaborative project conducted with the R&D group of PD Dr ès sci. Michel Prudent at “Transfusion Interrégionale Croix Rouge Suisse SA” in Epalinges. The aim is to develop a GMP method for tagging platelets with biotin in order to study their function in vivo in human subjects (Platelets 1997;8:373).

Our interests are:

• To assess platelet life span in various pathologic conditions.
• To investigate in vivo aging dependent alterations of platelet structure and function.
• To evaluate in vivo recirculation and function of platelets from concentrates produced with different techniques and stored at different temperatures.

Thrombin generation assays are “global coagulation assays” that have the capacity to give an overall evaluation of the individual coagulation potential. Our lab is equipped with the gold standard calibrated automated thrombogram (CAT) (Stago) and the novel Thrombodynamics Analyser System (Hemacore) and ST Genesia Thrombin Generation System (Stago). Recent work of our group has shown that:

1. Global coagulation assays are able to identify thrombophilic conditions, which are undetected by routine assays (Thromb Res. 2020;187:91; Res Pract Thromb Haemost. 2020;4:429).

2. Global assays, in particular those evaluating tissue factor independent coagulation, are able to identify the clinical phenotype of FXI deficient patients, in whom aPTT-based factor XI activity does not predict the risk of bleeding (Thromb Haemost 2020; doi: 10.1055/s-0040-1715899; Hämostaseologie 2020;40:491).

Our current interests are:

• To evaluate the diagnostic utility of novel global coagulations assays in rare bleeding disorders (such as hemophilia A and B) and novel factor replacement modalities (in particular extended half-life recombinant factors and factor activity replacing bispecific antibodies).
• To assess the in vivo anticoagulant effect of direct oral anticoagulants (Int J Lab Hematol 2018;40:e11). This project is a collaboration with Dr. med. Dino Kröll and Dr. med. Guido Stirnimann of the Department of Visceral Surgery and Medicine of the Inselspital Bern.
• To investigate and develop prediction models for thromboembolic complications in patients with haemato-oncological diseases, such as acute leukemia and lymphoma. This work is performed in collaboration with Dr. med. Mattia Rizzi (paediatric hematology) and Dr. med. Mariangela Costanza and PD Dr. med. Sabine Blum (adult hematology).

Building up on the expertise gained with the research work on global coagulation assays, we have started a very fruitful collaboration with Dr. med. Montserrat Fraga and Prof. Dr. med. Darius Moradpour of the Division of Gastroenterology and Hepatology of the CHUV, in order to investigate the clinical utility of thrombin generation and fibrin formation assays in patients with liver cirrhosis (Hepatology 2020;71:2135). Recent work of our group has shown that altered biomarkers of liver dysfunction, such as PT/INR, aPTT, factor V, albumin and bilirubin correlate with a prothrombotic and not with a prohemorrhagic profile in patients with cirrhosis (JHEP Rep 2020;2:100120).

Our current interest are:

• To assess incidence and underlying mechanisms of thromboembolic and hemorrhagic complications in the cohort of patients with liver cirrhosis cared for by the Division of Gastroenterology and Hepatology of the CHUV.
• To develop and subsequently prospectively validate a clinico-biological scoring system for predicting the occurrence of thromboembolic and bleeding complications in patients with liver cirrhosis.

To investigate the utility of global coagulation assays for monitoring the anticoagulation intensity in liver cirrhosis.

HIT represents a fascinating hemostatic paradox (thrombocytopenic anticoagulated patients develop a life-threatening prothrombotic state) and a challenging clinical problem. Over the years our group has investigated mechanistic, diagnostic, and therapeutic aspects of HIT (Thromb Haemost 2004;91:276; J Thromb Haemost 2009;7:1649; Blood 2009;113:2402). In particular, we have developed and prospectively validated a Bayesian diagnostic approach in order to reach a rapid exclusion or confirmation of suspected HIT, which has changed our clinical practice (Haematologica 2012;97:89; Blood 2020;135:1171).

Our current interests are:

• The dissection of platelet intracellular signaling events induced by anti-PF4/heparin-antibodies, specifically their ability to generate procoagulant COAT platelets.
• The ability of anti-platelet drugs to prevent anti-PF4/heparin antibody induced platelet aggregation. This project is a collaboration with Dr. med. Emmanuelle Scala and Dr. med. Carlos Marcucci of the Department of Anesthesiology of the CHUV (Anesth Analg 2020;131:622).