A case of factor X deficiency in a Chihuahua dog

Abstract

A juvenile Chihuahua dog developed hemoperitoneum after routine ovariohysterectomy. She was managed with packed red blood cell and fresh frozen plasma transfusions as well as an exploratory laparotomy to verify ligature sites. No recurrence of hemorrhage occurred. Factor X deficiency was diagnosed and confirmed with repeat analysis including during times of health.

Factor X deficiency is a rare bleeding disorder in humans, the incidence of which is approximately 1:500 000 to 1:1 000 000 (1–3). The incidence of this disease is unknown in veterinary medicine; however, it is thought to be rare (4). The heterozygous incidence may be as high as 1:500 with many dogs being asymptomatic. No humans with deletions of both factor X genes have been reported, indicating that complete deficiency of factor X is incompatible with life (5). To the authors’ knowledge, this is the first Chihuahua dog diagnosed with factor X deficiency (6,7). Repeated diminished activity of factor X, even during times of health, indicates the hemorrhagic event reported was secondary to congenital factor X deficiency.

Case description

A 7-month-old, 3.5 kg, spayed female Chihuahua dog was referred with a hemoperitoneum 5 d following routine ovariohysterectomy. She had initially recovered well but had become lethargic and anorexic over the preceding 24 h. She was receiving Tramadol (Teva, Sellersville, Pennsylvania, USA), 12.5 mg PO, q12h, for pain control. She was presented to her primary care veterinarian whose laboratory analysis revealed the following: elevated blood urea nitrogen [BUN; 13.9 mmol/L; reference interval (RI): 2.5 to 8.9 mmol/L], hypoproteinemia (38 g/L; RI: 54 to 82 g/L), and hypoglobulinemia (11 g/L; RI: 23 to 52 g/L). A complete blood (cell) count (CBC) revealed anemia [red blood cells (RBC) 1.71 × 10¹²/L; (RI: 5.5 to 8.5 × 10¹²/L), hemoglobin 33 g/L; (RI: 120 to 180 g/L), hematocrit 0.11 L/L; (RI: 0.37 to 0.55 L/L)], thrombocytopenia (18 × 10⁹/L; RI: 200 000 to 110 000/μL) and leukocytosis [white blood cells (WBC) 22.87 × 10⁹/L; RI: 6 to 17 × 10⁹/L]. Abdominal radiographs revealed diminished serosal detail and a point-of-care abdominal ultrasound revealed peritoneal fluid. Abdominocentesis revealed non-clotting blood.

Upon presentation the patient was recumbent with pale mucous membranes, tachycardia [200 beats/min (bpm)], tachypnea (40 breaths/min) and hypothermia (36.4°C). The dog had a grade II/VI holosystolic left apical heart murmur, a palpable abdominal fluid wave, and bruising on the ventral abdomen. Her blood pressure could not be obtained via Doppler. The CBC was similar to that performed prior to referral. Venous blood gas analysis (iSTAT EC8; Abbott Point of Care, Abbott Park, Illinois, USA) showed a metabolic acidosis [pH 7.281; RI: 7.35 to 7.45, base excess (BE) -10 mmol/L; RI: 0 to 6, hyponatremia (119 mmol/L; RI: 142 to 150] and an elevated BUN (17.9 mmol/L; RI: 3.57 to 9.28 mmol/L)]. A prothrombin time (PT) (IDEXX Coag Dx analyzer; IDEXX Laboratories, Westbrook, Maine, USA) was 70 s; RI: 11 to 17 s, and a partial thromboplastin time (aPTT) was 209 s; RI: 72 to 102 s. Venous lactate was not measured. Measurement may have provided further support for the presumed hypoperfusion secondary to hemorrhagic shock.

The patient’s elevated BUN was presumptively due to renal hypoperfusion from hypovolemia. Urine specific gravity, which was not evaluated due to a large volume of peritoneal effusion and concern for coagulopathy making cystocentesis of increased risk, may have provided further support for the presumed hypovolemia. Urine specific gravity > 1.030 would rule out kidney dysfunction. The patient’s metabolic acidosis was likely due to hypoperfusion causing hyperlactatemia; however, uremic acidosis cannot be entirely ruled out. Hyperlactatemia was unconfirmed. However, the presence of base deficit characterized by the base excess algorithm indicates unmeasured anions are present and lactate is most logical in this patient’s case (8).

