Background and aimsCancer provides challenges to the continuity of anticoagulant treatment in patients with atrial fibrillation (AF), e.g. through cancer-related surgery or complications. We aimed... Show moreBackground and aimsCancer provides challenges to the continuity of anticoagulant treatment in patients with atrial fibrillation (AF), e.g. through cancer-related surgery or complications. We aimed to provide data on the incidence and reasons for interrupting and discontinuing anticoagulant treatment in AF patients with cancer and to assess its contribution to the risk of thromboembolism (TE) and major bleeding (MB).MethodsThis retrospective study identified AF patients with cancer in two hospitals between 2012 and 2017. Data on anticoagulant treatment, TE and MB were collected during two-year follow-up. Incidence rates (IR) per 100 patient-years and adjusted hazard ratios (aHR) were obtained for TE and MB occurring during on- and off-anticoagulant treatment, during interruption and after resumption, and after permanent discontinuation.Results1213 AF patients with cancer were identified, of which 140 patients permanently discontinued anticoagulants and 426 patients experienced one or more interruptions. Anticoagulation was most often interrupted or discontinued due to cancer-related treatment (n = 441, 62 %), bleeding (n = 129, 18 %) or end of life (n = 36, 5 %). The risk of TE was highest off-anticoagulation and during interruptions, with IRs of 19 (14–25)) and 105 (64–13), and aHRs of 3.1 (1.9–5.0) and 4.6 (2.4–9.0), respectively. Major bleeding risk were not only increased during an interruption, but also in the first 30 days after resumption, with IRs of 33 (12–72) and 30 (17–48), and aHRs of 3.3 (1.1–9.8) and 2.4 (1.2–4.6), respectively.ConclusionsInterruption of anticoagulation therapy harbors high TE and MB risk in AF patients with cancer. The high incidence rates call for better (periprocedural) anticoagulant management strategies tailored to the cancer setting. Show less
von Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or... Show morevon Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or qualitative alterations of VWF cause von Willebrand disease (VWD), an inherited bleeding disorder. Conversely, increased VWF levels have been associated with various thrombotic conditions. In this thesis, we investigated the dual role of VWF in bleeding and thrombosis, focusing on VWD and deep vein thrombosis (DVT). In the first part of the thesis, we demonstrated the utility of in silico tools and heterologous cell systems in proving the disease-causing role of VWF variants thus contributing to the confirmation of patient diagnoses. In the second part, we focused on type 3 VWD, the most severe form of this disorder caused by a lack of VWF. We showed that patients with missense variants had a higher VWF propeptide/VWF antigen ratio than carriers of VWF null alleles. This suggested that secreted VWF is rapidly removed from circulation in these patients. Subsequently, we estimated the prevalence of VWF neutralizing and non-neutralizing antibodies, confirming that they are rare side effects of replacement therapy. We also demonstrated that the detection of epitope-specific VWF inhibitors is affected by the test used. In the last part of the thesis, we evaluated the role of ADAMTS13-VWF equilibrium in the pathogenesis of DVT, showing that a slight decrease in ADAMTS13 activity, particularly when combined with increased VWF levels, increases DVT risk. We then sequenced ADAMTS13, VWF, and F8 genes and confirmed that DVT patients carrying a rare ADAMTS13 variant exhibited lower ADAMTS13 activity than non-carriers. Show less
BACKGROUNDS: planchnic vein thrombosis (SVT) is a major complication of moderate and severe acute pancreatitis. There is no consensus on whether therapeutic anticoagulation should be started in... Show moreBACKGROUNDS: planchnic vein thrombosis (SVT) is a major complication of moderate and severe acute pancreatitis. There is no consensus on whether therapeutic anticoagulation should be started in patients with acute pancreatitis and SVT. AIM: To gain insight into current opinions and clinical decision making of pancreatologists regarding SVT in acute pancreatitis. METHODS: A total of 139 pancreatologists of the Dutch Pancreatitis Study Group and Dutch Pancreatic Cancer Group were approached to complete an online survey and case vignette survey. The threshold to assume group agreement was set at 75%. RESULTS: The response rate was 67% (n = 93). Seventy-one pancreatologists (77%) regularly prescribed therapeutic anticoagulation in case of SVT, and 12 pancreatologists (13%) for narrowing of splanchnic vein lumen. The most common reason to treat SVT was to avoid complications (87%). Acute thrombosis was the most important factor to prescribe therapeutic anticoagulation (90%). Portal vein thrombosis was chosen as the most preferred location to initiate therapeutic anticoagulation (76%) and splenic vein thrombosis as the least preferred location (86%). The preferred initial agent was low molecular weight heparin (LMWH; 87%). In the case vignettes, therapeutic anticoagulation was prescribed for acute portal vein thrombosis, with or without suspected infected necrosis (82% and 90%), and thrombus progression (88%). Agreement was lacking regarding the selection and duration of long-term anticoagulation, the indication for thrombophilia testing and upper endoscopy, and about whether risk of bleeding is a major barrier for therapeutic anticoagulation. CONCLUSION: In this national survey, the pancreatologists seemed to agree on the use of therapeutic anticoagulation, using LMWH in the acute phase, for acute portal thrombosis and in the case of thrombus progression, irrespective of the presence of infected necrosis. Show less
Hemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these... Show moreHemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these changes on current clinical outcomes is unknown.Therefore, we comprehensively assessed the changes in health status over time of patients with hemophilia using observational study data. Our results show that clinical outcomes of these patients have improved tremendously over the past decades. The annual bleeding rate and the proportion of patients with joint impairment have decreased strongly. In addition, HCV has almost been eradicated among patients with hemophilia in the Netherlands. As a result, life expectancy has increased to where it is almost equal to that of the general population.Although clinical outcomes have improved in many ways, inhibitor development continues to be a significant problem in patients treated with clotting factor products. Therefore, using three different study approaches, we also evaluated several methods to better predict the risk of inhibitor development (which is still a significant complication of treatment with FVIII). The results of these studies are promising and could be used to improve current inhibitor prediction strategies and inform future research on this topic. Show less
Rijnhout, T.W.H.; Noorman, F.; Horst, R.A. van der; Tan, E.C.T.H.; Viersen, V.V.A.; Waes, O.J.F. van; ... ; Hoencamp, R. 2022
Background The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere... Show moreBackground The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding. Methods The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding. Discussion The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings. Show less
Bleeding events are frequently encountered in hemato-oncology patients. To prevent this, in periods of thrombocytopenia patients receive prophylactic platelet transfusions, based on the platelet... Show moreBleeding events are frequently encountered in hemato-oncology patients. To prevent this, in periods of thrombocytopenia patients receive prophylactic platelet transfusions, based on the platelet counts. However, beside platelet counts many other patients factors likely contribute to the bleeding risk.In this thesis we focus on describing current clinical practice to prevent bleedings in a subpopulation of patients with persistent deep thrombocytopenia, risk factors for bleeding, and prediction of bleeding. We also describe a ongoing study which aims to identify and quantify risk factors in future.With this knowledge, in the ultimate goal is to predict bleeding more accurate based on patient characteristics and/or biomarkers. This could be a first step towards more personalized bleeding prevention strategies. Show less
There is a paucity of data on anticoagulation strategies and clinical outcomes after bleeding events for venous thromboembolism (VTE). In a multicenter Japanese registry enrolling 3027 patients... Show moreThere is a paucity of data on anticoagulation strategies and clinical outcomes after bleeding events for venous thromboembolism (VTE). In a multicenter Japanese registry enrolling 3027 patients with acute symptomatic VTE, after excluding 430 patients with thrombolysis and 207 patients without anticoagulation therapy, the current study population consisted of 2390 patients, who were divided into patients with major bleeding, clinically relevant non-major (CRNM) bleeding and no bleeding during anticoagulation therapy. All-cause death at 90 days after the bleeding events was evaluated as the primary outcome. There were 189 patients with major bleeding, 147 patients with CRNM bleeding, and 2054 patients without bleeding. Among 189 patients with major bleeding, 142 patients (75%) discontinued anticoagulants, of whom patients with temporary discontinuation and those with permanent discontinuation accounted for 63 patients (44%) and 79 patients (56%), and 58 patients (30.7%) died within 90 days after the bleeding events. The multivariable logistic regression model among patients with bleeding events revealed that active cancer and bleeding events within 90 days after VTE diagnosis were independently associated with 90-day mortality after the bleeding events (active cancer: OR 5.05, 95%CI 2.82-9.05; bleeding events within 90 days after VTE diagnosis: OR 2.23, 95%CI 1.25-3.96). In this practice-based large registry, anticoagulants were frequently discontinued in patients who experienced major bleeding events during anticoagulation therapy and nearly half of them restarted anticoagulants with mortality rate of approximately 30% within 90 days after the bleeding events, and active cancer was the most prevalent cause of death. Show less
Klok, F.A.; Ageno, W.; Ay, C.; Back, M.; Barco, S.; Bertoletti, L.; ... ; Pruszczyk, P. 2022
This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a... Show moreThis position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control. Show less
