Exploring coagulopathies in canine cutaneous mast cell tumors: A systematic review and a cross-sectional analysisABSTRACT
Mast cell tumors (MCTs) are common cutaneous neoplasms in dogs and are often associated with paraneoplastic syndromes, particularly coagulopathies, which may impact surgical management. However, the relationship between MCTs and coagulopathies remains unclear. This study aimed to evaluate the impact of MCTs on hemostasis through a systematic review and a cross-sectional study. A search in five databases identified 692 studies, of which only four met the inclusion criteria: two observational studies and two case reports, totaling 25 dogs with MCT evaluated for coagulation parameters. Reported abnormalities included prolonged coagulation time, increased activated partial thromboplastin time (aPTT), and increased fibrinogen levels. In the cross-sectional study, 20 dogs with MCT were assessed. Coagulation analysis revealed significantly lower fibrinogen levels in the MCT group (P < 0.05), while prothrombin time and aPTT did not differ significantly from the control group. Platelet counts were significantly higher in dogs with MCT (P<0.05). In conclusion, the limited number of studies in the systematic review precludes definitive conclusions about the association between MCTs and coagulopathies, underscoring the need for further research. Although thrombocytopenia was not observed in the cross-sectional analysis, altered fibrinogen levels may subtly affect both primary and secondary hemostasis in dogs with MCTs.
Keywords:
coagulogram; fibrinogen; paraneoplastic syndrome; platelets
RESUMO
Os mastocitomas (MCTs) são neoplasias cutâneas comuns em cães, frequentemente associadas a síndromes paraneoplásicas, como coagulopatias, que podem interferir no manejo cirúrgico. No entanto, essa relação ainda não está completamente elucidada. Este estudo teve como objetivo avaliar o impacto dos MCTs na hemostasia por meio de uma revisão sistemática e um estudo transversal. A revisão incluiu quatro estudos (dois observacionais e dois relatos de caso), totalizando 25 cães com MCT avaliados quanto à coagulação. As principais alterações incluíram tempo de coagulação prolongado, aumento do tempo de tromboplastina parcial ativada (aPTT) e níveis elevados de fibrinogênio. No estudo transversal, foram analisados 20 cães com MCT. Observou-se menor concentração de fibrinogênio no grupo com MCT (P < 0,05), sem diferença significativa no tempo de protrombina e no aPTT em comparação ao grupo controle. A contagem de plaquetas foi maior nos cães com MCT (P < 0,05). Conclui-se que o número limitado de estudos incluídos na revisão sistemática impede afirmar uma associação definitiva entre MCTs e coagulopatias. Embora a trombocitopenia não tenha sido observada na análise transversal, alterações nos níveis de fibrinogênio podem afetar sutilmente a hemostasia primária e secundária em cães com MCTs.
Palavras-chave:
coagulograma; fibrinogênio; síndrome paraneoplásica; plaquetas
INTRODUCTION
Mast cell tumors (MCTs) are primary cutaneous neoplasms in dogs, accounting for 17.8% of malignant neoplasms affecting canine skin (Oliveira et al., 2020). Certain breeds, such as Boxers, Golden Retrievers, and Weimaraners, are predisposed to these tumors. The exact etiology remains unclear, but alterations in genes that regulate c-kit tyrosine receptors are suspected to play a role in the development of this malignancy (Garrett, 2014). Clinically, MCTs typically present as nodules or subcutaneous plaques measuring approximately 3.0 cm that may ulcerate (Daleck and de Nardi, 2016).
MCT diagnosis can be confirmed through cytopathological examination; however, histopathological examination is essential for a definitive diagnosis. MCTs are classified into high- and low-grade tumors according to Kiupel’s classification, with high-grade tumors associated with a poor prognosis (Avallone et al., 2021). To aid in preliminary diagnosis, Camus et al. (2016) proposed a cytological categorization scheme based on Kiupel’s classification. This scheme evaluates four cellular characteristics: mitotic figures, binucleation, marked anisokaryosis, and nuclear pleomorphism. If two or fewer cytoplasmic granules are observed, the MCT is categorized as high cytological grade.
