Publications by authors named "Stavros Konstantinides"

306 Publications

Acute Pulmonary Embolism.

Dtsch Arztebl Int 2021 Sep;118(37):618-628

Institute for Anesthesiology, Universiy Hospital Essen; Canton Hospital Basel-Land, University of Basel, Switzerland; Radiology, Canton Hospital Lucerne, Switzerland; Hematology, Canton Hospital Lucerne, Switzerland; School of Medicine, University of Mainz Emergency Center,; Canton Hospital Lucerne, Switzerland.

Background: Physicians from many different specialties see patients suffering from acute pulmonary embolism (PE), which has an incidence of 39-115 cases per 100 000 persons per year. Because PE can be life-threatening, a rapid, targeted response is essential.

Methods: This review is based on pertinent publications retrieved by a selective literature search of international databases, with particular attention to current guidelines and expert opinions.

Results: Whenever PE is suspected, clinical assessment tools must be applied for risk stratification and diagnostic evaluation. The PERC (Pulmonary Embolism Rule-out Criteria) and the YEARS algorithm lead to more effective diagnosis. For hemodynamically unstable patients, bedside echocardiography is of high value and enables risk stratification. New oral anticoagulants have fewer hemorrhagic complications than vitamin K antagonists and are not inferior to them with respect to the risk of recurrent PE (hazard ratio 0.84-1.09). The duration of anticoagulation is set according to the risk of recurrence. Systemic thrombolysis is recommended for patients with a high-risk PE, in whom it significantly reduces mortality (odds ratio 0.53, number needed to treat 59). Surgical or interventional techniques can be considered if thrombolysis is contraindicated or unsuccessful.

Conclusion: Newly introduced diagnostic aids and algorithms simplify the diagnosis and treatment of acute PE while continuing to assure a high degree of patient safety.
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http://dx.doi.org/10.3238/arztebl.m2021.0226DOI Listing
September 2021

Splanchnic vein thrombosis-related mortality in the Veneto region (Italy), 2008-2019: Retrospective analysis of epidemiological data.

Thromb Res 2021 Nov 22;209:41-46. Epub 2021 Nov 22.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Angiology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Background: Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism. Epidemiological data on SVT-related mortality rate is not available to date.

Methods: We investigated time trends in SVT-related mortality rate, 2008-2019, in Veneto, an Italian high-income region of approximatively 5,000,000 inhabitants. SVT-related deaths were identified by the following ICD-10 codes: I81 (portal vein thrombosis), K75.1 (phlebitis of portal vein), K76.3 (liver infarction), K76.5 (hepatic veno-occlusive disease) or I82.0 (Budd-Chiari syndrome).

Results: During the study period, a total of 557,932 deaths were recorded. SVT was reported in 823 cases; 776 (94%) consisted of portal vein thrombosis. The age-standardized SVT-related mortality rate varied from 1.47 (year 2008) to 1.52 (year 2019) per 100,000 person-years. An increase in the cause-specific annual mortality rate was observed in women (0.56 in 2008 to 1.04 per 100,000 person-years in 2019; average annual percent change +5.7%, 95%CI +3.1; +8.3%). In men, the cause-specific mortality rate moved from 2.53 in 2008 to 2.03 per 100,000 person-years in 2019 (average annual percent change -1.2%, 95%CI -4.0; +1.6%). After conditioning for age and sex, the odds of having a concomitant liver disease were higher for SVT-related deaths (OR 31.6; 95%CI 17.1-37.0) compared with non-SVT-related deaths. This also applies to gastrointestinal cancers (OR 1.28; 95%CI 1.07-1.55), although to a lesser extent.

Conclusions: We report first epidemiological estimates of SVT-related mortality in a Western country. These values will serve as a reference to weight novel potential factors associated with SVT-related death and interpret them from an epidemiological perspective.
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http://dx.doi.org/10.1016/j.thromres.2021.11.005DOI Listing
November 2021

A model for estimating the health economic impact of earlier diagnosis of chronic thromboembolic pulmonary hypertension.

ERJ Open Res 2021 Jul 6;7(3). Epub 2021 Sep 6.

Dept of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

Background: Diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) exceeds 1 year, contributing to higher mortality. Health economic consequences of late CTEPH diagnosis are unknown. We aimed to develop a model for quantifying the impact of diagnosing CTEPH earlier on survival, quality-adjusted life-years (QALYs) and healthcare costs.

Material And Methods: A Markov model was developed to estimate lifelong outcomes, depending on the degree of delay. Data on survival and quality of life were obtained from published literature. Hospital costs were assessed from patient records (n=498) at the Amsterdam UMC - VUmc, which is a Dutch CTEPH referral center. Medication costs were based on a mix of standard medication regimens.

