Anticoagulation in combination with antiangiogenesis and chemotherapy for cancer patients: evidence and hypothesis

Abstract

Hypercoagulable state and disorganized angiogenesis are two conspicuous characteristics during tumor progression. There are a considerable number of clinical trials focusing on the effects of anticoagulant and antiangiogenic drugs on the survival of cancer patients. Favorable outcomes have been observed. Excessive blood coagulation not only causes cancer-associated thrombosis, which is a common complication and is the second leading cause of death in patients, but also decreases intratumoral perfusion rates and drug delivery by reducing the effective cross-sectional area of blood vessels. Meanwhile, structural and functional abnormalities of the tumor microvasculature also compromise convective drug transport and create a hypoxic and acidic microenvironment. Vascular normalization strategy can temporarily recover the abnormal state of tumor vasculature by improving blood density, dilation, and leakiness, resulting in enhanced penetration of chemotherapies and oxygen within a short time window. In this article, we first review the evidence to support the opinion that anticoagulant and antiangiogenic therapy can improve cancer survival through several underlying mechanisms. Next, we speculate on the feasibility and value of the combined strategy and discuss whether such a combination has a synergistic antineoplastic effect in cancer patients by way of increasing blood vessel perfusion and drug distribution.

Keywords: antiangiogenesis; anticoagulation; tumor microenvironment; tumor perfusion; vascular normalization.

Figure 1

Strategies to enhance blood vessel perfusion and drug penetration. Notes: Anticoagulant treatment depletes the deposition of fibrin or other plasma proteins on the blood vessel wall and the extravascular thrombosis, which increases the effective cross-sectional area of tumor blood vessels and improves perfusion. Vascular normalization remodels tumor vessels, which decreases vessel permeability and improves perfusion. Both strategies can be applied either alone or in combination based on whether tumor blood is hypercoagulable, vessels are aberrant, both of these, or neither. Abbreviations: EC, endothelial cell; BM, basement membrane; PC, pericyte.