Paraneoplastic syndromes in MCTs are associated with the release of substances such as heparin, interleukins, and proteases by the tumor cells (Garrett, 2014). Additionally, mast cells have been implicated in the development of coagulopathies in patients with anaphylaxis (Guilarte et al., 2017). Given that surgical excision is the primary treatment for this neoplasm, coagulopathies can significantly impact the prognosis of patients with MCTs (Oliveira et al., 2020). However, the relationship between MCTs and coagulopathies remain poorly understood. To address the need for further investigation in the association between canine cutaneous MCTs and hemostasis, a systematic review was conducted, followed by a cross-sectional study. These studies aimed to evaluate the impact of primary and secondary hemostasis in dogs with cutaneous MCTs employing coagulometric and hematobiochemical analysis.
ETHICAL ASPECTS
This research project was approved by the Ethics Committee on Animal Use (CEUA) of Federal University of Campina Grande (UFCG) (Process nº 034/2019) ensuring the welfare and ethical treatment of all animals involved.
MATERIAL AND METHODS
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Page et al., 2021), utilizing all relevant research data.
Five databases were searched (PubMed, ScienceDirect, SciELO, Scopus, and Web of Science) for studies evaluating the impact of MCTs on coagulation. Search terms for primary studies comprised: (mastocytoma OR skin tumor OR skin mast cell tumor) AND (coagulogram OR paraneoplastic syndrome OR coagulation) AND (canine OR dog). The citations of the identified studies containing the title and abstract were saved in BibTex format and viewed in the Mendeley bibliographic manager, in which duplicated works were excluded, and the titles and abstracts were read. The searches were carried out from August 1st to 15th, 2024.
During the selection of studies, there were no restrictions regarding the year in which the study was developed or published, the language, or the country where the study was conducted. Studies were considered eligible if they established a correlation between MCTs and hemostasis alterations, aligning with their cytological and histopathological classifications. Exclusion criteria included inaccessible or irrelevant studies, reviews, dissertations/thesis, conference proceedings, and technical manuals. Additionally, studies describing intervention protocols ranging from days to months, pertinent to diagnostic and therapeutic processes of surgery and chemotherapy, were not included in the primary analyses.
Two researchers independently reviewed the titles and abstracts of the primary studies, followed by a full-text reading. In cases of discrepancies, a third researcher was consulted to determine the inclusion of the study.
The data extracted from the articles were added to an Excel spreadsheet with the following information: characteristics of samples, animals’ demographics (including sex, age, and breed), mast cell tumor classification, methodology for evaluating primary and secondary hemostasis, and resultant interpretations. The data were qualitatively analyzed using descriptive statistics.
The selected animals included dogs of any breed, sex, or age with a definitive diagnosis of mast cell tumor (MCT). Exclusion criteria encompassed co-infections, inflammatory, parasitic, or other neoplastic diseases, as well as dogs that had not undergone chemotherapy and/or surgery prior to blood collection. Animals were selected for the control and MCT groups from February 2021 to May 2023 through a multicenter collaboration. Dogs were recruited from the caseloads of the Ivon Macedo Tabosa Teaching Veterinary Hospital at UFCG, Patos-PB (Lat: -7.06°; log: -37.28°), the Sylvio Barbosa Cardoso Teaching Veterinary Hospital at Ceará State University (UECE), Fortaleza, CE (Lat: -3.79°; log: -38.55°), and a private veterinary clinic, ETAVE, Fortaleza, CE (Lat: -3.75°; log: -38.53°).
