Arterial Thromboembolism in Patients with Cancer

Hintergrund: Herz-Kreislauf- und maligne Erkrankungen sind die beiden häufigsten Todesursachen in Industrienationen. Während es viel Wissen über die einzelnen Krankheiten gibt, ist nur wenig über deren Zusammenhang bekannt. Ein wesentlicher Grund dafür ist der Ausschluss von Patienten mit Krebserkrankung aus klinischen Studien der kardiovaskulären Medizin. Ziele: Das Hauptziel dieser Arbeit war es, die Häufigkeit von arteriellen Thromboembolien (ATE) bei PatientInnen mit Krebs und ihre Auswirkungen auf die Gesamtmortalität zu untersuchen. Ein weiteres Ziel der Arbeit war es, klinische Risikofaktoren und blutbasierte Biomarker zu identifizieren, die mit dem Risiko von ATE bei KrebspatientInnen verbunden sind. Methoden: Diese Dissertation wurde im Rahmen der Vienna Cancer and Thrombosis Study (CATS), einer prospektiven Kohortenstudie an PatientInnen mit einer Vielzahl von verschiedenen Tumorarten durchgeführt. Eingeschlossen wurden PatientInnen bei denen die Tumorerkrankung entweder neu oder im Rahmen eines Rückfalls nach Remission auftrat. Es wurde Blut entnommen, um verschiedene Parameter bei der Aufnahme in die Studie zu messen, und die PatientInnen wurden 2 Jahre beobachtet. CATS wurde ursprünglich entwickelt, um Prädiktoren für venöse Thromboembolien (VTE) bei PatientInnen mit Krebs zu untersuchen. Daten über das Auftreten von ATE wurden als Komorbidität während des Studienzeitraums erhoben. Resultate: Das kumulative 6-, 12- und 24-monatige Risiko für ATE bei KrebspatientInnen betrug 1.1%, 1.7% bzw. 2.6%. Männliches Geschlecht (Subdistribution Hazard Ratio [SHR]: 2.9; 95% Konfidenzintervall [95% CI]: 1.5-5.6), höheres Alter (SHR pro 10 Jahre Anstieg: 1.5; 1.2-1.7), Rauchen (2.0; 1.1-3.7), Bluthochdruck (3.1; 1.7-5.5), Diabetes (2.2; 1.2-4.4), eine Vorgeschichte von arteriellen Herz-Kreislauf-Erkrankungen (3.7; 1.9-7.2) und die Behandlung mit lipidsenkenden Mitteln (2.9; 1.5-5.3) oder Thrombozytenaggregationshemmern (5.0; 2.8-8.8) wurden als Risikofaktoren für krebsassoziierte ATE identifiziert. Darüber hinaus war das Risiko für die Entwicklung einer ATE bei PatientInnen mit Lungen- (SHR: 2.3; 1.2-4.2) und Nierenkrebs (3.8; 1.4-10.5) höher als bei PatientInnen mit anderen Tumorarten. Außerdem waren eine erhöhte Erythrozytenverteilungsbreite (SHR pro Verdoppelung: 4.4; 1.4-14.1), eine erhöhte absolute Leukozytenzahl (SHR pro Verdopplung: 1.2; 1.1-1.5), eine erhöhte absolute Neutrophilenzahl (SHR pro Verdopplung: 1.6; 1.1-2.3) und höhere lösliche P-Selektinspiegel (SHR pro Verdopplung: 1.9; 1.3-2.7) mit einem höheren Risiko für ATE verbunden. Die PatientInnen, die im Beobachtungszeitraum an ATE litten, hatten ein dreifach höheres Mortalitätsrisiko. Schlussfolgerung: Diese Arbeit zeigt, dass KrebspatientInnen einem ATE-Risiko ausgesetzt sind und untermauert den Zusammenhang von kardiovaskulären und malignen Erkrankungen. Im Vergleich zu VTE tritt die krebsassoziierte ATE weniger jedoch häufig auf. Allerdings ist das Risiko für ATE bei bestimmten Krebsarten hoch. Darüber hinaus konnten spezifische Risikofaktoren für ein höheres ATE-Risiko identifiziert