warfarin and Fibrosarcoma

We present a case of a 61-year-old female diagnosed with soft-tissue fibrosarcoma of the shoulder with a right atrial mass on transthoracic echocardiogram. To further assess the mass, contrast transoesophageal echo was performed. The mass was highly considered to be a thrombus due to the presence of multiple risk factors: atrial fibrillation, catheter use, and pulmonary embolism. However, a metastatic fibrosarcoma could not be excluded, given its enhancement with echo contrast. Finally, it was proved to be a thrombus with its rapid resolution while on anticoagulation. Therefore, it should be noted that in rare circumstances, thrombus may show enhancement with echo contrast and one needs to integrate all of the patient information to arrive at the correct diagnosis.

Topics: Anticoagulants; Echocardiography; Female; Fibrosarcoma; Heart Atria; Heparin; Humans; Middle Aged; Radionuclide Imaging; Thromboembolism; Warfarin

Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Cell Adhesion; Concanavalin A; Culture Media, Serum-Free; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Fibrin; Fibrosarcoma; Heparin; Injections, Intravenous; Lung; Lung Neoplasms; Macrophage Activation; Male; Neoplasm Proteins; Neoplasm Transplantation; Neoplastic Cells, Circulating; Pulmonary Circulation; Rats; T-Lymphocytes; Tumor Cells, Cultured; Warfarin

Experimental evidence suggests that many tumours can activate blood coagulation and that such interaction is part of the pathology of metastatic tumour growth. This study aimed to study the procoagulant activity of the methylcholanthrene-induced (MC28) fibrosarcoma to determine whether coagulation activation by these cells could explain the previously reported effects of oral anticoagulants on lung seeding in this model. MC28 cells shortened the recalcification times of normal and factor VII-deficient plasma and directly activated factor X in a chromogenic assay, but did not aggregate platelets in vitro in either whole blood or platelet-rich plasma. Cellular coagulant activity was calcium-dependent, blocked by DFP and concanavalin A but not inhibited by iodoacetamide, E-64 or antibodies to human tissue factor or factor VII. Injection of viable MC28 cells into hooded Lister rats induced a decrease in platelet count (P < 0.001), plasma factor X (P < 0.001) and fibrinogen (P < 0.05) and a marked increase in plasma haemoglobin (P < 0.001). These effects were either not observed or were considerably less marked in heparinized or warfarinized animals. Injection of MC28 cells treated with concanavalin A in vitro completely abolished the clotting changes observed with untreated cells. In conclusion, MC28 cells possessed a potent factor X-activating serine proteinase procoagulant in vitro, which had some of the characteristics of a tissue factor/factor VIIa complex. In vivo, MC28 cells caused clotting activation and intravascular fibrin generation. Since thrombocytopenia was abolished by heparin and the cells lacked platelet aggregating activity in vitro, thrombocytopenia was probably secondary to intravascular coagulation and thrombin generation. The trigger for intravascular clotting activation appeared to be the cellular procoagulant activity since it was abolished by prior in vitro blockade of the latter with concanavalin A.

Topics: Animals; Blood Coagulation; Concanavalin A; Factor X; Fibrinogen; Fibrosarcoma; Hemoglobins; Heparin; Male; Methylcholanthrene; Platelet Aggregation; Platelet Count; Rats; Tumor Cells, Cultured; Warfarin

Peri-tumour fibrin is a consistent feature of tumour stroma and is deposited shortly after tumour cell inoculation. Since there are several ways in which fibrin may be beneficial to tumour growth, it is possible that the ability of normal or malignant tissue to generate fibrin may influence metastasis. Many normal tissues and tumour cells possess a procoagulant activity that is due to a complex of tissue factor and factor VII. We have measured this tissue procoagulant activity in normal rats, rats stabilised on Warfarin and similarly anticoagulated animals injected with factor VII. The effect of Warfarin and factor VII administration on pulmonary seeding following injection of MC28 fibrosarcoma cells was also assessed. Procoagulant activity in adrenal, lung and colon was significantly reduced by Warfarin (P less than 0.001). Administration of factor VII significantly increased lung and adrenal tissue procoagulant activity in anticoagulated rats (P less than 0.02). Warfarinised rats had significantly slower primary tumour growth (P less than 0.001) and fewer lung deposits than control animals (P less than 0.001). Injection of factor VII restored pulmonary seeding to control levels (P less than 0.001). Warfarin did not affect the ability of the cells to adhere in vitro and did not reduce the number of tumour cells physically trapped in the lungs after intravenous injection. It is concluded that the procoagulant activity of normal tissues may influence their ability to support tumour growth and that the antimetastatic effect of Warfarin may be at least partly due to a reduction in the availability of the factor VII required for this activity.

Topics: Adrenal Glands; Animals; Cell Adhesion; Colon; Factor VII; Factor X; Fibrosarcoma; Liver; Lung; Lung Neoplasms; Neoplasm Seeding; Neoplasms, Experimental; Rats; Thromboplastin; Warfarin

Vitamin K deficiency, either dietary or pharmacologically induced by warfarin, was unable to affect the metastatic capacity of cells from a benzopyrene-induced fibrosarcoma in C57BL/6J mice. The same cells had a procoagulant activity, of tissue thromboplastin type, which was also completely unaffected by vitamin K antagonism or deficiency. In another murine model of spontaneous metastasis we previously suggested that depression of a particular procoagulant such as a direct factor X activator might contribute to the antimetastatic activity of warfarin. The failure of vitamin K deficiency to affect both the procoagulant and the metastatic capacity of the model reported here offers strong negative support to the same concept.

Topics: Animals; Fibrosarcoma; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Thromboplastin; Vitamin K Deficiency; Warfarin

Topics: Animals; Carcinoma, Squamous Cell; Fibrosarcoma; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma, Experimental; Warfarin