Search

Your search keyword '"H. ten Cate"' showing total 862 results
Start Over Author "H. ten Cate"
862 results on '"H. ten Cate"'

1. Diabetes- versus smoking-related thrombo-inflammation in peripheral artery disease

Author

T. Alnima, R. I. Meijer, H. M.H. Spronk, M. Warlé, and H. ten Cate

Subjects
Peripheral artery disease, Diabetes mellitus, Smoking, Thrombosis, Inflammation, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Peripheral artery disease (PAD) is a major health problem with increased cardiovascular mortality, morbidity and disabling critical limb threatening ischemia (CLTI) and amputation. Diabetes mellitus (DM) and cigarette smoke are the main risk factors for the development of PAD. Although diabetes related PAD shows an accelerated course with worse outcome regarding complications, mortality and amputations compared with non-diabetic patients, current medical treatment does not make this distinction and includes standard antiplatelet and lipid lowering drugs for all patients with PAD. In this review we discuss the pathophysiologic mechanisms of PAD, with focus on differences in thrombo-inflammatory processes between diabetes-related and smoking-related PAD, and hypothesize on possible mechanisms for the progressive course of PAD in DM. Furthermore, we comment on current medical treatment and speculate on alternative medical drug options for patients with PAD and DM.

Published
2023
Full Text
View/download PDF

2. Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study

Author

B. M. M. Kremers, J. H. C. Daemen, H. ten Cate, H. M. H. Spronk, B. M. E. Mees, and A. J. ten Cate-Hoek

Subjects
Atherosclerosis, Atherothrombosis, Peripheral artery disease, Cardiovascular risk, Antiplatelet therapy, High on-treatment platelet reactivity, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Background Patients with peripheral artery disease (PAD) are treated with preventive strategies to improve the cardiovascular risk. The incidence of cardiovascular events and mortality however remains high in PAD populations. We therefore aimed to better characterize PAD patients suffering from cardiovascular events and mortality in order to tailor preventive treatment. Methods Between 2018 and 2020, 246 PAD outpatients (17 newly diagnosed, 229 with known PAD) were prospectively enrolled in this observational cohort study. Patient data and blood samples were collected after inclusion, and the primary composite endpoint (myocardial infarction, elective coronary revascularization, ischemic stroke, acute limb ischemia, mortality) was evaluated after one year. Secondary outcomes included platelet reactivity, measured using the VerifyNow assay, and medication adherence, assessed using the Morisky Medication Adherence Scale-8 (MMAS-8). Logistic regression models were used to identify associations between characteristics and the occurrence of events. Results The cohort comprised 207 patients with claudication and 39 with chronic limb threatening ischemia. Twenty-six (10.6%) patients suffered from an event during follow-up. Prior myocardial infarction (OR 3.3 [1.4–7.7]), prior ischemic stroke (OR 4.5 [1.8–10.9]), higher levels of creatinine (OR 5.2 [2.2–12.6]), lower levels of high-density lipoprotein (OR 4.2 [1.5–10.6]) and lower haemoglobin levels (OR 3.1 [1.3–7.1]) were associated with events. Patients with events had more often high on-treatment platelet reactivity (HTPR) on aspirin (OR 5.9 [1.4–25.1]) or clopidogrel (OR 4.3 [1–19.3]). High adherence to medication was associated with the occurrence of events (OR 4.1 [1–18]). Conclusions Patients suffering from cardiovascular events and mortality were characterized by prior cardiovascular events as compared to patients who did not experience any events. Antiplatelet therapy was not optimally protective despite high medication adherence, and HTPR was independently associated with the occurrence of events. More research is needed on alternative treatment strategies such as dual antiplatelet therapy or combinations with anticoagulant drugs. Trial registration The Medical Ethics Committee (METC) of the MUMC+ approved the study (NL63235.068.17) and the study was registered in the Netherlands Trial Register ( NTR7250 ).

Published
2023
Full Text
View/download PDF

3. Discovery of four plasmatic biomarkers potentially predicting cardiovascular outcome in peripheral artery disease

Author

B. M. M. Kremers, J. N. Posma, S. Heitmeier, J. Glunz, H. ten Cate, A. Pallares Robles, J. H. C. Daemen, A. J. ten Cate-Hoek, B. M. E. Mees, and H. M. H. Spronk

Subjects
Medicine, Science
Abstract

Abstract Peripheral artery disease (PAD) patients have an increased cardiovascular risk despite pharmacological treatment strategies. Biomarker research improving risk stratification only focused on known atherothrombotic pathways, but unexplored pathways might play more important roles. To explore the association between a broad cardiovascular biomarker set and cardiovascular risk in PAD. 120 PAD outpatients were enrolled in this observational cohort study. Patients were followed for one year in which the composite endpoint (myocardial infarction, coronary revascularization, stroke, acute limb ischemia and mortality) was assessed. Patient data and blood samples were collected upon inclusion, and citrated platelet-poor plasma was used to analyze 184 biomarkers in Olink Cardiovascular panel II and III using a proximity extension assay. Fifteen patients reached the composite endpoint. These patients had more prior strokes and higher serum creatinine levels. Multivariate analysis revealed increased plasma levels of protease-activated receptor 1 (PAR1), galectin-9 (Gal-9), tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) and interleukin 6 (IL-6) to be most predictive for cardiovascular events and mortality. Positive regulation of acute inflammatory responses and leukocyte chemotaxis were identified as involved biological processes. This study identified IL-6, PAR1, Gal-9, TNFRSF11A as potent predictors for cardiovascular events and mortality in PAD, and potential drug development targets.

Published
2022
Full Text
View/download PDF

4. Calibrated automated thrombogram II: removing barriers for thrombin generation measurements

Author

P. L. A. Giesen, A. J. W. Gulpen, R. van Oerle, H. ten Cate, M. Nagy, and H. M. H. Spronk

Subjects
Thrombin generation, Calibrated automated thrombogram (CAT), ST®-Genesia, Direct oral anticoagulants (DOACS), Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Background Thrombin generation (TG) assessed by Calibrated Automated Thrombogram (CAT-I) reflects the overall capacity of plasma to generate thrombin, thus evaluating the balance between the anti- and procoagulant processes. However, with this method the calibrator curve is usually not measured until completion which has a severe impact on the calculation of the TG parameters, especially under conditions where almost all substrate is consumed. In addition, direct thrombin inhibitor (DTI) cannot be present in the calibration sample due to inhibition of the calibrator. We have developed a modified TG assay (CAT-II) and performed head-to-head comparison with the CAT-I method using the same fluorometer. Furthermore, we have compared our CAT-II method to a new automated TG instrument (ST®-Genesia) using the same calibration method. Methods TG was assessed with CAT-I and CAT-II using the same fulorometer and with ST®-Genesia in control plasma and plasma containing different anticoagulants (dabigatran, rivaroxaban, apixaban) and plasmas to which common interfering substances, bilirubin, hemoglobin and lipids were added. In CAT-I, calibration was against the same plasma containing calibrator in the presence of fluorogenic substrate (Z-GGR-AMC). In contrast, CAT-II method and ST®-Genesia used a standard concentration of thrombin in buffer and 7-amino-4-methylcoumarin (AMC) in a separate plasma sample for calibration. Results TG obtained from CAT-I using anticoagulant-free plasmas was lower compared with TG from CAT-II but both methods demonstrated an intra-assay variation less than 5% on all measured parameters. When comparing the two different calibration methods in the presence of different anticoagulants, a high correlation was seen in the presence of rivaroxaban and apixaban (R2 > 0.97), but not with dabigatran, a direct thrombin inhibitor. CAT-II method showed dose-dependent inhibition of TG in the presence of dabigatran, while CAT-I was not able to detect it. Both methods were able to correct for the interfering substances. Conclusions Our results showed high similarity between the results of CAT-I and CAT-II method when it is applied in control plasmas and plasmas not inhibited with a direct thrombin inhibitor. Furthermore, both the CAT-II method and ST-Genesia using the same calibration method were able to detect the effect of all oral anticoagulants. Taken together, applying a new calibration method is a significant improvement for monitoring patients on direct thrombin inhibitors while not introducing any bias to results obtained on other types of samples.

Published
2021
Full Text
View/download PDF

5. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory

Author

M. Hardy, T. Lecompte, J. Douxfils, S. Lessire, J. M. Dogné, B. Chatelain, S. Testa, I. Gouin-Thibault, Y. Gruel, R. L. Medcalf, H. ten Cate, G. Lippi, and F. Mullier

Subjects
Thrombosis, D-dimers, Anticoagulation, COVID-19, Coagulopathy, Hemostasis, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Coronavirus disease 2019 (COVID-19) is associated with extreme inflammatory response, disordered hemostasis and high thrombotic risk. A high incidence of thromboembolic events has been reported despite thromboprophylaxis, raising the question of a more effective anticoagulation. First-line hemostasis tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and D-dimers are proposed for assessing thrombotic risk and monitoring hemostasis, but are vulnerable to many drawbacks affecting their reliability and clinical relevance. Specialized hemostasis-related tests (soluble fibrin complexes, tests assessing fibrinolytic capacity, viscoelastic tests, thrombin generation) may have an interest to assess the thrombotic risk associated with COVID-19. Another challenge for the hemostasis laboratory is the monitoring of heparin treatment, especially unfractionated heparin in the setting of an extreme inflammatory response. This review aimed at evaluating the role of hemostasis tests in the management of COVID-19 and discussing their main limitations.

Published
2020
Full Text
View/download PDF

6. Changes in anticoagulant prescription in Dutch patients with recent-onset atrial fibrillation: observations from the GARFIELD-AF registry

Author

J. Seelig, F. W. A. Verheugt, M. E. W. Hemels, L. Illingworth, A. Lucassen, H. Adriaansen, M. C. M. Bongaerts, M. Pieterse, J. P. R. Herrman, P. Hoogslag, W. Hermans, B. E. Groenemeijer, L. V. A. Boersma, K. Pieper, H. ten Cate, and on behalf of the GARFIELD-AF Investigators

Subjects
Atrial fibrillation, Anticoagulants, Inappropriate prescribing, Guideline adherence, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Background For the improvement of AF care, it is important to gain insight into current anticoagulation prescription practices and guideline adherence. This report focuses on the largest Dutch subset of AF-patients, derived from the GARFIELD-AF registry. Methods Across 35 countries worldwide, patients with newly diagnosed ‘non-valvular’ atrial fibrillation (AF) with at least one additional risk factor for stroke were included. Dutch patients were enrolled in five, independent, consecutive cohorts from 2010 until 2016. Results In the Netherlands, 1189 AF-patients were enrolled. The prescription of non-vitamin K antagonist oral anticoagulants (NOAC) has increased sharply, and as per 2016, more patients were initiated on NOACs instead of vitamin K antagonists (VKA). In patients with a class I recommendation for anticoagulation, only 7.5% compared to 30.0% globally received no anticoagulation. Reasons for withholding anticoagulation in these patients were unfortunately often unclear. Conclusions The data from the GARFIELD-AF registry shows the rapidly changing anticoagulation preference of Dutch physicians in newly diagnosed AF. Adherence to European AF guidelines in terms of anticoagulant regimen would appear to be appropriate. In absence of structured follow up of AF patients on NOAC, the impact of these rapid practice changes in anticoagulation prescription in the Netherlands remains to be established.

Published
2020
Full Text
View/download PDF

7. Thrombin Generation as a Method to Identify the Risk of Bleeding in High Clinical-Risk Patients Using Dual Antiplatelet Therapy

Author

C. P. D. M. de Breet, S. Zwaveling, M. J. A. Vries, R. G. van Oerle, Y. M. C. Henskens, A. W. J. van't Hof, P. E. J. van der Meijden, L. Veenstra, H. ten Cate, and R. H. Olie

Subjects
thrombin generation, dual antiplatelet therapy, bleeding risk, percutaneous coronary intervention, coagulation factors, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Patients using dual antiplatelet therapy after percutaneous coronary intervention are at risk for bleeding. It is currently unknown whether thrombin generation can be used to identify patients receiving dual antiplatelet therapy with increased bleeding risk.Objectives: To investigate whether thrombin generation measurement in plasma provides additional insight into the assessment of bleeding risk for high clinical-risk patients using dual antiplatelet therapy.Methods: Coagulation factors and thrombin generation in platelet-poor plasma were measured in 93 high clinical-risk frail patients using dual antiplatelet therapy after percutaneous coronary intervention. During 12-month follow-up, clinically relevant bleedings were reported. Thrombin generation at 1 and 6 months after percutaneous coronary intervention was compared between patients with and without bleeding events.Results: One month after percutaneous coronary intervention, the parameters of thrombin generation, endogenous thrombin potential, peak height, and velocity index were significantly lower in patients with bleeding in the following months compared to patients without bleeding. At 6 months follow-up, endogenous thrombin potential, peak height, and velocity index were still (significantly) decreased in the bleeding group as compared to non-bleeders. Thrombin generation in the patients' plasma was strongly dependent on factor II, V, and VIII activity and fibrinogen.Conclusion: High clinical-risk patients using dual antiplatelet therapy with clinically relevant bleeding during follow-up show reduced and delayed thrombin generation in platelet-poor plasma, possibly due to variation in coagulation factors. Thus, impaired thrombin-generating potential may be a “second hit” on top of dual antiplatelet therapy, increasing the bleeding risk in high clinical-risk patients. Thrombin generation has the potential to improve the identification of patients using dual antiplatelet therapy at increased risk of bleeding.

Published
2021
Full Text
View/download PDF

8. Direct oral anticoagulant blood level monitoring in daily practice

Author

R. Bavalia, J.E. Veenhuizen, R.C.C. Hengeveld, D. Braeken, A.J.W. Gulpen, H. Ten Cate, S. Middeldorp, Y.M.C. Henskens, B.A. Hutten, M. Coppens, and A.K. Stroobants

Subjects
Factor Xa inhibitors, Thrombin inhibitors, Anti-Xa level, Anti-IIa level, Biomarkers, DOAC levels, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Introduction: Routine monitoring is not required in direct oral anticoagulant (DOAC) treatment, yet it is frequently performed. Guidance on the interpretation and management of DOAC level measurements is lacking and it is key to investigate which patients would benefit from monitoring. Our aims were to investigate why DOAC levels are requested and if they lead to changes in anticoagulant management. Methods: We retrospectively collected all clinically requested DOAC levels from 2012 until 2019 in two Dutch academic hospitals. Clinical data with regard to the first DOAC level of every patient was collected by chart review. Primary outcomes were settings, indications and changes in anticoagulant management of DOAC level measurement. In addition, we compared demographic and clinical characteristics in patients with and without changes in anticoagulant management. Results: In total, we included 604 DOAC levels. The majority was requested in an outpatient setting by the department of internal medicine. In 270 (45%) cases we identified a patient specific indication, with evaluation of DOAC accumulation being the most frequently requested. Of all 604 DOAC levels, 159 (26%) were followed by changes in anticoagulation management. The large majority of changes occurred in patients that had a patient specific indication. Patients who underwent changes were older and had more comorbidity than patients who did not (n ​= ​445). Conclusion: Almost half of the DOAC levels with a specific indication for monitoring were followed by a change in anticoagulant management. Future studies should investigate the relation between DOAC levels, the changes in anticoagulant management and clinical outcomes.

