Internal Medicine Case Study – Primary immune mediated haemolytic anaemia and thrombocytopenia in a four months old kitten
Internal Medicine Case Study
Jasmine had become acutely anorexic and lethargic about three days prior to presentation. On the day of presentation, there was further deterioration and haemorrhage was noticed from one of Jasmine’s ears. Veterinary attention was then sought. Her PCV was 9% and she was very weak, she was referred to SCVS for further investigations and management.
At the time of presentation, Jasmine was extremely depressed. There was moderate tachycardia (increased heart rate) and tachypnoea (increased respiratory rate) and a grade 2/6 systolic murmur was detected (suspected to be a haemic murmur). There was marked mucous membrane pallor and widespread petechial haemorrhages were seen affecting the abdominal skin, internal surface of the pinnae and the mucous membranes and there were areas of bruising affecting the neck. Dried blood was present in the right ear canal. Jasmine also had a flea infestation.
A feline profile revealed marked anaemia (suspected to be pre-regenerative at this time) and severe thrombocytopenia. A saline slide agglutination test was positive. There was marginal lymphocytosis. In-house clotting times were normal. Urea was mildly elevated and creatinine was low. Total protein and albumin were marginally low. PCR tests were requested for Mycoplasma haemofelis, Mycoplasma haemominutum and Mycoplasma turicensis. Results were negative but were pending at the time of starting therapy. FIV and FelV tests were negative.
At this stage, we suspected immune mediated haemolytic anaemia (IMHA) and thrombocytopenia (IMTP) were most likely. Thrombocytopenia is always difficult to interpret in cats but given the clear evidence of surface bleeding, it was considered real in this case. The slightly reduced total protein and albumin along with the elevated urea were suspected to be associated with gastric/intestinal haemorrhages. In the absence of haemorrhagic diarrhoea and because of the severity of both the anaemia and the thrombocytopenia, intestinal bleeding was thought to be secondary to thrombocytopenia rather than cause of the anaemia and thrombocytopenia.
Jasmine was initially too sick to undergo any further tests and she was blood typed in view of recruiting a blood donor. She was type A. Pending her blood transfusion, she received IV fluid therapy (to account for her ongoing physiologic losses as she was too weak to eat or drink, and to compensate for the visible surface haemorrhages), she was treated with doxycycline orally as Mycoplasma testing was outstanding, she received an immunosuppressive dose of dexamethasone (0.4 mg/kg q24h). Clopidogrel was not started at this stage given the clear bleeding tendency.
Jasmine was immediately better after the blood transfusion. Further investigations were performed in order to clarify whether this was a case of primary or secondary IMHA and IMTP.
Thoracic radiographs and abdominal ultrasonography failed to reveal any abnormality. It was concluded that Jasmine suffered from primary IMHA and IMTP. Jasmine made a full and rapid recovery. She was discharged from the hospital six days after admission. At the time of discharge Jasmine was receiving prednisolone 2.5 mg/kg q24h PO and doxycycline (10 mg/kg q24h). Doxycycline was stopped after 10 days. Prednisolone dose was slowly reduced over 4 months. Jasmine stopped treatment 6 months ago and is in remission to date.
