Indirect Activation of Blood Coagulation in Colon Cancer

Abstract

SummarySystemic activation of the coagulation mechanism is known to exist in patients with colon cancer. The mechanism of such activation was investigated using immunohistochemical techniques applied to fresh frozen sections of resected primary colon cancer specimens. Tumor cells stained for tissue factor, factor V, and urokinase-type plasminogen activator. Perivascular and intercellular areas stained for fibrinogen and the “a” subunit of factor XIII. Staining was minimal or absent for protein C, protein S, plasminogen activator inhibitors 1-3, factor VII, factor X, and fibrin (the antigenic site on the amino-terminal portion of Bβ chain that is exposed following thrombin cleavage of fibrinopeptide B was not detected). The lack of an intact thrombin- generating pathway in situ associated with viable colon cancer cells is consistent with the findings of others that coagulation activation in colon cancer may be triggered by a soluble tumor product that exerts its effect at sites distant from the tumor. These results may explain the absence of clinical responsiveness of colon cancer to antithrombotic drug therapy and may clarify therapeutic strategies for this common tumor.

Haemostasis Activation Markers in Plasma of Patients with Benign and Malignant Gynaecological Tumours: A Pilot Study

“…The elevated thrombinantithrombin HI levels are consistent with an earlier study on this topic, in which thrombin-antithrombin III was considered a marker of malignant gynaecological disease (17). In general, an explanation for the activation of blood coagulation in tumours is thought to be a direct interaction of the coagulation factors with tumour cells (18,19) or an indirect production of cytokines (20). The evidence for both of these etiologies are however based on immunohistological investigations.…”

Identification of Human Plasma Proteins as Major Clients for the Extracellular Chaperone Clusterin

“…As in ARMD, FGN deposition in such diseases is associated with the recruitment and activation of platelets and has been proposed as a mechanism for vascular injury (59). Deposition of FGN has been reported in breast cancer (60), mesothelioma (61), colon cancer (62), and lymphoma (63). Although the reasons for this are unknown, one potential implication of this observation is that FGN deposition promotes angiogenesis and cancer progression.…”

The role of fibrin in tumor metastasis

“…Of relevance here is the fact that distinctions can now be made between tumor types in terms of their coagulation biology that provide a basis for interpretation of results of completed clinical trials and the design of new clinical trials. For example, it has been shown that SCCL (that expresses tumor cell procoagulants and is associated with fibrin formation [28][29][30][31][32][33]) responded to therapy with both anticoagulants (warfarin [17][18][19] and heparin [22]) and fibrinolytic activators [20,21] while several other tumor types that do not share these properties did not respond to this treatment approach [18,34,37,38]. It might be reasonable to search for other as yet undiscovered procoagulant tumor types, to apply this treatment approach to procoagulant tumor types that have not yet been tested, and to extend studies in SCCL to clinical trials of combinations of anticoagulant plus fibrinolytic drugs or of more effective inhibitors of thrombin generation and activity.…”

“…Rather, the tumor cells expressed urokinase-type plasminogen activator (U-PA). Tumor types included in this category were non-small cell lung cancer (N-SCLC) [34], breast cancer [35,36], colon cancer [37], and prostate cancer [38]. A third category of tumors had neither tumor cell procoagulants nor plasminogen activators.…”