Published
2021
Full Text
View/download PDF

9. Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry

Author

Jitendra PS. Sawhney, Veerappa A. Kothiwale, Vikas Bisne, Rajashekhar Durgaprasad, Praveen Jadhav, Manoj Chopda, Velam Vanajakshamma, Ramdhan Meena, Govindan Vijayaraghavan, Kamaldeep Chawla, Jagan Allu, Karen S. Pieper, A. John Camm, Ajay K. Kakkar, Jean-Pierre Bassand, David A. Fitzmaurice, Samuel Z. Goldhaber, Shinya Goto, Sylvia Haas, Werner Hacke, Lorenzo G. Mantovani, Frank Misselwitz, Alexander G.G. Turpie, Martin van Eickels, Freek W.A. Verheugt, Gloria Kayani, Keith A.A. Fox, Bernard J. Gersh, Hector Lucas Luciardi, Harry Gibbs, Marianne Brodmann, Frank Cools, Antonio Carlos Pereira Barretto, Stuart J. Connolly, Alex Spyropoulos, John Eikelboom, Ramon Corbalan, Dayi Hu, Petr Jansky, Jørn Dalsgaard Nielsen, Hany Ragy, Pekka Raatikainen, Jean-Yves Le Heuzey, Harald Darius, Matyas Keltai, Sanjay Kakkar, Jitendra Pal Singh Sawhney, Giancarlo Agnelli, Giuseppe Ambrosio, Yukihiro Koretsune, Carlos Jerjes Sánchez Díaz, Hugo Ten Cate, Dan Atar, Janina Stepinska, Elizaveta Panchenko, Toon Wei Lim, Barry Jacobson, Seil Oh, Xavier Viñolas, Marten Rosenqvist, Jan Steffel, Pantep Angchaisuksiri, Ali Oto, Alex Parkhomenko, Wael Al Mahmeed, David Fitzmaurice, D.Y. Hu, K.N. Chen, Y.S. Zhao, H.Q. Zhang, J.Z. Chen, S.P. Cao, D.W. Wang, Y.J. Yang, W.H. Li, Y.H. Yin, G.Z. Tao, P. Yang, Y.M. Chen, S.H. He, Ying Wang, Yong Wang, G.S. Fu, X. Li, T.G. Wu, X.S. Cheng, X.W. Yan, R.P. Zhao, M.S. Chen, L.G. Xiong, P. Chen, Y. Jiao, Y. Guo, L. Xue, F.Z. Wang, H. Li, Z.M. Yang, C.L. Bai, J. Chen, J.Y. Chen, X. Chen, S. Feng, Q.H. Fu, X.J. Gao, W.N. Guo, R.H. He, X.A. He, X.S. Hu, X.F. Huang, B. Li, J. Li, L. Li, Y.H. Li, T.T. Liu, W.L. Liu, Y.Y. Liu, Z.C. Lu, X.L. Luo, T.Y. Ma, J.Q. Peng, X. Sheng, X.J. Shi, Y.H. Sun, G. Tian, K. Wang, L. Wang, R.N. Wu, Q. Xie, R.Y. Xu, J.S. Yang, L.L. Yang, Q. Yang, Y. Ye, H.Y. Yu, J.H. Yu, T. Yu, H. Zhai, Q. Zhan, G.S. Zhang, Q. Zhang, R. Zhang, Y. Zhang, W.Y. Zheng, B. Zhou, Z.H. Zhou, X.Y. Zhu, S. Kakkar, J.P.S. Sawhney, P. Jadhav, R. Durgaprasad, A.G. Ravi Shankar, R.K. Rajput, K. Bhargava, R. Sarma, A. Srinivas, D. Roy, U.M. Nagamalesh, M. Chopda, R. Kishore, G. Kulkarni, P. Chandwani, R.A. Pothiwala, M. Padinhare Purayil, S. Shah, K. Chawla, V.A. Kothiwale, B. Raghuraman, G. Vijayaraghavan, V.M. Vijan, G. Bantwal, V. Bisne, A. Khan, J.B. Gupta, S. Kumar, D. Jain, S. Abraham, D. Adak, A. Barai, H. Begum, P. Bhattacharjee, M. Dargude, D. Davies, B. Deshpande, P. Dhakrao, V. Dhyani, S. Duhan, M. Earath, A. Ganatra, S. Giradkar, V. Jain, R. Karthikeyan, L. Kasala, S. Kaur, S. Krishnappa, A. Lawande, B. Lokesh, N. Madarkar, R. Meena, P. More, D. Naik, K. Prashanth, M. Rao, N.M. Rao, N. Sadhu, D. Shah, M. Sharma, P. Shiva, S. Singhal, S. Suresh, V. Vanajakshamma, S.G. Panse, Y. Koretsune, S. Kanamori, K. Yamamoto, K. Kumagai, Y. Katsuda, K. Sadamatsu, F. Toyota, Y. Mizuno, I. Misumi, H. Noguchi, S. Ando, T. Suetsugu, M. Minamoto, Hiroshi Oda, K. Shiraishi, S. Adachi, K. Chiba, H. Norita, M. Tsuruta, T. Koyanagi, H. Ando, T. Higashi, K. Okada, S. Azakami, S. Komaki, K. Kumeda, T. Murayama, J. Matsumura, Y. Oba, R. Sonoda, K. Goto, K. Minoda, Y. Haraguchi, H. Suefuji, H. Miyagi, H. Kato, Tadashi Nakamura, Tsugihiro Nakamura, H. Nandate, R. Zaitsu, Yoshihisa Fujiura, A. Yoshimura, H. Numata, J. Ogawa, H. Tatematsu, Y. Kamogawa, K. Murakami, Y. Wakasa, M. Yamasawa, H. Maekawa, S. Abe, H. Kihara, S. Tsunoda, Katsumi Saito, Kazuyuki Saito, T. Fudo, K. Obunai, H. Tachibana, I. Oba, T. Kuwahata, S. Higa, M. Gushiken, T. Eto, H. Yoshida, D. Ikeda, Yoshitake Fujiura, M. Ishizawa, M. Nakatsuka, K. Murata, C. Ogurusu, M. Shimoyama, M. Akutsu, I. Takamura, F. Hoshino, N. Yokota, T. Iwao, K. Tsuchida, M. Takeuchi, Y. Hatori, Y. Kitami, Yoichi Nakamura, R. Oyama, M. Ageta, Hiroyuki Oda, Y. Go, K. Mishima, T. Unoki, S. Morii, Yuhei Shiga, H. Sumi, T. Nagatomo, K. Sanno, K. Fujisawa, Y. Atsuchi, T. Nagoshi, T. Seto, T. Tabuchi, M. Kameko, K. Nii, K. Oshiro, H. Takezawa, S. Nagano, N. Miyamoto, M. Iwaki, Yuichiro Nakamura, M. Fujii, M. Okawa, Masahiko Abe, Masatake Abe, Mitsunori Abe, T. Saito, T. Mito, K. Nagao, J. Minami, T. Mita, I. Sakuma, T. Taguchi, S. Marusaki, H. Doi, M. Tanaka, T. Fujito, M. Matsuta, T. Kusumoto, S. Kakinoki, K. Ashida, N. Yoshizawa, J. Agata, O. Arasaki, M. Manita, M. Ikemura, S. Fukuoka, H. Murakami, S. Matsukawa, Y. Hata, T. Taniguchi, T. Ko, H. Kubo, M. Imamaki, M. Akiyama, M. Inagaki, H. Odakura, T. Ueda, Y. Katsube, A. Nakata, H. Watanabe, M. Techigawara, M. Igarashi, K. Taga, T. Kimura, S. Tomimoto, M. Shibuya, M. Nakano, K. Ito, T. Seo, S. Hiramitsu, H. Hosokawa, M. Hoshiai, M. Hibino, K. Miyagawa, Hajime Horie, N. Sugishita, Yukio Shiga, A. Soma, K. Neya, Tetsuro Yoshida, Tomoki Yoshida, M. Mizuguchi, M. Ishiguro, T. Minagawa, M. Wada, H. Mukawa, F. Okuda, S. Nagasaka, Y. Abe, Sen Adachi, Susumu Adachi, T. Adachi, K. Akahane, T. Amano, K. Aoki, T. Aoyama, H. Arai, S. Arima, T. Arino, H. Asano, T. Asano, J. Azuma, T. Baba, T. Betsuyaku, H. Chibana, H. Date, J. Doiuchi, Y. Emura, M. Endo, Y. Fujii, R. Fujiki, A. Fujisawa, Y. Fujisawa, T. Fukuda, T. Fukui, N. Furukawa, T. Furukawa, W. Furumoto, T. Goto, M. Hamaoka, N. Hanazono, K. Hasegawa, T. Hatsuno, Y. Hayashi, K. Higuchi, K. Hirasawa, H. Hirayama, M. Hirose, S. Hirota, M. Honda, Hideki Horie, T. Ido, O. Iiji, H. Ikeda, K. Ikeda, K. Ikeoka, M. Imaizumi, H. Inaba, T. Inoue, F. Iseki, A. Ishihara, N. Ishioka, N. Ito, T. Iwase, H. Kakuda, J. Kamata, H. Kanai, H. Kanda, M. Kaneko, H. Kano, T. Kasai, T. Kato, Y. Kato, Y. Kawada, K. Kawai, K. Kawakami, S. Kawakami, T. Kawamoto, S. Kawano, J. Kim, T. Kira, H. Kitazawa, H. Kitazumi, T. Kito, T. Kobayashi, T. Koeda, J. Kojima, H. Komatsu, I. Komatsu, Y. Koshibu, T. Kotani, T. Kozuka, Y. Kumai, T. Kumazaki, I. Maeda, K. Maeda, Y. Maruyama, S. Matsui, K. Matsushita, Y. Matsuura, K. Mineoi, H. Mitsuhashi, N. Miura, S. Miyaguchi, S. Miyajima, H. Miyamoto, A. Miyashita, S. Miyata, I. Mizuguchi, A. Mizuno, T. Mori, O. Moriai, K. Morishita, O. Murai, Sho Nagai, Shunichi Nagai, E. Nagata, H. Nagata, A. Nakagomi, S. Nakahara, M. Nakamura, R. Nakamura, N. Nakanishi, T. Nakayama, R. Nakazato, T. Nanke, J. Nariyama, Y. Niijima, H. Niinuma, Y. Nishida, Y. Nishihata, K. Nishino, H. Nishioka, K. Nishizawa, I. Niwa, K. Nomura, S. Nomura, M. Nozoe, T. Ogawa, N. Ohara, M. Okada, K. Okamoto, H. Okita, M. Okuyama, H. Ono, T. Ono, Y. Onuki Pearce, S. Oriso, A. Ota, E. Otaki, Y. Saito, H. Sakai, N. Sakamoto, Y. Sakamoto, Y. Samejima, Y. Sasagawa, H. Sasaguri, A. Sasaki, T. Sasaki, Kazuki Sato, Kiyoharu Sato, M. Sawano, S. Seki, Y. Sekine, Y. Seta, K. Sezaki, N. Shibata, Y. Shiina, H. Shimono, Y. Shimoyama, T. Shindo, H. Shinohara, R. Shinohe, T. Shinozuka, T. Shirai, T. Shiraiwa, Y. Shozawa, T. Suga, C. Sugimoto, Kazuo Suzuki, Keita Suzuki, Shu Suzuki, Shunji Suzuki, Susumu Suzuki, Y. Suzuki, M. Tada, A. Taguchi, T. Takagi, Y. Takagi, K. Takahashi, S. Takahashi, H. Takai, C. Takanaka, S. Take, H. Takeda, K. Takei, K. Takenaka, T. Tana, G. Tanabe, K. Taya, H. Teragawa, S. Tohyo, S. Toru, Y. Tsuchiya, T. Tsuji, K. Tsuzaki, H. Uchiyama, O. Ueda, Y. Ueyama, N. Wakaki, T. Wakiyama, T. Washizuka, M. Watanabe, T. Yamada, T. Yamagishi, H. Yamaguchi, Kenichi Yamamoto, Kentaro Yamamoto, Kunihiko Yamamoto, T. Yamamoto, M. Yamaura, M. Yamazoe, K. Yasui, Y. Yokoyama, K. Yoshida, T.W. Lim, C.K. Ching, C.G. Foo, J.H. Chow, D.D. Chen, F.R. Jaufeerally, Y.M. Lee, G. Lim, W.T. Lim, S. Thng, S.Y. Yap, C. Yeo, S. Oh, H.N. Pak, J.-B. Kim, J.H. Kim, S.-W. Jang, D.H. Kim, D.R. Ryu, S.W. Park, D.-K. Kim, D.J. Choi, Y.S. Oh, M.-C. Cho, S.-H. Kim, H.-K. Jeon, D.-G. Shin, J.S. Park, H.K. Park, S.-J. Han, J.H. Sung, J.-G. Cho, G.-B. Nam, Y.K. On, H.E. Lim, J.J. Kwak, T.-J. Cha, T.J. Hong, S.H. Park, J.H. Yoon, N.-H. Kim, K.-S. Kim, B.C. Jung, G.-S. Hwang, C.-J. Kim, D.B. Kim, J.J. Ahn, H.J. An, H. Bae, A.L. Baek, W.J. Chi, E.A. Choi, E.H. Choi, H.K. Choi, H.S. Choi, S. Han, E.S. Heo, K.O. Her, S.W. Hwang, E.M. Jang, H.-S. Jang, S. Jang, H.-G. Jeon, S.R. Jeon, Y.R. Jeon, H.K. Jeong, I.-A. Jung, Hyeon Jeong Kim, Hyun Ju Kim, Ji Seon Kim, Jung Sook Kim, J.A. Kim, K.T. Kim, M.S. Kim, Sang Hee Kim, Sang Hyun Kim, Y.-I. Kim, C.S. Lee, E.H. Lee, G.H. Lee, H.Y. Lee, H.-Y. Lee, K.H. Lee, K.R. Lee, M.S. Lee, M.-Y. Lee, R.W. Lee, S.E. Lee, S.H. Lee, S. Lee, W.Y. Lee, I.K. Noh, A.R. Park, B.R. Park, H.N. Park, J.H. Park, M. Park, Y. Park, S.-Y. Seo, J. Shim, J.H. Sim, Y.M. Sohn, W.S. Son, Y.S. Son, H.J. Song, H.K. Wi, J.J. Woo, S. Ye, K.H. Yim, K.M. Yoo, E.J. Yoon, S.Y. Yun, P. Angchaisuksiri, S. Chawanadelert, P. Mongkolwongroj, K. Kanokphatcharakun, S. Cheewatanakornkul, T. Laksomya, S. Pattanaprichakul, T. Chantrarat, S. Rungaramsin, S. Silaruks, W. Wongcharoen, K. Siriwattana, K. Likittanasombat, P. Katekangplu, W. Boonyapisit, D. Cholsaringkarl, B. Chatlaong, P. Chattranukulchai, Y. Santanakorn, P. Hutayanon, P. Khunrong, T. Bunyapipat, S. Jai-Aue, P. Kaewsuwanna, P. Bamungpong, S. Gunaparn, S. Hongsuppinyo, R. Inphontan, R. Khattaroek, K. Khunkong, U. Kitmapawanont, C. Kongsin, B. Naratreekoon, S. Ninwaranon, J. Phangyota, A. Phrommintikul, P. Phunpinyosak, K. Pongmorakot, S. Poomiphol, N. Pornnimitthum, S. Pumprueg, S. Ratchasikaew, K. Sanit, K. Sawanyawisuth, B. Silaruks, R. Sirichai, A. Sriwichian, W. Suebjaksing, P. Sukklad, T. Suttana, A. Tangsirira, O. Thangpet, W. Tiyanon, Y. Vorasettakarnkij, T. Wisaratapong, W. Wongtheptien, A. Wutthimanop, S. Yawila, A. Oto, A. Altun, I. Ozdogru, K. Ozdemir, O. Yilmaz, A. Aydinlar, M.B. Yilmaz, E. Yeter, Z. Ongen, M. Cayli, H. Pekdemir, M. Ozdemir, M. Sucu, T. Sayin, M. Demir, H. Yorgun, M. Ersanli, E. Okuyan, D. Aras, H. Abdelrahman, O. Aktas, D. Alpay, F. Aras, M.F. Bireciklioglu, S. Budeyri, M. Buyukpapuc, S. Caliskan, M. Esen, M.A. Felekoglu, D. Genc, B. Ikitimur, E.B. Karaayvaz, S. Kılıç Karataş, S. Okutucu, E. Ozcelik, A. Quisi, H. Sag, L. Sahiner, B.Y. Sayin, T. Seker, D. Uzun Alkan, E. Yildirim, R. Yildirim, F. Yilmaz, V. Yuksekdag, H.L. Luciardi, N. Vensentini, A.C. Ingaramo, G.A. Sambadaro, V. Fernandez Caputi, S.G. Berman, P. Dragotto, A.J. Kleiban, N. Centurion, G. Giacomi, R.A. Ahuad Guerrero, D. Conde, G. Zapata, L.A. Di Paola, J.L. Ramos, R.D. Dran, J. Egido, A.A. Fernandez, M.J. Fosco, S. Sassone, V.A. Sinisi, L.R. Cartasegna, M.A. Berli, O.A. Gomez Vilamajo, F. Ferroni, E.D. Alaguibe, A. Alvarez D'Amelio, C. Arabetti, L. Arias, J.A. Belardi, L. Bergesio, F. Berli, M. Berli, S. Borchowiec, C. Buzzetti, R. Cabrini, V. Campisi, A.L. Cappi, R. Carrizo, F. Colombo Berra, J.P. Costabel, O.J.A. Costamagna, A.A. Damonte, I.N. De Urquiza, F. Diez, M.F. Edén, M. Fanuele, F. Fernandez Voena, M. Foa Torres, C. Funosas, M.P. Giacomi, C.H. Gimenez, E.P. Gurfinkel, M. de L.M. Had, V. Hansen, A.D. Hrabar, M. Ingratta, A. Lopez, G. Maehara, L. Maffei, A. Martinelli, C. Martinelli, J. Matkovich, B. Mautner, A. Meirino, R. Munguia, A. Navarro, V. Novas, G. Perez Prados, J. Pontoriero, R.N. Potito, C. Ricotti, M.A. Rodriguez, F. Rolandi, M.E. Said Palladino, M. Salinger, L.S. Sanziani, P.O. Schygiel, A. Sossich, J.F. Tinto, L. Tonelli, A.L. Tufare, M. Vallejo, M.E. Yunis, M. Zillo, F.J. Zurbrigk, A.C.P. Barretto, D.C. Sobral Filho, J. Jaber, D. Armaganijan, J. Faria Neto, A. Steffens, W. Kunz Sebba Barroso de Souza, J.D. de Souza Neto, J.M. Ribeiro, M. Silveira Teixeira, P.R. Ferreira Rossi, L. Pires, D. Moreira, J.C. Moura Jorge, A. Menezes Lorga Filho, L.C. Bodanese, M. Westerlund Montera, C.H. Del Carlo, T. Da Rocha Rodrigues, F.A. Alves da Costa, A. Lopes, R. Lopes, G.R. Araújo, E.R. Fernandes Manenti, J.F. Kerr Saraiva, J.C. Ferreira Braga, A. Negri, L. Souto, C. Moncada, D. Bertolim Precoma, F. Roquette, G. Reis, R.A. Ramos Filho, E. Lanna Figueiredo, R. Vieira Botelho, C. Munhoz da Fontoura Tavares, C.R. Costantini Frack, J. Abdalla Saad, H.C. Finimundi, C. Pisani, D. Chemello, M. Pereira Martins, C.C. Broilo França, F. Alban, G.B. Aranha Rosito, J.B. de Moura Xavier Moraes Junior, R.T. Tumelero, L. Nigro Maia, R. Simões de Almeida, N.C. do Carmo Borges, L.G. Gomes Ferreira, P. Agliardi, J. Alves de Oliveira Gomes, V. Araujo, M. Arruda Nakazone, T. Barbosa, S. Barroso, E. Belisario Falchetto, H. Bellotti Lopes, M.A. Benez Teixeira Lemos, G. Biazus, L. Borges Queiroz, F.E. Camazzola, M. Caporale, S. Cardoso Boscato, F. Chieza, M.O. Chokr, R. Clemente Mingireanov, N. Codonho Góes, C. Correa, M. Costa, C. Costantini Ortiz, L.S. da Silva, F. da Silva Paulitsch, J.A. da Silveira, E. Daros, G.R. de Araújo, M.I. Del Monaco, C. Dias, M.A. Dias, A.P. Drummond Wainstein, P. Ely Pizzato, D.C. Esteves, P. Fabri, T. Félix Lorenzato Fonseca, E. Fernandes, C. Fonseca, C.R. Frack Costantini, R. Franchin Ferraz, F. Freire, P. Gottardo, D. Guanaes, S. Guizzardi, E. Hettwer Magedanz, F. Igansi, F. Jannuzzi, G. Junior, D. Komar, E.G. Lino, D. Lopes, O. Lourenço da Silva Júnior, E. Lustosa, A.P. Macagnan, M.C. Marinho, M. Mazzoni, G. Melo, L. Mortari, O.M.C.C. Mouco, C. Nanzer