Cellular Haemostasis Group

Principal Investigator: János Kappelmayer, MD, PhD, DSc

Members of the group:
Adrienne Kerényi, MD, PhD; Béla Nagy Jr, MD, PhD; Judit Tóth Budai, MD; Renáta Hudák, MD; Zsolt Fejes, MSc; Gábor Szabó, MD;

Technician: Ildikó Beke Debreceni, BSc

Thrombosis is a multicellular process that implicates the involvement of platelets, leukocytes and endothelial cells. These events are governed by cell-cell interactions as well as released soluble markers. Our group investigates the effect of different agonists in vitro on the level of various cell surface-associated and soluble platelet activation markers like P-selectin and CD40L, platelet-leukocyte interactions, coated-platelet generation and platelet-derived microparticle formation. Special attention is paid to thrombotic (thrombin, collagen) and immunological/inflammatory (LPS, PAF, MASP-1) stimuli. We also investigate the effect of phosphatase inhibitors on these activation events. These studies are carried out in collaboration with the Department of Medical Chemistry at our University with the group of Prof. Ferenc Erdődi.

Platelet activation is also investigated in ex vivo clinical samples from patients with enhanced thrombotic tendency like diabetes, stroke and coronary disease. We also study the association of platelet polymorphisms on these events, and analyze platelet activation markers in relation to disease severity and clinical status. These studies are done in collaboration with the Departments of Internal Medicine and Cardiology. Our group has collaborations with the group of Prof. László Muszbek in Clinical Research Center in Debrecen, where several Glanzmann-patients have been extensively characterized in the past years.

Another aspect of the hemostatic multicellular process is the direct interaction of platelets with leukocytes, primarily the myeloid cells. We investigate the effect of the major ligand of P-selectin on thrombus formation in a mouse model. This protein entitled P-selectin Glycoprotein Ligand-1 (PSGL-1), and is a dimeric mucin that is crucial in the formation of such heterotypic complexes. We possess a mouse strain, where PSGL-1 is knocked out and we study the effect of the lack of PSGL-1 on thrombus formation and cellular release from the bone marrow. These studies are carried out in collaboration with the group of Prof. Rodger McEver at the Oklahoma Medical Research Foundation.

In addition, we maintain regular scientific discussions with Prof. Kenneth Clemetson (University of Berne, Switzerland), and Prof. Satya P. Kunapuli (Temple University, Philadelphia, PA).

The Cellular Hemostasis Group utilizes mostly flow cytometry, Western-blot and ELISA techniques, but we have access to PCR-RFLP and gene sequencing capabilities as well.

 

Representative publications:

