Though not completely understood, the interplay between neoplastic processes and the coagulation system is characterized by an imbalance between procoagulant and anticoagulant factors (1). Currently, it is theorized that the hemostatic system gets activated by procoagulant factors such as tissue factor that is produced by cancer cells. This activation results in local production of thrombin leading to fibrin deposition and platelet recruitment and ultimately resulting in thrombosis and consumption of coagulation factors (2). Paraneoplastic hyperfibrinolysis is thought to occur in two ways; the tumor cells either (A) produce profibrinolytic proteins, such as urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) or (B) tumor cell membranes carry the specific uPA receptor which can trigger the assembly of fibrinolytic components and subsequently result in excessive activation of the fibrinolytic cascade (3). In people, this phenomenon has been documented with prostatic adenocarcinoma (4–6). Among individuals with prostatic adenocarcinoma, the prevailing hemostatic disorder is disseminated intravascular coagulopathy (DIC). While prostatic adenocarcinoma-associated hyperfibrinolysis has been documented, it has only been reported to affect up to 1.65% of patients and typically manifests after surgical interventions (3). In veterinary medicine, severe bleeding caused by paraneoplastic disorders with secondary hyperfibrinolysis has not yet been reported. This report demonstrates the development of paraneoplastic secondary hyperfibrinolysis with severe bleeding in a dog with metastatic nasal adenocarcinoma.

An 8-year-old male neutered Border Collie (25.7 kg) was serially evaluated at a Veterinary Teaching Hospital (VTH) in January 2023 for recurrent epistaxis.

Disseminated intravascular coagulopathy is a complex disorder characterized by abnormal hemostatic activation, with clinical manifestation depending on the cause. Laboratory diagnosis of DIC is characterized by decreased platelet count, prolonged PT, prolonged aPTT, decreased plasma fibrinogen concentration, decreased plasma antithrombin (AT) activity, increased D-dimers, and increased plasma FDP (7, 8). While these criteria help identify DIC in veterinary medicine, this description does not encompass the various DIC phenotypes observed in human medicine. The International Society on Thrombosis and Hemostasis (ISTH) characterizes two distinct phenotypes of DIC: thrombotic and fibrinolytic. The thrombotic form often leads to organ dysfunction due to clotting, while the fibrinolytic form causes severe bleeding due to excessive clot breakdown (9, 10). In many cases, hemostatic abnormalities can precede clinical and diagnostic evidence of DIC and are reportedly triggered by a multitude of causes, including cancer (11–13). In veterinary medicine, such severe bleeding secondary to hyperfibrinolysis has not been reported in association with disseminated malignancy.

Primary sinonasal neoplasms are relatively uncommon, accounting for less than 2% of all known canine cancers (14, 15). The typical clinical signs include epistaxis, facial deformities, regional lymphadenopathy, and nasal airflow obstruction (16). Fortunately, these clinical signs often respond well with appropriate therapy. Interestingly, Maruyama et al. (7) have observed an association between DIC and dogs with solid malignant tumors, occurring in 9.6% of cases (20/208). Among these cases, 18 dogs were diagnosed with nasal adenocarcinoma, and the majority (16 of 18) showed no clinical or clinicopathologic evidence of DIC (7). This data suggest that delayed, spontaneous severe bleeding in dogs with nasal adenocarcinoma is uncommon.

When considering the present case report, approximately 5 months after radiotherapy, the first bleeding event was noted after tumor biopsy. At that time, no coagulation or platelet function testing was performed, and the excessive bleeding ceased overnight without any additional interventions. When the dog was represented 9 months after radiotherapy for persistent epistaxis, coagulation testing was suggestive of DIC and hyperfibrinolysis (Table 1). In human medicine, malignancy-associated DIC is categorized as subacute, acute, and chronic and has been most often associated with prostatic adenocarcinomas (4–6, 17–19). While the mechanisms underlying the association between cancer and DIC are multifactorial and partially understood, the most prominent theory centers on uPA acting as a primary agent in malignancy-associated DIC (19). uPA has been associated with cancer cell migration, invasion, and modulation of cell adhesion, thereby promoting the formation and progression of various cancers (19, 20). uPA is also known to catalyze the conversion of plasminogen into plasmin without negative feedback, resulting in the breakdown of fibrin clots and the degradation of the extracellular matrix (18, 21, 22). This pathogenesis results in the development of secondary hyperfibrinolysis as the resultant hypofibrinogenemia is the result of imbalanced excessive activation of structurally normal fibrinolytic enzymes or enhanced susceptibility of fibrin to proteolysis (23). In this case, the dog also had deficiencies in factors VII, VIII, and X, along with severe hypofibrinogenemia, all of which are suggestive of an impaired ability to form a clot and hemostatic dysfunction (Table 2). Moreover, the reduction in factor VIII specifically has been associated with upregulation of the fibrinolytic system, resulting in secondary hyperfibrinolysis (23). Thus, when taken in tandem with the dog’s history of confirmed metastatic adenocarcinoma, thrombocytopenia, regenerative anemia, hypocoagulable profile on TEG (Figure 1), and decreased platelet aggregation on impedance aggregometry (Figure 2), the most likely cause for the dog’s progressive clinical decline is chronic DIC with a concurrent paraneoplastic secondary hyperfibrinolysis, a rare diagnosis in veterinary medicine (21).