The control group consisted of clinically and laboratory-healthy dogs, selected following a comprehensive health assessment. This evaluation included a complete blood count and a thorough physical examination, which encompassed measurements of rectal temperature, heart and respiratory rates, skin turgor, capillary refill time, lymph node palpation, mucosal inspection, cardiac and pulmonary auscultation, abdominal palpation, and external genital inspection.
Blood analysis for the control and MCT groups was performed using jugular or cephalic venipuncture using a 22G needle attached to a 3mL syringe. Blood samples were placed tubes with EDTA as an anticoagulant and without an anticoagulant. For coagulogram analysis, blood was obtained via non-traumatic jugular or cephalic venipuncture and placed in tubes containing 3.8% (w/v) sodium citrate in a 9:1 ratio.
Additionally, in accordance with the manufacturer's instructions, serological samples from both groups were submitted to an immunochromatographic test (Dual Path Platform - DPP, Fiocruz, Rio de Janeiro, Brazil) and an in-clinic Enzyme Linked Immunosorbent Assay (ELISA) (SNAP 4Dx Plus Test for Anaplasma/Ehrlichia/Lyme/Heartworm, Idexx Laboratories, Westbrook, ME, USA) to rule out the presence of leishmaniasis and hemoparasites, respectively.
Mast cell tumors were diagnosed by cytopathological examination, following the method described by Fisher (Fisher, 2020). We obtained at least three slides of neoplastic lesions from suspected patients via fine-needle aspiration or aspirate biopsy. The slides were stained with rapid panoptic dye and evaluated under a light microscope. The diagnosis was confirmed through histopathological examination of samples obtained by surgical excision at the Animal Pathology Laboratory of UFCG (LPA-UFCG). Specimens were fixed in 10% formalin, embedded in paraffin, sectioned into thin slices using a microtome, and stained with hematoxylin and eosin. Following the diagnostic confirmation of MCT, animals were categorized into two groups based on cytological grade: high-grade (systemic) and low-grade (cutaneous) MCTs.
Samples were centrifuged at 1500×g, 15 minutes at room temperature and the citrated plasma was analyzed using a semi-automated coagulometer (Generalmed®, São Paulo, Brazil) to evaluate prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen.
PT was measured by incubating 100μL of pre-warmed citrated plasma at 37°C for 3 minutes. The sample was then transferred to a cup and further incubated at 37°C for 20 seconds using a semi-automated coagulometer. Subsequently, 200μL of pre-warmed thromboplastin reagent (TP CLOT, CLOT Produtos para Coagulação, Sorocaba, Brazil) was added, and the coagulation time was recorded.
The aPTT was determined by heating 100μL of citrated plasma at 37°C for 2 minutes. The sample was then transferred to a cup containing 100μL of pre-warmed ellagic acid reagent (TTPA CLOT, CLOT Produtos para Coagulação, Sorocaba, Brazil) at 37°C. Afterward, 100μL of pre-warmed calcium chloride (0.025Mol/L) was added, and the coagulation time was measured in seconds. To calculate the INR (International Normalized Ratio) in coagulation tests, the following formula was used: INR = (Patient’s Time/Normal Time) × ISI. ISI is the International Sensitivity Index of the reagent used.
Fibrinogen levels (Fibrinogênio CLOT, CLOT Produtos para Coagulação, Sorocaba, Brazil) were measured using a semi-automated coagulometer, following the manufacturer's protocol with slight modifications based on the method described by Clauss (1957). Citrated plasma was coagulated with excess thrombin, and the coagulation time was proportional to the fibrinogen content. Fibrinogen levels were calculated using a calibration curve.
The samples were processed using an automatic hematological analyzer (Poch-100iV Diff, Sysmex Corporation, Hyōgo, Japan) to assess total red blood cell count, white blood cell count, platelet count, hemoglobin (Hb) levels, hematocrit (HT), mean corpuscular volume (MCV), and mean corpuscular hemoglobin concentration (MCHC). Following the hematological analyses, blood smears were prepared and stained using rapid panoptic stain. Microscopic evaluation under light microscopy included differential leukocyte counts and an assessment of the morphotintorial characteristics of erythrocytes, leukocytes, and platelets, focusing on their shape, size, and the presence of parasites.
