Chemotherapy enhances endothelial cell reactivity to platelets

Abstract

Recent studies indicate that chemotherapy is a cause for thrombosis in breast cancer patients. We performed experiments to determine whether the enhanced thrombosis was due, in part, to an effect of chemotherapy on endothelial cell reactivity. Heparinized blood samples were obtained from stage II breast cancer patients receiving monthly adjuvant chemotherapy consisting of cyclophosphamide, epirubicin and 5-fluorouracil. Cultured human endothelial cells were incubated with the plasmas for 2 h, and then the reactivity of the endothelial cells to normal donor platelets was determined isotopically. Endothelial cell reactivity was increased when the endothelial cells were incubated with the post-chemotherapy plasmas. The plasma effect persisted after the chemotherapy drugs were cleared from the circulation, but this plasma effect was abolished when the plasmas were heat-inactivated. Furthermore, the increase in endothelial cell reactivity correlated with the level of interleukin-1 present in the post-chemotherapy plasmas. Finally, the increased endothelial cell reactivity was inhibited by the GRGDS peptide, or by an antibody to the endothelial cell vitronectin receptor. These observations suggest that chemotherapeutic drugs alter endothelial cell reactivity to platelets by inducing the release of interleukin-1 which, in turn, facilitates adhesion molecule expression on the endothelial cell surface. If so, these observations provide a possible explanation for one mechanism which may contribute to the thrombogenic effect seen in breast cancer patients undergoing chemotherapy.

Synergistic effects of TNF-α and melphalan in an isolated limb perfusion model of rat sarcoma: a histopathological, immunohistochemical and electron microscopical study

“…Necrosis was not confined to the tumour cells but also involved microvascular cells, both in the tumour and in the adjacent dermis. The potentiation of the TNF-ac-induced vascular effects by melphalan might be explained by additive cytotoxicity direct to the vascular endothelium (Regenass et al, 1987;Kachel and Martin, 1994;Alexander et al, 1987) and/or increased endothelial cell reactivity to platelets (Bertomen et al, 1990). Our (histo)pathological findings support the proposition by Lejeune (1995) that the combination of TNF-a and melphalan works through a dual targeting system.…”

Chemotherapy with gemcitabine‐containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma

“…However, two patients (aged 62 and 72 years) with no previous vascular risk factors had strokes and one patient had pulmonary embolism during chemotherapy. Although the association between chemotherapy and the risk of arterial or venous thromboembolism has been well documented among patients with metastatic breast or bladder carcinoma, [21][22][23] it remains uncertain whether the vascular events reported in this study could be directly attributed to the chemotherapy. Other hematologic toxicities such as neutropenia and thrombocytopenia were uncomplicated and there were no febrile episodes or life-threatening bleeding.…”

Peripheral arterial ischemic events in cancer patients

“…In general, mechanisms for these events have included chemotherapyinduced expression of macrophagemonocyte tissue factor, 64 endogenous procoagulantanticoagulant mismatch, 65,66 accentuated tumor and endothelial cell death, and cytokine release resulting in increased expression of tissue factor 67,68 and enhanced endothelial cell reactivity to platelets. 69 Certain chemotherapy agents (Table 3) have been associ ated with arterial thromboembolic events more than others: 5fluorouracil can decrease protein C levels and increase fibrinopeptide A levels 70 besides leading to endothelial damage and even endothelialindependent vasoconstriction via protein kinase C. 71 Gemcitabine has been associated with vascular events ranging from digital ischemia, VTE, thrombotic microangiopathy and systemic capillary leaks. 72 Cisplatin, a central component of several chemotherapeutic regimens, induces thrombosis by causing endothelial dam age, 73 activating platelets 74 and increasing monocyte tissue factor activity, 64 with a 12-17.6% risk 75 of strokes, recurrent peripheral arterial thromboembolic events and/or aortic thrombosis ( Figure 6).…”