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Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.

ABSTRACT: Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P < .001) and higher D-dimer levels (P < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; P =010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.

SUBMITTER: Riedl J

PROVIDER: S-EPMC5823234 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.

Riedl Julia J Preusser Matthias M Nazari Pegah Mir Seyed PM Posch Florian F Panzer Simon S Marosi Christine C Birner Peter P Thaler Johannes J Brostjan Christine C Lötsch Daniela D Berger Walter W Hainfellner Johannes A JA Pabinger Ingrid I Ay Cihan C

Blood 20170110 13

Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a ...[more]

PMID: 28073783

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Project description:BackgroundPosttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE.MethodsWe performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE.ResultsThe 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01]).ConclusionSeverely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens.Level of evidencePrognostic/Epidemiological; Level III.

Project description:Background Venous thromboembolism (VTE) is a threat to the prognosis of tumor patients, especially for critically ill patients. No uniform standard model of VTE risk for critically ill patients with tumors was formatted by now. We thus analyzed risk factors of VTE from the perspectives of patient, tumor, and treatment and assessed the predictive value of the ICU-VTE score, which consisted of six independent risk factors (central venous catheterization, 5 points; immobilization ≥ 4 days, 4 points; prior VTE, 4 points; mechanical ventilation, 2 points; lowest hemoglobin during hospitalization ≥ 90 g/L, 2 points; and baseline platelet count > 250,000/μL, 1 points). Methods We evaluated the data of tumor patients admitted to the intensive care unit of the Peking University Cancer Hospital between November 2011 and January 2022; 560 cases who received VTE-related screening during hospitalization were chosen for this retrospective study. Results The inhospital VTE occurrence rate in our cohort was 55.7% (312/560), with a median interval from ICU admission to VTE diagnosis of 8.0 days. After the multivariate logistic regression analysis, several factors were proved to be significantly associated with inhospital VTE: age ≥ 65 years, high tumor grade (G3–4), medical diseases, fresh frozen plasma transfusion, and anticoagulant prophylaxis. The medium-high risk group according to the ICU-VTE score was positively correlated with VTE when compared with the low-risk group (9–18 points vs. 0–8 points; OR, 3.13; 95% CI, 2.01–4.85, P < 0.001). The AUC of the ICU-VTE scores according to the ROC curve was 0.714 (95% CI, 0.67–0.75, P < 0.001). Conclusions The ICU-VTE score, as well as tumor grade, might assist in the assessment of inhospital VTE risk for critically ill patients with tumors. The predictive accuracy might be improved when combining two of them; further follow-up researches are needed to confirm it. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02705-z.

Project description:Rationale: Metabolic syndrome (MetS), the clinical clustering of hypertension, dyslipidemia, insulin resistance, and abdominal obesity, has been associated with a prothrombotic and hypofibrinolytic state, although data linking MetS with venous thromboembolism (VTE) remain limited.Objectives: The aim of this study was to measure the prevalence of MetS in patients with pulmonary embolism (PE) across a large population and to examine its impact on VTE recurrence.Methods: This was a retrospective, population-based analysis using deidentified information from a large statewide database, the Indiana Network for Patient Care. All patients with an International Classification of Diseases-defined diagnosis of PE from 2004 to 2017 were included. We measured the frequency with which patients with PE carried a comorbid diagnosis of each MetS component. Multiple logistic regression analysis was performed with VTE recurrence as the dependent variable to test the independent effect of MetS diagnosis, with a statistical model using a directed acyclic graph to account for potential confounders and mediators. Kaplan-Meier curves were constructed to compare rates of VTE recurrence over time based on the presence or absence of MetS and its individual components.Results: A total of 72,936 patients were included in this analysis. The most common MetS component was hypertension with a prevalence of 59%, followed by hyperlipidemia (41%), diabetes mellitus (24%), and obesity (22%). Of these patients, 69% had at least one comorbid component of MetS. The overall incidence of VTE recurrence was 17%, increasing stepwise with each additional MetS component and ranging from 6% in patients with zero components to 37% in those with all four. Logistic regression analysis yielded an adjusted odds ratio of 3.03 (95% CI, 2.90-3.16) for the effect of composite diagnosis requiring at least three of the four components of MetS diagnosis on VTE recurrence.Conclusions: The presence of comorbid MetS in patients with PE is associated with significantly higher rates of VTE recurrence, supporting the importance of recognizing these risk factors and initiating appropriate therapies to reduce recurrence risk.

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Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.

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Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.

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