Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study

Abstract

Objective: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer.

Methods: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests.

Results: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005).

Interpretation: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.

Figure 1. An example High Intensity Transient Signal (HITS) on transcranial Doppler.

This figure depicts an identified HITS in a patient with active lung cancer and acute ischemic stroke. In the top panel, power M-mode displays the left middle cerebral artery at depths of 33 to 55 mm. The horizontal yellow line denotes the specific depth (48 mm) that has been selected to display the single gate spectral waveform seen in the bottom panel. A HITS (i.e., microemboli) is identified traveling in one direction through the middle cerebral artery. It is characterized visually by a vertical bright streak and acoustically by a “chirping” sound.

Figure 2. Box-and-whisker plots comparing hematological biomarker values between the cancer-plus-stroke and stroke-only groups.

The upper box margins depict the upper quartiles, the lower box margins depict the lower quartiles, and the horizontal black lines depict the median values. The lower whiskers depict the 2.5 percentiles, and the upper whiskers depict the 97.5 percentiles. The Wilcoxon rank-sum test was used to compare biomarker values between groups and generate p-values. D-dimer, thrombin-antithrombin, thrombomodulin, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were log-transformed to meet model assumptions. Abbreviations: CS = cancer-plus-stroke, SO = stroke-only, TAT = thrombin-antithrombin, sICAM-1 = soluble intercellular adhesion molecule-1, sVCAM-1 = soluble vascular cell adhesion molecule-1.