Science & Research

Patients with cancer are at an increased risk of developing venous thromboembolism, a major contributor to morbidity and mortality. The risk of cancer-associated thrombosis varies significantly among patients depending on treatment-, disease-, and patient-specific factors, and its prevention and management pose challenges for physicians. Furthermore, the haemostatic system plays a crucial role in cancer development and progression by promoting metastasis, invasion, and angiogenesis.

The Vienna Cancer and Thrombosis Study (CATS) was established in 2003 with the aim of predicting and preventing venous thromboembolism in patients with cancer. To date, more than 2,200 patients have been included in this prospective, observational cohort study. CATS has had a significant impact in the field by identifying major risk factors and predictive biomarkers for venous thromboembolism in cancer patients. Furthermore, recent research has revealed an increased risk of arterial thrombotic events in cancer patients, and an emerging focus of the study is now 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 heterogeneous group of 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, such as 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. To date, the pathogenesis of thrombotic manifestations in LA-positive patients remains incompletely understood and the clinical impact of aPLA positivity is still 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. Through several publications in high-ranking journals, we have reported data on risk factors for thrombosis and pregnancy complications, as well as 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 corresponding genes, which are located on the X chromosome. The severity of the disease is determined by residual factor levels with <1% of normal being classified as severe, 1-5% as moderate, and >5-40% as mild haemophilia. Patients with severe haemophilia often suffer from spontaneous bleeding episodes, primarily into joints and muscles, whereas bleeding in mild haemophilia is typically prolonged following trauma or surgery.

To better understand the nature of the disorder and investigate the efficacy of treatment, the Austrian Haemophilia Registry was established in 2006 as a collaboration between Austrian haemophilia treatment centres and the Austrian Haemophilia Society (ÖHG). With ongoing data collection and evaluation, approximately 80% of the expected haemophilia patients in Austria are currently enrolled.

The established standard of care in haemophilia is the replacement of the deficient coagulation factor aiming to maintain trough levels at or above 1%. Half-lives of both factor VIII and IX are relatively short, requiring frequent infusions, though they can vary considerably between individuals. Our research group investigated factors influencing half-life in a cohort of 42 patients with severe or moderate haemophilia A with further studies ongoing in collaboration with other institutions.

With increasing interest in the mild and moderate forms of haemophilia, and with most research to date focusing on the severe type, we 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.
Over the past century, haemophilia treatment has advanced significantly, leading to an improved quality of life and a life expectancy approaching that of the general population. While novel therapies continue to emerge, haemophilia, as a monogenic bleeding disorder, also represents a prime candidate 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, low von Willebrand factor levels, platelet function defects, and various mild clotting factor deficiencies are characterized by similar clinical symptoms such as easy bruising, epistaxis, and menorrhagia: However, they can also lead to severe postoperative and postpartum bleeding.

Diagnosing patients is often challenging, even for hemostasis experts. Moreover, a significant number of patients remain undiagnosed despite extensive diagnostic testing

The Vienna bleeding biobank (VIBB) is an observational, single-center cohort study that includes patients with a mild-to-moderate bleeding tendency without a prior diagnosis of an established bleeding disorder. This collection of comprehensive clinical data and samples of our patients enables us to investigate pathophysiological mechanisms underlying bleeding tendencies, particularly in patients with unexplained bleeding. In collaboration with the University of Cambridge as part of the ThromboGenomics project—a high-throughput sequencing platform for genes encoding hemostatically relevant factors—genetic data from patients have been made available for analysis. Our aim is to better understand the underlying pathological mechanisms to improve patient counseling and treatment for those 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 a central component of the hemostatic system but have also been reported to play a role in immune processes, among others.

In addition to investigating 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. Primary ITP is especially rare, and data about this patient group is scarce. To expand clinical knowledge, we have established a registry and biobank for patients with primary ITP to identify predictive factors for disease progression, treatment response, and the bleeding phenotype. This unique sample collection enables us to investigate underlying pathophysiological processes and 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.