Pharmacological correction of the hemostasis system for the surgical treatment of bitches with tumours of the mammary gland

Keywords: neoplasia; electrocoagulation; dogs; low molecular weight heparins; non-steroidal anti-inflammatory drugs; hemostatic status.


We carried out the clinical validation of pathogenetically substantiated protocols for the treatment of female dogs with tumour lesions of the mammary gland. The positive effect of corrective therapy was characterized by a decrease in the physiological level of fibrinogen: in benign tumours in 10 days, malignant – in 14 days against the background of its stable high level in control animals with malignant neoplasia. In the postoperative period in experimental animals, the functioning of the internal coagulation unit was restored, as evidenced by the normalization of the activated partial thromboplastin time for benign tumours by days 10–14, malignant – by 14 days. In control patients, these changes were detected only for benign neoplasms. Shifts of the external mechanism of blood coagulation in the experimental groups were eliminated in benign neoplasia cases in 10 days, malignant cases in 14 days against the background of severe disorders in this link in control patients throughout the observation period. The positive effect of complex treatment regimens is confirmed by the restoration of total fibrinolytic activity by days 10–14 due to the normalization in the same terms of the plasminogen activator and tissue plasminogen activator by days 3–7. In control animals, the total fibrinolytic activity was consistent with those of clinically healthy animals only for benign neoplasms. The balancing of coagulation and fibrinolytic mechanisms was accompanied by a decrease in the activity of proteolytic inhibitors: α2-macroglobulin in experimental groups with benign neoplasia by day 10, malignant – by days 10–14, and control – respectively, by days 3 and 14; α1-proteinase inhibitor in all groups by day 3. Concentration of nitric oxide after extirpation of benign tumors already at day 3 of the postoperative period in all groups corresponded to the indexes of clinically healthy dogs, with the removal of malignant tumours – in experimental animals at day 3, control – at day 14. The content of malondialdehyde and ceruloplasmin against the background of pharmacological correction was restored by days 10–14, whereas in control animals – only with benign neoplasms by day 14. Postoperative pharmacological correction of the hemostasis system can significantly improve the results of treatment in cancer patients.


Andreeva, L.  I., Kozhemjakin, L.  A., & Kishkun, A.  A. (1988). Modifikacija metoda opredelenija perekisej lipidov v teste s tiobarbiturovoj kislotoj [Modification of the method for determination of lipid peroxides in the test with thiobarbituric acid]. Laboratornoe Delo, 11, 41–43 (in Russian).

Abdullah, M. A., Almufty, B. I., Yasin, M. I., & Hassan, N. J. (2014). Clinical and histopathological study of mammary tumors in foreing dogs breeds in Kurdistan region of Iraq. Basrah Journal of Veterinary Research, 1(1), 11–19.

Astrup, T., & Mullertz, S. (1952). The fibrin plate metod for estimating fibrinolitic activity. Archives of Biochemistry and Biophysics, 40, 346–351.

Beha, G., Brunetti, B., Asproni, P., Muscatello, L., Millanta, F., Poli, A., Sarli, G., & Benazzi, C. (2012). Molecular portrait-based correlation between primary canine mammary tumor and its lymph node metastasis: Possible prognostic-predictive models and/or stronghold for specific treatments? Biomed Central Veterinary Research, 8, 219–228.

Belicer, V. O., Varec'ka, T. V., & Veremjejenko, K. M. (1997). Kil'kisne vyznachennja fibrynogenu v plazmi krovi ljudyny [Quantitative determination of fibrinogen in human plasma]. Laboratorna Diagnostyka, 2, 53–55 (in Ukrainian).

Boccaccio, C., & Medico, E. (2006). Cancer and blood coagulation. Cellular and Molecular Life Sciences, 63(9), 1024–1027.

Bonnett, B. N., Egenvall, A., Hedhammar, А., & Olson, Р. (2005). Mortality in over 350,000 insured Swedish dogs from 1995–2000: I. Breed-, gender-, age- and cause-specific rates. Acta Veterinaria Scandinavica, 46(3), 105–120.

Brønden, L. B., Flagstad, A., & Kristensen, A. T. (2007). Veterinary cancer Registries in companion animal cancer: A review. Veterinary and Comparative Oncology, 5(3), 133–144.

Brown, W. A., Skinner, S. A., Malcontenti-Wilson, C., Vogiagis, D., & O'Brien, P. E. (2001). Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation. British Medical Journal, 48, 660–666.

Corte, M. D., Vérez, P., Rodríguez, J. C., Roibás, A., Domínguez, M. L., Lamelas, M. L., Vázquez, J., García Muñiz, J. L., Allende, M. T., González, L. O., Fueyo, A., & Vizoso, F. (2005). Tissue-type plasminogen activator (tPA) in breast cancer: Relationship with clinicopathological parameters and prognostic significance. Breast Cancer Research, 90(1), 33–40.