Vital, C. Ormundo, S. Oss Emmer, E. Palmegiani, R. Pavani, L. Pereira, V.L. Pereira, R. Perreira, S. Poletti, S.C. Quaia Fortunato, C. Queirantes, N. Ramos Pereira, R.L. Rech, S. Ribeiro, A. Rodrigues, H. Roesch, T. Ruaro Reichert, D. Santos, I. Santos, M. Santos, M.V. Seroqui, S. Silva, L. Soares, L. Spolaor, C. Stoll, N. Toazza Duda, L. Trama, B. Unterkircher, M.V. Valois, T. Vargas, T. Viana, C. Vicente, L. Vidal Armaganijan, R. Vieira Homem, L.G. Vieira Torres, L. Vila Boas, F. Villaça Guimarães Filho, R. Corbalan, G. Eggers, C. Bugueño Gutiérrez, G. Arriagada, S. Potthoff Cardenas, B.A.J. Stockins Fernandez, C. Conejeros, C. Houzvic, P. Marin Cuevas, H. Montecinos, A. Forero, F. Lanas, M. Larico Gómez, G. Charme Vilches, C. Rey, C. Astudillo, J. Aguilar, Y. Campisto, C. Lara, E. Molina, J. Munoz Oyarzon, V. Olguin, M. Vergara, C. Villan, C.J. Sánchez Díaz, J. Illescas Diaz, R. Leal Cantú, M.G. Ramos Zavala, R. Cabrera Jardines, N. Espinola Zavaleta, S. Villarreal Umaña, E. López Rosas, G. Llamas Esperón, G. Pozas, E. Cardona Muñoz, N. Matadamas Hernández, A. Leyva Rendón, N. García Hernández, M. de los Ríos Ibarra, L. Virgen Carrillo, D. López Villezca, C. Hernández Herrera, J.J. López Prieto, R. Gaona Rodríguez, E. Villeda Espinosa, D. Flores Martínez, J. Velasco Barcena, R. Yong, I. Rodríguez Briones, J.L. Leiva Pons, H. Álvarez López, R. Olvera Ruiz, C. Díaz de la Vega, C. Cantú Brito, E. Chuquiure Valenzuela, R. Reyes-Sanchez, A. Bazzoni Ruiz, O. Nandayapa Flores, M. Benavides Gonzalez, R. Arriaga Nava, J.D. Morales Cerda, O. Fierro Fierro, P. Fajardo Campos, T.A.A. Alfaro, S. Altamirano Bellorin, R. Avena, M. Chavarria, I. Espinosa, F. Flores Silva, R.H. Garcia Nava, K. Godoy, E.J. Gonzalez Felix, C.L. Gonzalez Garcia, L.G. Gonzalez Salas, P. Guajardo, S. Hernandez Gonzalez, T. Izquierdo, M.C. Mancilla Ortiz, D. Martinez Vasquez, N. Mendoza, J. Morales, N. Nikitina, S. Ochoa Aybar, A. Ortiz, P. Padilla Macias, F. Perez, J.A. Perez Sanchez, S. Piña Toledano, M. Ramos Gonzalez, C. Rivera Ramos, V. Roa Castro, G. Romero Cardona, M. Ruiz Cornejo, A. Salinas, G. Santana, P. Sida Perez, A.C. Tovar Castaneda, R. Trujillo Cortes, M. Brodmann, K. Lenz, H. Drexel, J. Foechterle, C. Hagn, A. Podczeck-Schweighofer, K. Huber, M. Winkler, B. Schneeweiß, A. Gegenhuber, W. Lang, S. Eichinger-Hasenauer, P. Kaserer, J. Sykora, H. Rasch, M. Pichler, E. Schaflinger, B. Strohmer, R. Breier, K.-M. Ebner, L. Eischer, F. Freihoff, A. Lischka-Lindner, T. Mark, A. Mirtl, A. Said, C. Stöcklöcker, B. Vogel, A. Vonbank, C. Wöhrer, D. Zanolin, F. Cools, G. Paparella, P. Vandergoten, J.-L. Parqué, L. Capiau, G. Vervoort, B. Wollaert, P. Desfontaines, G. Mairesse, T. Boussy, P. Godart, A. De Wolf, J. Voet, A. Heyse, G. Hollanders, W. Anné, J. Vercammen, P. Purnode, I. Blankoff, D. Faes, Y. Balthazar, M. Beutels, P. Maréchal, S. Verstraete, O. Xhaet, H. Striekwold, J. Thoeng, K. Hermans, B. Alzand, A.-K. Ascoop, F. Banaeian, A.-M. Barbuto, A.C. Billiaux, M. Blockmans, C. Bouvy, C. Brike, H. Capiau, T. Casier, A. Conde Y Bolado, D. De Cleen, M. De Coninck, M. de Vos, N. de Weerdt, M. Delforge, M. Delvigne, D. Denie, K. Derycker, E. Deweerd, F. Dormal, S. Drieghe, M. Everaert, T. Eykerman, E. Feys, M. Ghekiere, F. Gits, S. Hellemans, L. Helvasto, C. Jacobs, S. Lips, I. Mestdagh, J. Nimmegeers, V. Piamonte, P. Pollet, A. Postolache, M. Raepers, E. Raymenants, J. Richa, H. Rombouts, J. Salembier, C. Scheurwegs, O. Semeraro, N. Simons, C. Smessaert, W. Smolders, I. Stockman, S. Tahon, V. Thyssen, G. Tincani, F. Van Durme, D. Van Lier, H. Vandekerckhove, Y. Vandekerckhove, D. Vandenbroeck, A. Vandorpe, E. Vanhalst, B. Vanhauwaert, C. Vantomme, L. Vergauwen, H. Verloove, T. Vydt, T. Weyn, P. Jansky, P. Reichert, R. Spacek, V. Machova, E. Zidkova, O. Ludka, J. Olsr, L. Kotik, K. Plocova, B. Racz, R. Ferkl, J. Hubac, I. Kotik, Z. Monhart, H. Burianova, O. Jerabek, J. Pisova, I. Petrova, V. Dedek, M. Honkova, P. Podrazil, J. Spinar, J. Vitovec, M. Novak, J. Lastuvka, V. Durdil, P. Antonova, L. Bockova, J. Bultas, J. Chlumsky, L. Dastychova, T. Drasnar, J. Honek, M. Horejsi, V. Hubacova, L. Janska, I. Kopeckova, R. Kratochvilova, E. Krcova, R. Labrova, A. Lindourkova, J. Lipoldova, H. Lubanda, A. Ludkova, L. Mahdalikova, M. Majerníkova, D. Michalik, P. Potuznik, E. Prochazkova, A. Sulc, J. Sveceny, M. Valtova, M. Zidek, J. Zika, J. Nielsen, H. Nielsen, S. Husted, U. Hintze, S. Rasmussen, A. Bremmelgaard, J. Markenvard, J. Boerger, J. Solgaard, P. Simonsen, T. Loekkegaard, M. Bruun, J. Mertz, H. Domínguez, K. Skagen, K. Egstrup, H. Ibsen, I. Raymond, T. Bang-Hansen, C. Ellervik, E. Eriksen, L. Jensen, M. Jensen, M. Leth, A. Nygaard, J. Park, M. Schou, A. Therkelsen, J. Tilma, K. Vesterager, P. Raatikainen, J. Airaksinen, O. Arola, J. Koistinen, H. Nappila, K. Peltomäki, V. Rasanen, T. Vasankari, J.-Y. Le Heuzey, M. Galinier, Y. Gottwalles, F. Paganelli, P. Loiselet, J.-J. Muller, M.B. Koujan, A. Marquand, S. Destrac, O. Piot, N. Delarche, J.-P. Cebron, S. Boveda, M. Guenoun, D. Guedj-Meynier, D. Galley, J. Ohayon, S. Assouline, M. Zuber, P. Amarenco, E. Ellie, J. Kadouch, P.-Y. Fournier, J.-P. Huberman, M. Lemaire, G. Rodier, L. Milandre, X. Vandamme, I. Sibon, J.-P. Neau, M.H. Mahagne, A. Mielot, M. Bonnefoy, J.-B. Churet, V. Navarre, F. Sellem, G. Monniot, J.-P. Boyes, B. Doucet, M. Martelet, D. Obadia, B. Crousillat, J. Mouallem, E. Bearez, P. Nazeyrollas, J.P. Brugnaux, A. Fedorowsky, F. Casassus, J.-B. Berneau, F. Chemin, N. Falvo, J.-M. Perron, J.-E. Poulard, A. Barreau, C. Beltra, E. Corrihons, N. Decarsin, B. Dubois, E. Ducasse, X. Giry, A. Kemmel, S. Ledure, N. Lemaire, F. Robin, N. Rosolin, D. Sanchez, A. Suissa, H. Darius, G. Königer, J. Purr, U. Gerbaulet, B.-T. Kellner, A. Kopf, T. Schäfer, H. Zauzig, P. Riegel, H. Hohensee, E. Eißfeller, W. Eder, G. Rehling, D. Glatzel, S. Zutz, G.-U. Heinz, H. Menke, A. Pustelnik, P. Sandow, N. Ludwig, H. Wiswedel, W. Wildenauer, C. Axthelm, T. Schwarz, A. Babyesiza, G. Stuchlik, H.-H. Zimny, M. Kropp, F. Kahl, A. Caspar, S. Omankowsky, T. Läßig, H.-J. Hartmann, G. Lehmann, H.-W. Bindig, G. Hergdt, D. Reimer, J. Hauk, W. Dorsch, J. Dshabrailov, H. Michel, K.-A. Rapp, R. Vormann, P. Mayer, U. Horstmeier, V. Eissing, H. Hey, H. Leuchtgens, V. Lilienweiß, K. Kolitsch, C. Schubert, H. Lauer, T. Buchner, G. Brauer, S. Kamin, K. Müller, M. Abdel-Qader, S. Baumbach, H.-H. Ebert, C. Schwencke, S. Schellong, P. Bernhardt, L. Karolyi, B. Sievers, W. Haverkamp, P. Salbach, J.-U. Röhnisch, S. Schoen, W. Erdle, T. Mueller, H. Mueller, V. Mitrovic, Z. Babjakova, K. Bergner, S. Boehme, K. Bonin, D. Buckert, F. Busch, U. Dichristin, S. Diez, A. Fleck, K. Flint, H. Floegel, C. Fritz, R. Frommhold, J. Gehre, J. Geyer, A. Grytzmann, M. Hahn, K. Helgert, K. Hubert, K. Kirchner-Volker, V. Klein, D. Kroll, A. Krueger, R. Lehmann, L. Mann, A. Maselli, G. Menken, K. Mikes, H. Mortan, N. Nasser, D. Nicolaus, A. Plauskat, L. Pomper, A. Quietzsch, C. Ravenhorst, C. Reichelt, C. Reimer, B. Schaefer, S. Scharrer, K. Schirmer, K. Schmidt, R. Schoene, J. Schulze, M. Schuppe, S. Simon, S. Sommer, K. Spranger, A. Talkenberger, K. Tauber, A. Tetlak, T. Toennishoff, R. Voelkel-Babyesiza, B. Voigts, U. Weiser, S. Wesendorf, S. Wildenauer, T. Wolf, J. Wurziger, J. Zak, H.-D. Zauzig, S. Ziefle, S. Zincke, M. Keltai, S. Vangel, G. Szalai, B. Merkely, S. Kancz, Z. Boda, A. Nagy, Z. Laszlo, A. Matoltsy, B. Gaszner, P. Polgar, T. Habon, E. Noori, G. Juhasz, N. Kanakaridisz, I. Szentpeteri, F. Juhasz, A. Vertes, A. Papp, Z. May, J. Ferenczi, M. Egyutt, E. Kis, G. Engelthaler, G. Szantai, E. Fulop, P. Gombos, D. Gulyas, P. Jen, E. Kiralyhazine Gyorke, M. Kovacs, S. Kovacsne Levang, S. Marianna, Z. Radics, N. Sydó, R. Szalo, A. Szilagyi, F. Sztanyik, B. Vandrus, G. Agnelli, G. Ambrosio, E. Tiraferri, R. Santoro, S. Testa, G. Di Minno, M. Moia, T.M. Caimi, G. Martini, M. Tessitori, R. Cappelli, D. Poli, R. Quintavalla, F. Melone, F. Cosmi, A. Pizzini, G. Piseddu, R. Fanelli, C. Latella, R. Santi, L. Pancaldi, R. De Cristofaro, G. Palareti, A. De Blasio, J. Salerno Uriarte, F. Minetti, E.M. Pogliani, L.M. Lonati, M. Accogli, N. Ciampani, S. Malengo, M. Feola, A. Raisaro, L. Fattore, P. Grilli, F. Germini, M. Settimi, M. Alunni, G. Duranti, L. Tedeschi, G. Baglioni, G. Avanzino, M. Berardi, V. Pannacci, A. Giombolini, S. Nicoli, T. Scarponi, B. Allasia, P. Ricciarini, R. Nasorri, A. Argena, P. Bossolasco, P. Ronchini, A. Filippi, F. Tradati, C. Bulla, L. Donzelli, L. Foppa, M.L. Bottarelli, A. Tomasello, A. Mauric, C. Femiano, R. Reggio, F. Lillo, A. Mariani, F. Forcignanò, M. Volpe, M. D'Avino, M.G. Bongiorni, S. Severi, A. Capucci, C. Lodigiani, E. Salomone, G. Serviddio, C. Tondo, P. Golino, C. Mazzone, S. Iacopino, V. Pengo, M. Galvani, L. Moretti, P. Ambrosino, E. Banfi, V. Biagioli, A. Bianchi, G. Boggian, M. Breschi, S. Brusorio, F. Calcagnoli, G. Campagna, M. Carpenedo, C. Ciabatta, G. Ciliberti, G. Cimmino, C. D'Arienzo, L. Di Gennaro, M. Fedele, P.M. Ferrini, K. Granzow, G. Guazzaloca, F. Guerra, A. Lo Buglio, S. Longo, F. Macellari, E. Mesolella, E. Mollica Poeta, P. Occhilupo, V. Oriana, G. Rangel, L. Salomone, A. Scaccianoce, C. Scarone, L. Segreti, G. Sottilota, R. Villani, C. Zecca, H. ten Cate, J.H. Ruiter, H. Klomps, M. Bongaerts, M.G.C. Pieterse, C. Guldener, J.-P. Herrman, G. Lochorn, A. Lucassen, H. Adriaansen, S.H.K. The, P.R. Nierop, P.A.M. Hoogslag, W. Hermans, B.E. Groenemeijer, W. Terpstra, C. Buiks, L.V.A. Boersma, M. Boersma-Slootweg, F. Bosman, M. Bosschaert, S. Bruin, I. Danse, J. De Graaf, J. de Graauw, M. Debordes, S. Dols, F. Geerlings, K. Gorrebeeck, A. Jerzewski, W. Jetten, M. Kelderman, T. Kloosterman, E.M. Koomen, J. Krikken, P. Melman, R. Mulder, A. Pronk, A. Stallinga-de Vos, J. te Kaat, P. Tonino, B. Uppelschoten, R. van de Loo, T. van der Kley, G. van Leeuwen, J.J. van Putten, L. Westerman, D. Atar, E. Berge, P.A. Sirnes, E. Gjertsen, T. Hole, K. Erga, A. Hallaråker, G. Skjelvan, A. Østrem, B. Ghezai, A. Svilaas, P. Christersson, T. Øien, S. Høegh Henrichsen, J. Berg-Johansen, J.E. Otterstad, H. Antonsen, K. Ausen, H. Claussen, I. Dominguez, A. Jekthammer, A.B. Lensebraaten, V. Nilsen, M. O'Donovan, K. Ringdalen, S. Strand, J. Stepinska, R. Korzeniak, A. Gieroba, M. Biedrzycka, Marcin Ogorek, B. Wozakowska-Kaplon, K. Loboz-Grudzien, J. Kosior, W. Supinski, J. Kuzniar, R. Zaluska, J. Hiczkiewicz, L. Swiatkowska-Byczynska, L. Kucharski, M. Gruchala, P. Minc, M. Olszewski, G. Kania, M. Krzciuk, Z. Lajkowski, B. Ostrowska-Pomian, J. Lewczuk, E. Zinka, A. Karczmarczyk, M. Chmielnicka-Pruszczynska, M. Trusz-Gluza, G. Opolski, M. Bronisz, Michal Ogorek, G. Glanowska, P. Ruszkowski, K. Jaworska, R. Sciborski, B. Okopien, P. Kukla, I. Wozniak-Skowerska, K. Galbas, K. Cymerman, J. Jurowiecki, P. Miekus, W. Myszka, S. Mazur, R. Lysek, J. Baszak, T. Rusicka-Piekarz, G. Raczak, E. Domanska, J. Nessler, J. Lesnik, M. Ambicka, D. Andrzejewski, J. Araminowicz, A. Barszcz, R. Bartkowiak, J. Bartnik, M. Basiak, E. Bekieszczuk, L. Bernat, L. Biedrzycki, A. Biernacka, D. Blaszczyk, E. Broton, W. Brzozowski, M. Brzustowska, R. Bzymek, A. Chmielowski, P. Chojnowski, R. Cichomski, K. Cieslak, A. Cieszynska, B. Curyllo, M. Czamara, L. Danilowicz-Szymanowicz, B. Dolecka, L. Drelich, B. Dudzik-Richter, T. Dybala, M. Dziuba, W. Faron, M. Figura-Chmielewska, A. Frankiewicz, W. Gadzinski, E. Gasior, B. Gosciniecka, P. Gutknecht, M. Guziewicz, A. Jackun-Podlesna, G. Jaguszewska, J. Jankielewicz, A. Jaremczuk-Kaczmarczyk, M. Jargiello-Baszak, A. Jarzebowski, E. Jaskulska-Niedziela, M. Jaworska-Drozdowska, J. Kabat, A. Kaczmarzyk-Radka, K. Kalin, R. Kaliszczak, M. Kiliszek, M. Klata, M. Kluczewski, I. Kobielusz-Gembala, E. Kochanska, D. Kociolek, A. Kolodzinska, A. Komlo, A. Konopka, E. Korczowska, E. Kowal, H.K. Kowalczyk, E. Kremis, D. Kruczyk, A. Krzesiak-Lodyga, M. Krzyzanowski, W. Kurdzielewicz, D. Kustrzycka-Kratochwil, D. Lesniewska-Krynska, J. Leszczynski, E. Lewicka, E. Lichota, K. Lip, M. Loboz-Rudnicka, J. Luka, A. Lysek-Jozefowicz, M. Machnikowska, K. Majewska, R. Mariankowski, A. Markiewicz, M. Mazur, A. Metzgier-Gumiela, E. Miedlar, M. Mielcarek, J. Neubauer-Geryk, J. Niedek, A. Niemirycz-Makurat, A. Nowak, S. Nowak, B. Opielowska-Nowak, M. Ozgowicz, A. Pawelska-Buczen, E. Pawlik-Rak, R. Piotrowicz, P. Ptaszynski, A. Raczynska, W. Rogowski, J. Romanek, R. Romaszkiewicz, P. Rostoff, N. Roszczyk, D. Rozewska-Furmanek, J. Rychta, B. Rzyczkowska, A. Sidor, J. Skalska, M. Smichura, M. Splawski, P. Staneta, E. Staniszewska, J. Starak-Marciniak, M. Stopyra-Poczatek, M. Sukiennik-Kujawa, J. Szafranski, P. Szalecki, A. Szczepanska, W. Szkrobka, E. Szuchnik, A. Szulowska, G. Szumczyk-Muszytowska, M. Szwoch, T. Traczyk, M. Troszczynska, G. Trzcinski, S. Tybura, P. Walasik, M. Wegrzynowska, K. Wesolowska, W. Wieczorek, A. Wierzbicka, P. Wilczewski, M. Wilgat-Szecowka, P. Wojewoda, L. Wojnowski, M. Wrobel, K. Zakutynska-Kowalczyk, M. Zyczynska-Szmon, E. Panchenko, V. Eltishcheva, R. Libis, S. Tereshchenko, S. Popov, G. Kamalov, D. Belenky, A. Zateyshchikova, E. Kropacheva, A. Kolesnikova, K. Nikolaev, L. Egorova, A. Khokhlov, E. Yakupov, M. Poltavskaya, D. Zateyshchikov, O. Drapkina, A. Vishnevsky, O. Barbarash, O. Miller, E. Aleksandrova, P. Chizhov, M. Sergeev, E. Shutemova, E. Mazur, K. Zrazhevskiy, T. Novikova, V. Kostenko, Y. Moiseeva, E. Polkanova, K. Sobolev, M. Rossovskaya, G. Zubeeva, Y. Shapovalova, O. Nagibovich, A. Edin, A. Agakhanyan, R. Batalov, Y. Belenkova, F. Bitakova, S. Chugunnaya, A. Dumikyan, S. Erofeeva, E. Gorbunova, T. Gorshkova, A. Gubanov, M. Gurmach, Y. Ivanova, T. Kolesova, D. Konyushenko, O. Korneeva, O. Kropova, P. Kuchuk, O. Kungurtseva, T. Kupriyanova, B. Kurylo, M. Kuvanova, O. Lebedeva, E. Lileeva, O. Machilskaya, T. Medvedeva, G. Monako, I. Motylev, G. Nagibovich, E. Novikova, Y. Orlov, Y. Osmolovskaya, A. Ovsannikova, D. Platonov, S. Rachkova, O. Sinitsina, S. Speshilova, O. Suslova, A. Ushakov, O. Volodicheva, O. Zemlianskaia, I. Zhirov, E. Zhuravleva, I. Zotova, X. Viñolas, P. Alvarez