Prevalence of thrombosis, and predictors of thrombosis and metastasis in canine carcinoma and sarcoma

Abstract

Tumours are common in people, with an incidence of 442 per 100,000 people annually. In dogs an incidence of 310-958 per 100 000 dogs annually has been reported. Carcinomas comprise 90% of cancers in people, while approximately 50% of tumour-bearing dogs are diagnosed with either a carcinoma or sarcoma. Cancer-associated coagulopathy in people is characterised by activation of the haemostatic system ranging from an asymptomatic hypercoagulable state to thrombotic complications such as deep vein thrombosis or disseminated intravascular coagulation (DIC). Inflammation in cancer, evidenced by leukocytosis and elevated acute phase proteins, combined with tissue factor expression, platelet hyperactivity and turbulent tumour neovascularisation results in activation of haemostasis. Cancer-associated coagulopathy also plays an important role in metastasis through its associated haemostatic changes and the formation of fibrin-platelet-tumour cell complexes. In people, thrombotic complications secondary to cancer are common, occurring in 10-20% of patients. The prevalence of thromboemboli in dogs, specifically microthrombi, is unknown, but cancer has been identified as one of the most common underlying disease processes in dogs with clinical thrombosis. Haemostatic alterations in various canine tumours have been described, but their predictive value for the presence of thrombosis, particularly microthrombi, and the alterations in haematological and haemostatic variables in tumour-bearing dogs with macro- and microthrombi, have not been investigated. Identification of haemostatic abnormalities in dogs with thromboembolic disease may allow earlier intervention, reduce the occurrence of further thrombus formation and importantly, possibly limit metastasis. Metastasis of a primary tumour is the most common cause of death in people and of death or euthanasia in dogs diagnosed with cancer. Clinico-pathological predictors of the presence of metastasis would allow earlier intervention and potentially improve disease free interval and survival. Clinical predictors of metastasis for specific cancer types have been identified in people, but are poorly investigated in dogs. The main aims of this thesis were to 1) identify the presence and characteristics of thromboembolic disease in dogs with carcinoma or sarcoma; 2) determine the presence and characteristics of the coagulopathy associated with cancer in tumour-bearing dogs; 3) determine if clinico-pathological variables can predict the presence of thromboembolic disease, specifically microthrombi, in tumour-bearing dogs; and 4) identify differences in commonly measured clinico-pathological variables between tumour-bearing dogs with and without metastasis exist, and determine if those variables can predict the presence of metastasis The main objectives of this thesis were to 1) estimate the prevalence and characteristics of thromboembolic disease, through histopathological evaluation of tumours and all organs of dogs diagnosed with carcinomas and sarcomas; 2) identify differences in haematological, acute phase proteins and haemostatic variables between healthy unaffected age-controlled dogs and tumour-bearing dogs that allow characterisation of cancer-associated coagulopathy; 3) identify, through multivariable analysis, haematological, acute phase protein or haemostatic variables that could help predict the presence of thromboembolic disease, specifically microthrombi; and 4) compare haematological, biochemical and haemostatic variables in tumour-bearing dogs with and without metastasis, and identify predictors of metastasis through multivariable analysis. The first study was undertaken to determine the prevalence and predisposed sites of thromboembolic disease, in dogs with carcinoma, sarcoma, lymphoma and mast cell tumours, and estimate if the prevalence of thrombosis in dogs is similar to people. This retrospective study evaluated the veterinary faculty’s pathology database which contained 28895 dogs, of which 2274 solid tumours were identified and sarcomas and carcinomas made up 52%. A 2.6% prevalence of thrombosis, all of which were microthrombi, was identified. Intra-tumoural microthrombi made up 91% of the thrombi identified with 70% found in sarcomas and 15% in carcinomas. Tumour-cell emboli were detected in 1.7% of cases, 80% being distant from the primary tumour, and 74% associated with carcinoma. Due to the retrospective nature of the study, histological evaluation of all organs and standard evaluation and reporting of samples was not possible. The study successfully identified the presence and nature of thromboembolic disease in dogs with solid tumours, but it was likely that the true prevalence of thromboembolic disease was underestimated. A prospective study was justified and necessary to allow a more accurate estimation of the prevalence and distribution of thromboembolic disease in dogs.