  • Fejes Z, Póliska S, Czimmerer Z, Káplár M, Penyige A, Gál Szabó G, Beke Debreceni I, Kunapuli SP, Kappelmayer J, Nagy B Jr. Hyperglycemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost. 2016 Dec 15. [Epub ahead of print]
  • Nagy B Jr, Nagy B, Fila L, Clarke LA, Gönczy F, Bede O, Nagy D, Újhelyi R, Szabó Á, Anghelyi A, Major M, Bene Z, Fejes Z, Antal-Szalmás P, Bhattoa HP, Balla G, Kappelmayer J, Amaral MD, Macek M Jr, Balogh I. Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis. Chest. 2016 Sep;150(3):661-72.
  • Szük T, Fejes Z, Debreceni IB, Kerényi A, Édes I, Kappelmayer J, Nagy B Jr. Integrity® bare-metal coronary stent-induced platelet and endothelial cell activation results in a higher risk of restenosis compared to Xience® everolimus-eluting stents in stable angina patients. Platelets. 2016 Jul;27(5):410-9.
  • Kappelmayer J, Beke Debreceni I, Vida A, Antal-Szalmás P, Clemetson KJ, Nagy B Jr. Distinct effects of Re- and S-forms of LPS on modulating platelet activation. J Thromb Haemost 2013, 11:775-778
  • Nagy V, Kolozsvari B, Balogh Z, Csutak A, Kasza M, Nagy B Jr, Kardos L, Berta A, Pfliegler G. Increased level of platelet P-selectin in nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2013, 251(3):917-922
  • Reményi G, Szász R, Debreceni IB, Szarvas M, Batár P, Nagy B Jr, Kappelmayer J, Udvardy M. Comparison of coated-platelet levels in patients with essential thrombocythemia with and without hydroxyurea treatment. Platelets 2012, Dec 5.
    doi: 10.3109/09537104.2012.731112 (in press)
  • Nagy B Jr, Miszti-Blasius K, Kerényi A, Clemetson KJ, Kappelmayer J. Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation. Curr Med Chem 2012, 19(4):518-531
  • Shemirani AH, Nagy B Jr, Takáts AT, Zsóri KS, András C, Kappelmayer J, Csiki Z. Increased mean platelet volume in primary Raynaud’s phenomenon. Platelets 2012, 23:312-316
  • Olah Z, Kerényi A, Kappelmayer J, Schlammadinger A, Razso K, Boda Z. Rapid-onset heparin-induced thrombocytopenia without previous heparin exposure. Platelets 2012, 23:495-498
  • Csongrádi É, Nagy B Jr, Fulop T, Varga Z, Karányi Z, Magyar MT, Oláh L, Papp M, Facskó A, Kappelmayer J, Paragh G, Káplár M. Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients. Thromb Haemost 2011, 106:683-92
  • Nagy B Jr, Jianguo J, Ashby B, Reilly MP, Kunapuli SP. Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. J Thromb Haemost 2011, 9:810-9
  • Miszti-Blasius K, Beke Debreceni I, Felszeghy S, Dezso B, Kappelmayer J. Lack of P-selectin glycoprotein ligand-1 protects mice from thrombosis after collagen/epinephrine challenge. Thromb Res 2011, 127:228-234
  • Simon Z, Kiss A, Erdödi F, Setiadi H, Beke Debreceni I, Nagy B Jr, Kappelmayer J. Protein phosphatase inhibitor calyculin-A modulates activation markers in TRAP-stimulated human platelets. Platelets 2010, 21:555-562
  • Bagoly Z, Fazakas F, Marosi A, Török O, Bereczky Z, Haramura G, Kappelmayer J, Muszbek L. Variant type Glanzmann thrombasthenia caused by homozygous 724R/X mutation in beta3 integrin. Thromb Res 2010, 125:427-431
  • Nagy B Jr, Szük T, Debreceni IB, Kappelmayer J. Platelet-derived microparticle levels are significantly elevated in patients treated by elective stenting compared to subjects with diagnostic catheterization alone. Platelets 2010, 21:147-151
  • Toth J, Kappelmayer J, Udvardy ML, Szanto T, Szarvas M, Rejto L, Soltesz P, Udvardy M, Harsfalvi J. Increased platelet glycoprotein Ib receptor number, enhanced platelet adhesion and severe cerebral ischaemia in a patient with polycythaemia vera. Platelets 2009, 20:282-287
  • Bynagari YS, Nagy B Jr, Tuluc F, Bhavaraju K, Kim S, Vijayan KV, Kunapuli SP. Mechanism of activation and functional role of protein kinase Ceta in human platelets. J Biol Chem 2009, 284:13413-13421
  • Chari R, Getz T, Nagy B Jr, Bhavaraju K, Mao Y, Bynagari YS, Murugappan S, Nakayama K, Kunapuli SP. Protein kinase C[delta] differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol 2009, 29:699-705
  • Nagy B Jr, Bhavaraju K, Getz T, Bynagari YS, Kim S, Kunapuli SP. Impaired activation of platelets lacking protein kinase C-theta isoform. Blood 2009, 113:2557-2567
  • Nagy B Jr, Simon Z, Bagoly Z, Muszbek L, Kappelmayer J. Binding of plasma factor XIII to thrombin-receptor activated human platelets. Thromb Haemost 2009, 101:83-89
  • Miner J, Xia L, Yago T, Kappelmayer J, Liu X, Klopocki AG, Shao B, McDaniel M, Setiadi H, Schmidtke D, McEver RP. Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow. Blood 2008, 112:2035-2045
  • Nagy B Jr, Csongrádi É, Bhattoa HP, Balogh I, Blaskó G, Paragh G, Kappelmayer J, Káplár M. Investigation of Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in type 2 diabetes mellitus. Thromb Haemost 2007, 98:186-191
  • Szük T, Nagy B Jr, Bereczky Z, Köszegi Z, Édes I, Kappelmayer J. Effects of “ad hoc” clopidogrel loading versus pre-treatment on P-selectin expression after coronary stent implantation. Platelets 2006, 17:344-346
  • Losonczy G, Rosenberg N, Kiss Cs, Kappelmayer J, Vereb G, Kerényi A, Balogh I, Muszbek L. A novel homozygous mutation (1619delC) in GPIIb gene associated with Glanzmann thrombasthenia, the decay of GPIIb-mRNA and the synthesis of a truncated GPIIb unable to form complex with GPIIIa. Thromb Haemost 2005, 93:904-909
  • Kerényi A, Soltész P, Veres K, Szegedi G, Muszbek L.  Monitoring platelet function by PFA-100 closure time measurements during thrombolytic therapy of patients with myocardial infarction. Thromb Res 2005, 116:139-144
  • Kappelmayer J, Nagy B Jr, Miszti-Blasius K, Hevessy Z, Setiadi H. The emerging value of P-selectin as a disease marker. Clin Chem Lab Med 2004, 42:475-486