Garcia, M.F. López Fernández, L. Tercedor, S. Tranche Iparraguirre, P. Torán Monserrat, E. Márquez Contreras, J. Isart Rafecas, J. Motero Carrasco, P. García Pavía, C. Gómez Pajuelo, C. Moro Serrano, L.F. Iglesias Alonso, A. Grande Ruiz, J. Mercé Klein, J.R. Gonzalez Juanatey, G. Barón Esquivias, I. Monte Collado, H. Palacín Piquero, C. Brotons Cuixart, M. Rodríguez Morató, J. Bayo I Llibre, C. Corros Vicente, M. Vida Gutierrez, F. Epelde Gonzalo, C.A. Almeida Fernández, N. Del Val Plana, E. Escrivá Montserrat, J.J. Montero Alía, M. Barreda González, M.A. Moleiro Oliva, J. Iglesias Sanmartín, M. Jiménez González, M. Rodriguez Álvarez, J. Herreros Melenchon, T. Ripoll Vera, F. Ridocci Soriano, L. Garcia Riesco, M.D. Marco Macian, J. Quiles Granado, M. Jimenez Navarro, J. Cosin Sales, J.V. Vaquer Perez, M. Vazquez Caamano, M.F. Arcocha Torres, G. Marcos Gomez, A. Iñiguez Romo, M.A. Prieto Diaz, Carmela Alonso, Concepcion Alonso, D. Alvarez, M. Alvarez, M. Amaro, N. Andere, J. Aracil Villar, R. Armitano Ochoa, A. Austria, S. Barbeira, E. Barraquer Feu, A. Bartes, V. Becerra Munoz, F.J. Bermudez Jimenez, A. Branjovich Tijuan, J. Cabeza Ramirez, M. Cabrera Ramos, E. Calvo Martinez, M. Campo Moreno, G. Cancho Corchado, M. Casanova Gil, M. Castillo Orive, D. Castro Fernandez, M. Cebollada del Misterio, R. Codinachs Alsina, A. Cortada Cabrera, J. Costa Pinto Prego de Faria, S. Costas, M.I. Cotilla Marco, M. Dachs, C.M. Diaz Lopez, A. Domenech Borras, A. Elorriaga Madariaga, A. Espallargas, M. Fernandez, E. Fernandez Escobar, E. Fernandez Mas, A. Ferrer, J. Fosch, M. Garcia Bermudez, V. Garcia Millan, M. Gavira Saenz, C. Gines Garcia, C. Gomez, Y. Gomez Perez, A. Gonzales Segovia, P. Gonzalez, L. Grigorian, A. Guerrero Molina, M. del C. Gutierrez del Val, B. Herrero Maeso, E. Hevia Rodriguez, A. Iglesias Garcia, M.J. Jimenez Fernandez, B. Jimeno Besa, P. Juan Salvadores, M.B. Lage Bouzamayor, I. Lasuncion, L.E. Lezcano Gort, M. Llobet Molina, M. Lopez, A. Manzanal Rey, J. Mara Guerra, S. Marcus, A. Martin Vila, M. Martinez Mena, P. Mazon, F. Mendez Zurita, G. Millán, M. Molina, P. Montero Alia, D. Montes, M. Moure Gonzalez, R.B. Munoz Munoz, A. Negrete Palma, H.N. Orellana Figueroa, V.M. Ortega, C. Ortiz Cortes, D. Otero Tomera, N. Palomo Merchan, I. Pareja Ibar, E. Pena Garcia, M. Pereda Armayor, M. Perez Carasa, I. Prieto, V. Quintern, R. Renom, L.M. Rincon Diaz, V. Rios, L. Riquelme Sola, R. Rivera, X. Robiro Robiro, M. Roca, C. Roca Saumell, C. Rodrigo, E. Rodriguez, M. Rodriguez Garcia, S. Saez Jimenez, P. Sanchez Calderon, L. Sanchez Mendez, S. Sanchez Parra, C. Santolaya, M.R. Senan Sanz, A. Seoane Blanco, E. Serralvo, N. Sierra, C. Simon Valero, J. Sorribes Lopez, M. Teixido Fontanillas, M. Terns Riera, G. Tobajas, C. Torres, J. Torres Marques, M. Ubeda Pastor, M. Rosenqvist, A. Wirdby, J. Linden, K. Henriksson, M. Elmersson, A. Egilsson, U. Börjesson, G. Svärd, B. Liu, A. Lindh, L.-B. Olsson, M. Gustavsson, Lars Andersson, Lisbeth Andersson, L. Benson, C. Bothin, A. Hajimirsadeghi, K. Kadir, M. Ericsson, A. Ohlsson, H. Lindvall, P. Svensson, K. Thorne, H. Handel, P. Platonov, B. Eriksson, I. Timberg, K. Romberg, M. Crisby, J.-E. Karlsson, S.A. Jensen, A. Andersson, L. Malmqvist, B. Martinsson, F. Bernsten, J. Engdahl, J. Thulin, A. Hot-Bjelac, P. Stalby, H. Aaröe, E. Ahbeck, H. Ahlmark, F. Al-Khalili, G. Bonkowski, S. Dzeletovic, A.-B. Ekstrand, G.-B. Eriksson, K. Floren, C. Grässjö, S. Hahn, P. Jaensson, B. Jansson, J.-H. Jansson, R.-M. Kangert, A. Koch, D. Kusiak, A. Lettenström, A. Lindberg, C.-J. Lindholm, A. Mannermyr, K. Mansson, M. Millborg, C. Nilsson, A.-M. Ohlin, A. Olofsson, A. Osberg, A. Pedersen, K. Risbecker, K. Rosenberg, J. Samuelsson, M. Shayesteh, K. Skoglund, M. Stjernberg, C. Thorsen, J. Steffel, J.H. Beer, J. Debrunner, D. Amstutz, J. Bruegger, G. Elise, A. Grau, A. Guinand, I. Henriette, E. Saga, S. Winnik, A. Parkhomenko, I. Rudyk, V. Tseluyko, O. Karpenko, S. Zhurba, I. Kraiz, I. Kupnovytska, N. Serediuk, Y. Mostovoy, O. Ushakov, O. Koval, I. Kovalskyi, Y. Svyshchenko, O. Sychov, M. Stanislavchuk, O. Kraydashenko, A. Yagensky, S. Tykhonova, I. Fushtey, R. Belegai, G. Berko, L. Burdeuna, O. Chabanna, I. Daniuk, A. Ivanov, E. Kamenska, P. Kaplan, O. Khyzhnyak, S. Kizim, O. Matova, O. Medentseva, V. Mochonyi, M. Mospan, V. Nemtsova, T. Ovdiienko, O. Palamarchuk, M. Pavelko, R. Petrovskyy, D. Plevak, O. Proshak, S. Pyvovar, L. Rasputina, O. Romanenko, O. Romanova, A. Sapatyi, O. Shumakov, R. Stets, L. Todoriuk, V. Varenov, D. Fitzmaurice, N. Chauhan, D. Goodwin, P. Saunders, R. Evans, J. Leese, P.S. Jhittay, A. Ross, M.S. Kainth, G. Pickavance, J. McDonnell, A. Williams, T. Gooding, H. Wagner, S. Suryani, A. Singal, S. Sircar, R. Bilas, P. Hutchinson, A. Wakeman, M. Stokes, N. Paul, M. Aziz, C. Ramesh, P. Wilson, S. Franklin, S. Fairhead, J. Thompson, V. St Joseph, G. Taylor, D. Tragen, D. Seamark, C. Paul, M. Richardson, A. Jefferies, H. Sharp, H. Jones, C. Giles, M. Page, O. Oginni, J. Aldegather, S. Wetherwell, W. Lumb, P. Evans, F. Scouller, N. Macey, Y. Stipp, R. West, S. Thurston, P. Wadeson, J. Matthews, P. Pandya, A. Gallagher, T. Railton, B. Sinha, D. Russell, J.A. Davies, P. Ainsworth, C.P. Jones, P. Weeks, J. Eden, D. Kernick, W. Murdoch, L. Lumley, R.P. Patel, S.W. Wong, M. Saigol, K. Ladha, K. Douglas, D.F. Cumberlidge, C. Bradshaw, G. Van Zon, K.P. Jones, M.J. Thomas, E. Watson, B. Sarai, N. Ahmad, W. Willcock, J. Cairns, S. Sathananthan, N. de Kare-Silver, A. Gilliland, E. Strieder, A. Howitt, B. Vishwanathan, N. Bird, D. Gray, M. Clark, J. Bisatt, J. Litchfield, E. Fisher, T. Fooks, A.R. Kelsall, E. Alborough, J. Wakeling, M. Parfitt, K. Milne, S. Rogers, R. Priyadharshan, J.L. Oliver, E. Davies, S. Abushal, M. Jacobs, C. Hutton, N.I. Walls, R. Thompson, C. Chigbo, S.M.A. Zaidi, M. Howard, K.C. Butter, S. Barrow, H. Little, I.U. Haq, L. Gibbons, S. Glencross, A.J. McLeod, K. Poland, C. Mulholland, A. Warke, P. Conn, G. Burns, R.N. Smith, S. Lowe, R. Kamath, H.S. Dau, J. Webster, I. Hodgins, S. Vercoe, P.C. Roome, H. Pinnock, J.R.A. Patel, A. Ali, N. Hart, R. Davies, E. Stuart, C.A. Neden, M. Danielsen, R. Heath, P. Sharma, S. Galloway, C. Hawkins, R. Oliver, M. Aylward, S. Mannion, M. Braddick, D. Edwards, A.C. Rothwell, A. Sabir, F. Choudhary, S. Khalaque, A. Wilson, S. Peters, W. Coulson, N. Roberts, A. Heer, S. Coates, B. Ward, D. Jackson, S. Walton, D. Shepherd, M. Sterry, T. Wong, M. Boon, R. Bunney, R. Haria-Shah, R.T. Baron, S. Davies, T. Schatzberger, N. Hargreaves, T. Stephenson, H. Choi, R. Batson, L. Lucraft, T. Myhill, S. Estifano, D. Geatch, J. Wilkinson, R. Veale, K. Forshaw, T. Davies, K. Zaman, P. Vinson, C. Liley, M. Bandrapalli, P. McGinty, R. Wastling, P. McEleny, A. Beattie, P. Cooke, M. Wong, J. Gunasegaram, M. Pugsley, S. Ahmad, C. A'Court, J. Ayers, J. Bennett, S. Cartwright, S. Dobson, C. Dooldeniya, A. Flynn, R. Fox, J. Goram, A. Halpin, A. Hay, P. Jacobs, L. Jeffers, L. Lomax, I. Munro, R. Muvva, M. Nadaph, K. Powell, S. Randfield, D. Redpath, R. Reed, M. Rickenbach, G. Rogers, P.B. Saunders, C. Seamark, J. Shewring, P. Simmons, H. Simper, H. Stoddart, A. Sword, N. Thomas, A. Thomson, H. Gibbs, A. Blenkhorn, B. Singh, W. Van Gaal, W. Abhayaratna, R. Lehman, P. Roberts-Thomson, J. Kilian, D. Coulshed, A. Catanchin, D. Colquhoun, H. Kiat, D. Eccleston, J. French, L. Zimmett, B. Ayres, T. Phan, P. Blombery, D. Crimmins, D. O'Donnell, A. Choi, P. Astridge, M. Arstall, N. Jepson, M. Binnekamp, A. Lee, J. Rogers, G. Starmer, P. Carroll, J. Faunt, A. Aggarwala, L. Barry, C. Batta, R. Beveridge, A. Black, M. Bonner, J. Boys, E. Buckley, M. Campo, L. Carlton, A. Connelly, B. Conway, D. Cresp, H. Dimitri, S. Dixon, M. Dolman, M. Duroux, M. Eskandari, R. Eslick, A. Ferreira-Jardim, T. Fetahovic, D. Fitzpatrick, R. Geraghty, J. Gibbs, T. Grabek, M.H. Modi, K. Hayes, M.P. Hegde, L. Hesketh, B. Hoffmann, B. Jacobson, K. Johnson, C. Juergens, I. Kassam, V. Lawlor, M. Lehman, S. Lehman, D. Leung, S. Mackay, M. MacKenzie, C. McCarthy, C. McIntosh, L. McKeon, H. Morrison, C. Mussap, J.-D. Myers, V. Nagalingam, G. Oldfield, V. O'May, J. Palmer, L. Parsons, K. Patching, T. Patching, V. Paul, M. Plotz, S. Preston, H. Rashad, M. Ratcliffe, S. Raynes, J. Rose, L. Sanders, M. Seremetkoska, H. Setio, S. Shone, P. Shrestha, C. Singh, C. Singleton, N. Stoyanov, S. Sutcliffe, K. Swaraj, J. Tarrant, S. Thompson, I.M. Tsay, M. Vorster, A. Waldman, L. Wallis, E. Wilford, K. Wong, S.J. Connolly, A. Spyropoulos, J. Eikelboom, R. Luton, M. Gupta, A.S. Pandey, S. Cheung, R. Leader, P. Beaudry, F. Ayala-Paredes, J. Berlingieri, J. Heath, G. Poirier, M. Du Preez, R. Nadeau, G. Dresser, R. Dhillon, T. Hruczkowski, B. Schweitzer, B. Coutu, P. Angaran, P. MacDonald, S. Vizel, S. Fikry, R. Parkash, A. Lavoie, J. Cha, B. Ramjattan, J. Bonet, K. Ahmad, L. Aro, T. Aves, K. Beaudry, C. Bergeron, J. Bigcanoe, N. Bignell, L. Breakwell, E. Burke, L. Carroll, B. Clarke, T. Cleveland, S. Daheb, P. Dehghani, I. Denis, Z. Djaidani, P. Dorian, S. Douglass, J. Dunnigan, A. Ewert, D. Farquhar, A. Fearon, L. Ferleyko, D. Fournier, B. Fox, M.-C. Grenier, W. Gulliver, K. Haveman, C. Hines, K. Hines, A.M. Jackson, C. Jean, G. Jethoo, R. Kahlon, S. Kelly, R. Kim, V. Korley, J. Kornder, L. Kwan, J. Largy, C. Lewis, S. Lewis, I. Mangat, R. Moor, J. Navratil, I. Neas, J. Otis, R. Otis, M. Pandey, F. Petrie, A. Pinter, M. Raines, P. Roberts, M. Robinson, G. Sas, S. Schulman, L. Snell, S. Spearson, J. Stevenson, T. Trahey, S. Wong, D. Wright, H. Ragy, A. Abd El-Aziz, S.K. Abou Seif, M.G. El Din, S. El Etriby, A. Elbahry, A. El-Etreby, M. Elkhadem, A. Katta, T. Khairy, A. Mowafy, M. Nawar, A. Ohanissian, A. Reda, M. Reda, H. Salem, N. Sami, S. Samir, M. Setiha, M. Sobhy, A. Soliman, N. Taha, M. Tawfik, E. Zaatout, D. Kettles, J. Bayat, H. Siebert, A. Horak, Y. Kelfkens, R. Garda, T. Pillay, M. Guerra, L. van Zyl, H. Theron, A. Murray, R. Louw, D. Greyling, P. Mntla, V. Ueckermann, R. Loghdey, S. Ismail, F. Ahmed, J. Engelbrecht, A. Ramdass, S. Maharajh, W. Oosthuysen, G. Angel, C. Bester, M. Booysen, C. Boshoff, C. Cannon, S. Cassimjee, C. Chami, G. Conway, A. Davids, L. de Meyer, G. Du Plessis, T. Ellis, L. Henley, M. Karsten, E. Loyd, J. Marks, L. Mavhusa, M. Mostert, A. Page, L. Rikhotso, M. Salie, J. Sasto, F. Shaik, A. Skein, L. Smith, G. Tarr, T. Tau, F. van Zyl, W. Al Mahmeed, G. Yousef, A. Agrawal, M. Nathani, M. Ibrahim, E.M. Esheiba, R. Singh, A. Naguib, M. Abu-Mahfouz, M. Al Omairi, A. Al Naeemi, R. Maruthanayagam, N. Bazargani, A. Wassef, R. Gupta, M. Khan, B. Subbaraman, A. Abdul, A. Al Mulla, S. El Bardisy, P. Haridas, S. Jadhav, K. Magdaluyo, M. Makdad, I. Maqsood, R. Mohamed, N. Sharma, R. Sharma, M. Thanzeel, S.Z. Goldhaber, R. Canosa, P. Rama, E. Blumberg, J. Garcia, P. Mullen, V. Wilson, A. Quick, K. Ferrick, W.M. Kutayli, M. Cox, M. Franco, S. Falkowski, R. Mendelson, M. Williams, S. Miller, S. Beach, A. Alfieri, T. Gutowski, I. Haque, R. Reddy, W. Ahmed, P. Delafontaine, D. Diercks, D. Theodoro, K. Remmel, M. Alberts, R. Ison, H. Noveck, P. Duffy, S. Pitta, D. Nishijima, C. Treasure, N. Asafu-Adjaye, K. Ball, M. Bartlett, M. Bentley, S. Bowers, A. Brown, A. Browne, J. Cameron-Watts, M. Canova, D. Cassidy, K. Cervellione, S. Congal, J. DePauw, A. Dickerson, M. Eley, L. Evans, S. Felpel, K. Ferdinand, D. Fielder, P. Gentry, A. Haideri, F. Hakimi, T. Harbour, E. Hartranft, B. Hawkins, M. Headlee, L. Henson, C. Herrick, T. Hicks, S. Jasinski, A. Jones, L. Jones, P. Jones, S. Karl, M. Keeling, J. Kerr, P. Knowles, J. Langdon, M. Lay, J.A. Lee, T. Lincoln, E. Malone, A. Merliss, D. Merritt, J. Minardo, B. Mooso, C. Orosco, V. Palumbo, M. Parker, T. Parrott, S. Paserchia, G. Pearl, J. Peterson, N. Pickelsimer, T. Purcell, J. Raynor, S. Raziano, C. Richard, T. Richardson, C. Robertson, A. Sage, T. Sanghera, P. Shaw, J. Shoemaker, K. Smith, B. Stephanie, A. Thatcher, H. Theobald, N. Thompson, L. Treasure, T. Tripti, C. Verdi, and V. Worthy