The scope of the thesis is: “bleeding in patients with hypoproliferative thrombocytopenia”. Despite platelet transfusions bleeding occurs frequently in these patients and besides highlighting the... Show moreThe scope of the thesis is: “bleeding in patients with hypoproliferative thrombocytopenia”. Despite platelet transfusions bleeding occurs frequently in these patients and besides highlighting the variance in methodology of assessing bleeding symptoms and reporting in different bleeding scales, various risk factors for bleeding are illustrated in the introduction of the thesis. In the three following chapters the scoring of bleeding symptoms, the adjudication of symptoms in bleeding scales and the methodology concerning these aspects and more of a large platelet transfusion trial comparing pathogen reduced platelets (by using the Mirasol technique) to control platelet products is described. Chapter five describes the results of this randomized controlled trial and in the following chapter the association between endothelial damage (as measured by microalbuminuria in patients) and bleeding is described. Alternative bleeding scales besides the WHO bleeding scale are described in chapter seven and the last chapter summarizes the findings. Show less
Introduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular... Show moreIntroduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular population are scarce. Current study assesses incidence, timing and predictors of VTE in pancreatic cancer through different phases of disease. Methods: All pancreatic cancer patients treated in our tertiary referral center between 2013 through 2017 were studied. Occurrence of VTE was evaluated from diagnosis through end of follow-up or death. Relevant de-terminants of VTE were identified in logistic regression models. Hazard ratios were calculated to evaluate impact of VTE on overall survival. Results: In total, 361 patients were followed for a median period of 43 months; 64 were diagnosed with VTE (18%). Most were tumor related thrombosis (59%), incidental (75%) and occurred after anti-cancer treatment had been stopped (80%), only 1.6% occurred during remission phase. Stage IV pancreatic cancer was a predictor for VTE (hazard ratio (HR) 2.46, 95% confidence interval (CI) 0.9-6.8). Biliary drainage (HR 0.52, 95%CI 0.28-0.98) and tumor resection (HR 0.45, 95%CI 0.45-1.83) were protective factors. VTE was not associated with worse survival (HR 1.3; 95% CI 0.97-1.74). Conclusions: VTE in pancreatic cancer is disease-stage dependent, with 80% occurring in advanced phases of disease when patients no longer receive active treatment. We speculate that this is the main reason for the absence of a survival effect of VTE in our cohort. These practice-based findings should be taken into account when considering wide-spread introduction of primary thromboprophylaxis in patients with pancreatic cancer. Show less
Milicic, D.; Avraham, B. ben; Chioncel, O.; Barac, Y.D.; Goncalvesova, E.; Grupper, A.; ... ; Gal, T. ben 2021
The improvement in left ventricular assist device (LVAD) technology and scarcity of donor hearts have increased dramatically the population of the LVAD-supported patients and the probability of... Show moreThe improvement in left ventricular assist device (LVAD) technology and scarcity of donor hearts have increased dramatically the population of the LVAD-supported patients and the probability of those patients to present to the emergency department with expected and non-expected device-related and patient-device interaction complications. The ageing of the LVAD-supported patients, mainly those supported with the 'destination therapy' indication, increases the risk for those patients to suffer from other co-morbidities common in the older population. In this second part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, definitions and structured approach to the LVAD-supported patient presenting to the emergency department with bleeding, neurological event, pump thrombosis, chest pain, syncope, and other events are presented. The very challenging issue of declaring death in an LVAD-supported patient, as the circulation is artificially preserved by the device despite no other signs of life, is also discussed in detail. Show less
Blood coagulation is a complex system in which the proteins of the coagulation cascade play an important role. Aberrations in pro- or anticoagulant protein levels may be at the basis of coagulation... Show moreBlood coagulation is a complex system in which the proteins of the coagulation cascade play an important role. Aberrations in pro- or anticoagulant protein levels may be at the basis of coagulation-related pathological events, such as bleeding or thrombosis. Here the relations of altered coagulation factor levels and venous thromboembolism, the tissue factor threshold which needs to be overcome to initiate coagulation and the in vitro validation of APC-resistant FV as a possible alternative treatment of factor XI deficiency are explored. Show less