werden. Da eine ATE mit einem erhöhten Mortalitätsrisiko einhergeht, sind Studien zum besseren Verständnis und zur Verhinderung der Folgen einer krebsassoziierten ATE erforderlich.Background: Cardiovascular- and malignant diseases are the two most common causes auf death in industrialized countries. While there is much knowledge about these individual diseases, little is known about their association with each other. One main reason for this is the exclusion of patients with cancer from clinical trials in cardiovascular medicine. Objectives: The primary aim of this thesis was to investigate the incidence of arterial thromboembolism (ATE) in patients with cancer and its impact on all-cause mortality. Another goal of the work was to identify clinical risk factors and blood-based biomarkers associated with the risk of ATE in patients with cancer. Methods: The PhD thesis was performed within the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study of patients with a variety of different tumor types, which were newly diagnosed or relapsed after remission. Blood was taken to measure various parameters at inclusion in the study and patients were followed for 2 years. CATS was originally designed to investigate predictors for venous thromboembolism (VTE) in patients with cancer. Data regarding ATE occurrence was collected as a comorbid condition during the study period. Results: The cumulative 6-, 12-, and 24-months risk of ATE in patients with cancer was 1.1%, 1.7%, and 2.6%, respectively. Male sex (subdistribution hazard ratio [SHR]: 2.9; 95% confidence interval [95% CI]: 1.5-5.6), higher age (SHR per 10 years increase: 1.5; 1.2-1.7), smoking (2.0; 1.1-3.7), hypertension (3.1; 1.7-5.5), diabetes (2.2; 1.2-4.4), a history of arterial cardiovascular disease (3.7; 1.9-7.2), and treatment with lipid-lowering agents (2.9; 1.5-5.3) or platelet aggregation inhibitors (5.0; 2.8-8.8) were identified as risk factors for cancer-associated ATE. In addition, the risk of developing ATE was higher in patients with lung (SHR: 2.3; 95% CI: 1.2-4.2), and kidney cancer (3.8; 1.4-10.5) than in patients with other tumor entities. Furthermore, a higher red cell distribution width (SHR per doubling: 4.4; 1.4-14.1), higher absolute leukocyte count (SHR per doubling: 1.2; 1.1-1.5), higher absolute neutrophil count (SHR per doubling: 1.6; 1.1-2.3), and higher soluble P-selectin levels (SHR per doubling: 1.9; 1.3-2.7) were associated with a higher risk of ATE. Those patients who suffered from ATE during the observation period had a 3-fold higher risk of mortality. Conclusion: This work/thesis demonstrates that patients with cancer are at risk of ATE and provides evidence for an association of cardiovascular disease and cancer. Compared to VTE, cancer-associated ATE is less frequent. However, the risk of ATE is high in certain types of cancer. In addition, specific risk factors for a higher ATE risk could be identified. As ATE was linked to an increased risk of mortality, further clinical research is needed to reduce the burden of cancer-associated ATE.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2019(VLID)447110