Results: For 63-year-old CTEPH patients with a 14-month diagnostic delay of CTEPH (median age and delay of patients in the European CTEPH Registry), lifelong healthcare costs were estimated at EUR 117 100 for a mix of treatment options. In a hypothetical scenario of maximal reduction of current delay, improved survival was estimated at a gain of 3.01 life-years and 2.04 QALYs. The associated cost increase was EUR 44 654, of which 87% was due to prolonged medication use. This accounts for an incremental cost-utility ratio of EUR 21 900/QALY.

Conclusion: Our constructed model based on the Dutch healthcare setting demonstrates a substantial health gain when CTEPH is diagnosed earlier. According to Dutch health economic standards, additional costs remain below the deemed acceptable limit of EUR 50 000/QALY for the particular disease burden. This model can be used for evaluating cost-effectiveness of diagnostic strategies aimed at reducing the diagnostic delay.
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http://dx.doi.org/10.1183/23120541.00719-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628742PMC
July 2021

An update on the global use of risk assessment models and thromboprophylaxis in hospitalized patients with medical illnesses from the World Thrombosis Day steering committee: systematic review and meta-analysis.

J Thromb Haemost 2021 Nov 25. Epub 2021 Nov 25.

Department of Angiology, University Hospital Zurich, Zurich, Switzerland.

Introduction: Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. The majority of VTE events are hospital-associated. In 2008, the ENDORSE multinational survey reported that only around 40% of medical patients at risk of VTE received adequate thromboprophylaxis.

Methods: In our systematic review and meta-analysis, we aimed at providing updated figures concerning the use of thromboprophylaxsis globally. We focused on: (i) the frequency of patients with an indication to thromboprophylaxis according with individual models; (ii) the use of adequate thromboprophylaxis; (iii) reported contraindications to thromboprophylaxis. Observational non-randomized studies or surveys focusing on medically ill patients were considered eligible.

Results: After screening, we included 27 studies from 20 countries for a total of 137,288 patients. Overall, 50.5% (95%CI: 41.9%-59.1%, I 99%) of patients had an indication to thromboprophylaxis: of these, 54.5% (95%CI: 46.2%-62.6%, I 99%) received adequate thromboprophylaxis. The use of adequate thromboprophylaxis was 66.8% in Europe (95%CI: 50.7% to 81.1%; I 98%), 44.9% in Africa (95%CI: 31.8% to 58.4% I 96%), 37.6% in Asia (95%CI: 25.7%-50.3%, I 97%), 58.3% in South America (95%CI 31.1%-83.1%, I 99%), and 68.6% in North America (95%CI 64.9%-72.6%, I 96%). No major differences in adequate thromboprophylaxis use were found across risk assessment models. Bleeding, thrombocytopenia, and renal/hepatic failure were the most frequently reported contraindications to thromboprophylaxis.

Conclusions: The use of anticoagulants for VTE prevention has been proven effective and safe, but thromboprophylaxis prescriptions are still unsatisfactory among hospitalized medically ill patients around the globe with marked geographical differences.
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http://dx.doi.org/10.1111/jth.15607DOI Listing
November 2021

[Diagnosis and treatment of pulmonary embolism].

Herz 2021 Dec 22;46(6):589-604. Epub 2021 Nov 22.

Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland.

Pulmonary embolism (PE) frequently presents a diagnostic and therapeutic challenge in the clinical practice. Established diagnostic algorithms enable the prevention of unnecessary use of imaging with ionizing radiation, so that now standardized algorithms could also be validated in pregnant patients with suspected acute PE. In risk stratification the assessment of the right ventricle plays a decisive role in addition to clinical parameters, especially if early discharge and outpatient treatment of PE is an option. Direct oral anticoagulants are currently the first-line treatment for the majority of patients with PE, whereas reperfusion treatment following discussion in the interdisciplinary PE team is indicated for those with overt or imminent decompensation. Systematic follow-up observation and care of patients with PE is emphasized in order to decide on the extension or termination of anticoagulation and for detection and treatment of late sequelae, such as chronic thromboembolic pulmonary hypertension.
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http://dx.doi.org/10.1007/s00059-021-05078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607403PMC
December 2021

Variation of platelet function in clinical phenotypes of acute venous thromboembolism - Results from the GMP-VTE project.

J Thromb Haemost 2021 Nov 16. Epub 2021 Nov 16.

Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Background: The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute phase of the disease.

Objective: To characterize platelet function according to VTE phenotypes.

Patients/methods: In total, 154 subjects (isolated pulmonary embolism [iPE], n = 28; isolated deep vein thrombosis [iDVT], n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)-200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select clinical and platelet biomarkers that distinguish between VTE phenotypes.

