This case describes fibrinogen deficiency, an extremely rare congenital bleeding disorder in dogs [1, 8]. Very little data is published on the subject in veterinary medicine, with only three case reports on dogs with afibrinogenemia: a Bernese mountain dog [3], a Chihuahua [4], and a Bichon Frise [5]. In an international registry of animal hemostatic disorders, Dodds mentioned a case of dysfibrinogenemia in an inbred family of Borzois and a case of hypofibrinogenemia in a family of Saint Bernard dogs [6] but to our knowledge these cases have not been reported in detail in a peer-reviewed journal.
In human medicine, congenital fibrinogen deficiency represents 7% of rare congenital bleeding disorders, hemophilia-excluded [2, 9]. Three categories of fibrinogen deficiency have been described: afibrinogenemia when fibrinogen is not detectable; hypofibrinogenemia when the value is below the lower limit of the reference interval; and dysfibrinogenemia when the fibrinogen molecule is abnormal and dysfunctional. The only way to differentiate hypofibrinogenemia from dysfibrinogenemia in humans is a low fibrinogenemia assessed by coagulometry with a concurrent normal or subnormal fibrinogen concentration by an immunologic method. Unfortunately, such a method is not routinely available in veterinary medicine [10, 11]. Therefore dysfibrinogenemia was not completely excluded in our dog. However, because the fibrinogen concentration was similarly decreased with both coagulometric method and heat precipitation method, we concluded it was hypofibrinogenemia.
The clinical presentation of ocular signs in this case is unusual. Ocular ultrasonography was suggestive of a retrobulbar cellulitis with effusion. To confirm this diagnosis, cytological and bacteriological analysis of a fine needle aspiration of retrobulbar space is needed. In this case, the first hypothesis was a hematoma because the ocular problems started after the dog was hit on the head and the patient had a background history of sustained increase of coagulation times and abnormal bleeding following a benign gingival wound. However, the nature of the retrobulbar ultrasonographic abnormality could not be confirmed by fine needle aspiration due to the risk of bleeding. Given the extreme pain associated with jaw opening, a primary hematoma with secondary inflammation/infection was a possible hypothesis. The dog was therefore treated with antibiotic and anti-inflammatory drugs. The rapid clinical improvement after onset of the treatment in a dog, whose signs had been stable for the previous 10 days was consistent with this hypothesis.
When hypofibrinogenemia is detected, the first clinical step is to exclude all possibility of a preanalytic error and to confirm the fibrinogen value using another method such as Millar’s method. If the decreased concentration is confirmed, all other causes of decreased fibrinogen production or increased fibrinogen consumption need to be explored before considering a diagnosis of congenital hypofibrinogenemia. Liver function must be assessed because fibrinogen is produced by the liver. In our case, normal clinical examination and bile acid test excluded decreased hepatic fibrinogen synthesis. The second step is to rule out increased and sustained fibrinogen consumption by activation of the coagulation cascade, namely DIC or chronic bleeding, by laboratory work-up and diagnostic imaging. No systemic disease, bleeding or inflammatory site, other than the ocular bulging, was suspected in our dog. No signs of chronic blood loss were detected on CBC, and normal platelet count, AT and DDi concentrations were inconsistent with DIC.
In our patient, the only hemostatic abnormality other than hypofibrinogenemia was FDPs in the grey zone. FDPs reflect the action of the fibrinolytic enzyme, plasmin, on fibrin and fibrinogen whereas DDi appear only when fibrin is degraded by plasmin [12]. Decreased FDPs clearance due to a failing liver or kidney was excluded by the laboratory results. The FDPs value results could indicate primary hyperfibrinolysis (ie spontaneous activation of plasmin not triggered by coagulation activation). However, primary hyperfibrinolysis had not previously been described in dogs and was considered very unlikely in our case for other reasons including the absence of primary diseases causing hyperfibrinolysis in humans, such as liver cirrhosis [13] or bronchiectasis [14]. Moreover, if the severe hypofibrinogenemia in this dog had been caused by hyperfibrinogenolysis, FDPs would have been very high and not only slightly increased. Finally, the dog’s fibrinogen concentration remained low at the 1 and 2 month follow-ups which was not compatible with a primary hyperfibrinogenolysis that is not a persistent condition. Therefore, we hypothesized that the slight increase of the FDPs could be the consequence of the suspected retrobulbar hematoma.
Furthermore, the unusual context of this case’s clinical scenario made it difficult to determine whether the disorder was congenital or acquired. The onset of the condition, discovered by the veterinarian in association with a strong suspicion of snake bite, was initially confusing. It concerned an adult dog, with no previous coagulation profile evaluation or surgical history, making it impossible to determine if the coagulation disorders were present prior to this episode. According to the owner, the dog had been perfectly healthy which is consistent with the few cases of hypofibrinogenemia described in the veterinary literature [1, 8].
Because the PT and aPTT values were consistently above the reference intervals after the presumed envenomation, the hypothesis of circulating anticoagulants, such as antibodies that would have developed after envenomation and would be directed against fibrinogen, or would impair the coagulation reactions involved in the transformation of fibrinogen into fibrin, had to be investigated. The dilution method with a PHDP is a simple method used to explore circulating anticoagulants. It is easily performed in-house when coagulation times are sufficiently increased (at least 1.5 times the upper limit of RI), only requiring the measurement of PT or aPTT in PHDP, the citrated plasma of the affected animal and a 1/1 (vol/vol) mixture of the two. If PT or aPTT are not normalized in the mixture, it strongly suggests a circulating anticoagulant/antibody against a coagulation factor [15]. In our case, we chose to measure the fibrinogen concentration ([Fibrinogen]) using a coagulometric method rather than coagulation times. Because the fibrinogen concentration in the mixture was close to [PHDP Fibrinogen]/2 + [affected dog’s Fibrinogen]/2, we ruled out the presence of a circulating anticoagulant in the plasma of the affected dog. A possible limitation to this approach would be that serial dilutions might have been more sensitive to detect a circulating antibody if the optimal concentrations had not been obtained at the 1/1 dilution. However, in the only case report of circulating antibody against fibrinogen described in the dog [5], the fibrinogen concentration of the 1/1 mixture was more than 50% below the expected theoretical concentration. A circulating anticoagulant was therefore considered unlikely in our case. Once all the hypotheses had been excluded, the final diagnosis was consistent with a congenital fibrinogen deficiency.
Testing the parents and the siblings to assess coagulation abnormalities would have been interesting to investigate the disorder in the whole family and document a possible genetic/hereditary background. Unfortunately, this was not possible in our case.
Cryoprecipitate is the treatment of choice for fibrinogen deficiencies because it supplies high concentrations of fibrinogen in a low volume. Fresh frozen plasma is an alternative product when cryoprecipitate is unavailable. For patients with active hemorrhage and decreased PCV, a blood transfusion is also indicated. The target fibrinogen value is 1.0 g/L [16]. The half-life of fibrinogen is 4.2 days and relatively long compared to most coagulation factors [17]. Therefore, fewer transfusions are often sufficient to temporarily support haemostasis in such patients.