Frequency, risk factors, and impact on mortality of arterial thromboembolism in patients with cancer

In contrast to venous thromboembolism, little is known about arterial thromboembolism in patients with cancer. The aim of this study was to quantify the risk and explore clinical risk factors of arterial thromboembolism in patients with cancer, and investigate its potential impact on mortality. Patients with newly-diagnosed cancer or progression of disease after remission were included in a prospective observational cohort study and followed for two years. Between October 2003 and October 2013, 1880 patients (54.3% male; median age 61 years) were included. During a median follow up of 723 days, 48 (2.6%) patients developed arterial thromboembolism [20 (41.7%) myocardial infarction, 16 (33.3%) stroke and 12 (25.0%) peripheral arterial events], 157 (8.4%) developed venous thromboembolism, and 754 (40.1%) patients died. The cumulative 3-, 6-, 12-, and 24-month risks of arterial thromboembolism were 0.9%, 1.1%, 1.7%, and 2.6%, respectively. Male sex (subdistribution hazard ratio=2.9, 95%CI: 1.5-5.6; P=0.002), age (subdistribution hazard ratio per 10 year increase=1.5, 1.2-1.7; P<0.001), hypertension (3.1, 1.7-5.5; P<0.001), smoking (2.0, 1.1-3.7; P=0.022), lung cancer (2.3, 1.2-4.2; P=0.009), and kidney cancer (3.8, 1.4-10.5; P=0.012) were associated with a higher arterial thromboembolism risk. Furthermore, the occurrence of arterial thromboembolism was associated with a 3.2-fold increased risk of all-cause mortality (hazard ratio=3.2, 95%CI: 2.2-4.8; P<0.001). Arterial thromboembolism is a less common complication in patients with cancer than venous thromboembolism. The risk of arterial thromboembolism is high in patients with lung and kidney cancer. Patients with cancer who develop arterial thromboembolism are at a 3-fold increased risk of mortality.(VLID)470074

Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability

In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel electrophoresis. The examined platelet proteome was unchanged in patients with brain cancer, but considerably affected in lung cancer with 15 significantly altered proteins. Amongst these, the endoplasmic reticulum (ER) proteins calreticulin (CALR), endoplasmic reticulum chaperone BiP (HSPA5) and protein disulfide-isomerase (P4HB) were significantly elevated. Accelerated conversion of the fibrin stabilising factor XIII was detected in platelets of patients with lung cancer by elevated levels of a coagulation factor XIII (F13A1) 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma levels of the plasmin–α-2-antiplasmin complex and D-dimer suggests its enhanced degradation by the fibrinolytic system. Protein association network analysis showed that lung cancer-related proteins were involved in platelet degranulation and upregulated ER protein processing. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. These new data on the differential behaviour of platelets in various cancers revealed F13A1 and ER chaperones as potential novel diagnostic and therapeutic targets in lung cancer patients

British Journal of Haematology / Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

Prior studies indicate that neutrophil extracellular traps (NET s) are associated with arterial thromboembolism (ATE ) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cellfree DNA [cfDNA], and nucleosomes) and the risk of ATE and allcause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Ninehundred and fiftyseven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·71·4, P = 0·949), 1·0 per 100 ng/ml (0·91·2, P = 0·494) increase and 1·1 per 1unit increase (1·01·2, P = 0·233), respectively. Threehundred and seventyeight (39·5%) patients died. The hazard ratio (HR ) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·01·1, P < 0·001) and 1·1 (1·01·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1unit increase was 1·0 (1·01·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.(VLID)510148

Extracellular Vesicle-Associated Tissue Factor Activity in Prostate Cancer Patients with Disseminated Intravascular Coagulation

Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer controls without DIC, and 10 age-matched healthy male individuals. EV-TF activity was highly elevated in prostate cancer patients with DIC (11.40 pg/mL; range: 4.34–27.06) compared with prostate cancer patients without DIC (0.09 pg/mL; range: 0.00–0.30, p = 0.001) and healthy controls (0.18 pg/mL; range: 0.09–0.54; p = 0.001). Only EVs from patients with DIC reduced fibrin clot formation time of pooled plasma in a TF-dependent manner. Next, we performed in vitro co-culture experiments including EVs derived from a prostate cancer cell line with high (DU145) and low (LNCaP) TF expression, peripheral blood mononuclear cells (PBMCs), and platelets. Co-incubation of DU145 EVs with PBMCs and platelets significantly increased EV-TF activity in conditioned medium and induced TF activity on monocytes. No such effects were seen in co-culture experiments with LNCaP EVs. In conclusion, the findings indicate that elevated EV-TF activity plays a role in the development of prostate-cancer-related DIC and may result from interactions between tumor-derived EVs, monocytes, and platelets

Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D-Dimer analysis: A prospective study.