Results: PFA-200 results did not differ between VTE phenotypes. LTA from DVT+PE subjects showed lowest maximum aggregation after epinephrine and adenosine diphosphate compared to iPE and iDVT. Lower % of PAC-1-positive platelets after in-vitro trigger were present in DVT+PE and iPE compared to iDVT. TG in PRP had lower peak height and velocity in DVT+PE and iPE against iDVT. The results of LASSO regression for the distinction between DVT+PE vs iDVT identified 18 variables (AUC =0.93) of which 72% were platelet biomarkers. For distinction between iPE and iDVT, 10 variables were selected (AUC = 0.96) of which 50% were platelet-related. Obesity was the only variable weakly discriminating between DVT+PE vs iPE (AUC = 0.66).

Conclusion: This explorative study suggests an important distinction between PE-related phenotypes and iDVT when considering clinical and platelet function data. Lower platelet-dependent TG along with reduced platelet reactivity suggest higher platelet degranulation in PE-dependent phenotypes compared to iDVT.
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http://dx.doi.org/10.1111/jth.15595DOI Listing
November 2021

Diabetes mellitus and its impact on mortality rate and outcome in pulmonary embolism.

J Diabetes Investig 2021 Nov 14. Epub 2021 Nov 14.

Department of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Aims/introduction: In patients with pulmonary embolism (PE), the impact of diabetes mellitus on patient profile and outcome is not well investigated.

Material And Methods: The German nationwide inpatient sample of the years 2005-2018 was analyzed. Hospitalized PE patients were stratified for diabetes, and the impact of diabetes on in-hospital events was investigated.

Results: Overall, 1,174,196 PE patients (53.8% aged ≥70 years, 53.5% women) and, among these, 219,550 (18.7%) diabetes patients were included. In-hospital mortality rate amounted to 15.8%, and was higher in diabetes patients than in non-diabetes patients (19.8% vs 14.8%, P < 0.001). PE patients with diabetes had a higher prevalence of cardiovascular risk factors, comorbidities, right ventricular dysfunction (31.8% vs 27.7%, P < 0.001), prolonged in-hospital stay (11.0 vs 9.0 days, P < 0.001) and higher rates of adverse in-hospital events. Remarkably, diabetes was independently associated with increased in-hospital mortality (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.20-1.23, P < 0.001) when adjusted for age, sex and comorbidities. Within the observation period of 2005-2018, a relevant decrease of in-hospital mortality in PE patients with diabetes was observed (25.5% to 16.8%). Systemic thrombolysis was more often administered to diabetes patients (OR 1.18, 95% CI 1.01-3.49, P < 0.001), and diabetes was associated with intracerebral (OR 1.19, 95% CI 1.12-1.26, P < 0.001), as well as gastrointestinal bleeding (OR 1.11, 95% CI 1.07-1.15, P < 0.001). Type 1 diabetes mellitus was shown to be a strong risk factor in PE patients for shock, right ventricular dysfunction, cardiopulmonary resuscitation and in-hospital death (OR 1.75, 95% CI 1.61-1.90, P < 0.001).

Conclusions: Despite the progress in diabetes treatments, diabetes is still associated with an unfavorable clinical patient profile and higher risk for adverse events, including substantially increased in-hospital mortality in acute PE.
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http://dx.doi.org/10.1111/jdi.13710DOI Listing
November 2021

Assessment of pulmonary embolism severity and the risk of early death.

Pol Arch Intern Med 2021 Nov 15. Epub 2021 Nov 15.

Currently, venous thromboembolism, encompassing deep vein thrombosis and acute pulmonary embolism (PE), is  globally the third most frequent acute cardiovascular syndrome with rising incidence rates. The clinical presentation of PE is heterogenous: from incidental findings in imaging studies to sudden cardiac death. Hemodynamic instability indefinites patients at high risk of early mortality. In patients without hemodynamic instability, further stratification into intermediate and low-risk categories is advised, preferably using a combined risk assessment strategy based on clinical parameters, laboratory findings,  and imaging markers. Treatment should be tailored to the risk of early death, with more aggressive treatments reserved for patients at higher risk of complications. This review offers an update on the current strategies for assessing PE severity and the risk of early death and discusses developments in the field of PE mortality risk prediction.
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http://dx.doi.org/10.20452/pamw.16134DOI Listing
November 2021

Clinical use and outcome of extracorporeal membrane oxygenation in patients with pulmonary embolism.

Resuscitation 2021 Oct 12. Epub 2021 Oct 12.

Department of Cardiology, University Medical Center Mainz, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Germany; Medical Clinic VII, University Hospital Heidelberg, Germany.

Aim Of The Study: Extracorporeal membrane oxygenation (ECMO) is considered a life-saving treatment option for patients in cardiogenic shock or cardiac arrest undergoing cardiopulmonary resuscitation (CPR) due to acute pulmonary embolism (PE). We sought to analyze use and outcome of ECMO with or without adjunctive treatment strategies in patients with acute PE.