Serum samples were obtained after centrifugation at 1,610×g for 5 minutes and analyzed using the automated biochemical analyzer Cobas C111 (Roche Diagnostics, Indianapolis, IN, USA). The following analytes were measured: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Albumin (ALB), Alkaline Phosphatase (ALP), Total Protein (TP), Creatinine (CRE), and Urea (U). The concentration of globulins (GLOB) was obtained by subtracting the ALB value from the TP value. The albumin:globulin ratio (A:G) was obtained by dividing the ALB value by the GLOB value.
The hematobiochemical and coagulometric variables were assessed for normality using the D'Agostino and Pearson test, with a significance level of 5%. Data were expressed as mean and standard deviation. To compare the control and MCT groups, a two-way analysis of variance (ANOVA) was performed, followed by a Bonferroni post hoc test using GraphPad Prism® for Windows (GraphPad Software Inc., San Diego, CA, USA). Statistical significance was set at p<0.05.
RESULTS
The search method initially returned a total of 692 studies. After removing duplicates, 637 articles remained. These articles were then screened based on predetermined exclusion and inclusion criteria, resulting in a selection of only four articles for this review. Among these, two studies were observational studies, while two articles were case reports. In total, 25 animals with MCT were evaluated for coagulation parameters. Following the recommendations of PRISMA group, the search and selection steps are outlined in the flowchart shown in Figure 1. The selected studies were performed in four different countries (Brazil, Canada, Republic of Korea, and United States), and were published from 1965 to 2020.
Due to the limited number of studies in the final sample, a meta-analysis was not conducted, and the articles were analyzed qualitatively. The main characteristics of the sampled dogs in the studies are shown in Table 1. All dogs presented cutaneous MCT, except for one that presented a presumptive primary pulmonary MCT. The main diagnosis technique used was histopathology. Hemostasis was evaluated through coagulation time, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, and platelet count. The main alterations described in coagulation assessment were prolonged mean coagulation time, elevated aPTT, and elevated fibrinogen levels (Table 2).
In the multicenter study, all selected patients presented with non-systemic, low-grade cutaneous mast cell tumors (Table 3). Coagulation analysis revealed significantly lower fibrinogen levels in the mast cell tumor group (P<0.05), whereas PT and aPTT did not differ significantly from those of the control group (Table 4). Regarding hematological parameters, no significant differences were observed between dogs with mast cell tumors and the control group in any of the assessed variables, except for platelet count, which was significantly higher in dogs with neoplasia (P<0.05) (Table 5). Analysis of serum biochemical parameters indicated that only ALP levels were elevated in the mast cell tumor group compared to the control group (P<0.05) (Table 6).
Characteristics of the sampled dogs diagnosed with mast cell tumor (MCT) that underwent coagulation assessment
Characteristics and description of mast cell tumors (MCTs) diagnosed in dogs from the studies included in the systematic review
DISCUSSION
The present research investigated the association between MCT and coagulopathies in dogs through a systematic review and a cross-sectional study. Information regarding this topic is still very scarce in the literature, which was reflected in the limited number of studies included in the systematic review, only four. Moreover, these studies collectively analyzed a small sample of 25 dogs and assessed different coagulation parameters, allowing only a qualitative analysis.
In the study conducted by Anjos et al. (2018), nine dogs with MCT were evaluated using a coagulogram. The results exhibited elevated plasma fibrinogen levels in affected animals compared to the control group, likely due to the inflammatory process associated with neoplasia, as fibrinogen is a positive acute-phase inflammatory protein. Additionally, approximately 33% of the dogs presented thrombocytopenia, which may be attributed to inflammatory processes or the formation of metastatic tumor emboli facilitated by the neoplasms (Falanga et al., 2014). Moreover, an increase in PT alone was observed in patients with changes in coagulograms (PT and aPTT) (Anjos et al., 2018). This is associated with modifications in the extrinsic coagulation pathway. Tumors can release tissue factors at the insertion site and promote the production of extracellular vesicles containing pro-coagulant proteins and tissue factors, thereby elevating PT (Falanga et al., 2014).
