Congenital protein C deficiency and thrombosis in a dog.

Abstract Congenital protein C deficiency is an important cause of thrombosis in humans but is not described in dogs. A 4‐year‐old Hungarian Vizsla was presented for investigation of acute onset of ascites. Computed tomography of the chest and abdomen and echocardiography confirmed a large thrombus within the right ventricle. A cause for thrombosis was not initially identified. The clinical signs resolved rapidly and the dog was administered clopidogrel and discharged. Plasma protein C activity measured 2 and 6 weeks later was markedly lower than expected on both occasions. All known causes of acquired protein C deficiency were excluded, and the dog was diagnosed with a congenital protein C deficiency. After diagnosis, the administration of clopidogrel was stopped and administration of rivaroxaban was started. The dog remains well with no evidence of recurrent thrombosis with 6 months of follow‐up.

While severe congenital deficiencies in people are associated with clinical signs during the neonatal period, mild deficiencies can be asymptomatic or result in recurrent episodes of venous thrombosis later in life.
A single case report of congenital protein C deficiency in animals describes the disease in a thoroughbred foal. Acquired protein C deficiency can occur in people because of hepatic dysfunction, kidney disease, administration or intoxication with vitamin K antagonists, sepsis, and disseminated intravascular coagulopathy. Acquired protein C deficiencies in animals occur in association with liver failure and congenital portosystemic shunts, sepsis, acute inflammatory states, and disseminated intravascular coagulopathy. This is a case of a congenital deficiency of protein C in a dog, causing unprovoked thrombosis. (288 U/L; reference range 0.0-25.0 U/L) activity. Postprandial bile acids were within reference range (3.3 mg/L; reference range 0.0-9.8 mg/L).

| CASE HISTORY AND DIAGNOSTIC FINDINGS
No abnormalities were detected on full urine analysis. Urine protein : creatinine ratio was 0.15 (reference range 0.0-1.0), and urine specific gravity was 1.040. Prothrombin and activated-partial thromboplastin times were within reference ranges. Plasma fibrinogen concentration was slightly below reference range on the day of presentation (1.96 g/L; reference range 2.0-4.0 g/L) but was found to be normal on the day after presentation (3.33 g/L). D-dimer concentrations were elevated on the day of presentation (>250 to <500 ng/mL; reference range <250 ng/mL) and the day after presentation (>500 to <1000 ng/mL). While genetic testing can prove useful in certain cases to differentiate congenital from acquired protein C deficiency (where the possibility of an acquired cause cannot be excluded), genetic testing might be most useful to assist with family counseling, antenatal diagnosis, and making a definitive diagnosis in severely affected neonates.
Chromogenic assays are recommended for initial evaluation of protein C deficiency in humans because interferences that falsely prolong or shorten clotting times in clot-based assays cannot operate in chromogenic assays whose analytical principles are independent of coagulation pathways. A canine-specific assay for measurement of protein C is not available but adaption of a human chromogenic assay has been validated for use in dogs. Published reference values for protein C activity in dogs, measured with functional chromogenic assays developed for use in humans, have been established at 75%-135%.
A chromogenic assay with the same analytic principles as those previously published in dogs was used to measure plasma protein C activity in this case. Protein C is stable in both human and canine samples for at least 2 weeks when stored frozen at −20 C. In this case, samples taken at 2 and 6 weeks after diagnosis showed a persistent and marked decrease in plasma protein C concentrations and in the absence of any conditions known to cause an acquired protein C deficiency, the findings are consistent with a congenital deficiency. Genetic testing or measurement of plasma protein C activity in the parents or another first-degree relative could not be performed. Rivaroxaban is a DOAC, which inhibits factor Xa, and its use has been described in human patients with congenital protein C deficiency.
Rivaroxaban has in vitro and in vivo anticoagulant effects in dogs. Its use has been described in the clinical setting in dogs with confirmed thromboembolic disease and for prophylaxis in dogs with immune-mediated hemolytic anemia. In this case, administration of the previously prescribed clopidogrel was stopped, and administration of rivaroxaban was started upon the finding of protein C deficiency and based on the use of this drug for thromboprophylaxis in affected human patients. Measurement of prothrombin time was scheduled at 3 monthly intervals ongoing to monitor the effect of rivaroxaban administration. Achieving a 1.5-1.9 times delay of prothrombin time from baseline might be a practical method for therapeutic monitoring of dogs receiving rivaroxaban.
The clinical signs associated with thrombosis resolved relatively quickly in this case and the dog remains well at home 6 months after initial presentation with no clinical signs suggestive of recurrent thrombosis. The dog is to remain on daily rivaroxaban indefinitely. Congenital thrombophilic disease should be considered in dogs with thrombosis for which an underlying disease classically thought to predispose to a hypercoagulable state cannot be found. Long-term treatment with DOACs is likely appropriate.

CONFLICT OF INTEREST DECLARATION
Gary Moore was employed by the commercial laboratory at which the testing for potential thrombophilic diseases was performed.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.