Investigation of proposed mechanisms of chemotherapy-induced venous thromboembolism: endothelial cell activation and procoagulant release due to apoptosis.
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.
Institute of Cancer, University of Manchester, University Hospital of South Manchester, Wythenshawe, Manchester, United Kingdom cliona.kirwan@manchester.ac.uk.
Cliona C
CC
Kirwan
Department of Academic Surgery, University Hospital of South Manchester, Wythenshawe, Manchester, United Kingdom.
C N
CN
McCollum
School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom.
G
G
McDowell
Department of Academic Surgery, University Hospital of South Manchester, Wythenshawe, Manchester, United Kingdom.
G J
GJ
Byrne
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001943:Breast Neoplasms / Q000150:complications*; D015331:Cohort Studies; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D019851:Thrombophilia / Q000150:complications*; D054556:Venous Thromboembolism / Q000139:chemically induced*
deep venous thrombosis; hypercoagulability; venous thromboembolism