Dhami, M. A., Tank, P. H., Karle, A. S., Vedpathak, H. S., & Bhatia, A. S. (2010). Epidemiology of canine mammary gland tumours in Gujarat. Veterinary World, 3(6), 282–285.

Dierssen-Sotos, T., Gómez-Acebo, I., Pedro, M., Pérez-Gómez, B., Servitja, S., Moreno, V., Amiano, P., Fernandez-Villa, T., Barricarte, A., Tardon, A., Diaz-Santos, M., Peiro-Perez, R., Marcos-Gragera, R., Lope, V., Gracia-Lavedan, E., Alonso, M. H., Michelena-Echeveste, M. J., Garcia-Palomo, A., Guevara, M., Castaño-Vinyals, G., Aragonés, N., Kogevinas, M., Pollán, M., & Llorca, J. (2016). Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-Control (MCC) study. BioMed Central Cancer, 16, 660.

Eierskyte, A., Zamokas, G., Grigonis, A., & Juodiiukyniene, N. (2011). The retrospective analysis of mammary tumors in dogs. Veterinarija ir Zootechnika, 53, 3–8.

Ferreira, E., Gobbi, H., Saraiva, B. S., & Cassali, G. D. (2011). Histological and immunohistochemical identification of atypical ductal mammary hyperplasia as a preneoplastic marker in dogs. Veterinary Pathology, 49(2), 322–329.

Fürdös, I., Fazekas, J., Singer, J., & Jensen-Jarolim, E. (2015). Translating clinical trials from human to veterinary oncology and back. Journal of Translational Medicine, 13, 265.

Gardner, H. L., Fenger, J. M., & London, C. A. (2016). Dogs as a model for cancer. Annual Review of Animal Biosciences Journal Impact, 4, 199–222.

Glazunova, L. A., & Koneva, A. V. (2014). Sravnitel'naja effektivnost' razlichnyh prijomov pri lechenii novoobrazovanij molochnoj zhelezy u sobak i koshek [Comparative effectiveness of various methods in the treatment of neoplasms of the breast in dogs and cats]. Sovremennye Problemy Nauki i Obrazovanija, 6, 18–24 (in Russian).

Golikov, P. P. (2004). Oksid azota v klinike neotlozhnyh zabolevanij [Nitric oxide in the clinic for urgent diseases]. Medpraktika, Moscow (in Russian).

Grandi, F., Colodel, M. M., Monteiro, L. N., Leão, J. R., & Rocha, N. S. (2016). Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: Cytological and histopathological assessment. Biomed Central Veterinary Research, 6, 45.

Gundim, L. F., de Araújo, C. P., Blanca, W. T., Guimarães, E. C., & Medeiros, A. A. (2016). Clinical staging in femaleses with mammary tumors: influence of type and histological grade. Canadian Journal of Veterinary Research, 80(4), 318–322.

Harris, R. E., Chlebowski, R. T., Jackson, R. D., Frid, D. J., Ascenseo, J. L., Anderson, G., Loar, A., Rodabough, R., White, E., & McTiernan, A. (2003). Breast cancer and nonsteroidal anti-inflammatory drugs prospective results from the women’s health initiative. Cancer Research, 63, 6096–6101.

Heading, K. L., Brockley, L. K., & Bennett, P. F. (2011). CCNU (lomustine) toxicity in dogs: A retrospective study (2002–07). Australian Veterinary Journal, 89(4), 109–116.

Hegmans, J. P., & Aerts, J. G. (2014). Immunomodulation in cancer. Current Opinion in Pharmacology, 17, 17–21.

Heyman, B., & Yang, Y. (2016). Mechanisms of heparanase inhibitors in cancer therapy. Experimental Hematology, 44(11), 1002–1012.

Hevia, G., Pablos, I., Clavell, M., Raymond, J., Labrada, M., & Fernández, L. E. (2017). Cyclooxygenase inhibition in cancer immunotherapy: Combination of indomethacin with cancer vaccines is not always beneficial. Journal of Cancer Therapy, 8, 188–209.

Horn, S. L., & Fentiman, I. S. (2010). The role of non-steroidal anti-inflammatory drugs in the chemoprevention of breast cancer. Pharmaceuticals, 3, 1550–1560.

Hussain, M., Javeed, A., Ashraf, M., Al-Zaubai, N., Stewart, A., & Mukhtar, M. M. (2012). Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy. Pharmacological Research, 66(1), 7–18.

Jessen, L. R., Wiinberg, B., Kjelgaard-Hansen, M., Jensen, A. L., Rozanski, E., & Kristensen, A. T. (2010). Thrombin-activatable fibrinolysis inhibitor activity in healthy and diseased dogs. Veterinary Clinical Pathology, 39(3), 296–301.