In the other observational study included in the systematic review, Hottendorf et al. (1965) evaluated 14 female and male dogs of various breeds. These authors assessed changes in secondary hemostasis using the Lee and White and capillary tube coagulation methods. Their findings indicated that approximately 33% of dogs with MCT exhibited prolonged clotting times compared to healthy controls. Moreover, in one animal that underwent clotting tests before and after tumor removal, postoperative results showed a reduction of approximately 55% in clotting time compared to preoperative measurements. It is likely that after tumor removal there was a reduction in the production of tryptases and heparin, which induce deeper stages of hypocoagulability (Seidel et al., 2021).
Two case reports were included in the systematic review. In the first case, a 14-year-old mixed-breed female dog with a presumptive primary pulmonary mast cell tumor showed no alterations in the coagulogram or platelet count (Campbell et al., 2017). The second case involved a 10-year-old female Yorkshire Terrier with a mast cell tumor located in the muzzle and nasal planum, which presented coagulopathy (Kim and Kim, 2020). A significant prolongation of aPTT, consistent with the observations of Anjos et al. (2018). However, no changes in primary hemostasis were found.
Conversely, in a case report of systemic mastocytosis in a Greyhound dog, thrombocytopenia, increased D-dimer and fibrinogen levels, and prolonged aPTT were described. Additionally, numerous mast cells were observed in the skin, bone marrow, and various visceral organs (Aceino et al., 2021). Hemostatic disorders observed in systemic mastocytosis in both humans (Johansen et al., 2019) and veterinary patients may be associated with the production of tryptases and heparin, which induce deeper stages of hypocoagulability and hyperfibrinolysis (Seidel et al., 2021) compared to cutaneous MCTs.
The main diagnostic method used in the selected studies has histopathology, preceded or not by cytopathology. According to Avallone et al. (2021), cytomorphological classification presents challenges due to its relatively low accuracy compared to histopathological examination, which is rarely requested. When evaluating 100 cells, the accuracy was approximately 75%; while it reaches 82% accuracy when evaluating 1,000 cells. However, assessing so many cells is often impractical due to factors such as sample quality and the observer’s level of experience.
In the cross-sectional study presented here, hemostasis was evaluated in 20 dogs with low-grade cutaneous MCT through the analysis of fibrinogen, aPTT, PT, and platelet count. The MCT group showed significantly lower fibrinogen levels and non-significantly higher platelet counts compared to the control group, in contrast to the findings reported by Anjos et al. (2018), in which fibrinogen levels were elevated due to the inflammatory response and pro-coagulant effects associated with the release of mediators by tumor mast cells. However, although fibrinogen plays an important role in tumor angiogenesis and neoplasia-mediated inflammation, tumor mast cells may release substances that activate the coagulation cascade, leading to the consumption of clotting factors and fibrinogen itself (Staton et al., 2003; Guilarte et al., 2017). Furthermore, as fibrinogen is part of the common pathway, alterations in its levels may impair secondary hemostasis, resulting in a significant increase in platelet count (Thrall et al., 2015). Tumors, especially those located in the skin, can release tissue factors and pro-coagulant factors at the site of neoplasia, causing an increase in PT (Falanga et al., 2014). However, no significant PT alterations were observed in this study, contrasting the findings reported by Anjos et al. (2018). Alterations in secondary hemostasis may compromise intraoperative and postoperative outcomes, leading to inadequate bleeding control during surgery and prolonged wound healing (Neveleff et al., 2010).