BACKGROUND:Venous thromboembolism (VTE) is a frequent complication of cancer. Elevated D-Dimer is associated with an increased risk of cancer-associated VTE. Whether changes in D-Dimer over time harbor additional prognostic information that may be exploited clinically for dynamic prediction of VTE is unclear. OBJECTIVES:To explore the potential role of longitudinal D-Dimer trajectories for personalized prediction of cancer-associated VTE. PATIENTS/METHODS:167 patients with active malignancy were prospectively enrolled (gastrointestinal: n=59 (35%), lung: n=56 (34%), brain: n=50 (30%), others: n=2 (1%); metastatic disease: n=74 (44%)). D-Dimer (median=0.8µg/mL [25th -75th percentile: 0.4-2.0]) was measured at baseline and during 602 monthly follow-up visits. Joint models of longitudinal and time-to-event data were implemented to quantify the association between D-Dimer trajectories and prospective risk of VTE. RESULTS:VTE occurred in 20 patients (250-day VTE risk=12.1%, 95%CI: 7.8-18.5). D-Dimer increased by 34%/month (0.47µg/mL/month, 95%CI: 0.22-0.72, p<0.0001) in patients who developed VTE, but remained constant in patients who did not develop VTE (change/month=-0.06µg/mL/month, 95%CI: -0.15-0.02, p=0.121). In joint modeling, a doubling of the D-Dimer trajectory was associated with a 2.8-fold increase in the risk of VTE (Hazard ratio=2.78, 95%CI: 1.69-4.58, p<0.0001). This finding was independent of established VTE risk factors. Highly personalized, dynamic predictions of VTE conditional on individual patients' D-Dimer trajectories could be obtained. CONCLUSIONS:D-Dimer increases before the onset of cancer-associated VTE, but remains constant over time in patients without VTE. This study represents proof-of-concept that longitudinal trajectories of D-Dimer may advance the personalized assessment of VTE risk in the oncologic setting

Prevalence of Atrial Fibrillation and Antithrombotic Therapy in Hemodialysis Patients: Cross-Sectional Results of the Vienna InVestigation of AtriaL Fibrillation and Thromboembolism in Patients on HemoDIalysis (VIVALDI)

Background Atrial fibrillation (AF) adds significant risk of stroke and thromboembolism in patients on hemodialysis (HD). The aim of this study was to investigate the prevalence of AF in a population-based cohort of HD patients and practice patterns of antithrombotic therapy for stroke prevention in AF. Methods The Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemodialysis (VIVALDI), an ongoing prospective observational cohort study, investigates the prevalence of AF and the risk of thromboembolic events in HD patients in Vienna, Austria. We analyzed cross-sectional data of 626 patients (63.4% men, median age 66 years, approx. 73% of HD patients in Vienna), who provided informed consent. A structured interview with each patient was performed, recent and archived ECGs were viewed and medical histories were verified with electronic records. Results The overall prevalence of AF was 26.5% (166 patients, 71.1% men, median age 72 years) of which 57.8% had paroxysmal AF, 3.0% persistent AF, 32.5% permanent AF, and 6.6% of patients had newly diagnosed AF. The median CHA2DS2-VASc Score was 4 [25th-75th percentile 35]. In multivariable analysis, AF was independently associated with age (odds ratio: 1.05 per year increase, 95% confidence interval: 1.031.07), male sex (1.7, 1.12.6), history of venous thromboembolism (2.0, 1.13.6), congestive heart failure (1.7, 1.12.5), history of or active cancer (1.5, 1.02.4) and time on HD (1.08 per year on HD, 1.031.13). Antithrombotic treatment was applied in 84.4% of AF patients (anticoagulant agents in 29.5%, antiplatelet agents in 33.7%, and both in 21.1%). In AF patients, vitamin-K-antagonists were used more often than low-molecular-weight heparins (30.1% and 19.9%). Conclusions The prevalence of AF is high amongst HD patients and is associated with age, sex, and distinct comorbidities. Practice patterns of antithrombotic treatment indicate a lack of consensus for stroke prevention in HD patients with AF.(VLID)486840