Khamis, Z. I., Sahab, Z. J., & Sang, Q.-X. A. (2012). Active roles of tumor stroma in breast cancer metastasis. International Journal of Breast Cancer, 2012, 1–10.

Khanna, C., Rosenberg, M., & Vail, D. M. (2015). A review of paclitaxel and novel formulations including those suitable for use in dogs. Journal of Veterinary Internal Medicine, 29(4), 1006–1012.

Koh, Y. W., Park, C, Yoon, D. H., Suh, C., & Huh, J. (2013). Prognostic significance of COX-2 expression and correlation with Bcl-2 and VEGF expression, microvessel density, and clinical variables in classical Hodgkin lymphoma. The American Journal of Surgical Pathology, 37(8), 1242–1251.

Korobova, N. V. (2005). Opyt primenenija Ronkolejkina na pozdnih stadijah onkologicheskih zabolevanij molochnyh zheljoz [Experience in the use of Roncoleukin in the late stages of oncological diseases of the mammary glands]. Veterinarnaja Klinika, 34, 21 (in Russian).

Leach, T. N., Childress, M. O., Greene, S. N., Mohamed, A. S., Moore, G. E., Schrempp, D. R., Lahrman, S. R., & Knapp, D. W. (2012). Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Veterinary and Comparative Oncology, 10(2), 102–112.

Levine, M. N., Lee, A. Y., & Kakkar, A. K. (2005). Thrombosis and cancer. Proceedings of the Annual Meeting of the American Society for Clinical Oncology, 13–17, 748–747.

Losiewicz, K., Chmielewska-Krzesinska, М., Socha, P., Jakimiuk, A., & Wąsowicz, K. (2014). MiRNA-21, miRNA-10b, and miRNA-34a expression in canine mammary gland neoplasms. Bulletin of the Veterinary Institute in Pulawy, 58, 447–451.

Marchetti, M., Vignoli, A., Russo, L., Balducci, D., Pagnoncelli, M., Barbui, T., & Falanga, A. (2008). Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thrombosis Research, 121(5), 637–645.

Marchetti, V., Giorgi, M., Fioravanti, A., Finotello, R., Citi, S., Canu, B., Orlandi, P., Desidero, T. D., Danesi, R., & Bocci, G. (2012). First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumours: A pilot study. Investigational New Drugs, 30(4), 1725–1730.

Masljakova, G. N., Fedorov, V. J., Krekova, N. J., & Cheburkaeva, M. J. (2017). Izmenenija gemokoaguljacii pri progressirovanii raka molochnoj zhelezy [Changes in hemocoagulation in the progression of breast cancer]. Medicinskij Al'manah, 2, 151–154 (in Russian).

Mischke, R., Fehr, M., & Nolte, I. (2005). Efficacy of low molecular weight heparin in a canine model of thromboplastin-induced acute disseminated intravascular coagulation. Research in Veterinary Science, 79(1), 69–76.

Mousa, S. A. (2010). Heparin and low-molecular weight heparins in thrombosis and beyond. Anticoagulants, Antiplatelets, and Thrombolytics, 663, 109–132.

Mysak, A. R. (2010). Porivnjal'ni aspekty monitoryngu neoplazij u sobak [Comparative aspects of neoplasia monitoring in dogs]. Naukovyj Visnyk Veterynarnoi' Medycyny, 76(4), 75–80 (in Ukrainian).

Ostrander, E. A., & Engl, N. (2012). Both ends of the leash – the human links to good dogs with bad genes. The New England Journal of Medicine, 367, 636–646.

Owen, L. N. (Ed.). (1980). TNM classification of tumors in domestic animals. Geneva, World Health Organization.

Pinho, S. S., Carvalho, S., Cabral, J., Reis, C. A., & Gärtner, F. (2012). Canine tumors: A spontaneous animal model of human carcinogenesis. American Journal of Translational Research, 3, 165–172.

Promzeleva, N. V., Zorina, V. N., & Zorin, N. A. (2012). Belki semejstva macroglobulinov pri rake molochnoj zhelezy [Proteins of the family of macroglobulins in breast cancer]. Voprosy Onkologii, 5, 688–690 (in Russian).

Rublenko, M. V., & Bilyj, D. D. (2012). Funkcional'ni porushennja ta systemni rozlady gemostazu za novoutvoren' u sobak [Functional disorders and systemic haemostasis disorders due to neoplasms in dogs]. Naukovo-Tehnichnyj Bjuleten', 13, 142–145 (in Ukrainian).

Rublenko, M. V., & Bilyj, D. D. (2014). Znachennja oksydantnogo stresu v patogenezi puhlyn molochnoi' zalozy u sobak [Significance of oxidative stress in the pathogenesis of breast cancer in dogs]. Problemy Zooinzhenerii' ta Veterynarnoi' Medycyny, 29(2), 75–78 (in Ukrainian).