Haemodynamic instability and right ventricular dysfunction are the key determinants of short-term prognosis in patients with acute pulmonary embolism (PE). Residual thrombi and persistent right... Show moreHaemodynamic instability and right ventricular dysfunction are the key determinants of short-term prognosis in patients with acute pulmonary embolism (PE). Residual thrombi and persistent right ventricular dysfunction may contribute to post-PE functional impairment, and influence the risk of developing chronic thromboembolic pulmonary hypertension. Patients with haemodynamic instability at presentation (high-risk PE) require immediate primary reperfusion to relieve the obstruction in the pulmonary circulation and increase the chances of survival. Surgical removal of the thrombi or catheter-directed reperfusion strategies is alternatives in patients with contraindications to systemic thrombolysis. For haemodynamically stable patients with signs of right ventricular overload or dysfunction (intermediate-risk PE), systemic standard-dose thrombolysis is currently not recommended, because the risk of major bleeding associated with the treatment outweighs its benefits. In such cases, thrombolysis should be considered only as a rescue intervention if haemodynamic decompensation develops. Catheter-directed pharmaco-logical and pharmaco-mechanical techniques ensure swift recovery of echocardiographic and haemodynamic parameters and may be characterized by better safety profile than systemic thrombolysis. For survivors of acute PE, little is known on the effects of reperfusion therapies on the risk of chronic functional and haemodynamic impairment. In intermediate-risk PE patients, available data suggest that systemic thrombolysis may have little impact on long-term symptoms and functional limitation, echocardiographic parameters, and occurrence of chronic thromboembolic pulmonary hypertension. Ongoing and future interventional studies will clarify whether 'safer' reperfusion strategies may improve early clinical outcomes without increasing the risk of bleeding and contribute to reducing the burden of long-term complications after intermediate-risk PE. Show less
Wall, S.J. van der; Rein, N. van; Bemt, B. van den; Kruip, M.J.H.A.; Meijer, K.; Boome, L.C.J. te; ... ; Huisman, M. 2019
Aims Because practice-based data on the usage of idarucizumab for urgent dabigatran reversal is unavailable, we evaluated the appropriateness of idarucizumab usage, its haemostatic effectiveness... Show moreAims Because practice-based data on the usage of idarucizumab for urgent dabigatran reversal is unavailable, we evaluated the appropriateness of idarucizumab usage, its haemostatic effectiveness and clinical outcomes.Methods and results An observational cohort study was performed including consecutive patients who were treated with idarucizumab between 2016 and 2018. Appropriate usage was assessed with predefined criteria. Post-reversal effectiveness was evaluated according to International Society on Thrombosis and Haemostasis (ISTH) recommendations. Patients were followed for 90 days for occurrence of thromboembolism, (re-) bleeding and death. Idarucizumab was used in 88 patients, of whom 53 (60%) presented with severe bleeding (20 gastrointestinal and 18 intracranial) and 35 (40%) requiring urgent surgical intervention. Use of idarucizumab was judged inappropriate in 25 patients (28%). Effective haemostasis was achieved in 32 of 48 (67%) bleeding patients in whom assessment was possible. Seven of 16 patients with major bleeding who did not achieve effective haemostasis (five intracranial) died, compared with two of 32 patients with effective haemostasis (relative risk 7.0, 95% confidence interval 1.6-30). Four patients (4.2%) developed thromboembolism [2 (2.1%) within 30 days] and four patients (4.2%) re-bleeding, all within 10 days. Seventeen patients (19%) died; 10 (11%) within 5 days.Conclusion In this practice-based cohort, idarucizumab use was considered inappropriate in 28% of patients. Effective haemostasis was achieved in two-third of bleeding patients and was associated with lower mortality risk. Clinical outcomes were similar to those observed in the RE-VERSE AD trial, comprising re-bleeds and thromboembolism, and a high-mortality rate. Show less
The overall goal of this thesis was to identify patients who are at high risk for major bleedings during anticoagulant treatment and to reduce the number of major bleeds. The first part looks... Show moreThe overall goal of this thesis was to identify patients who are at high risk for major bleedings during anticoagulant treatment and to reduce the number of major bleeds. The first part looks into methodology of observational studies. It shows that biases in observational studies may be an explanation why statins seem to have many unintended effects. The second part looks into bleeding complications and shows that patient with three concomitant anticoagulants experience high major bleeding rates. Also, a study was performed in which plasma and DNA of participants was collected, to identify risk factors for major bleeds in the future. The first results show that damage to vessel walls increases the risk of major bleeding. Interventions to reduce the number of bleeding events were to dose nadroparin od instead of bid. In addition, multi-dose drug dispensing may increase adherence of medication. Also, vitamin K1 tablets are easier to ingest and this thesis shows that the tablets are as effective in reducing the INR as the oral solution. Show less
This thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome,... Show moreThis thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome, outlines current management, evaluates risks of missing a diagnosis of FNAIT, studies the efficacy of a lower dose of immunoglobulins in preventing bleedingcomplications,shows the time of bleeding onset of fetal ICH during pregnancy and illustrates the longterm outcome of children with ICH. Show less