Methods: We retrospectively analyzed data on patient characteristics, treatments, and in-hospital outcomes for all PE patients (ICD-code I26) undergoing ECMO in Germany between 2005 and 2018.

Results: At total of 1,172,354 patients were hospitalized with PE; of those, 2,197 (0.2%) were treated with ECMO support. Cardiac arrest requiring cardiopulmonary resuscitation was present in 77,196 (6.5%) patients. While more than one fourth of those patients were treated with systemic thrombolysis alone (n = 20,839 patients; 27.0%), a minority of patients received thrombolysis and VA-ECMO (n = 165; 0.2%), embolectomy and VA-ECMO (n = 385; 0.5%) or VA-ECMOalone (n = 588; 0.8%). A multivariable logistic regression analysis indicated the lowest risk for in-hospital death in patients who received embolectomy in combination with VA-ECMO (OR, 0.50 [95% CI, 0.41-0.61], p < 0.001), thrombolysis and VA-ECMO (0.60 [0.43-0.85], p = 0.003) or VA-ECMO alone (0.68 [0.57-0.82], p < 0.001) compared to thrombolysis alone (1.04 [0.99-1.01], p = 0.116).

Conclusion: Our findings suggest that the use of VA-ECMO alone or as part of a multi-pronged reperfusion approach including embolectomy or thrombolysis might offer survival advantages compared to thrombolysis alone in patients with PE deteriorating to cardiac arrest.
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http://dx.doi.org/10.1016/j.resuscitation.2021.10.007DOI Listing
October 2021

Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Eur Heart J 2021 Oct 8. Epub 2021 Oct 8.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.

Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.
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http://dx.doi.org/10.1093/eurheartj/ehab642DOI Listing
October 2021

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 2021

Impact of Systemic Atherosclerosis on Clinical Characteristics and Short-term Outcomes in Patients with Deep Venous Thrombosis or Thrombophlebitis.

Am J Med Sci 2021 Sep 19. Epub 2021 Sep 19.

Department of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Background: Venous thromboembolism (VTE) and atherosclerosis are accompanied by substantial cardiovascular mortality; links between both disease entities were reported. We aimed to investigate the impact of systemic atherosclerosis on adverse outcomes in patients with deep venous thrombosis or thrombophlebitis (DVT) and to identify differences in DVT patients with and without systemic atherosclerosis.

Methods: The German nationwide inpatient sample was used for this analysis. Patients admitted for DVT were included in this study and stratified by systemic atherosclerosis (composite of coronary artery disease, myocardial infarction, ischemic stroke, and/or atherosclerotic arterial diseases). We compared DVT patients with (DVT+Athero) and without (DVT-Athero) systemic atherosclerosis and analysed the impact of systemic atherosclerosis on adverse outcomes.

Results: Overall, 489,679 patients with DVT (55.7% females) were included in this analysis. Among these, 53,309 (10.9%) were coded with concomitant systemic atherosclerosis with age-dependent incline. Concomitant PE (4.1% vs.3.8%, P=0.001) was more frequently in DVT-Athero and risk for PE in DVT patients was independently associated with absence of systemic atherosclerosis (OR 0.87 [95%CI 0.83-0.91], P<0.001). In-hospital mortality (3.4% vs.1.4%, P<0.001) and adverse in-hospital events (2.2% vs.0.8%,P<0.001) were more prevalent in DVT+Athero compared to DVT-Athero; both, in-hospital mortality (OR 1.52 [95%CI 1.41-1.63], P<0.001) and adverse in-hospital events (OR 1.49 [95%CI 1.40-1.58], P<0.001) were affected independently of sex, age and comorbidities by systemic atherosclerosis.

Conclusions: Systemic atherosclerosis in DVT patients was accompanied by poorer outcomes. Systemic atherosclerosis was associated with higher bleeding rate and with isolated DVT (without concomitant PE).
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http://dx.doi.org/10.1016/j.amjms.2021.09.002DOI Listing
September 2021

Psoriasis and its impact on the clinical outcome of patients with pulmonary embolism.

Int J Cardiol 2021 Nov 1;343:114-121. Epub 2021 Sep 1.

Department of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, Germany.

Background: An increased risk for venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep venous thrombosis, has been reported in psoriasis patients. The impact of psoriasis on prognosis of VTE patients is widely unknown.

Methods: Hospitalized PE patients were stratified for psoriasis and the impact of psoriasis on outcome was investigated in the German nationwide inpatient sample of the years 2005-2017.

