Blood Advances

Comparison of anticoagulants and risk of ischemic stroke in patients with acute cancer-associated venous thromboembolism

Abstract Venous thromboembolism (VTE) is a frequent occurrence in patients with cancer. However, it is not known whether treatment with different classes of anticoagulants impacts the risk of subsequent arterial thromboembolism. We performed a retrospective, population-based cohort study using Surveillance, Epidemiology, and End Results data linked with Medicare claims. Patients were eligible for study inclusion if they had a diagnosis of primary brain, colorectal, gastric, pancreatic, lung, or ovarian cancer between 2007 and 2015, were diagnosed with VTE, and had a prescription claim for a direct oral anticoagulant (DOAC), low-molecular-weight heparin (LMWH), or warfarin. We matched patients by propensity score in a 1:1:1 ratio into anticoagulant treatment groups based on their baseline demographic information, cancer-specific characteristics, and cardiovascular comorbidities. The primary aim of the study was to determine and compare the 6-month cumulative incidence of ischemic stroke across anticoagulant classes. The study comprised 4875 total patients with 1625 in each treatment group. At 6 months, the cumulative incidence of ischemic stroke was 5.6% (95% confidence interval [CI], 5.0-6.3) overall and 6.8% (95% CI, 5.6-8.1) in the DOAC, 4.9% (95% CI, 3.9-6.0) in the LMWH, and 5.2% (95% CI, 4.1-6.2) in the warfarin treatment groups (P = .040). We identified hypertension (odds ratio [OR], 1.75), atrial fibrillation/flutter (OR, 1.37), DOAC use (OR, 1.36), and previous stroke (OR, 3.59) as statistically significant risk factors for ischemic stroke in the multivariable modeling. In conclusion, ischemic stroke is a common occurrence after cancer-associated VTE and may occur more frequently in patients treated with DOACs.

Impact of clinical factors on accuracy of ovarian cancer detection via platelet RNA profiling

Abstract Ovarian cancer (OC) presents a diagnostic challenge, often resulting in poor patient outcomes. Platelet RNA sequencing, which reflects host response to disease, shows promise for earlier OC detection. This study examines the impact of sex, age, platelet count, and the training on cancer types other than OC on classification accuracy achieved in the previous platelet-alone training data set. A total of 339 samples from healthy donors and 1396 samples from patients with cancer, spanning 18 cancer types (including 135 OC cases) were analyzed. Logistic regression was applied to verify our classifiers’ performance and interpretability. Models were tested at 100% specificity and 100% sensitivity levels. Incorporating patient age as an additional feature along with gene expression increased sensitivity from 68.6% to 72.6%. Models trained on data from both sexes and on female-only data achieved a sensitivity of 68.6% and 74.5%, respectively. Training solely on OC data reduced late-stage sensitivity from 69.1% to 44.1% but increased early-stage sensitivity from 66.7% to 69.7%. This study highlights the potential of platelet RNA profiling for OC detection and the importance of clinical variables in refining classification accuracy. Incorporating age with gene expression data may enhance OC diagnostic accuracy. The inclusion of male samples deteriorates classifier performance. Data from diverse cancer types improves advanced cancer detection but negatively affects early-stage diagnosis.

The effect of platelet G proteins on platelet extravasation and tumor growth in the murine model of ovarian cancer

Abstract We and other investigators have shown that platelets promote metastasis and the growth of tumors. Our rationale for conducting this study is that platelets’ prometastatic and progrowth effects depend on a close encounter between platelets and cancer cells. This interaction occurs inside blood vessels with circulating tumor cells and outside blood vessels with cancer cells residing in the tumor parenchyma. Our hypothesis was that platelet extravasation is required for the effect of platelets on tumor growth. Platelets respond to environmental stimuli by activation of G protein–coupled receptors on their surface. We investigated the impact of various platelet G proteins on the growth of ovarian cancer tumors and platelet extravasation. We used mice with platelet-specific deficiency of Gαi2 (Gi), Gα13 (G13), or Gαq (Gq) in a syngeneic ovarian cancer model. We measured the total weight of tumor nodules resected from tumor-bearing mice. We developed methods for automated whole-slide image acquisition and unbiased computerized image analysis to quantify extravasated platelets. We compared the number of platelets inside tumor nodules of platelet G protein–deficient tumor-bearing mice. We found that deficiency of Gi and G13, but not Gq, in platelets resulted in smaller tumors compared with those in corresponding littermates. Deficiency of Gi and G13 in platelets reduced the number of extravasated platelets by >90%, but deficiency of Gq did not reduce the number of extravasated platelets significantly. The lack of Gi or G13 in platelets reduced platelet extravasation into the tumor and tumor growth.

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

Abstract In ovarian cancer, platelet extravasation into the tumor and resulting metastasis is thought to be regulated mostly by the vascular endothelium. Because it is difficult to dissect complex underlying events in murine models, organ-on-a-chip methodology is applied to model vascular and platelet functions in ovarian cancer. This system (OvCa-Chip) consists of microfluidic chambers that are lined by human ovarian tumor cells interfaced with a 3-dimensional endothelialized lumen. Subsequent perfusion with human platelets within the device’s vascular endothelial compartment under microvascular shear conditions for 5 days uncovered organ-to-molecular–level contributions of the endothelium to triggering platelet extravasation into tumors. Further, analysis of effluents available from the device’s individual tumor and endothelial chambers revealed temporal dynamics of vascular disintegration caused by cancer cells, a differential increase in cytokine expression, and an alteration of barrier maintenance genes in endothelial cells. These events, when analyzed within the device over time, made the vascular tissue leaky and promoted platelet extravasation. Atorvastatin treatment of the endothelial cells within the OvCa-Chip revealed improved endothelial barrier function, reduction in inflammatory cytokines and, eventually, arrest of platelet extravasation. These data were validated through corresponding observations in patient-derived tumor samples. The OvCa-Chip provides a novel in vitro dissectible platform to model the mechanisms of the cancer-vascular-hematology nexus and the analyses of potential therapeutics.