A universal type packed red blood cell (pRBC) transfusion was administered, followed by a fresh frozen plasma (FFP) transfusion [20 mL/kg body weight (BW)]. The dog’s blood pressure normalized at 120 mmHg (Doppler systolic) following administration of a 30-mL pRBC bolus (8.5 mL/kg BW) administered over 15 min. Following the FFP transfusion, crystalloid therapy was initiated with Plasmalyte-A (Abbott Animal Health, Abbott Park, Illinois, USA) with 20 mEq/L potassium chloride (Hospira, Lake Forest, Illinois, USA) at 7 mL/h (48 mL/kg BW per day). Post-pRBC transfusion the packed cell volume (PCV) was 0.24 L/L with total protein (TP) of 42 g/L, which rapidly declined over 6 h to 0.18 L/L and 40 g/L, respectively. The patient became clinical for the aforementioned anemia, displaying tachycardia (180 bpm), pallor, and quieter mentation. With evidence of clinical anemia, an additional PRBC transfusion (30 mL) was administered. Post-pRBC transfusion PCV was 0.30 L/L with a TP of 53 g/L. The PT and aPTT were normal at 15 s and 91 s, respectively. Epsilon aminocaproic acid (Hospira), 50 mg/kg BW, IV, q8h, was administered.

Laparotomy was elected to evaluate the ovariohysterectomy ligature sites. This patient was sedated with hydromorphone (West-Ward Pharmaceuticals, Eatontown, New Jersey, USA), 0.05 mg/kg BW, IV, prior to induction of anesthesia with propofol (Abbott Animal Health), 4.3 mg/kg BW, IV. The patient was intubated and maintained on Sevoflurane (Zoetis Animal Health, Florham Park, New Jersey) inhalant anesthesia. During surgery 280 mL of bloody fluid was evacuated from the abdomen. Blood clots were located around the uterine stump and ovarian artery ligations. All ligatures were intact. The uterine body was again ligated and Gel Foam (Pfizer, New York, New York, USA) was applied to the right ovarian pedicle region. There was no evidence of active hemorrhage. The abdomen was closed routinely and the dog recovered uneventfully. Postoperative pain was controlled with hydromorphone (West-Ward Pharmaceuticals), 0.05 mg/kg BW, IV, q4 to 6 h.

Due to the inability to rule out inherited coagulopathy and recent laparotomy, an additional FFP transfusion (17 mL/kg BW) was administered on recovery to assure adequate factor activity. Following completion of the post-operative FFP transfusion, intravenous fluid therapy was continued with the pre-operative crystalloid and rate.

Throughout the day post-surgery, the dog’s PCV remained stable between 0.33 and 0.36 L/L with her TP between 64 and 72 g/L. The dog was normotensive (110 to 156 mmHg) and her vital parameters were normal. Over the following 24 h, the dog’s vitals remained stable with PCV and TP of 0.37 L/L and 68 g/L, respectively. Hydromorphone was discontinued and tramadol (Amneal Pharmaceuticals, Bridgewater, New Jersey, USA), 3.5 mg/kg BW, PO, q8h was started.

A citrated whole blood sample collected ~36 h after the last FFP transfusion revealed PT and aPTT to be prolonged at 31s and 139 s, respectively. The dog’s PCV was 0.38 L/L with a TP of 71 g/L. Citrated plasma was submitted to Cornell University Animal Health Diagnostic Center Comparative Coagulation Laboratory for coagulation factor analysis. The patient remained stable and was discharged 2 d after surgery with epsilon aminocaproic acid (Akorn Pharmaceuticals), 35 mg/kg BW, PO, q8h, tramadol, 3.5 mg/kg BW, PO, q12h, and vitamin K (VetOne, Boise, Idaho, USA), 3.5 mg/kg BW, PO, q24h. Factor analysis results revealed diminished factor X activity (45%; RI: 80% to 175%), with normal factor II, VII, VIII, IX, Von Willebrand factor and fibrinogen activity.

At recheck examination 16 d after surgery, the patient was reported to be acting normally following discharge. Repeat factor X analysis revealed persistent factor X deficiency (29%), consistent with congenital factor X deficiency. At 18 mo post-hemorrhage, the patient was reported to be clinically normal without evidence of hemorrhage with play or standard veterinary care (i.e., vaccinations). Recheck blood analysis revealed moderate factor X deficiency (37%). The PT and aPTT were prolonged, 37.3 s (RI: 10 to 17 s) and 51.6 s (RI: 11 to 16 s), respectively, compatible with factor X deficiency.