Results: Overall, 1,076,384 hospitalizations of PE patients (53.7% females, median age 72.0 [60.0-80.0] years) were recorded in Germany 2005-2017. Among these, 3145 patients had psoriasis (0.3%). Psoriatic PE patients were younger (68.0 [57.0-76.0] vs. 72.0 [60.0-80.0] years,P < 0.001) and more often male (64.1% vs. 46.3%,P < 0.001). The prevalence of VTE risk factors, traditional cardiovascular risk factors and cardiovascular comorbidities was higher in psoriatic than in non-psoriatic individuals. Psoriatic PE patients showed a lower in-hospital case-fatality rate (11.1% vs. 16.0%,P < 0.001), confirmed by logistic regressions showing an independent association of psoriasis with reduced case-fatality rate (OR 0.73 [95%CI 0.65-0.82],P < 0.001), despite higher prevalence of pneumonia (24.8% vs. 23.2%,P = 0.029). Psoriasis was an independent predictor for gastro-intestinal bleeding (OR 1.35 [95%CI 1.04-1.75],P = 0.023) and transfusion of blood constituents (OR 1.23 [95%CI 1.11-1.36],P < 0.001).

Conclusions: PE patients with psoriasis were hospitalized in median four years earlier than those without. Although psoriasis was associated with an unfavorable cardiovascular-risk and VTE-risk profile in PE patients, our data demonstrate a lower in-hospital mortality in psoriatic PE, which might be mainly driven by younger age. Our findings may improve the clinical management of these patients and contribute evidence for relevant systemic manifestation of psoriasis.

Translational Perspective: An increased risk for venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep venous thrombosis, has been reported in psoriasis patients, but the impact of psoriasis on prognosis of VTE patients is widely unknown. PE patients with psoriasis were younger and psoriasis was associated with an unfavorable cardiovascular-risk and VTE-risk profile. In-hospital mortality was lower in psoriatic PE patients, which might be mainly driven by younger age. Our findings improve the clinical management of PE patients and contribute evidence for relevant systemic manifestation of psoriasis.

One Sentence Summary: Psoriasis with chronic inflammation promotes PE development, is associated with an unfavorable cardiovascular and VTE-risk profile, but lower in-hospital mortality.
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http://dx.doi.org/10.1016/j.ijcard.2021.08.042DOI Listing
November 2021

[Trends in mortality related to pulmonary embolism in the DACH countries].

Med Klin Intensivmed Notfmed 2021 Aug 24. Epub 2021 Aug 24.

Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland.

Background: Pulmonary embolism (PE)-related mortality is decreasing worldwide.

Aim: Little is known about the burden imposed by pulmonary embolism for Germany, Austria and Switzerland (DACH countries).

Materials And Methods: We aimed to assess pulmonary embolism-related mortality and time trends for the DACH countries based on data from the WHO Mortality Database. Deaths were considered pulmonary embolism-related if the International Classification of Disease-10 code for acute pulmonary embolism or any code for deep or superficial vein thrombosis was listed as the primary cause of death.

Results: Between 2000 and 2015, age-standardized annual pulmonary embolism-related mortality rates decreased linearly from 15.6 to 7.8 deaths per 1000 population. In the 5‑year period between 2012 and 2016, an average of 9127 pulmonary embolism-related deaths occurred annually in the DACH countries with a population of 98,273,329. Interestingly, pulmonary embolism-related mortality rates were considerably higher among women aged 15-55 years compared to age-matched men.

Conclusion: The observed decreasing trends in pulmonary embolism-related mortality might reflect improved management of the disease including new treatment options as well as advances in imaging technologies. However, pulmonary embolism remains a substantial contributor to total mortality, especially among women aged 15-55 years. For this reason, campaigns to increase physician and public awareness are urgently required to further improve the management and treatment of this preventable thrombotic disorder, which still remains the leading preventable cause of death.
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http://dx.doi.org/10.1007/s00063-021-00854-9DOI Listing
August 2021

Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany.

Eur J Prev Cardiol 2021 Aug;28(9):990-997

Department of Cardiology, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Germany.

Aims: We investigated trends in incidence, case fatality rate, patient characteristics and adverse inhospital events of patients hospitalised for heart failure in Germany.

Methods And Results: The German nationwide inpatient sample (2005-2016) was used for this analysis. Patients hospitalised due to heart failure were selected for analysis. Temporal trends in the incidence of hospitalisations, case fatality rate and treatments were analysed and predictors of inhospital death were identified. The analysis comprised a total number of 4,539,140 hospitalisations (52.0% women, 81.0% aged ≥70 years) due to heart failure. Although hospitalisations increased from 381 (2005) to 539 per 100,000 population (2016) (β estimate 0.06, 95% confidence interval (CI) 0.06 to 0.07, P < 0.001) in parallel with median age and prevalence of comorbidities, the inhospital case fatality rate decreased from 11.1% to 8.1% (β estimate -0.36, 95% CI -0.37 to -0.35, P < 0.001) and the rate of major adverse cardiovascular and cerebrovascular events (β estimate -0.24, 95% CI -0.25 to -0.23, P < 0.001) decreased from 12.7% to 10.3%. Age 70 years and older (odds ratio (OR) 2.60, 95% CI 2.57 to 2.63, P < 0.001) and cancer (OR 1.93, 95% CI 1.91 to 1.96, P < 0.001) were independent predictors of inhospital death.