In addition to hemostatic alterations, mast cell tumors can induce other paraneoplastic syndromes, such as anemia due to iron sequestration, inefficient erythropoietin activity, reduced lifespan of circulating erythrocytes, along with leukocytosis, primarily eosinophilia (Daleck and de Nardi, 2016). In animals with MCTs, thrombocytopenia is attributed to the production of adenosine diphosphate and thrombin, which promote platelet activation and aggregation at the tumor site (Stokes and Granger, 2012). This response may result from stimulation, as platelets participate in inflammatory processes, and the expansion may be due to local inflammation caused by chronic MCT (London and Seguin, 2003; Thrall et al., 2015).
In the present study, all dogs presented non-systemic cutaneous MCTs, which represent the most common manifestation of the disease in dogs. Reports of malignant systemic mast cell tumors remain rare (Pierini et al., 2019; Aceino et al., 2021). Surgical excision is the first-line treatment, even for benign non-systemic cutaneous forms. However, achieving a safe surgical margin poses a challenge for this treatment modality. Furthermore, wound healing complications may arise due to the release of tumor-derived heparin and histamine, which can inhibit keratinocyte proliferation and exacerbate hemostatic disturbances (Killick et al., 2011; Selmic and Ruple, 2020).
In biochemical analysis, ALP was the only parameter found to be altered in dogs with MCT. This enzyme can be affected by an influenced by endogenous cortisol levels associated with chronic stress (Thrall et al., 2015). Dogs with MCT often present with clinical signs of pain, itching, and nodules that may ulcerate (Daleck and de Nardi, 2016). Another potential factor contributing to elevated ALP levels is the reduced osteogenic capacity and inhibition of bone mineralization mediated by mast cell granules, leading to an increase in the bone fraction of ALP in the serum (Maximiano et al., 2017). Marconato et al. (2008) reported elevated ALT levels following hepatic tumor infiltration. However, no alterations were observed in transaminases or other biochemical markers, suggesting the absence of disseminated lesions, as all cases were restricted to non-systemic low-grade cutaneous MCTs.
Several diagnostic methodologies are available for assessing hemostatic disorders, especially in cases of hypercoagulability. These include thromboelastographic, fibrin degradation products (FDP), and D-dimers (Burton and Jandrey, 2020). In a study conducted by Andreasen et al. (2012) it was observed that 58.3% of patients with mast cell tumors presented hypercoagulability, presenting increases in thromboelastographic values, D-dimers, prolonged aPTT, and increased fibrinogen levels. Recognizing this paraneoplastic syndrome associated with MCTs is important; however, thromboelastographic, FDP, and D-dimers are costly and not widely accessible tests, which precluded their inclusion in the present study. Nevertheless, future research should incorporate these parameters to better characterize hypercoagulability in dogs with both high- and low-grade cytological mast cell tumors.
In conclusion, due to the low number of studies included in the systematic review and the lack of standardization on the coagulation parameter assessment across the studies, it is not possible to determine whether the presence of MCT dogs is associated with coagulation disorders. Although alterations in hemostasis have been reported in dogs with MCT, future studies with larger sample sizes and correlations with histological grading are necessary to better evaluate the relationship between MCT and coagulation disturbances. Regarding the cross-sectional study, although no quantitative platelet alterations were observed, altered fibrinogen levels could slightly affect primary and secondary hemostasis in patients with non-systemic low-grade cutaneous mast cell tumors. The absence of high-grade or systemic cutaneous mast cell tumors reduced the observational spectrum of this cross-sectional study. The lack of data regarding the number of nodules and their dimensions is another limitation, as it may distort the hemostasis data collected from patients.
ACKNOWLEDGMENTS
The authors (Jorge SM, Cunha AR, and Sedrim FBL) thank the Brazilian National Council for Scientific and Technological Development (CNPq) and the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) for supporting their scholarships.
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The research data are available within the article itself.
