Science & Research

Patients with cancer are at an increased risk to develop venous thromboembolism, which is a major contributor to morbidity and mortality. Risk of cancer-associated thrombosis largely differs between patients according to treatment-, disease and patient-specific factors and its prevention and treatment is challenging for treating physicians.  Further, the haemostatic system has been implicated in playing an important role in cancer development and progression by promoting metastasis, invasion and angiogenesis.

The Vienna Cancer and Thrombosis Study (CATS) has been established in 2003, with the aim to help predict and prevent venous thromboembolism in patients with cancer. Until today, more than 2200 patients have been included in this prospective, observational cohort study. CATS has had a tremendous impact in the field by identifying major risk factors and predictive biomarkers for venous thromboembolism in patients with cancer. Further, recent work has helped identify an increased risk of arterial thrombotic events in patients with cancer and an emerging aim of the study now is to investigate the role of the haemostatic system in cancer progression.

Risk calculator catscore: a clinical prediction model for cancer-associated venous thromboembolism.
» Risk calculator catscore

Selected publications:

1. Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter EM, Di Nisio M, Cesarman-Maus G, Kraaijpoel N, Zielinski CC, Büller HR, Ay C. A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. The Lancet Haematology 2018: 5(7): e289-e298.
    
2. Grilz E, Königsbrügge O, Posch F, Schmidinger M, Pirker R, Lang IM, Pabinger I, Ay C. Frequency, risk factors, and impact on mortality of arterial thromboembolism in patients with cancer. Haematologica 2018: 103(9): 1549-1556.
    
3. Ay C, Dunkler D, Simanek R, Thaler J, Koder S, Marosi C, Zielinski C, Pabinger I. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011: 29(15): 2099-2103.
    
4. Ay C, Vormittag R, Dunkler D, Simanek R, Chiriac AL, Drach J, Quehenberger P, Wagner O, Zielinski C, Pabinger I. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009: 27(25): 4124-4129.
    
5. Moik F, Posch F, Grilz E, Scheithauer W, Pabinger I, Prager G, Ay C. Haemostatic biomarkers for prognosis and prediction of therapy response in patients with metastatic colorectal cancer. Thrombosis research 2020: 187: 9-17.

Antiphospholipid antibodies (aPLAs) are a group of heterogeneous circulating autoantibodies that are directed against anionic phospholipids or affiliated plasma proteins and comprise the lupus anticoagulant (LA), anticardiolipin antibodies (aCLs), and antibodies against ß2-glycoprotein I (anti-ß2GPI). These antibodies are frequently associated with clinical manifestations, like arterial and/or venous thromboses and/or pregnancy complications, resulting in the rare diagnosis of the antiphospholipid syndrome (APS). Still, aPLAs are also found in healthy individuals or are associated with infections without clinical manifestations of APS. So far, the pathogenesis of thrombotic manifestations in LA-positive patients is not completely understood and the clinical impact of aPLA positivity is as yet unclear.

Within the Vienna Lupus anticoagulant and thrombosis study, a prospective, single-center cohort study established in May 2001, we aim to identify risk factors for clinical manifestations in persistently LA-positive patients. In several publications in high-ranked journals we so far have reported data on risk factors for thrombosis and pregnancy complications, and the adverse impact of clinical manifestations on patient survival.

Publications:

1. Gebhart J, Posch F, Koder S, Perkmann T, Quehenberger P, Zoghlami C, Ay C, Pabinger I. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood 2015: 125(22): 3477-3483.
    
2. Posch F, Gebhart J, Rand JH, Koder S, Quehenberger P, Pengo V, Ay C, Pabinger I. Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant. BMC Med 2017: 15(1): 54.
    
3. Gebhart J, Posch F, Koder S, Quehenberger P, Perkmann T, Kuessel L, Ay C, Pabinger I. High risk of adverse pregnancy outcomes in women with a persistent lupus anticoagulant. Blood advances 2019: 3(5): 769-776.
    
4. Hell L, Lurger K, Mauracher L-M, Grilz E, Reumiller CM, Schmidt GJ, Ercan H, Koder S, Assinger A, Basilio J, Gebhart J, Ay C, Pabinger I, Zellner M. Altered platelet proteome in lupus anticoagulant (LA)-positive patients—protein disulfide isomerase and NETosis as new players in LA-related thrombosis. Experimental & Molecular Medicine 2020: 52(1): 66-78.

Haemophilia is a rare disease caused by defective factor VIII or IX activity due to mutations in the encoding genes, located on the X-chromosome. The severity of the disease is defined by residual factor levels with <1% of normal being classified as severe, 1-5% as moderate, and >5 to 40% as mild haemophilia. Patients with severe haemophilia often suffer from spontaneous bleeding episodes, most notably into joints and muscles, while bleeding in mild haemophilia is typically prolonged following trauma or surgery.

In order to better understand the nature of the disorder and investigate the efficacy of treatment, the Austrian Haemophilia Registry was launched in 2006 as a cooperation of Austrian haemophilia treatment centres and the Austrian Haemophilia Society (ÖHG). With ongoing data collection and evaluation, about 80% of the expected number of patients with haemophilia in Austria are currently enrolled.

The established standard of care in haemophilia is the replacement of the deficient coagulation factor aiming to keep trough levels above 1% or higher. Half-lives of both factor VIII and IX are relatively short, necessitating rather frequent infusion, but can vary considerably between individuals. Our research group investigated influencing parameters on factor half-life in a group of 42 severe and moderate haemophilia A patients with further investigations still ongoing in cooperation with other institutions.