Subjects
Surgery, RD1-811, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Published
2018
Full Text
View/download PDF

10. A Rare Case of Intermittent Claudication Associated with Impaired Arterial Vasodilation

Author

J. J. Posthuma, K. D. Reesink, M. Schütten, C. Ghossein, M. E. Spaanderman, H. ten Cate, and G. Schep

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Exercise-related intermittent claudication is marked by reduced blood flow to extremities caused by either stenosis or impaired vascular function. Although intermittent claudication is common in the elderly, it rarely occurs in the young and middle-aged individuals. Here, we report a case of exercise-related claudication in a 41-year-old woman, in the absence of overt vascular pathology. Using a series of imaging and functional tests, we established that her complaints were due to impaired arterial vasodilation, possibly due to a defect in nitrous oxide-mediated dilation. The symptoms were reversible upon administration of a calcium antagonist, showing reversibility of the vascular impairment. Identification of reversible vascular “stiffness” merits consideration in young and otherwise healthy subjects with claudication of unknown origin.

Published
2017
Full Text
View/download PDF

11. Leukocyte Counts, Myeloperoxidase, and Pregnancy-Associated Plasma Protein A as Biomarkers for Cardiovascular Disease: Towards a Multi-Biomarker Approach

Author

M. B. I. Lobbes, M. E. Kooi, E. Lutgens, A. W. Ruiters, V. Lima Passos, S. H. J. G. Braat, M. Rousch, H. Ten Cate, J. M. A. van Engelshoven, M. J. A. P. Daemen, and S. Heeneman

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

We evaluated leukocyte counts and levels of CRP, fibrinogen, MPO, and PAPP-A in patients with stable and unstable angina pectoris, acute myocardial infarction, and healthy controls. All biomarkers were analyzed again after 6 months. Leukocyte counts and concentrations of fibrinogen, CRP, MPO, and PAPP-A were significantly increased in patients with acute myocardial infarction. Leukocyte counts and concentrations of MPO were significantly increased in patients with unstable angina pectoris compared with controls. After 6 months, leukocyte counts and MPO concentrations were still increased in patients with acute myocardial infarction when compared to controls. Discriminant analysis showed that leukocyte counts, MPO, and PAPP-A concentrations classified study group designation for acute coronary events correctly in 83% of the cases. In conclusion, combined assessment of leukocyte counts, MPO, and PAPP-A was able to correctly classify acute coronary events, suggesting that this could be a promising panel for a multibiomarker approach to assess cardiovascular risk.