Salman, T., Bilici, A., & Ustaalioglu, B. O. (2009). The correlation of thrombin-activated fibrinolysis inhibitor (TAFI) levels and clinicopathologic factors in advanced colorectal cancer patients. Journal of Clinical Oncology, 27, 27–32.

Sarrau, S., Jourdan, J., Dupuis-Soyris, F., & Verwaerde, P. (2007). Effects of postoperative ketamine infusion on pain control and feeding behaviour in femaleses undergoing mastectomy. Journal of Small Animal Practice, 48, 670–676.

Shafiee, R., Javanbakht, J., Atyabi, N., Kheradmand, P., Kheradmand, D., Bahrami, A., Daraei, H., & Khadivar, F. (2013). Diagnosis, classification and grading of canine mammary tumours as a model to study human breast cancer: An clinico-cytohistopathological study with environmental factors influencing public health and medicine. Cancer Cell International, 13, 469.

Sorenmo, K. U., Kristiansen, V. M., Cofone, M. A., Shofer, F. S., Breen, A. M., Langeland, M., Mongil, C. M., Grondahl, A. M., Teige, J., & Goldschmidt, M. H. (2009). Canine mammary gland tumours; A histological continuum from benign to malignant; clinical and histopathological evidence. Veterinary and Comparative Oncology, 7(3), 162–172.

Talahadze, N. T., Zurrida, S., Vorotnikov, I. G., Chhikvadze, N. V., Nechushkin, M. I., Petrovskij, A. V., Paolo, A., Dzhjermana, L., Dzhuzeppe, V., Dzhjermana, L., & Umberto, V. (2012). Klassifikacija zlokachestvennyh opuholej molochnoj zhelezy po sisteme TNM: Neobhodimost' peremen [Classification of malignant tumors of the breast by the TNM system: The need for changes]. Vestnik RONC imeni N. N. Blohina, 23(1), 69–76 (in Russian).

Tran-Thanh, D., Buttars, S., Wen, Y., Wilson, C., & Done S. J. (2010). Cyclooxygenase-2 inhibition for the prophylaxis and treatment of preinvasive breast cancer in a HER-2/Neu mouse model. Cancer Prevention Research, 3(2), 202–211.

Tripp, C. D., Fidel, J., Anderson, C. L., Patrick, M., Pratt, C., Sellon, R., & Bryan, J. N. (2011). Tolerability of metronomic administration of lomustine in dogs with cancer. Journal of Veterinary Internal Medicine, 25(2), 278–284.

Vareckaja, T. V., Mihajlovskaja, L. I., & Svital'skaja, L. A. (1992). Opredelenie rastvorimogo fibrina v plazme krovi [Determination of soluble fibrin in blood plasma]. Klinicheskaja Laboratornaja Diagnostika, 7–8, 10–14 (in Russian).

Veremeenko, K. N., Volohonskaja, L. I., & Kizim, A. I. (1978). Metody opredelenija prekallikrein-kallikreinovoj sistemy v krovi cheloveka [Methods for the determination of prekallikrein-kallikrein system in human blood]. Kyiv (in Russian).

Vilar Saavedra, P., Lara García, A., Zaldívar López, S., & Couto, G. (2011). Hemostatic abnormalities in dogs with carcinoma: A thromboelastographic characterization of hypercoagulability. Veterinary Journal, 190(2), 78–83.

Wilson, H., Chadalapaka, G., Jutooru, I., Sheppard, S., Pfent, C., & Safe, S. (2012). Effect of tolfenamic acid on canine cancer cell proliferation, specificity protein (sp) transcription factors, and sp-regulated proteins in canine osteosarcoma, mammary carcinoma, and melanoma cells. Journal of Veterinary Internal Medicine, 26(4), 977–986.

Yin, W., Zhang, J., Jiang, Y., & Juan, S. (2014). Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice. Experimental and Therapeutic Medicine, 8(4), 1213–1218.

Zlatnik, E. A., & Nikipelova, O. F. (2012). Regressija opuholi i lokal'nye immunenye reakcii pri razlichnyh sposobah vvedenija ronkolejkina v jeksperimente [Tumor regression and local immune responses in various ways of administering Roncoleukin in the experiment]. Nauchnye Vedomosti. Serija Medicina, Farmacija, 129(10), 147–151 (in Russian).

How to Cite
Bely, D. D., Rublenko, M. V., Rublenko, S. V., Yevtushenko, I. D., Suslova, N. I., & Samoyuluk, V. V. (2018). Pharmacological correction of the hemostasis system for the surgical treatment of bitches with tumours of the mammary gland. Regulatory Mechanisms in Biosystems, 9(3), 353-362.

Most read articles by the same author(s)