When exploring other reasons for severe bleeding, severe hypofibrinogenemia is unusual and rarely linked to neoplasia in veterinary medicine or more specifically with dogs with nasal adenocarcinoma. Differentials such as primary hyperfibrinolysis, acquired hypofibrinogenemia, and late-radiation toxicity were considered as potential causes for the dog’s excessive bleeding. In this case, the dog had severe hypofibrinogenemia, which could represent primary hyperfibrinolysis, or an absolute quantitative or qualitative abnormality of proteins was directly involved in the fibrinolytic process (23). However, primary hyperfibrinolysis typically occurs with increased FDP values and normal D-dimers, which would not fit with coagulation abnormalities of the dog. Moreover, TEG analysis which is indicative of primary hyperfibrinolysis would showcase rapid clot formation and subsequent rapid clot lysis (24). In this case, this dog’s TEG profile revealed a prolonged initiation to clot formation, delayed clot kinetics, and a weak clot, consistent with fibrin degradation and DIC or secondary hyperfibrinolysis, further supporting the notion of a secondary hyperfibrinolysis, as observed in the context of underlying malignancy-induced coagulopathy. Next, due to cytotoxic agents (chemotherapy), hypofibrinogenemia is considered as it has been linked to acute myeloid leukemia in people (25). Notably, this phenomenon has never been reported in veterinary medicine. Moreover, in this case, the dog had not received any cytotoxic chemotherapeutic agents. Instead, immunotherapy and radiation therapy had been pursued for approximately 9 months prior to the bleeding events, and thus, it was also excluded as a differential. Other causes for this type of severe hypofibrinogenemia and other coagulation abnormalities could have included synthetic liver failure, but clinically, diagnostically, or histologically there was no evidence to support this diagnosis. Finally, we also considered late radiation toxicity after radiotherapy, but it was deemed unlikely due to the delayed onset of bleeding, unusual tissue response, and the presence of other clotting abnormalities. Irrespective of the etiology, the treatment of choice for hypofibrinogenemia is cryoprecipitate, which contains factor VIII, von Willebrand factor (vWF), fibrinogen, factor XIII, and fibronectin (26). In this case, treatments such as cryoprecipitate infusions, multiple FFP transfusions, and several days of ACA administration were short lived, further reinforcing the diagnosis of severe secondary paraneoplastic hyperfibrinolysis (27–29).

Finally, regenerative anemia and mild thrombocytopenia of the dog could have represented a response to ongoing hemorrhage experienced for multiple days. The decreased platelet aggregability that was noted in this patient is suspected to be related to several factors such as a consumptive process from the severe epistaxis, an in vitro change due to the thrombocytopenia, and platelet dysfunction secondary to metastatic neoplasia (30–33).

This case report presents the first documented instance of paraneoplastic secondary hyperfibrinolysis in a dog with metastatic nasal adenocarcinoma, necessitating multiple blood product transfusions and a prolonged course of ACA due to severe and recurrent bleeding. Although coagulopathies account for less than 5% of cases in dogs with epistaxis (34), the literature suggests that coagulopathies occur in approximately 56% of dogs with malignant neoplasia (7). As such, clinicians should consider systematic coagulation testing in patients with malignant neoplasia presenting with acute bleeding episodes. Such coagulation profiles can guide the administration of anti-fibrinolytic medications and blood products.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethical approval was not required for the studies involving animals in accordance with the local legislation and institutional requirements because this animal study is a case report. Written informed consent was obtained from the owners for the participation of their animals in this study.

KG: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. TP: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. M-KB: Conceptualization, Data curation, Investigation, Methodology, Software, Supervision, Writing – review & editing. LG: Writing – review & editing. SS: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Supervision, Writing – review & editing.