With increasing interest in the mild and moderate forms of haemophilia and most research so far focused on the severe type, we also aimed to study the characteristics of the bleeding phenotype and its relationship with laboratory parameters in a cohort of patients with moderate and mild haemophilia.
During the last century, treatment of haemophilia has evolved immensely, resulting in improved quality of life and a life expectancy approximating figures seen in the general population. While novel therapies are continuously developed, haemophilia, being a monogenic bleeding disorder, also presents itself as a prime target for gene therapy raising hopes for a definitive cure in the not-too-distant future.

Selected publications:

1. Reitter S, Sturn R, Horvath B, Freitag R, Male C, Muntean W, Streif W, Pabinger I, Mannhalter C. Spectrum of causative mutations in patients with haemophilia A in Austria. Thrombosis and haemostasis 2010: 104(1): 78-85.
    
2. Reitter S, Streif W, Schabetsberger T, Wozak F, Hartl H, Male C, Muntean W, Pabinger I. Austrian Hemophilia Registry: design, development and set of variables. https://link.springer.com/article/10.1007%2Fs00508-009-1156-0Wiener klinische Wochenschrift 2009: 121(5-6): 196-201.
    
3. Kepa S, Horvath B, Reitter-Pfoertner S, Schemper M, Quehenberger P, Grundbichler M, Heistinger M, Neumeister P, Mannhalter C, Pabinger I. Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A. Haemophilia 2015: 21(3): 343-350.
    
4. Hofbauer CJ, Kepa S, Schemper M, Quehenberger P, Reitter-Pfoertner S, Mannhalter C, Reipert BM, Pabinger I. FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors. Blood 2016: 128(2): 293-296.
    
5. Rejtő J, Königsbrügge O, Grilz E, Hofer S, Mauracher L-M, Gabler C, Schuster G, Feistritzer C, Sunder-Plaßmann R, Quehenberger P, Gebhart J, Ay C, Pabinger I. Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non-severe haemophilia A. Journal of thrombosis and haemostasis : JTH 2020: 18(5): 1081-1086.

Mild bleeding disorders including von Willebrand disease type I or low von Willebrand factor, platelet function defects and several mild clotting factor deficiencies are characterized by similar clinical symptoms such as easy bruising, epistaxis or menorrhagia, but can also lead to massive post-operative and post-partum bleedings.   

The diagnosis of patients is usually challenging, even for hemostasis experts. In addition, a large number of patients remains without diagnosis, despite thorough diagnostic testing.

The Vienna bleeding biobank (VIBB) is a an observational, single-center cohort study including patients with mild-to-moderate bleeding tendency without a previous diagnosis of an established bleeding disorder. This collection of comprehensive clinical data and samples of our patients enables us to investigate pathophysiological mechanisms, underlying the bleeding tendency especially in patients with bleeding of unknown cause. A cooperation with the University of Cambridge within the ThromboGenomics project, a high-throughput sequencing platform of genes of hemostatically relevant factors, made genetic data from patients available for analysis. Our aim is to better understand underlying pathological mechanism in order for better counseling and treatment of patients with a mild-to-moderate bleeding tendency.

Selected publications:

1. Gebhart J, Hofer S, Panzer S, Quehenberger P, Sunder-Plassmann R, Hoermann G, Eigenbauer E, Haslacher H, Kepa S, Kyrle PA, Eichinger S, Knöbl P, Eischer L, Mannhalter C, Ay C, Pabinger I. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). Haemophilia 2018: 24(3): 405-413.
    
2. Gebhart J, Kepa S, Hofer S, Koder S, Kaider A, Wolberg AS, Haslacher H, Quehenberger P, Eigenbauer E, Panzer S, Mannhalter C, Pabinger I. Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause. Ann Hematol 2017: 96(3): 489-495.
    
3. Hofer S, Ay C, Rejtö J, Wolberg AS, Haslacher H, Koder S, Pabinger I, Gebhart J. Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause. Journal of Thrombosis and Haemostasis 2019: 17(9): 1478-1488.
    
4. Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, Symington E, Thomas W, Thys C, Tolios A, Penkett CJ, BioResource N, Ouwehand WH, Abbs S, Laffan MA, Turro E, Simeoni I, Mumford AD, Henskens YMC, Pabinger I, Gomez K, Freson K. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood 2019: 134(23): 2082-2091.

Platelets are not only one central component of the hemostatic system, but also have been reported to be involved in immune processes, amongst others.

Besides the investigation of platelet function defects and hereditary platelet function disorders, we are especially interested in primary immune thrombocytopenia (ITP), a rare acquired autoimmune disorder. In ITP, autoantibodies lead to an imbalance between platelet production and destruction, which results in low platelet counts and can lead to excessive bruising and bleeding. Especially primary ITP is rare and data about this patient group is scarce. To gain clinical knowledge we have established a register and biobank for patients with primary ITP in order to identify predictive factors for the disease progression, treatment response, and the bleeding phenotype. The unique sample collection allows us to work on the investigation of underlying pathophysiological processes and to link them to clinical data and patient outcomes.

Selected publications:

1. Haselboeck J (Gebhart J), Pabinger I, Ay C, Koder S, Panzer S. Platelet activation and function during eltrombopag treatment in immune thrombocytopenia. Ann Hematol 2012: 91(1): 109-113.
    
2. Haselboeck J (Gebhart J), Kaider A, Pabinger I, Panzer S. Function of eltrombopag-induced platelets compared to platelets from control patients with immune thrombocytopenia. Thrombosis and haemostasis 2013: 109(4): 676-683.