Published
2010
Full Text
View/download PDF

13. P520 Thromboembolic and major adverse cardiovascular events among patients in the filgotinib clinical trial programme

Author

J van der Woude, S Schreiber, L Peyrin-Biroulet, Z Szekanecz, E H Choy, P J Stiers, P Van Hoek, K Van Beneden, A de Haas, C Rudolph, and H ten Cate

Subjects
Gastroenterology, General Medicine
Abstract

Background The once-daily, oral, Janus kinase 1 preferential inhibitor filgotinib (FIL) is approved for the treatment of moderately to severely active rheumatoid arthritis (RA) and ulcerative colitis (UC) in the UK, the EU and Japan.1 To further understand the safety profile of FIL across indications, we evaluated the risk of major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) in patients treated with FIL 200 mg (FIL200) or FIL 100 mg (FIL100). Methods An integrated analysis was conducted with RA data from five phase 2/3 trials and two long-term extension (LTE) trials of FIL, and UC data from two phase 2/3 trials and one LTE trial of FIL (herein termed ‘overall’ data). Subgroup analyses by age and cardiovascular (CV) risk factors (excluding age) were conducted. Real-world data were extracted from a systematic literature review. Exposure-adjusted incidence rates (EAIRs) or incidence rates per 100 patient-years of exposure and 95% confidence intervals (CIs) were estimated for MACEs and VTEs. For clinical trial data, MACEs and VTEs included positively adjudicated events only. Results In pooled data, baseline characteristics were generally similar across treatment arms for RA and UC (Tables 1 and 2). In the RA data, MACE EAIRs were 0.29 and 0.41 for the overall FIL200 and FIL100 arms, respectively (Figure 1). MACE IRs were 0.45–0.77 for the general RA population. Higher MACE EAIRs were reported in the subgroup of patients with RA aged ≥65 years vs In the UC data, MACE rates were 0.29, 0.35 and 0.87 in the overall FIL200 and FIL100 arms and in the general UC population, respectively (Figure 2). VTE rates were 0.08, 0.18 and 0.39 in the overall FIL200 and FIL100 arms and in the general UC population, respectively. For both MACE and VTE EAIRs, wide CIs were reported in patients with UC aged ≥65 years and in those with CV risk, owing to low numbers of events and/or patients in these subgroups. Conclusion No association was identified between FIL200 treatment and an increased risk of MACEs or VTEs compared with the general RA or UC population. Patients aged ≥65 years or with CV risk had slightly higher rates of MACEs and VTEs than those in other subgroups; however, overlapping CIs suggested no real difference. Further work should examine real-world data from FIL-treated patients and longer follow-up. 1. https://www.ema.europa.eu/en/medicines/human/EPAR/jyseleca

Published
2023
Full Text
View/download PDF

15. Antithrombotic therapy in high-risk patients after percutaneous coronary intervention; study design, cohort profile and incidence of adverse events

Author

J. M. ten Berg, H. ten Cate, Yvonne M. C. Henskens, P.E.J. van der Meijden, A. W. J. van ’t Hof, Renske H. Olie, Leo Veenstra, Minka J A Vries, Interne Geneeskunde, MUMC+: HVC Pieken Trombose (9), RS: Carim - B04 Clinical thrombosis and Haemostasis, Biochemie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H01 Clinical atrial fibrillation, Cardiologie, Faculteit FHML Centraal, MUMC+: DA CDL Algemeen (9), MUMC+: MA Alg Interne Geneeskunde (9), and MUMC+: HVC Trombosezorg (8)

Subjects
medicine.medical_specialty, Prasugrel, medicine.medical_treatment, Coronary artery disease, VALIDATION, Percutaneous coronary intervention, Anticoagulation, Antithrombotic, medicine, PRASUGREL, ARTERY-DISEASE, TREATMENT PLATELET REACTIVITY, business.industry, Antiplatelet therapy, Bleeding, DUAL ANTIPLATELET THERAPY, medicine.disease, Clopidogrel, BLEEDING SCORE, DEFINITION, CLOPIDOGREL, Cohort, Emergency medicine, Original Article, Antithrombotic treatment, IMPLANTATION, Cardiology and Cardiovascular Medicine, business, CONSENSUS, Ticagrelor, medicine.drug, Cohort study
Abstract

Background Patients with multiple clinical risk factors are a complex group in whom both bleeding and recurrent ischaemic events often occur during treatment with dual/triple antithrombotic therapy after percutaneous coronary intervention. Decisions on optimal antithrombotic treatment in these patients are challenging and not supported by clear guideline recommendations. A prospective observational cohort study was set up to evaluate patient-related factors, platelet reactivity, genetics, and a broad spectrum of biomarkers in predicting adverse events in these high-risk patients. Aim of the current paper is to present the study design, with a detailed description of the cohort as a whole, and evaluation of bleeding and ischaemic outcomes during follow-up, thereby facilitating future research questions focusing on specific data provided by the cohort. Methods We included patients with ≥ 3 predefined risk factors who were treated with dual/triple antithrombotic therapy following PCI. We performed a wide range of haemostatic tests and collected all ischaemic and bleeding events during 6–12 months follow-up. Results We included 524 high-risk patients who underwent PCI within the previous 1–2 months. All patients used a P2Y12 inhibitor (clopidogrel n = 388, prasugrel n = 61, ticagrelor n = 75) in combination with aspirin (n = 397) and/or anticoagulants (n = 160). Bleeding events were reported by 254 patients (48.5%), necessitating intervention or hospital admission in 92 patients (17.5%). Major adverse cardiovascular events (myocardial infarction, stroke, death) occurred in 69 patients (13.2%). Conclusion The high risk for both bleeding and ischaemic events in this cohort of patients with multiple clinical risk factors illustrates the challenges that the cardiologist faces to make a balanced decision on the optimal treatment strategy. This cohort will serve to answer several future research questions about the optimal management of these patients on dual/triple antithrombotic therapy, and the possible value of a wide range of laboratory tests to guide these decisions.

Published
2021
Full Text
View/download PDF

16. Atrial fibrillation and age synergistically increase clotting potential and promote atrial structural remodeling in goats

Author

E D’ Alessandro, B Scaf, V Sobota, A Van Hunnik, M Kuiper, J Winters, R Van Oerle, HMH Spronk, FA Van Nieuwenhoven, H Ten Cate, S Verheule, and U Schotten

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Netherlands Heart Foundation, European Union Background Age is a risk factor for atrial fibrillation (AF) as well as for stroke in patients with AF. However, the effect of ageing on AF mechanisms and on coagulation activity is not well understood. Purpose To evaluate the effect of age and AF on coagulation activity, AF characteristics, and atrial structural remodeling. Methods Four groups of female goats were investigated: Young sham (Y-Sh: sinus rhythm, 8 years old, n=6), and Old AF (O-AF, 4 weeks of AF, >8 years old, n=8). Groups were matched for body weight. AF was maintained using implantable pacemakers in both AF groups. Clotting potential, expressed as the ability of activated plasma to generate thrombin, was measured using tissue factor-induced thrombin generation assays at baseline and 4 weeks (final). A terminal experiment was performed with atrial contact mapping to study electrophysiological AF properties and to collect atrial tissue for histological analysis. Results Thrombin generation analysis showed that 4 weeks of AF induced a significant increase in clotting potential in old, but not in young goats. AF complexity and hemodynamics were not affected by age alone. AF, however, significantly increased the right atrial pressure in old (O-Sh: 6.4±1.9 vs. O-AF: 11.4±3.1 mmHg, p=0.02), but not in young goats. AF induced atrial myocyte hypertrophy and left atrial epicardial endomysial fibrosis in old goats, while this was not the case in young goats. Conclusion Four weeks of AF and advanced age synergistically enhanced coagulation potential and promoted atrial structural remodeling in goats. Complexity of atrial conduction was affected by AF, but not by age.

Published
2022
Full Text
View/download PDF

17. The 3S-AF scheme, rather than the 4S-AF scheme, predicts progression in patients with paroxysmal atrial fibrillation: data from RACE V study

Author

V Artola, B Geelhoed, M Van Lande, N Khalilian Ekrami, R De With, V Weberndorfer, D Linz, H Ten Cate, H Spronk, T Koldenhof, RG Tieleman, U Schotten, HJG Crijns, I Van Gelder, and M Rienstra

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON 2014-9: Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling, and Vascular destabilisation in the progression of AF (RACE V). Purpose To assess whether the 4S-AF scheme predicts AF progression, cardiovascular hospitalizations and mortality in patients with self-terminating paroxysmal AF. Methods We analysed well-phenotyped patients with paroxysmal AF from the Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF (RACE V study). From the 417 patients included in RACE V, 341 (82%) had echocardiography available. Patient had continuous monitoring with implantable loop recorders or pacemakers. Primary endpoint of RACE V was AF progression, defined as (1) progression to persistent or permanent AF, or (2) progression of PAF with >3% burden increase. Median follow-up was 2.2 (1.6-2.8) years. Patients were given a score based on the components of the 4S-AF scheme (St, stroke=1; Sy, symptoms=2; Sb, Severity of burden=2; Su, Substrate=5) to a total maximum of 10 points (table 1). Left atrial fibrosis was not evaluated in our patients and therefore not included into the score. A score of zero (0) in the AF burden domain was given to all patients due to the presence of paroxysmal AF in all. A modified 4S-AF scheme was designed by eliminating the symptom domain, resulting in a 3S-AF scheme. Logistic regression was performed to assess AF progression and the composite endpoint of cardiovascular hospitalizations and mortality, C-statistic to assess prediction of the score, for both using the 4S-AF and the modified 3S-AF scheme. Results Mean age was 65 (IQR 58-71) years, 149 (44%) were women, 103 (48%) had heart failure (HFrEF 6 [2%]; HFpEF 97 [46%]), 276 (81%) had hypertension, 38(11%) had coronary artery disease and 162(48%) atherosclerosis (Table 2, Panel A). Based on the 4S-AF scheme, patients had an average score of 4.5±1.3, the majority had a score under 5 (n=272, 80%), 20% of the score was explained by the S1 domain (stroke), 16% of the score was explained by the Sy domain (symptoms), and 64% of the score was explained by the Su domain (substrate). The score points from the 4S-AF scheme did not predict the risk of AF progression (OR 1.08 95%CI 0.84 – 1.39, C-statistic 0.53) nor the composite endpoint (OR 0.79 95%CI 0.53 – 1.20, C-statistic 0.42, Table 2, Panel B). However, when excluding the Sy domain (symptoms) from the scheme, the 3S-AF scheme, it predicted the risk of progression (OR 1.54 95%CI 1.12 – 2.18, C-statistic 0.61, Table 2, Panel B). Conclusion In paroxysmal AF patients the 4S-AF scheme does not predict AF progression nor the composite endpoint cardiovascular hospitalizations and mortality. Although symptoms are important for choosing the treatment strategy, they may be less relevant to determine AF progression, cardiovascular hospitalization and mortality. To assess progression, the 3S-AF scheme may be more appropriate.

Published
2022
Full Text
View/download PDF

18. Organisation of care for patients using direct oral anticoagulants

Author

H. ten Cate, Simon Schalla, N L Damen, A. J. ten Cate-Hoek, Anouk J. W. Gulpen, J K van Dijk, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), Interne Geneeskunde, MUMC+: HVC Trombosezorg (8), MUMC+: MA Alg Interne Geneeskunde (9), MUMC+: HVC Pieken Trombose (9), RS: Carim - B04 Clinical thrombosis and Haemostasis, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H01 Clinical atrial fibrillation, and Biochemie

Subjects
medicine.medical_specialty, Anticoagulation care, 030204 cardiovascular system & hematology, GUIDELINES, WARFARIN, Direct oral anticoagulation, EDOXABAN, 03 medical and health sciences, 0302 clinical medicine, Daily practice, MANAGEMENT, medicine, In patient, Functional resonance analysis method, 030212 general & internal medicine, Intensive care medicine, Point of View, Stroke, business.industry, DABIGATRAN, RIVAROXABAN, Atrial fibrillation, Systemic embolism, medicine.disease, APIXABAN, Resonance analysis, Cardiology and Cardiovascular Medicine, business
Abstract

Direct oral anticoagulants (DOACs) are recommended by several scientific societies as first-line therapy for the prevention of stroke and systemic embolism in patients with atrial fibrillation. However, there is uncertainty regarding the organisation of anticoagulation care, with various caregivers being involved. Patients and caregivers are often confronted by uncertainty about the coordination of treatment. With the functional resonance analysis method we visualised the process of anticoagulation care in daily practice in the Maastricht region. This resulted in recommendations on how to improve the organisation of anticoagulation care for DOAC patients.

Published
2020
Full Text
View/download PDF

27. Direct oral anticoagulant blood level monitoring in daily practice

Author

Roisin Bavalia, Barbara A. Hutten, Dionne C.W. Braeken, Michiel Coppens, J.E. Veenhuizen, H. ten Cate, Saskia Middeldorp, Anouk J. W. Gulpen, R.C.C. Hengeveld, An K. Stroobants, Yvonne M. C. Henskens, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Graduate School, Laboratory for General Clinical Chemistry, Epidemiology and Data Science, ACS - Diabetes & metabolism, APH - Aging & Later Life, and APH - Health Behaviors & Chronic Diseases

Subjects
Blood level, medicine.medical_specialty, Future studies, medicine.drug_class, Daily practice, Diseases of the circulatory (Cardiovascular) system, Medicine, In patient, skin and connective tissue diseases, DOAC levels, Thrombin inhibitors, business.industry, Anticoagulant, Hematology, Patient specific, medicine.disease, Comorbidity, Factor Xa inhibitors, Anti-Xa level, RC666-701, Anti-IIa level, Emergency medicine, Oral anticoagulant, sense organs, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract

Introduction Routine monitoring is not required in direct oral anticoagulant (DOAC) treatment, yet it is frequently performed. Guidance on the interpretation and management of DOAC level measurements is lacking and it is key to investigate which patients would benefit from monitoring. Our aims were to investigate why DOAC levels are requested and if they lead to changes in anticoagulant management. Methods We retrospectively collected all clinically requested DOAC levels from 2012 until 2019 in two Dutch academic hospitals. Clinical data with regard to the first DOAC level of every patient was collected by chart review. Primary outcomes were settings, indications and changes in anticoagulant management of DOAC level measurement. In addition, we compared demographic and clinical characteristics in patients with and without changes in anticoagulant management. Results In total, we included 604 DOAC levels. The majority was requested in an outpatient setting by the department of internal medicine. In 270 (45%) cases we identified a patient specific indication, with evaluation of DOAC accumulation being the most frequently requested. Of all 604 DOAC levels, 159 (26%) were followed by changes in anticoagulation management. The large majority of changes occurred in patients that had a patient specific indication. Patients who underwent changes were older and had more comorbidity than patients who did not (n ​= ​445). Conclusion Almost half of the DOAC levels with a specific indication for monitoring were followed by a change in anticoagulant management. Future studies should investigate the relation between DOAC levels, the changes in anticoagulant management and clinical outcomes.

Published
2021

31. Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave

Author

Lucia J.M. Kroft, Sje Braken, C Marechal, J Leentjens, H Endeman, B C T van Bussel, F.A. Klok, Marieke J. H. A. Kruip, M A M Stals, Diederik Gommers, C Visser, F H J Kaptein, C van Guldener, M V Huisman, L Tjepkema, E. de Jonge, H. ten Cate, M E Kevenaar, Y L Soei, Mjjh Grootenboers, Suzanne C. Cannegieter, Dutch Covid Thrombosis Coalition, S Koster, Jacobus Burggraaf, Nicole P. Juffermans, K.M. Kant, MUMC+: MA Medische Staf IC (9), RS: CAPHRI - R5 - Optimising Patient Care, Interne Geneeskunde, MUMC+: HVC Trombosezorg (8), MUMC+: MA Alg Interne Geneeskunde (9), MUMC+: HVC Pieken Trombose (9), RS: Carim - B04 Clinical thrombosis and Haemostasis, Intensive Care, and Hematology

Subjects
Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Hospitalized patients, Critical Illness, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Netherlands/epidemiology, 030204 cardiovascular system & hematology, Venous Thromboembolism/etiology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, 80 and over, Medicine, Humans, Cumulative incidence, Netherlands, Aged, Proportional Hazards Models, Aged, 80 and over, SARS-CoV-2, Proportional hazards model, business.industry, Incidence (epidemiology), Incidence, SARS-CoV-2/isolation & purification, Hazard ratio, COVID-19, Anticoagulants, Thrombosis, Venous Thromboembolism, Hematology, Middle Aged, Confidence interval, Hospitalization, Critical Illness/mortality, 030220 oncology & carcinogenesis, COVID-19/complications, Diagnostic imaging, Blood coagulation disorders, Female, Pulmonary Embolism/etiology, Pulmonary Embolism, business, Thrombosis/etiology, Thrombotic complication
Abstract

Introduction In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. Methods We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. Results In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8–15%), 16% (13–19%) and 21% (17–25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41–0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65–1.2). Conclusions Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted., Highlights • Half overall mortality in the second wave compared to first wave COVID-19 patients. • Still high incidence of thrombotic complications in second wave. • More subsegmental PE in second wave than in first wave.

