Analysis of longitudinal changes in hemostasis biomarkers among cancer patients

Hintergrund: Hämostaseparameter sind bekannte Prädiktoren für das Auftreten einer VTE bei KrebspatientInnen. Zudem wurde bereits ein Zusammenhang zwischen Hämostaseparameterlevels und dem Erkrankungsstadium, der Patientenprognose und dem Überleben von KrebspatientInnen beschrieben. Das Risiko, eine VTE zu entwickeln, variiert zwischen den einzelnen Tumorentitäten und ist am höchsten bei PatientInnen mit Pankreaskarzinom. Zum Verhalten der Hämostaseparameter im zeitlichen Verlauf bei KrebspatientInnen gibt es kaum Daten. Es ist auch nicht bekannt, ob und wie sich die diversen Parameter während der Chemotherapie und im Verlauf der Erkrankung verändern und wie diese potentiellen Änderungen mit dem Auftreten einer VTE bzw. mit dem Überleben korrelieren.^ ^Daher war es das Ziel der vorliegenden Studie, longitudinale Veränderungen von Hämostaseparametern bei KrebspatientInnen sowie ihre mögliche prädiktive Rolle im Krankheitsverlauf, bezogen auf das Auftreten einer VTE und das Überleben, zu evaluieren. Patienten und Methoden: Die vorliegende Longitudinalstudie ist eine Substudie der “Vienna Cancer and Thrombosis Study (CATS)”, einer laufenden, prospektiven Beobachtungsstudie, welche am Allgemeinen Krankenhaus der Stadt Wien mit Zustimmung der lokalen Ethikkommission durchgeführt wird. Für die Substudie wurden PatientInnen mit Pankreaskarzinom und Glioblastom (welche HochrisikopatientInnen in Bezug auf VTE-Entwicklung repräsentieren) sowie PatientInnen mit Lungen- und kolorektalem Karzinom (welche PatientInnen mit mittlerem Risiko in Bezug auf VTE-Entwicklung repräsentieren), die in CATS eingeschlossen wurde, über einen Zeitraum von 250 Tagen beobachtet.^ ^Während dieses Beobachtungszeitraumes wurden monatlich Hämoglobin, Thrombozyten- und Leukozytenzahl, FVIII, sP-Selektin, peak height thrombin, Fibrinogen, Prothrombinfragment 1+2, D-Dimer und ATIII bestimmt. Studienendpunkte waren Tod, Auftreten einer VTE oder Ende der Beobachtungsdauer von 250 Tagen. Ergebnisse: Insgesamt wurden 112 PatientInnen, davon 39 mit Glioblastom, 41 mit Lungen-, 15 mit kolorektalem und 17 mit Pankreaskarzinom, eingeschlossen. Das mediane Alter lag bei 62,4 Jahren. Während des Beobachtungszeitraumes, entwickelten 14 PatientInnen (12,5 %) eine VTE und 17 (16,2 %) verstarben. PatientInnen mit Fernmetastasierung hatten höhere sP-Selektin- und D-Dimer-Levels als die ohne. Eine komplette Remission war mit niedrigeren F1+2-, D-Dimer- und Fibrinogen-Levels assoziiert. Die untersuchten Parameter zeigten in den 4 betrachteten Tumorentitäten unterschiedliche Verläufe.^ ^Peak height Thrombin-, AT III- und Hämoglobin-Werte zeigten bei allen Tumorarten im Verlauf einen Abfall. Bei PatientInnen, die eine VTE entwickelten, zeigten sich im Verlauf vor Auftreten der VTE ansteigende FVIII-, sP-Selektin- und D-Dimer-Werte. Stetig ansteigende FVIII-, sP-Selektin- und D-Dimer-Werte im Verlauf waren mit höherer Mortalität assoziiert. Schlussfolgerung: Unsere Ergebnisse deuten auf einen Zusammenhang zwischen Hämostaseparametern und Erkrankungsstadium, Prognose (Mortalität) und VTE-Risiko hin, nicht nur zum Zeitpunkt der Diagnose, sondern auch während des Krankheitsverlaufs.Background: Hemostasis parameters are known predictors for VTE occurrence in patients with cancer. Furthermore, an association between hemostasis parameter levels and disease state, patients prognosis as well as survival in cancer patients has been described previously. VTE risk differs among various tumor entities, being highest in patients with pancreatic cancer. Data on the longitudinal behavior of hemostasis parameters in cancer patients are scarce. It is also not known if and how the various hemostasis parameters alter in cancer patients during chemotherapy and along the course of disease and how these alterations might correlate with VTE occurrence and survival.^ ^Therefore, we aimed to investigate longitudinal changes of hemostasis parameters in cancer patients in order to evaluate their possible predictive role along time regarding VTE occurrence and survival, respectively. Patients and Methods: The present longitudinal analysis was performed as a sub-study of the “Vienna Cancer and Thrombosis Study (CATS)”, an ongoing, prospective observational single-center study at the General Hospital of Vienna, which was approved by the local Ethics Committee. For the sub-study, patients with pancreatic cancer, glioblastoma (representing patients at high risk for VTE occurrence) as well as patients with lung and colorectal cancer (representing an intermediate risk for VTE occurrence), who have been included in CATS were followed longitudinally for a time period of 250 days.^ ^During this time period, hemoglobin, platelet and leucocyte count, FVIII, sP-selectin, peak height thrombin, fibrinogen, prothrombin fragment 1+2, D-dimer and ATIII were determined on a monthly basis. Study end points were death, VTE and study completion. Results: Overall, 112 patients, thereof 39 with brain, 41 with lung, 15 with colorectal and 17 with pancreatic cancer, were enrolled. Their median age was 62.4 years. During the observation period, 14 patients (12.5 %) had a VTE and 17 (16.2 %) died. Patients with distant metastases had higher levels of sP-selectin and D-dimer than those without. Complete remission was associated with lower F1+2, D-dimer and fibrinogen levels. Regarding the four investigated tumor entities, the hemostasis parameter levels showed a different behaviour: Levels of thrombin (peak height), ATIII and hemoglobin decreased in the four tumor subgroups over time. VTE patients had higher values of D-dimer, FVIII and sP-selectin before VTE occurred.^ ^Steadily increasing D-dimer, FVIII or sP-selectin levels correlated with a higher mortality. Conclusion: Our results indicate that in cancer patients an association of hemostasis parameters with VTE risk, disease state and prognosis (mortality) exists- both, at diagnosis and thereafter.Eva-Maria ReitterMedizinische Universität Wien, Diss., 201

