Investigation of proposed mechanisms of chemotherapy-induced venous thromboembolism: endothelial cell activation and procoagulant release due to apoptosis.

Abstract

UNLABELLED:

Venous thromboembolism (VTE) during chemotherapy is common, with 7% mortality in metastatic breast cancer (MBC). In a prospective cohort study of patients with breast cancer, we investigated whether vascular endothelial cell activation (VECA), and whether apoptosis, is the cause of chemotherapy-induced VTE.

METHODS:

Serum markers of VECA, E-selectin (E-sel), vascular cell adhesion molecule 1 (VCAM-1) and d-dimer (fibrin degradation and hypercoagulability marker) were measured prechemotherapy and at 1, 4, and 8 days following chemotherapy. Clinical deep vein thrombosis (DVT) or pulmonary embolism and occult DVT detected by duplex ultrasound imaging were recorded as VTE-positive (VTE+). In patients with MBC, hypercoagulable response to chemotherapy was compared between patients with and without cancer progression. Development of VTE and cancer progression was assessed 3 months following starting chemotherapy.

RESULTS:

Of the 134 patients, 10 (7.5%) developed VTE (6 [17%] of 36 MBC receiving palliation, 0 of 11 receiving neoadjuvant to downsize tumor, and 4 [5%] of 87 early breast cancer receiving adjuvant chemotherapy, P = .06). Levels of E-sel and VCAM-1 decreased in response to chemotherapy (P < .001) in both VTE+ and patients not developing VTE (VTE-). However, decrease in VECA markers was similar in VTE+ and VTE- patients, implying this is not the cause of VTE. In patients with MBC following chemotherapy, d-dimer (geometric mean) increased by 36% in the 21 patients with MBC responding to chemotherapy but steadily decreased by 11% in the 15 who progressed (day 4, P < .01), implying patients with tumor response (apoptosis) had an early hypercoagulable response.

CONCLUSIONS:

During chemotherapy for breast cancer, VECA is induced; however, this is not the primary mechanism for VTE. Chemotherapy-induced apoptosis may enhance hypercoagulability and initiate VTE.

• Authors: Cliona C Kirwan, C N McCollum, G McDowell, G J Byrne
• Journal: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis (Clin Appl Thromb Hemost) Vol. 21 Issue 5 Pg. 420-7 (Jul 2015) ISSN: 1938-2723 [Electronic] United States
• PMID: 25748178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015.

Topics

• Adult
• Aged
• Apoptosis
• Breast Neoplasms (complications)
• Cohort Studies
• Endothelial Cells
• Female
• Humans
• Induction Chemotherapy (methods)
• Middle Aged
• Neoplasm Metastasis
• Prospective Studies
• Thrombophilia (complications)
• Venous Thromboembolism (chemically induced)