Discussion

This report describes the diagnosis and management of a patient with hemoperitoneum due to factor X deficiency. It notes a breed not previously reported. There are 2 previous reports of factor X deficiency in dogs, 1 in a family of American cocker spaniels, and 1 in a Jack Russell terrier (JRT). The JRT was also evaluated for hemorrhage after routine ovariohysterectomy but had significant hemorrhage with eruption of permanent dentition and required multiple plasma transfusions prior to evaluation. The JRT had significantly lower factor X (3% to 13%) compared to this patient (29% to 45%), likely explaining the more frequent and serious hemorrhagic events (6). The family of American cocker spaniels in which factor X deficiency in the dog was first described had factor X levels (18% to 68%) similar to this patient and displayed mild to moderate hemorrhage with frequent neonatal mortality. Autosomal dominant inheritance was displayed based on test breeding which differs from the autosomal recessive inheritance demonstrated in humans (7). It was also reported that homozygotes were more significantly affected than heterozygotes. This likely leads to underreporting of factor X deficiency due to severity of hemorrhage and death in homozygous puppies.

Factor X is produced in the liver and is dependent on adequate availability of vitamin K. Factor X is the start of the common pathway of the coagulation cascade, bridging the intrinsic and extrinsic pathways. Deficiency leads to prolongation in both PT and aPTT, as the common pathway is evaluated by both tests. These abnormalities were noted in this patient.

The cell-based model of coagulation elucidates the importance of adequate factor X. This model involves 3 phases of coagulation: initiation, amplification, and coagulation. Factor X is involved in producing small amounts of thrombin during the initiation phase during which it is activated by FVIIa/TF complex on a cell surface. Activated factor X (FXa) binds with FVa (prothrombinase complex) on the TF-bearing cells. Prothrombinase cleaves prothrombin (FII) to thrombin (FIIa). Thrombin then diffuses from the TF-bearing cell and activates platelets (amplification). Activated platelets activate FV and FXI on the platelet surface. The FXIa activates FIX allowing FXa to be formed on the activated platelet surface by FIXa/VIIIa complex. The FXa then rapidly binds with FVa on the platelet surface to produce a burst of thrombin generation large enough to convert fibrinogen to fibrin (propagation) (6,9,10). Based on this model of coagulation, it is clear that the remainder of coagulation falters with factor X deficiency as it has a central role in generation of thrombin.

Acquired factor X deficiency must be ruled out before attributing decreased factor activity to an inherited disease. Liver failure, amyloidosis, anticoagulant rodenticide ingestion, and consumptive coagulopathy also must be ruled out. Initial laboratory tests indicated no evidence of hepatopathy with normal liver enzymes and bilirubin, elevated BUN, and low normal albumin. Hepatic failure was thought to be unlikely in this patient. If there had been concern for hepatic dysfunction, bile acids response test or ammonia level may have been considered.

Consumptive coagulopathy was an initial likely differential diagnosis with this patient’s history and recent surgical procedure. Consumptive coagulopathy occurs when clotting factors are consumed trying to control active hemorrhage. Another form of consumptive coagulopathy is disseminated intravascular coagulopathy (DIC), which occurs when clotting factors are consumed due to activation by inflammation without a source of hemorrhage. Hemorrhage is uncommon in DIC with organ dysfunction occurring more commonly. In this patient there was no source of significant inflammation to incite activation of systemic coagulation, aside from recent surgery, as the patient was reportedly healthy prior to ovariohysterectomy (11). This patient was initially suspected to have a consumptive coagulopathy due to hemorrhage into the abdomen from slipped ligature from recent ovariohysterectomy. This seemed logical with the prolongation in coagulation times and presence of intra-abdominal hemorrhage. Due to the extended time from ovariohysterectomy with the sudden clinical decline, slipped ligature alone did not fully explain the hemorrhage that occurred.

The patient displayed severe thrombocytopenia which could have predisposed her to the cavitary hemorrhage and secondary coagulopathy; however, thrombocytopenia is an uncommon source of cavitary hemorrhage, more commonly causing small petechial hemorrhage. Cavity hemorrhage may occur if severely thrombocytopenic patients undergo invasive procedures, such as ovariohysterectomy. Other signs of thrombocytopenia, such as melena, gingival, or petechial hemorrhage would have been suspected if this patient had been profoundly thrombocytopenic prior to surgery. As pre-ovariohysterectomy laboratory testing had not been performed, it is not possible to fully rule out that thrombocytopenia was pre-existing and contributed to cavitary hemorrhage. The patient had no other evidence of severe thrombocytopenia (i.e., petechia, melena, hematemesis); therefore, pre-existing severe thrombocytopenia is considered unlikely. Differentials for this patient’s thrombocytopenia outside of consumption via hemorrhage include immune mediated thrombocytopenia (primary and secondary) and primary bone marrow dysfunction.