Conclusion: Hospitalisations for heart failure increased in Germany from 2005 to 2016, whereas the major adverse cardiovascular and cerebrovascular event rate and inhospital case fatality rate decreased during this period despite higher patient age and increasing prevalence of comorbidities.
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http://dx.doi.org/10.1177/2047487320936020DOI Listing
August 2021

Acute Pulmonary Embolism–Its Diagnosis and Treatment From a Multidisciplinary Viewpoint.

Dtsch Arztebl Int 2021 09 17(Forthcoming). Epub 2021 Sep 17.

Background: Physicians from many different specialties see patients suffering from acute pulmonary embolism (PE), which has an incidence of 39-115 cases per 100 000 persons per year. Because PE can be life-threatening, a rapid, targeted response is essential.

Methods: This review is based on pertinent publications retrieved by a selective literature search of international databases, with particular attention to current guidelines and expert opinions.

Results: Whenever PE is suspected, clinical assessment tools must be applied for risk stratification and diagnostic evaluation. The PERC (Pulmonary Embolism Rule-out Criteria) and the YEARS algorithm lead to more effective diagnosis. For hemodynamically unstable patients, bedside echocardiography is of high value and enables risk stratification. New oral anticoagulants have fewer hemorrhagic complications than vitamin K antagonists and are not inferior to them with respect to the risk of recurrent PE (hazard ratio 0.84-1.09). The duration of anticoagulation is set according to the risk of recurrence. Systemic thrombolysis is recommended for patients with a high-risk PE, in whom it significantly reduces mortality (odds ratio 0.53, number needed to treat 59). Surgical or interventional techniques can be considered if thrombolysis is contraindicated or unsuccessful.

Conclusion: Newly introduced diagnostic aids and algorithms simplify the diagnosis and treatment of acute PE while continuing to assure a high degree of patient safety.
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http://dx.doi.org/10.3238/arztebl.m2021.0226DOI Listing
September 2021

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

Lancet Haematol 2021 Sep 4;8(9):e627-e636. Epub 2021 Aug 4.

Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.

Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).

Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.

Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.

Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2352-3026(21)00203-9DOI Listing
September 2021

COVID-19 as a Potential Trigger for Immune Thrombotic Thrombocytopenic Purpura and Reason for an Unusual Treatment: A Case Report.

Hamostaseologie 2021 Jul 29. Epub 2021 Jul 29.

Department of Internal Medicine III, Comprehensive Cancer Center, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder characterized by severely reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) due to autoantibodies. This leads to the development of pathogenic multimers of VWF, causing a thrombotic microangiopathy with decreased number of platelets, hemolysis, and life-threatening tissue ischemia of mostly brain, heart, and kidneys. Standard treatment of iTTP involves daily plasma exchange to remove ultra large multimers of VWF, inhibitors, substituting ADAMTS13, and the accompaniment of an immunosuppressive treatment with steroids. Recently, caplacizumab was approved for iTTP. Caplacizumab is a nanobody binding the A1 domain of VWF, blocking its interaction with glycoprotein Ib-IX-V platelet receptor and therefore preventing platelet aggregation. VWF activities may serve as therapeutic drug monitoring of caplacizumab, whereas ADAMTS13 activities may be used for biomarkers to guide caplacizumab treatment modalities and overall treatment duration. Additional immunosuppressive treatment by inhibiting autoantibody formation (e.g., the use of Rituximab, a chimeric monoclonal antibody directed against the B-cell antigen CD20) is a further treatment option. Infections are well-known causes for an acute episode for patients with iTTP. The novel SARS-CoV-2 virus is mainly associated with acute respiratory distress as well as diffuse endothelial inflammation and increased coagulopathy. However, little is known about an infection with SARS-CoV-2 virus triggering iTTP relapses. We herein report the case of an acute iTTP episode accompanying a SARS-CoV-2 infection.
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http://dx.doi.org/10.1055/a-1497-1054DOI Listing
July 2021

A targeted proteomics investigation of the obesity paradox in venous thromboembolism.

Blood Adv 2021 07;5(14):2909-2918

Preventive Cardiology and Preventive Medicine, Center for Cardiology.

The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass-related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.
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http://dx.doi.org/10.1182/bloodadvances.2020003800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341360PMC
July 2021

Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries.