Published
2021

32. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory

Author

Sarah Lessire, Thomas Lecompte, Isabelle Gouin-Thibault, Yves Gruel, Giuseppe Lippi, Sophie Testa, Jonathan Douxfils, H. ten Cate, J. M. Dogne, Bernard Chatelain, R. L. Medcalf, Michael Hardy, François Mullier, CHU UCL Namur, Hôpitaux Universitaires de Genève (HUG), Université de Genève = University of Geneva (UNIGE), Université de Namur [Namur] (UNamur), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Monash University [Clayton], Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Università degli studi di Verona = University of Verona (UNIVR), Fonds National de la Recherche Scientifique Fonds de la Recherche Scientifique - FNRS [40002796], Université de Genève (UNIGE), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Verona (UNIVR), UCL - (MGD) Service d'anesthésiologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (MGD) Laboratoire de biologie clinique

Subjects
medicine.medical_specialty, Thrombin generation, PARTIAL THROMBOPLASTIN TIME, Anticoagulation, COVID-19, Coagulopathy, D-dimers, Fibrinolysis, Hemostasis, Heparin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], D-DIMER, D-dimers, Review, 030204 cardiovascular system & hematology, PLASMINOGEN-ACTIVATOR INHIBITOR-1, Fibrinogen, MONITORING UNFRACTIONATED HEPARIN, SOLUBLE FIBRIN, 03 medical and health sciences, Anticoagulation, 0302 clinical medicine, CLINICAL CHARACTERISTICS, LOW FIBRINOGEN LEVELS, Coagulopathy, Heparin-induced thrombocytopenia, Fibrinolysis, medicine, 030212 general & internal medicine, PNEUMATIC TUBE SYSTEM, Intensive care medicine, CITRATE STORAGE, Prothrombin time, VENOUS THROMBOEMBOLISM, Hemostasis, medicine.diagnostic_test, Viscoelastic tests, business.industry, lcsh:RC633-647.5, Heparin, COVID-19, Thrombosis, Hematology, lcsh:Diseases of the blood and blood-forming organs, medicine.disease, 3. Good health, HEPARIN-INDUCED THROMBOCYTOPENIA, business, medicine.drug, Partial thromboplastin time
Abstract

Coronavirus disease 2019 (COVID-19) is associated with extreme inflammatory response, disordered hemostasis and high thrombotic risk. A high incidence of thromboembolic events has been reported despite thromboprophylaxis, raising the question of a more effective anticoagulation. First-line hemostasis tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and D-dimers are proposed for assessing thrombotic risk and monitoring hemostasis, but are vulnerable to many drawbacks affecting their reliability and clinical relevance. Specialized hemostasis-related tests (soluble fibrin complexes, tests assessing fibrinolytic capacity, viscoelastic tests, thrombin generation) may have an interest to assess the thrombotic risk associated with COVID-19. Another challenge for the hemostasis laboratory is the monitoring of heparin treatment, especially unfractionated heparin in the setting of an extreme inflammatory response. This review aimed at evaluating the role of hemostasis tests in the management of COVID-19 and discussing their main limitations.

Published
2020
Full Text
View/download PDF

33. Antithrombotic Therapy: Prevention and Treatment of Atherosclerosis and Atherothrombosis

Author

R H, Olie, P E J, van der Meijden, H M H, Spronk, and H, Ten Cate

Subjects
Aspirin, Fibrinolytic Agents, Animals, Humans, Atherosclerosis, Platelet Aggregation Inhibitors, Clopidogrel
Abstract

Atherosclerosis is a multifactorial vascular disease that develops in the course of a lifetime. Numerous risk factors for atherosclerosis have been identified, mostly inflicting pro-inflammatory effects. Vessel injury, such as occurring during erosion or rupture of atherosclerotic lesions triggers blood coagulation, in attempt to maintain hemostasis (protect against bleeding). However, thrombo-inflammatory mechanisms may drive blood coagulation such that thrombosis develops, the key process underlying myocardial infarction and ischemic stroke (not due to embolization from the heart). In the blood coagulation system, platelets and coagulation proteins are both essential elements. Hyperreactivity of blood coagulation aggravates atherosclerosis in preclinical models. Pharmacologic inhibition of blood coagulation, either with platelet inhibitors, or better documented with anticoagulants, or both, limits the risk of thrombosis and may potentially reverse atherosclerosis burden, although the latter evidence is still based on animal experimentation.Patients at risk of atherothrombotic complications should receive a single antiplatelet agent (acetylsalicylic acid, ASA, or clopidogrel); those who survived an atherothrombotic event will be prescribed temporary dual antiplatelet therapy (ASA plus a P2Y12 inhibitor) in case of myocardial infarction (6-12 months), or stroke (6 weeks), followed by a single antiplatelet agent indefinitely. High risk for thrombosis patients (such as those with peripheral artery disease) benefit from a combination of an anticoagulant and ASA. The price of gained efficacy is always increased risk of (major) bleeding; while tailoring therapy to individual needs may limit the risks to some extent, new generations of agents that target less critical elements of hemostasis and coagulation mechanisms are needed to maintain efficacy while reducing bleeding risks.

Published
2020

34. Complex clinical scenarios with the use of direct oral anticoagulants in patients with atrial fibrillation: a multidisciplinary expert advisory board

Author

N. van Es, J. M. ten Berg, H. B. Bearda Bakker, Michiel Rienstra, D. J. Drenth, Geert-Jan Geersing, G.J. de Borst, H. ten Cate, Martin E.W. Hemels, Bart A. Mulder, and L. J. Kappelle

Subjects
medicine.medical_specialty, ANTITHROMBOTIC THERAPY, PERCUTANEOUS CORONARY INTERVENTION, Review Article, 030204 cardiovascular system & hematology, GUIDELINES, WARFARIN, european-society, 03 medical and health sciences, Anticoagulation, THROMBOEMBOLISM, 0302 clinical medicine, prevention, Multidisciplinary approach, Daily practice, Stroke prevention, MANAGEMENT, Medicine, In patient, 030212 general & internal medicine, Co-morbidities, Intensive care medicine, rivaroxaban, Stroke, METAANALYSIS, Oral anticoagulation, Rivaroxaban, business.industry, Atrial fibrillation, medicine.disease, stroke, Cardiology and Cardiovascular Medicine, business, medicine.drug, Direct oral anticoagulant
Abstract

The risk of developing atrial fibrillation (AF) and the risk of stroke both increase with advancing age. As such, many individuals have, or will develop, an indication for oral anticoagulation to reduce the risk of stroke. Currently, a large number of anticoagulants are available, including vitamin K antagonists, direct thrombin or factor Xa inhibitors (the last two also referred to as direct oral anticoagulants or DOACs), and different dosages are available. Of the DOACs, rivaroxaban can be obtained in the most different doses: 2.5 mg, 5 mg, 15 mg and 20 mg. Many patients develop co-morbidities and/or undergo procedures that may require the temporary combination of anticoagulation with antiplatelet therapy. In daily practice, clinicians encounter complex scenarios that are not always described in the treatment guidelines, and clear recommendations are lacking. Here, we report the outcomes of a multidisciplinary advisory board meeting, held in Utrecht (The Netherlands) on 3 June 2019, on decision making in complex clinical situations regarding the use of DOACs. The advisory board consisted of Dutch cardiovascular specialists: (interventional) cardiologist, internist, neurologist, vascular surgeon and general practitioners invited according to personal title and specific field of expertise.

Published
2020

35. Tissue factor (:Factor VIIa) in the heart and vasculature: More than an envelope

Author

Henri M. H. Spronk, H. ten Cate, Elisa D'Alessandro, and Jens Posma

Subjects
0301 basic medicine, Inflammation, Factor VIIa, 030204 cardiovascular system & hematology, PROTEASE-ACTIVATED RECEPTORS, FACTOR PATHWAY INHIBITOR, FACTOR EXPRESSION, 03 medical and health sciences, Tissue factor, chemistry.chemical_compound, Mice, 0302 clinical medicine, Thrombin, medicine, Animals, Humans, Platelet, FACTOR XA, CARDIAC FIBROSIS, Factor VII, business.industry, Heart, Hematology, BLOOD-VESSEL FORMATION, Blood coagulation, Fibrosis, Cell biology, FACTOR CYTOPLASMIC DOMAIN, 030104 developmental biology, chemistry, Coagulation, Hemostasis, ENDOTHELIAL GROWTH-FACTOR, ATRIAL-FIBRILLATION, Endothelium, Vascular, Signal transduction, medicine.symptom, business, ARTERIAL THROMBOSIS, medicine.drug
Abstract

Blood coagulation comprises a complex cellular and molecular mechanism that maintains vascular integrity, protects against bleeding (hemostasis) and responds to injury. However, several elements of the coagulation system, including several coagulation factors and platelets, are also involved in other physiological and pathological processes. Tissue factor (TF) is a cell surface glycoprotein expressed in a vast variety of cell types and essential for hemostasis. Upon exposure of the TF-rich subendothelium to the blood stream, Factor VII (FVII) can bind to TF. TF subsequently facilitates the activation of FVII into activated FVII (FVIIa) thereby initiating the extrinsic coagulation pathway followed by the activation of FX and thrombin formation. Besides its hemostatic role in the vasculature, the TF:FVIIa pathway is active in many other compartments and organs where it can take part and mediate different physiological and pathological processes. The so-called non-hemostatic functions of TF:VIIa play a role in diverse processes such as inflammation, atherosclerosis and vascular and cardiac remodeling. This narrative review aims to reassess the most important and recent findings regarding the complex signaling pathways initiated by the TF:FVIIa complex, with an emphasis on the heart and blood vessels. Understanding how the mechanisms of TF:FVIIa signaling contribute to both physiological and pathological processes, is one of the keys to the development of new treatment strategies in cardiovascular disease.

Published
2018
Full Text
View/download PDF

36. Pleiotropic effects of the hemostatic system

Author

Henri M. H. Spronk, H. ten Cate, and Bram Kremers

Subjects
0301 basic medicine, anticoagulants, Cell signaling, Proteases, 030204 cardiovascular system & hematology, ACUTE CORONARY SYNDROME, Proinflammatory cytokine, 03 medical and health sciences, Tissue factor, 0302 clinical medicine, Thrombin, medicine, PROTEINASE-ACTIVATED RECEPTOR-2, coagulation, FACTOR XA, Receptor, thrombosis, E-DEFICIENT MICE, Chemistry, protease-activated receptors, SMOOTH-MUSCLE, Hematology, ENDOTHELIAL-CELLS, Cell biology, 030104 developmental biology, TISSUE FACTOR, Coagulation, ATHEROSCLEROTIC LESION FORMATION, CARDIOVASCULAR-DISEASE, ATRIAL-FIBRILLATION, atherosclerosis, Signal transduction, medicine.drug
Abstract

Atherothrombosis is characterized by the inflammatory process of atherosclerosis combined with a hypercoagulable state leading to superimposed thrombus formation. In atherosclerotic plaques, cell signaling can occur via protease-activated receptors (PARs), four of which have been identified so far (PAR1-PAR4). Proteases that are able to activate PARs can be produced systemically, but also at the sites of lesions, and they include thrombin and activated factor X. After PAR activation, downstream signaling can lead to both proinflammatory effects and a hypercoagulable state. Which specific effect occurs depends on the type of protease and activated PAR, and the site of activation. Hypercoagulable effects are mainly exerted through PAR1 and PAR4, whereas proinflammatory responses are mostly seen after PAR1 and PAR2 activation. PAR signaling pathways contribute to atherothrombosis, suggesting that inhibition of these pathways possibly prevents cardiovascular events based on this pathophysiological mechanism. In this review, we highlight the pathways by which PAR activation leads to proinflammatory responses and a hypercoagulable state. Furthermore, we give an overview of potential pharmacological treatment targets that promote vascular protection.

Published
2018
Full Text
View/download PDF

37. Predictive value of D-dimer testing for the diagnosis of venous thrombosis in unusual locations: A systematic review

Author

Francisco Galeano-Valle, Bram Kremers, Lucía Ordieres-Ortega, Pablo Demelo-Rodríguez, A. J. ten Cate-Hoek, and H. ten Cate

Subjects
medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Cochrane Library, Sensitivity and Specificity, Fibrin Fibrinogen Degradation Products, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Upper Extremity Deep Vein Thrombosis, D-dimer, medicine, Humans, DEEP-VEIN THROMBOSIS, education, UPPER EXTREMITY DEEP, Venous Thrombosis, education.field_of_study, business.industry, CLINICAL-FEATURES, Hematology, medicine.disease, Thrombosis, Portal vein thrombosis, Venous thrombosis, Splanchnic vein thrombosis, 030220 oncology & carcinogenesis, Predictive value of tests, RISK-FACTORS, Radiology, business
Abstract

Background The value of D-dimer testing for the diagnosis of thrombosis in unusual sites is not properly established and evidence is scarce. We performed a systematic review of the literature. Methods The search was conducted in MEDLINE and Cochrane Library for papers published in the last 10 years including different presentations of thrombosis in unusual sites. Twenty-three articles were included, from January 1, 2008, to December 31, 2018, comprising 3378 patients with thrombosis in unusual sites (upper extremity deep vein thrombosis, cerebral vein thrombosis and splanchnic vein thrombosis). The Newcastle-Ottawa scale was used to assess the quality of the studies. Results Two articles were related to upper extremity thrombosis, showing a high sensitivity and negative predictive value for D-dimer testing. Twelve articles concerned cerebral vein thrombosis, concluding that the timing of D-dimer testing was important, and that patients with a shorter duration of symptoms showed higher D-dimer levels. Sensitivity and specificity in these patients ranged from 58% to 97% and from 77% to 97.5%, respectively. Nine articles were related to splanchnic vein thrombosis. One described a population of patients with mesenteric venous thrombosis, and the rest included patients with portal vein thrombosis. The D-dimer testing methods and the proposed cut-off levels were remarkably different among the included studies. Conclusion D-dimer testing should not be currently recommended for the diagnosis of thrombosis in unusual sites as a first line diagnostic tool. The development of algorithms combining biomarkers such as D-dimer and clinical decision tools could improve the diagnosis.

Published
2019

38. The Relation between Coagulant and Vascular Function in Adult Survivors of Childhood Cancer

Author

Natalie Arnold, Marie A. Neu, Marina Panova-Noeva, Hiltrud Merzenich, Susan Eckerle, J.H. Prochaska, H. ten Cate, Thomas Münzel, Bianca Wagner, K.J. Lackner, P.S. Wild, Astrid Schneider, Jörg Faber, Markus Nagler, and Henri M. H. Spronk

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, Childhood cancer, medicine, Vascular function, business
Published
2019
Full Text
View/download PDF

39. P4403Inhibitory mechanisms of very low dose rivaroxaban in non-ST-elevation myocardial infarction

Author

M. Gawaz, Dominik Rath, Lisa K. Jennings, Tobias Geisler, Roland Tegtmeyer, Nada Alnaggar, H. ten Cate, Oliver Borst, Sascha Geue, Patrick Muenzer, Dominick J. Angiolillo, Henri M. H. Spronk, and Johan W. M. Heemskerk

Subjects
Rivaroxaban, medicine.medical_specialty, business.industry, St elevation myocardial infarction, Internal medicine, Low dose, Cardiology, Medicine, Cardiology and Cardiovascular Medicine, business, medicine.drug
Published
2018
Full Text
View/download PDF

40. 355Effects of the PAR-1 receptor antagonist vorapaxar on platelet activation and coagulation biomarkers in patients with stable coronary artery disease

Author

Renske H. Olie, H. ten Cate, Dennis W.T. Nilsen, P.E.J. van der Meijden, Vernon V.S. Bonarjee, Henri M. H. Spronk, R. van Oerle, and Ståle Barvik

Subjects
medicine.medical_specialty, business.industry, medicine.drug_class, Coronary arteriosclerosis, medicine.disease, Receptor antagonist, Coronary artery disease, Coagulation, Internal medicine, medicine, Cardiology, In patient, Platelet activation, Cardiology and Cardiovascular Medicine, business, Vorapaxar, medicine.drug
Published
2018
Full Text
View/download PDF

41. Direct oral anticoagulants: When to consider laboratory testing?

Author

A. J. ten Cate-Hoek, Renske H. Olie, Yvonne M. C. Henskens, H. ten Cate, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: HVC Pieken Trombose (9), and MUMC+: DA CDL Algemeen (9)

Subjects
CHRONIC KIDNEY-DISEASE, medicine.medical_specialty, Clinical Biochemistry, direct oral anticoagulant, Thromboembolic stroke, 030204 cardiovascular system & hematology, Laboratory testing, 03 medical and health sciences, 0302 clinical medicine, Dose adjustment, medicine, Humans, 030212 general & internal medicine, Laboratory assay, Intensive care medicine, anticoagulation, OLDER-ADULTS, thrombosis, RISK, business.industry, Clinical Laboratory Techniques, laboratory assay, Biochemistry (medical), Anticoagulants, Disease Management, Hematology, General Medicine, medicine.disease, Drug accumulation, bleeding, Thrombosis, ATRIAL-FIBRILLATION, Drug Monitoring, business, Venous thromboembolism
Abstract

Introduction: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic stroke, as well as for prevention and treatment of venous thromboembolism. Dose adjustment based on laboratory testing is not required; however, there are several potential situations that deserve insight into a DOAC plasma activity level. Methods: Based on a series of real-life case descriptions, we discuss indications for dedicated DOAC testing, as well as the interpretation and consequences. Results: Testing of DOACs in selected patients may help to better interpret acute situations such as bleeding or thrombosis while on anticoagulation, but also suspected drug failure, drug accumulation, or lack of adherence. Conclusion: The 24/7 availability of target-specific tests with adequate calibration is recommended to support the clinician in the interpretation and where needed adjustment of the management of patients on DOACs. The relevance of laboratory-guided DOAC management, particularly in the elderly, merits further study.

