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. 2022 Sep;20(9):2046-2057.
doi: 10.1111/jth.15779. Epub 2022 Jun 21.

Ischemic stroke with cancer: Hematologic and embolic biomarkers and clinical outcomes

Babak B Navi  1   2 , Cenai Zhang  1 , Carla P Sherman  1 , Richard Genova  1 , Natalie M LeMoss  1 , Hooman Kamel  1 , Scott T Tagawa  3 , Ashish Saxena  3 , Allyson J Ocean  3 , Scott E Kasner  4 , Mary Cushman  5 , Mitchell S V Elkind  6 , Ellinor Peerschke  7 , Lisa M DeAngelis  2
Affiliations

Ischemic stroke with cancer: Hematologic and embolic biomarkers and clinical outcomes

Babak B Navi et al. J Thromb Haemost. 2022 Sep.

Abstract

Background: Patients with cancer and acute ischemic stroke (AIS) face high rates of recurrent thromboembolism or death.

Objectives: To examine whether hematologic and embolic biomarkers soon after AIS are associated with subsequent adverse clinical outcomes.

Methods: We prospectively enrolled 50 adults with active solid tumor cancer and AIS at two hospitals from 2016 to 2020. Blood was collected 72-120 h after stroke onset. A 30-min transcranial Doppler (TCD) microemboli detection study was performed. The exposure variables were hematologic markers of coagulation (D-dimer, thrombin-antithrombin), platelet (P-selectin), and endothelial activation (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1]), and the presence of TCD microemboli. The primary outcome was a composite of recurrent arterial/venous thromboembolism or death. We used Cox regression to evaluate associations between biomarkers and subsequent outcomes.

Results: During an estimated median follow-up time of 48 days (IQR, 18-312), 43 (86%) participants developed recurrent thromboembolism or death, including 28 (56%) with recurrent thromboembolism, of which 13 were recurrent AIS (26%). In unadjusted analysis, D-dimer (HR 1.6; 95% CI 1.2-2.0), P-selectin (HR 1.9; 95% CI 1.4-2.7), sICAM-1 (HR 2.2; 95% CI 1.6-3.1), sVCAM-1 (HR 1.6; 95% CI 1.2-2.1), and microemboli (HR 2.2; 95% CI 1.1-4.5) were associated with the primary outcome, whereas thrombin-antithrombin and thrombomodulin were not. D-dimer was the only marker associated with recurrent AIS (HR 1.2; 95% CI 1.0-1.5). Results were generally consistent in analyses adjusted for important prognostic variables.

Conclusions: Markers of hypercoagulability and embolic disease may be associated with adverse clinical outcomes in cancer-related stroke.

Keywords: biomarkers; neoplasms; stroke; thrombophilia; thrombosis.

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Conflict of interest statement

Disclosures

Hooman Kamel, co-PI for the ARCADIA trial, has received in-kind study drug from BMS-Pfizer Alliance and in-kind study assays from Roche Diagnostics; serves as Deputy Editor for JAMA Neurology, a steering committee member of Medtronic’s Stroke AF trial, an endpoint adjudication committee member for a Boehringer-Ingelheim trial, and an advisory board member for Roivant Sciences. Scott Tagawa has served as a consultant or advisor for Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, and Seattle Genetics; and has received research funding from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millenium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, and Clovis Oncology. Ashish Saxena has received research funding from AstraZeneca; and has served as a consultant or advisor for Genentech, AstraZeneca, Blueprint Medicines, and Jazz Pharmaceuticals. Allyson Ocean has served as a consultant for Tyme Inc and on the speaker’s bureau for Daiichi Sankyo. Scott Kasner has received grant funding from NIH, Bristol Meyers Squibb, Bayer, Daiichi Sankyo, Genentech, WL Gore, and Medtronic; personal consulting fees from Bristol Meyers Squibb, Abbott, AbbVie; and royalties from UpToDate and Elsevier. Mitchell Elkind has received royalties from UpToDate. Lisa DeAngelis has received personal funds for serving on the scientific advisory board for Sapience Therapeutics. The other authors have no disclosures.

Figures

Figure 1.
Figure 1.
Kaplan-Meier curves estimating the cumulative incidence of major thromboembolic events or death among participants enrolled in the MOST-Cancer study. The red line depicts cancer-plus-stroke participants, the blue line depicts stroke-only participants, and the green line depicts cancer-only participants. The numbers at risk over time for each group are listed at the bottom.
Figure 2.
Figure 2.
Time-to-event curves estimating the cumulative incidence function of recurrent acute ischemic stroke (continuous lines) while adjusting for the competing risk of death (dashed lines) among enrolled participants. The red line depicts cancer-plus-stroke participants, the blue line depicts stroke-only participants, and the green line depicts cancer-only participants.
Figure 3.
Figure 3.
Kaplan-Meier survival curves for the cancer-plus-stroke group versus the stroke-only group. The log-rank test was used to compare overall survival rates and generate a p-value. The red line depicts cancer-plus-stroke participants and the blue line depicts stroke-only participants. The numbers at risk over time for each group are listed at the bottom.
Figure 4.
Figure 4.
Box-and-whisker plots of hematologic biomarker values for cancer-plus-stroke participants stratified by the subsequent development of a major thromboembolic event or death. The upper box margins depict the upper quartiles, the lower box margins depict the lower quartiles, and the thick horizontal lines depict the median values. The lower whiskers depict the 2.5 percentiles, and the upper whiskers depict the 97.5 percentiles. Dots represent individual patient values. To avoid distorting the figure’s scale, extreme outliers beyond the 2.5 and 97.5 percentiles are not represented. TAT = thrombin-antithrombin, sICAM-1 = soluble intercellular adhesion molecule-1, sVCAM-1 = soluble vascular cell adhesion molecule-1.
Figure 5.
Figure 5.
Box-and-whisker plots of hematologic biomarker values for cancer-plus-stroke participants stratified by the subsequent development of recurrent ischemic stroke. The upper box margins depict the upper quartiles, the lower box margins depict the lower quartiles, and the thick horizontal lines depict the median values. The lower whiskers depict the 2.5 percentiles, and the upper whiskers depict the 97.5 percentiles. Dots represent individual patient values. To avoid distorting the figure’s scale, extreme outliers beyond the 2.5 and 97.5 percentiles are not represented. TAT = thrombin-antithrombin, sICAM-1 = soluble intercellular adhesion molecule-1, sVCAM-1 = soluble vascular cell adhesion molecule-1.
See this image and copyright information in PMC

References

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