Res Pract Thromb Haemost 2021 Jul 15;5(5):e12520. Epub 2021 Jun 15.

Center for Thrombosis and Hemostasis University Medical Center Mainz Mainz Germany.

Introduction: Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports.

Methods: We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization.

Results: We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity.

Conclusions: Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.
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http://dx.doi.org/10.1002/rth2.12520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268665PMC
July 2021

Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry.

Thromb Haemost 2021 Jul 13. Epub 2021 Jul 13.

Institute of Biostatistics and Mathematical Modelling, Goethe University, Frankfurt, Germany.

Background:  Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations.

Methods:  A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life ( ), tested in repeat samples, were evaluated.

Results:  A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients was 17.3 hours (95% confidence interval [CI]: 15.4-19.7) without significant difference in both groups (major bleeding: 16.7 hours, 95% CI: 14.7-19.3; urgent surgery: 19.7 hours, 95% CI: 15.2-27.9;  = 0.292). In apixaban-treated patients was 25.0 hours (95% CI: 22.9-27.6) with a longer after urgent surgery ( : 30.8 hours; 95% CI: 26.9-36.4) compared with severe bleeding ( : 20.8 hours; 95% CI: 18.8-23.2;  < 0.001).

Conclusion:  Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer .
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http://dx.doi.org/10.1055/a-1549-6556DOI Listing
July 2021

Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function.

Eur J Prev Cardiol 2021 Jul 13. Epub 2021 Jul 13.

Department of Cardiology, Dupuytren University Hospital and Inserm 1094, Tropical Neuroepidemiology, School of Medicine, 2 avenue martin Luther-King 87042 Limoges, France.

This consensus document is proposed to clinicians to provide the whole spectrum of deep vein thrombosis management as an update to the 2017 consensus document. New data guiding clinicians in indicating extended anticoagulation, management of patients with cancer, and prevention and management of post-thrombotic syndrome are presented. More data on benefit and safety of non-vitamin K antagonists oral anticoagulants are highlighted, along with the arrival of new antidotes for severe bleeding management.
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http://dx.doi.org/10.1093/eurjpc/zwab088DOI Listing
July 2021

Outcome of patients with different clinical presentations of high-risk pulmonary embolism.

Eur Heart J Acute Cardiovasc Care 2021 Oct;10(7):787-796

German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany.

Aims: The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition.

Methods And Results: Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P < 0.001). Patients with cardiac arrest had the highest rate of an in-hospital adverse outcome (78.4%) and mortality (59.5%; both P < 0.001 compared to intermediate-high-risk patients). Obstructive shock and persistent hypotension had similar rates of adverse outcomes (15.8% and 18.2%, respectively; P = 0.46), but the only obstructive shock was associated with an increased all-cause mortality risk. Use of an optimised venous lactate cut-off value (3.8 mmol/L) to diagnose obstructive shock allowed differentiation of adverse outcome risk between patients with shock (21.4%) and persistent hypotension (9.5%), resulting in a net reclassification improvement (0.24 ± 0.08; P = 0.002).

Conclusion: The revised ESC 2019 guidelines definition of high-risk PE stratifies subgroups at different risk of in-hospital adverse outcomes and all-cause mortality. Risk prediction can be improved by using an optimised venous lactate cut-off value to diagnose obstructive shock, which might help to better assess the risk-to-benefit ratio of systemic thrombolysis in different subgroups of high-risk patients.
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http://dx.doi.org/10.1093/ehjacc/zuab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483764PMC
October 2021

Prevalence of pulmonary embolism in 127 945 autopsies performed in cancer patients in the United States between 2003 and 2019.

J Thromb Haemost 2021 06;19(6):1591-1593

Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.1111/jth.15321DOI Listing
June 2021

Prognostic value of right atrial dilation in patients with pulmonary embolism.

ERJ Open Res 2021 Apr 24;7(2). Epub 2021 May 24.

Dept of Internal Medicine and Cardiology, Charité - University Medicine Berlin, Berlin, Germany.

Aims: Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE).

Methods: Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration.

Results: Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84-152) 102 (78-134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2-2.4) 1.3 (1.1-1.7); p<0.001) and MR-proANP levels (282 (157-481) 129 (64-238) pmol·L; p<0.001) compared to patients with a favourable outcome. Overall, 499 patients (81.9%) had a RA/LA volume ratio ≥1.0 and a calculated cut-off value of 1.8 (area under the curve 0.64, 95% CI 0.56-0.71) predicted an adverse outcome, both in unselected (OR 3.1, 95% CI 1.9-5.2) and normotensive patients (OR 2.7, 95% CI 1.3-5.6). MR-proANP ≥120 pmol·L was identified as an independent predictor of an adverse outcome, both in unselected (OR 4.6, 95% CI 2.3-9.3) and normotensive patients (OR 5.1, 95% CI 1.5-17.6).