Published
2018

42. Antithrombotic medication in cancer-associated thrombocytopenia: Current evidence and knowledge gaps

Author

H. ten Cate, Anna Falanga, Avi Leader, Galia Spectre, Erik A M Beckers, Leader, A, Ten Cate, H, Spectre, G, Beckers, E, and Falanga, A

Subjects
medicine.medical_specialty, Acute coronary syndrome, 030204 cardiovascular system & hematology, ACUTE CORONARY SYNDROME, HEMATOLOGIC MALIGNANCIES, RECURRENT VENOUS THROMBOEMBOLISM, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Neoplasms, Antithrombotic, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, Platelet transfusion, Aspirin, business.industry, Arterial thrombosi, Bleeding, Anticoagulant, Arterial thrombosis, ELEVATION MYOCARDIAL-INFARCTION, LOW-DOSE ASPIRIN, Anticoagulants, Hematology, MOLECULAR-WEIGHT HEPARIN, medicine.disease, STEM-CELL-TRANSPLANTATION, Thrombosis, Thrombocytopenia, PROPHYLACTIC PLATELET TRANSFUSIONS, Regimen, Platelet aggregation inhibitor, Oncology, ATRIAL-FIBRILLATION, RISK-FACTORS, Neoplasm, business, Fibrinolytic agent, Platelet Aggregation Inhibitors, medicine.drug, Venous thromboembolism
Abstract

In cancer patients, antithrombotic medications (i.e. anticoagulation or antiplatelet therapy) are frequently prescribed for prior or new indications such as venous thromboembolism or stoke prevention in atrial fibrillation. Balancing the risks of bleeding and thrombosis during periods of thrombocytopenia represents a significant challenge. Management is informed mainly by expert opinion and several recent retrospective studies on venous thromboembolism. The main management options include no change, temporarily withholding antithrombotic therapy, reducing dose, changing the regimen, and increasing the platelet transfusion threshold. Important recent advances in knowledge include the prognostic importance and apparent safety of aspirin in acute myocardial infarction and thrombocytopenia and data suggesting a low risk of recurrent venous thromboembolism in autologous stem cell transplantation patients who had anticoagulation withheld. This paper will review the literature on antithrombotic medication in thrombocytopenic patients with cancer. The significant knowledge gaps will be summarized and considerations for practice and research will be provided.

Published
2018

43. Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis

Author

Mayken Visser, Ömer Erküner, Magdolna Nagy, Renske H. Olie, Jelle J. Posthuma, Nathan L Asquith, R H van Gorp, Athan Kuliopulos, Constance C.F.M.J. Baaten, Ulrich Schotten, J Winters, Anouk J. W. Gulpen, Elisa D'Alessandro, Paul Harrison, Diederik W.J. Dippel, Thomas Renné, Johan W. M. Heemskerk, Frederique E C M Peeters, P.E.J. van der Meijden, Pieter H. Reitsma, Elton A. M. P. Dudink, Yvonne M. C. Henskens, N A Alshaikh, Jens Posma, Henri M. H. Spronk, Joylene E. Siland, Suzanne Zwaveling, T Baglin, S Dólleman, Avi Leader, Harry J.G.M. Crijns, Martijn Moorlag, Philip Wenzel, Robert A. S. Ariëns, W Chayouâ, Paul Declerck, Fraser L. Macrae, Jürgen H. Prochaska, Alexandra C.A. Heinzmann, Alisa S. Wolberg, Daniëlle Coenen, Rory R. Koenen, A C van der Wal, Wolfram Ruf, Marco Heestermans, H. ten Cate, Gordon D.O. Lowe, Billy Scaf, Harry R. Büller, A. J. ten Cate-Hoek, H.M.M. van Beusekom, Nigel Mackman, Anders Själander, Jonathan Douxfils, Joost C. M. Meijers, Kartika Ratna Pertiwi, Laurent O. Mosnier, Tanja Vajen, L van der Vorm, Minka J A Vries, V J Strijbis, T Padro, John W. Eikelboom, Erasmus MC other, Cardiology, and Neurology

Subjects
0301 basic medicine, medicine.medical_specialty, anticoagulants, ADJUST ANTIPLATELET THERAPY, PERCUTANEOUS CORONARY INTERVENTION, 030204 cardiovascular system & hematology, arterial thrombosis, Article, antiplatelet therapy, ACTIVATED PROTEIN-C, RED-BLOOD-CELLS, 03 medical and health sciences, 0302 clinical medicine, VITAMIN-K ANTAGONISTS, Internal medicine, atherothrombosis, Ischaemic stroke, NONVALVULAR ATRIAL-FIBRILLATION, medicine, Platelet, atrial fibrillation, ACUTE ISCHEMIC-STROKE, coagulation, ATOMIC-FORCE MICROSCOPY, Cardiovascular mortality, ischaemic stroke, Atomic force microscopy, business.industry, Consensus conference, Hematology, medicine.disease, Thrombosis, 030104 developmental biology, myocardial infarction, Coagulation, platelets, DIRECT ORAL ANTICOAGULANTS, Cardiology, Position paper, SYMPTOMATIC VENOUS THROMBOEMBOLISM, atherosclerosis, business
Abstract

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Published
2018
Full Text
View/download PDF

44. Laboratory Testing In Patients Treated With Direct Oral Anticoagulants:A Practical Guide For Clinicians

Author

J. M. Dogne, Sarah Lessire, H. ten Cate, Peter Verhamme, Walter Ageno, François Mullier, Jonathan Douxfils, and C-M Samama

Subjects
Administration, Oral, COAGULATION ASSAYS, 030204 cardiovascular system & hematology, Laboratory testing, chemistry.chemical_compound, Practical management, 0302 clinical medicine, HEMOSTASIS TESTS, Rivaroxaban, Edoxaban, Apixaban, dabigatran, rivaroxaban, Blood coagulation test, INVASIVE PROCEDURES, Anticoagulant, Hematology, Dabigatran, 030220 oncology & carcinogenesis, Blood Coagulation Tests, Drug Monitoring, medicine.drug, medicine.medical_specialty, DABIGATRAN ETEXILATE, PLASMA-CONCENTRATIONS, medicine.drug_class, EX-VIVO SAMPLES, apixaban, Hemorrhage, Antithrombins, 03 medical and health sciences, Predictive Value of Tests, medicine, Humans, Intensive care medicine, Blood Coagulation, business.industry, PERIPROCEDURAL MANAGEMENT, Anticoagulants, Reproducibility of Results, IN-VITRO, PAIN-PROCEDURES, Clinical trial, chemistry, laboratory testing, Betrixaban, ATRIAL-FIBRILLATION, edoxaban, practical management, business, Factor Xa Inhibitors
Abstract

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors. ispartof: Journal of Thrombosis and Haemostasis vol:16 issue:2 pages:209-219 ispartof: location:England status: published

Published
2018
Full Text
View/download PDF

45. The hypercoagulable profile of patients with stent thrombosis

Author

R. van Oerle, H. ten Cate, J. M. ten Berg, Henri M. H. Spronk, Thea C. Godschalk, Rinske Loeffen, Christian M. Hackeng, Promovendi CD, MUMC+: DA CDL Analytisch cluster 1K (9), Interne Geneeskunde, Biochemie, MUMC+: MA Alg Interne Geneeskunde (9), RS: CARIM - R1 - Thrombosis and haemostasis, and MUMC+: DA CDL Algemeen (9)

Subjects
Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Coronary Artery Disease, Thrombomodulin, Thrombophilia, Thrombin, Percutaneous Coronary Intervention, Coronary thrombosis, Predictive Value of Tests, Risk Factors, Internal medicine, Coronary stent, medicine, Humans, Blood Coagulation, Blood coagulation test, Aged, Netherlands, business.industry, Coronary Thrombosis, Middle Aged, medicine.disease, Thrombosis, Treatment Outcome, Case-Control Studies, Cardiology, Female, Stents, Blood Coagulation Tests, Cardiology and Cardiovascular Medicine, business, Protein C, medicine.drug
Abstract

Objective Coronary stent thrombosis is a devastating complication after percutaneous coronary intervention (PCI). The mechanisms underlying stent thrombosis are multifactorial. Whether the coagulation system is involved in the pathophysiology of stent thrombosis is unclear. We hypothesised that thrombin generation, reflecting the coagulation potential, is enhanced in patients with stent thrombosis. Methods A case–control study was performed, including 63 patients with PCI: 23 cases (stent thrombosis) and 40 controls (no stent thrombosis). Thrombin generation was measured using 0, 1 and 5 pM tissue factor (TF) triggers. Active site-inhibited factor VIIa (ASIS) and recombinant thrombomodulin were added to study the contact activation system and the protein C pathway, respectively. Results Thrombin generation was significantly increased for all TF triggers in cases compared with controls. Addition of ASIS to the measurement without exogenous TF revealed significantly enhanced contact activation in cases compared with controls; mean peak height: 241 vs 183 nM. Thrombin generation was also significantly increased in cases compared with controls in the presence of exogenous TF; mean peak height: 263 vs 233 nM (5 pM TF). Addition of thrombomodulin reduced thrombin generation by 23% in cases and 31% in controls (p

Published
2015

46. Clinical and economic impact of compression in the acute phase of deep vein thrombosis

Author

Edith H Klappe, Saskia Middeldorp, Karina Meijer, M. H. W. van de Poel, Guy Mostard, S. M. van den Heiligenberg, S van Wissen, Erik H. Serné, Elham E. Amin, Paolo Prandoni, Sabina Villalta, Manuela A. Joore, Lidwine W. Tick, H. ten Cate, M. Ten Wolde, A. J. ten Cate-Hoek, Hans-Martin Otten, Anatomy and neurosciences, Internal medicine, ACS - Diabetes & metabolism, ACS - Microcirculation, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, Interne Geneeskunde, RS: CAPHRI - R2 - Creating Value-Based Health Care, Health Services Research, MUMC+: KIO Kemta (9), MUMC+: MA Alg Interne Geneeskunde (9), Biochemie, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), ACS - Pulmonary hypertension & thrombosis, Vascular Medicine, and ARD - Amsterdam Reproduction and Development

Subjects
VENOUS THROMBOSIS, medicine.medical_specialty, POSTTHROMBOTIC SYNDROME, Deep vein, Population, costs, 030204 cardiovascular system & hematology, THERAPY, 03 medical and health sciences, LONG-TERM COMPLICATIONS, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, prevention, Quality of life, QUALITY-OF-LIFE, Edema, medicine, 030212 general & internal medicine, education, POPULATION, LEG, education.field_of_study, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Hematology, medicine.disease, Compression (physics), Thrombosis, Surgery, signs and symptoms, Venous thrombosis, medicine.anatomical_structure, quality of life, STATES, STOCKINGS, TRIAL, medicine.symptom, business, Post-thrombotic syndrome
Abstract

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase. Summary: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoLint). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoLint 0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoLint 0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. Trial registration: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.

Published
2018
Full Text
View/download PDF

47. 2861Role of glycemic state for the relationship between abdominal obesity and markers of inflammation and hemostasis in the population

Author

H. ten Cate, Anja Leuschner, Norbert Pfeiffer, Manfred E. Beutel, Thomas Muenzel, K.J. Lackner, Henri M. H. Spronk, Andreas Schulz, Natalie Arnold, P.S. Wild, Antonio Pinto, J.H. Prochaska, Volker Schmitt, Harald Binder, and C. Juenger

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, Inflammation, Gastroenterology, Surgery, Hemostasis, Internal medicine, medicine, medicine.symptom, Cardiology and Cardiovascular Medicine, education, Hemostatic function, business, Abdominal obesity, Glycemic
Published
2017
Full Text
View/download PDF

49. P3453Platelet-associated thrombin generation and cardiovascular risk factors, results from a population-based study

Author

Henri M. H. Spronk, Manfred E. Beutel, Andreas Schulz, H. ten Cate, Norbert Pfeiffer, J.H. Prochaska, Dagmar Laubert-Reh, M.I. Hermanns, Marina Panova-Noeva, Thomas Muenzel, K.J. Lackner, P.S. Wild, and Natalie Arnold

Subjects
Population based study, Oncology, medicine.medical_specialty, business.industry, Internal medicine, Cardiovascular risk factors, Medicine, Cardiology and Cardiovascular Medicine, business, Thrombin generation
Published
2017
Full Text
View/download PDF

50. e-Health-based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study

Author

Andreas Schulz, Roland Hardt, Sebastian Göbel, Michael Lauterbach, Christoph Bickel, K.J. Lackner, Philipp S. Wild, Harald Binder, Karsten Keller, Meike Coldewey, Thomas Münzel, Christine Espinola-Klein, Alexander Ullmann, Matthias Michal, J.H. Prochaska, H. ten Cate, H. Schinzel, Heidrun Lamparter, MUMC+: MA Alg Interne Geneeskunde (9), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, and Interne Geneeskunde

Subjects
Male, Pediatrics, Vitamin K, Administration, Oral, Comorbidity, 030204 cardiovascular system & hematology, Rate ratio, SERVICE, 0302 clinical medicine, Risk Factors, Germany, USUAL MEDICAL-CARE, Clinical endpoint, Prospective Studies, 030212 general & internal medicine, Aged, 80 and over, OUTCOMES, Hazard ratio, DABIGATRAN, Hematology, Middle Aged, Hospitalization, Treatment Outcome, Cohort, delivery of healthcare, Female, epidemiology, Patient Safety, telemedicine, Cohort study, medicine.drug, medicine.medical_specialty, anticoagulants, Hemorrhage, Lower risk, patient outcome assessment, WARFARIN, 03 medical and health sciences, Thromboembolism, medicine, NONVALVULAR ATRIAL-FIBRILLATION, Humans, QUALITY, International Normalized Ratio, Adverse effect, Blood Coagulation, METAANALYSIS, Aged, Proportional Hazards Models, Rivaroxaban, business.industry, STROKE PREVENTION, RIVAROXABAN, business, Follow-Up Studies
Abstract

Essentials e-Health based health care by an expert centre may advance management of oral anticoagulation. Outcome of patients was compared between an e-health based coagulation service and regular care. Patients in the coagulation service cohort experienced a significantly better clinical outcome. Lower risk for adverse events was related to anticoagulation-specific and non-specific outcome. SummaryBackground Management of oral anticoagulation (OAC) therapy is essential to minimize adverse events in patients receiving vitamin K-antagonists (VKAs). Data on the effect of e-health-based anticoagulation management systems on the clinical outcome of OAC patients are limited. Objectives To compare the clinical outcome of OAC patients managed by an e-health-based coagulation service (CS) with that of patients receiving regular medical care (RMC). Methods The prospective multicenter cohort study thrombEVAL (NCT01809015) comprised 1558 individuals receiving RMC and 760 individuals managed by a CS. Independent study monitoring and adjudication of endpoints by an independent review panel were implemented. Results The primary study endpoint (composite of thromboembolism, clinically relevant bleeding and death) occurred in 15.7 per 100 patient-years (py) with RMC and in 7.0 per 100 py with the CS (rate ratio [RR], 2.3; 95% confidence interval [CI], 1.7–3.1). Rates for major and clinically relevant bleeding were higher with RMC than with the CS: 6.8 vs. 2.6 and 10.1 vs. 3.6 per 100 py, respectively. Thromboembolic events showed an RR of 1.5 (95% CI, 0.8–2.6) comparing RMC with the CS. Hospitalization (RR, 2.6; 95% CI, 2.3–3.0) and all-cause mortality (RR, 4.6; 95% CI, 2.8–7.7) were markedly more frequent with RMC. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, treatment characteristics and sociodemographic status, hazard ratios (HR) for the primary endpoint (HR, 2.2; 95% CI, 1.5–3.4), clinically relevant bleeding (HR, 3.1; 95% CI, 1.7–5.5), hospitalization (HR, 2.2; 95% CI, 1.8–2.8) and all-cause mortality (HR, 5.6; 95% CI, 2.9–11.0) favored CS treatment. Conclusions In this study, e-health-based management of OAC therapy was associated with a lower frequency of OAC-specific and non-specific adverse events.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results