Haemophilia A in a Dog

WHAT IS YOUR DIAGNOSIS? A 6 month old female neutered Pembrokeshire Corgi presented to the R(D)SVS Emergency and Critical Care Service for investigation and treatment of sudden onset haemothorax, collapse and anaemia. She was neutered nine days previously and had been progressively lethargic since that date, with periods of exercise intolerance. No haemorrhage was seen by the owners and there was no report of toxin exposure. She had been receiving penicillin and a non-steroidal for suspected cystitis. She had received crystalloids and oxyglobin to stabilise her before travelling to the R(D)SVS. Physical examination revealed the patient was alert and anxious with increased respiratory rate (60rpm) and effort. Breaths were shallow and SpO2 was reduced at 89% on room air. Percussion of the ventral thorax was dull bilaterally. There was bruising around a previous jugular venepuncture site and bilateral bruises on her thorax consistent with previous positions of thoracocentesis. There was tachycardia, with a heart rate of 140bpm, with no pulse deficits or murmurs detected. Mucous membranes were pale with a brisk capillary refill time of 1 second. page 1 of 6 1) What was her problem list at presentation requiring investigation but also emergency support? Her problem list included: a) b) c) d) Hypovolaemia Anaemia Dyspnoea Reduced oxygenation All could be caused by a significant haemothorax, but should be considered individually both for treatment and for continued investigation. 2) What are the main differential diagnoses for the bleeding patient? a. Primary haemostasis disorder (thromobocytopenia, platelet dysfunction) b. Secondary haemostasis disorder (liver disease, rodenticide toxicity, inherited e.g. haemophiliia) c. Vasculitis d. Disseminated intravascular coagulation e. Infectious: Parasitic; Angiostrongylus vasorum f. Trauma g. Anomalous vessel h. Neoplasia- bleeding lesion or paraneoplastic coagulation abnormality 3) What part of the coagulation pathway is likely to be affected in this patient and how would we investigate this? Defects in primary haemostasis typically present as capillary bleeding. Classically, we see petechiation of mucosal surfaces and ecchymosis of skin, particularly high friction sites. There can be bruising of venepuncture sites and less commonly patients can present with epistaxis, pulmonary or gastrointestinal haemorrhage. (Platelet function and endothelium) Defects of secondary haemostasis usually result in larger bleeds such as those into cavities, e.g. haemothorax, haemoabdomen. Haematomas are also seen and excessive bleeding after surgery or trauma. They can also cause epistaxis, melaena and bleeding at needle sites in some cases. (Intrinsic and extrinsic coagulation pathways). The presence of haemothorax and the absence of petechiation suggest that a secondary haemostatic disorder may be present. TESTS PERFORMED  Routine haematology revealed increased MCHC at 63% (ref 32 – 36%), due to the previous oxyglobin administration.  Platelets were mildly decreased at 101x109/l (ref 200 – 500 x109/l) confirmed with a manual platelet count, likely due to consumption. Although reduced, this value would be sufficient for haemostasis (a result lower than 50 x109/l could be the cause of haemorrhage). page 2 of 6  There was a neutrophilia of 19.23 x109/l (ref 3.6 – 12), and increased monocytes which is consistent with a stress leukogram or inflammatory process.  Haemoglobin (Hb) concentration at admission was 4.4 g/dL with a calculated haematocrit (HCT) of 13% (actual Packed Cell Volume = 9%).  Slide saline agglutination test was negative and had a non-regenerative anaemia on blood smear analysis with no spherocytes. Serum colour was also clear, showing no signs of intravascular haemolysis.  An Angiostrongylus Snap test (Idexx) was negative A PCV, blood smear analysis and saline slide agglutination are simple in house tests and the results of these tests made haemolysis an unlikely diagnosis. The patient was more likely to have an abnormality of secondary haemostasis given the presentation so clotting tests were performed:  A coagulation profile revealed a normal PT excluding traditional rodenticide toxicities. The APTT was prolonged at 173secs and 146secs (repeated) (Ref 72- 102 secs). This increase could be secondary to consumption or a congenital deficiency in the intrinsic pathway. 4) Which clotting factors should be tested if the APTT is prolonged but the PT is normal? PT tests the extrinsic and common pathways of secondary haemostasis. APTT tests the intrinsic and common pathways. Therefore, the defect has to be in the Intrinsic Pathway. Clotting factors in the intrinsic pathway are XII, XI, IX and VIII. Factor XII deficiency is not thought to be clinically significant (dolphins don’t even have factor XII and can still clot!). Blood was taken for clotting factor analysis- this needs to be done before providing a source of clotting factors if possible. PATIENT STABILISATION and FURTHER DIAGNOSTIC TESTS  A quick ultrasound scan of the thorax and abdomen showed a large volume of pleural fluid, no pericardial fluid and no abdominal fluid. The pleural fluid was not resampled due to risk of further bleeding.  Oxygen therapy at admission with flow by oxygen and continued with oxygen cage (starting at 40% and reducing over the following 48 hours).  15ml/kg fresh frozen plasma and 90ml packed red blood cells were provided.  The APTT had normalised after the fresh frozen plasma and Hb had increased to 7.7, with a calculated HCT of 21%. page 3 of 6  Drainage of the haemothorax was considered to treat the dyspnoea, but the dog was no longer dyspnoeic with oxygen supplementation and there were several disadvantages: Disruption of a forming clot, further bleeding, loss of iron for new red blood cell formation, and (less likely) the risk of pneumothorax and infection. Thoracic radiography the following day, revealed a mild volume of pleural fluid. There was no evidence for the causative factor, though the cranial mediastinum was obscured by fluid. Ultrasound of this area was unremarkable. The cervical stump was also scanned and appeared normal. page 4 of 6 Right lateral and dorsoventral radiograph of the thorax demonstrating presence of fluid in the pleural space (albeit reduced from previously). 5) What are the coagulation conditions that could be implicated? a) Haemophilia A (Factor VIII) b) Haemophilia B (Factor IX) c) Factor XI deficiency DIAGNOSIS Factor VIII 6 % of normal (50 - 200 % of normal) Compatible with a diagnosis of Haemophilia A (Factor VIII deficiency). However, the gene for Factor VIII is on the X chromosome, and haemophilia A is a recessive trait. Therefore, this is an unexpected finding in a female; most clinically affected dogs are male. The differentials for congenital FVIII deficiency in a female include homozygosity for haemophilia A mutations on the X chromosome. This results from mating a haemophilic male to carrier female. Alternatively, FVIII deficient females can result from non-random inactivation of X chromosome (in a heterozygous carrier female), or from gross chromosomal abnormalities (X0or X0/XX mosaic karyotype). Acquired Factor VIII deficiency may occur as an autoimmune process. The dog showed a steady gradual improvement in PCV, the haemothorax resolved and oxygen therapy was discontinued and the patient was discharged. Repeat measurement of page 5 of 6 factor VIII is advisable when the patient becomes clinically normal to definitively confirm diagnosis. This was discussed, but was declined along with genetic testing as the dog is doing extremely well and back to her normal playful self. The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. www.ed.ac.uk/vet/hfsa-int-med page 6 of 6