A case report of septic shock syndrome caused by S. pneumoniae in an immunocompromised patient despite of vaccination

Abstract Background and case presentation We report a case of septic shock syndrome caused by Streptococcus pneumoniae in a patient who had undergone splenectomy due to an autoimmune lymphoproliferative syndrome (ALPS), which is characterized as a dysfunction of immunoregulation. Although the patient was vaccinated with a conjugated polysaccharide vaccine after the splenectomy, he was still susceptible to S. pneumoniae infection, because the isolated serovar (24F), a serovar long thought to be apathogenic, is not covered by any vaccine currently approved, neither a conjugated nor an unconjugated polysaccharide one. Conclusions This case demonstrates that, due to presence of different serovars, also infections with bacteria against which patients are vaccinated have to be considered as differential diagnosis. Although vaccine development has extended the coverage of S. pneumoniae from 7 to 23 serovars within recent years, there is still demand for novel vaccines which can provide broader protection also against so-thought “apathogenic” strains, especially for groups at high risk

Red cell distribution width and other red blood cell parameters in patients with cancer: association with risk of venous thromboembolism and mortality.

BACKGROUND:Cancer patients are at high risk of developing venous thromboembolism (VTE). Red cell distribution width (RDW) has been reported to be associated with arterial and venous thrombosis and mortality in several diseases. Here, we analyzed the association between RDW and other red blood cell (RBC) parameters with risk of VTE and mortality in patients with cancer. METHODS:RBC parameters were measured in 1840 patients with cancers of the brain, breast, lung, stomach, colon, pancreas, prostate, kidney; lymphoma, multiple myeloma and other tumor sites, that were included in the Vienna Cancer and Thrombosis Study (CATS), which is an ongoing prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Primary study outcome is occurrence of symptomatic VTE and secondary outcome is death during a maximum follow-up of 2 years. RESULTS:During a median follow-up of 706 days, 131 (7.1%) patients developed VTE and 702 (38.2%) died. High RDW (>16%) was not associated with a higher risk of VTE in the total study cohort; in competing risk analysis accounting for death as competing variable the univariable subhazard ratio (SHR) was 1.34 (95% confidence interval [CI]: 0.80-2.23, p = 0.269). There was also no significant association between other RBC parameters and risk of VTE. High RDW was associated with an increased risk of mortality in the total study population (hazard ratio [HR, 95% CI]: 1.72 [1.39-2.12], p<0.001), and this association prevailed after adjustment for age, sex, hemoglobin, leukocyte and platelet count (HR [95% CI]: 1.34 [1.06-1.70], p = 0.016). CONCLUSIONS:RDW and other RBC parameters were not independently associated with risk of VTE in patients with cancer and might therefore not be of added value for estimating risk of VTE in patients with cancer. We could confirm that high RDW is an independent predictor of poor overall survival in cancer

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

A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts

Background: Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism. Methods: We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts. Findings: Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41–2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12–1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63–0·67) in CATS and 0·68 (0·62–0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts. Interpretation: An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis. Funding: Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals

Red blood cell parameters and risk of VTE in patients with solid tumors (n = 1286). Significant results are highlighted in bold.

<p>Red blood cell parameters and risk of VTE in patients with solid tumors (n = 1286). Significant results are highlighted in bold.</p

Kaplan-Meier estimates for cumulative survival probability of cancer patients (total study cohort) with red blood cell distribution width (RDW)>16% and below (≤16%), respectively.

<p>Survival rates were significantly lower in patients with high RDW in comparison to those with a non-elevated RDW (p<0.001). Numbers in parentheses indicate numbers of deaths in the respective group and time period.</p

Red blood cell parameters and risk of mortality in the total study cohort (n = 1840). Significant results are highlighted in bold.

<p>Red blood cell parameters and risk of mortality in the total study cohort (n = 1840). Significant results are highlighted in bold.</p

Red blood cell parameters and risk of VTE in the total study cohort (n = 1840).

<p>Red blood cell parameters and risk of VTE in the total study cohort (n = 1840).</p