Conclusions: RA dilation is a frequent finding in patients with PE. However, the prognostic performance of RA dilation appears inferior compared to established risk stratification markers. MR-proANP predicted an in-hospital adverse outcome, both in unselected and normotensive PE patients, integrating different prognostic relevant information from comorbidities.
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http://dx.doi.org/10.1183/23120541.00414-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141828PMC
April 2021

Antithrombotics and new interventions for venous thromboembolism: Exploring possibilities beyond factor IIa and factor Xa inhibition.

Res Pract Thromb Haemost 2021 May 18;5(4). Epub 2021 May 18.

Center for Thrombosis and Hemostasis (CTH) University Medical Center of the Johannes Gutenberg University Mainz Germany.

Direct oral anti-activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end-stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose-finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small-molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter-directed, pharmacomechanical antithrombotic strategies have been developed for high- and intermediate-risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.
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http://dx.doi.org/10.1002/rth2.12509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130658PMC
May 2021

Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Pulm Circ 2021 Apr-Jun;11(2):20458940211008069. Epub 2021 Apr 28.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.

Chronic thromboembolic pulmonary hypertension is considered as a rare but severe complication after acute pulmonary embolism and is potentially curable by pulmonary endarterectomy. We aimed to evaluate, over an 11-year period, time trends of in-hospital outcomes of pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension patients and to investigate predictors of the in-hospital course. We analyzed data on the characteristics, comorbidities, treatments, and in-hospital outcomes for all chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy in the German nationwide inpatient sample between 2006 and 2016. Overall, 1398 inpatients were included. Annual number of pulmonary endarterectomy increased from 67 in 2006 to 194 in 2016 ( < 0.001), in parallel with a significant decrease of in-hospital mortality (10.9% in 2008 to 1.5% in 2016;  < 0.001). Patients' characteristics shifted slightly toward older age and higher prevalence of chronic renal insufficiency and obesity over time, whereas duration of hospital stay decreased over time. Independent predictors of in-hospital mortality were age (OR 1.03 (95%CI: 1.01-1.05);  = 0.001), right heart failure (2.55 (1.37-4.76);  = 0.003), in-hospital complications such as ischemic stroke (6.87 (1.06-44.70);  = 0.044) and bleeding events like hemopneumothorax (24.93 (6.18-100.57);  < 0.001). Annual pulmonary endarterectomy volumes per center below 10 annual procedures were associated with higher rates of adverse in-hospital outcomes. Annual numbers of chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy increased markedly in Germany between 2006 and 2016, in parallel with a decrease of in-hospital mortality. Our findings suggest that perioperative management of pulmonary endarterectomy, institutional experience, and patient selection is crucial and has improved over time.
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http://dx.doi.org/10.1177/20458940211008069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108078PMC
April 2021

Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease.

Eur Respir J 2021 Dec 2;58(6). Epub 2021 Dec 2.

Center for Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany

Background: Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.

Methods: ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.

Results: Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.

Conclusion: Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.
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http://dx.doi.org/10.1183/13993003.04196-2020DOI Listing
December 2021

Homoarginine and methylarginines independently predict long-term outcome in patients presenting with suspicion of venous thromboembolism.

Sci Rep 2021 05 5;11(1):9569. Epub 2021 May 5.

Department of Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease (CVD). Our study reports the first analysis, whether homoarginine, ADMA and SDMA predict venous thromboembolism (VTE) recurrence and overall mortality in patients with suspected acute VTE. We assessed serum levels of homoarginine, ADMA and SDMA by LC-MS/MS in 865 individuals from a prospective consecutive cohort of patients with clinical suspicion of VTE. The median follow-up time for mortality was 1196 days. VTE was confirmed by imaging in 418 patients and excluded in 447 patients. Low levels of homoarginine and high levels of ADMA or SDMA independently predicted all-cause mortality after adjustment for sex, age, oral anticoagulants, body mass index, arterial hypertension, diabetes mellitus, smoking, dyslipidemia, chronic heart failure, history of stroke, creatinine and cancer both in patients with VTE and without VTE. Interestingly, none of those parameters was predictive for VTE recurrence. We provide the first report that low circulating levels of homoarginine and high circulating levels of ADMA and SDMA independently predict all-cause mortality in patients with suspected VTE. These parameters might serve as markers of "frailty" and should be considered for future risk stratification approaches in this clinical population. Taking into account that homoarginine supplementation is protective in animal models of CVD and safe in healthy human volunteers, our study provides the basis for future homoarginine supplementation studies in patients with suspected VTE to investigate possible direct protective effects of homoarginine in this population.
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http://dx.doi.org/10.1038/s41598-021-88986-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100302PMC
May 2021
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