The patient presented in hemorrhagic shock. Blood products were elected for stabilization over crystalloid fluids due to diagnosis of hemoperitoneum and severe anemia. In our hospital, universal packed red blood cells are always available for transfusion thereby eliminating the need for initial crystalloid therapy in favor of a product which would not only rectify the patient’s hypovolemia but also help to correct the severe anemia which was the cause of the patient’s clinical status. The patient’s blood pressure normalized after receiving a pRBC bolus and remained normal thereafter, indicating improved intravascular volume. Due to the diagnosis of coagulopathy, after completing the pRBC transfusion, it was elected to immediately begin an FFP transfusion. Crystalloid fluid therapy was not administered during this transfusion, or the pRBC transfusion, to limit the risk of transfusion associated circulatory overload due to the patient’s small size and relatively high fluid rates with both pRBC and FFP transfusions (102 mL/kg BW per day and 82 mL/kg BW per day, respectively).

This patient was pre-medicated for surgery with hydromorphone. Since this patient’s treatment, our hospital has begun to use methadone or fentanyl for premedication of the more critically ill patients due to fewer cardiovascular and respiratory side effects. If this patient presented to our hospital currently, the anesthetic protocol would likely be adjusted to include a fentanyl CRI throughout surgery to diminish inhalant requirement and minimize cardiovascular complications.

Classification of factor X deficiency categories are as follows in humans: severe (FX:C < 10%, spontaneous major hemorrhage), moderate (FX:C 10% to 40%, mild spontaneous or triggered hemorrhage), and mild (FX:C > 40%, mostly asymptomatic) (12). There is no classification scheme for veterinary patients. This patient’s initial factor activity level was higher than that reported in human medicine as a cause of coagulopathy, but residual factor activity from the FFP transfusion may have contributed to this result. All subsequent factor X levels were consistent with moderate factor X (29%, 37%) which correlates with the patient’s clinical status (development of hemorrhage after surgery). The factor X level noted in this study is similar to that of the previously reported cocker spaniels. This is likely due to a heterozygous condition, as heterozygotes are less prone to hemorrhage. Based on human literature, if this patient is heterozygous for factor X deficiency, her risk of clinical hemorrhage should be lower, which is supported by her tolerance of routine veterinary care and rough play. She remains at risk of hemorrhage with trauma or surgery and it is recommended she be treated prophylactically or therapeutically if these events occur.

Due to the rarity of this disease, research into therapy recommendations for factor X deficiency is lacking. For minor bleeds, topical hemostatic agents and antifibrinolytic therapy, have been recommended (1,13). For more serious hemorrhagic events, factor X replacement is required with FFP, cryosupernatant, prothrombin complex concentrate (PCC), or factor X concentrate (2,11,12,14). Prothrombin complex concentrate is a highly purified concentrate of coagulation factors, containing factors II, IX and X or II, VII, IX and X, in concentrations approximately 25 times that of FFP (12). Factor X concentrate and PCC are unavailable in veterinary medicine; therefore, FFP remains the therapy of choice.

Fresh frozen plasma is not recommended for prolonged PT and aPTT alone, as these tests are not predictive of spontaneous hemorrhage, and in patients with inherited coagulopathy PT and aPTT are likely to be prolonged (15). However, in patients with prolonged PT and aPTT undergoing invasive procedures (i.e., aspiration of highly vascular organs or surgery), FFP is recommended to prevent clinically significant hemorrhage and the need for emergency transfusion therapy. As FFP transfusion is not benign it should only be used when clinically significant hemorrhage is on-going or expected (15).

In conclusion, inherited factor X deficiency caused development of hemoperitoneum and hemorrhagic shock following standard ovariohysterectomy in this dog but is rare in veterinary medicine. The patient was successfully treated with transfusion therapy and underwent uneventful laparotomy. Coagulation factor analysis is recommended in cases of unexpected hemorrhage, following treatment, to attempt to prevent future events of hemorrhage. Further study into the incidence of factor X deficiency is required to determine the prevalence and clinical relevance of this condition.