Total protein * 52 g/L Low (54.0 -80.0 )
Albumin * 24 g/L Low (26.0 -42.0 )
Globulin 28 g/L (15.0 -60.0 )
Sodium 147 mmol/L (125 -160 )
Potassium 4.5 mmol/L (3.6 -6.0 )
Na:K ratio 33 (32 -41 )
Chloride 113 mmol/L (110 -140 )
Total calcium 2.15 mmol/L (2.0 -3.0 )
Phosphate 2.40 mmol/L (1.2 -2.6 )
Urea * 14.9 mmol/L High (4.0 -12.0 )
Creatinine * 75 umol/L Low (80.0 -180.0)
Alk Phos * 57 U/L High (0.0 -50.0 )
ALT 40 U/L (0.0 -40.0)
Gamma GT 0 U/L (0.0 -10.0)
Total bilirubin 3 umol/L (0.0 -10.0)
Bile acids 4 umol/L (0.1 -10.0)
Glucose * 6.9 mmol/L High (3.5 -6.6)
CK * 224 U/L High (0.0 -152.0)
RBC * 1.99 x10^12/L Low (5.5 -10.0)
Hb * 2.8 g/dl Low (9.0 -17.0 )
HCT * 8.1 % Low (27.0 -50.0 )
MCV 40.7 fl (40.0 -55.0 )
MCH 14.1 pg (13.0 -21.0 )
MCHC 34.6 g/dl (28.0 -36.0 )
RDW * 16.9 % Low (18 -23 )
Platelets * 8 x10^9/L Low (170 – 650 )
WBC 14.89 x10^9/L (4.0 -15.0 )
Neutrophils 6.85 x10^9/L (2.5 -12.5 )
Lymphocytes * 7.06 x10^9/L High (1.5 -7.0)
Monocytes 0.77 x10^9/L (0.0 -0.8 )
Eosinophils 0.18 x10^9/L (0.0 -1.5 )
Basophils 0.03 x10^9/L (0.0 -0.2 )
Reticulocyte % 1.9 %
Reticulocyte count 37.81 x10^9/L
Platelet comment Platelet count confirmed in film – no giant platelets or platelet clumps seen in film. No clot found in EDTA tube.
RBC Comment: Polychromasia +/++, Anisocytosis +, Burr cells +, Occasional metarubricytes and rubricytes noted in film. Occasional Howell-Jolly body, Occasional keratocytes, No mycoplasma structures seen in film. Occasional Heinz bodies.
Leukocyte Comment Occasional reactive lymphocytes.
What were our differentials for Jasmine?
Jasmine presented with very severe anaemia and thrombocytopenia. The anaemia was non regenerative at the time of presentation.
A non regenerative anaemia can be seen in acute cases prior to the regenerative response being visible in the peripheral blood, as this process takes about 5 days. It can be due to immune mediated destruction of precursors. Other causes include bone marrow failure (neoplasia, drug reaction, fibrosis) which is typically manifested by pancytopenia or sometimes isolated neutropenia in early cases as white blood cells have the shortest half life. Bone marrow failure was felt to be very unlikely in this case in the absence of neutropenia and the two former differentials were most likely.
Anaemia and thrombocytopenia could have been either from blood loss or destruction. Blood loss rarely causes significant thrombocytopenia but severe thrombocytopenia can lead to severe anaemia. However acute haemorrhage leading to a PCV of 8% would probably not be compatible with life. A positive saline agglutination test and the severity of both the anaemia and the thrombocytopenia made IMHA and IMTP most likely. However one has to be cautious in cats as both positive saline agglutination test and direct antiglobulin test (DAT or Coomb’s test) have been positive in a number of secondary IMHA cases (FelV, Mycoplasma spp.) and a number of inflammatory diseases (pyothorax, cholangitis, pancreatitis…).
While primary IMHA is very rare in cats, secondary IMHA is a little more common. Secondary immune-mediated haemolytic anaemia (sIMHA) can be seen secondary to other diseases such as feline leukaemia virus infection, lymphoproliferative disease (e.g. lymphoma), haemoplasma infections (e.g. Cytauxzoon felis, Babesia spp, Mycoplasma spp, Hepatozoon spp, Rickettsia spp, Bartonella spp, Ehrlichia spp) or drug reactions. However most of these haemoplasmas are not endemic in the UK and the only cases we encounter are cases secondary to Mycoplasma spp. Primary IMHA in cats can be regenerative or non-regenerative.
Primary IMTP is even rarer than primary IMHA in cats, there are only few isolated case reports or small case series published. Causes of secondary IMTP as for IMHA include inflammatory, infectious, neoplastic and toxic causes.
In the absence of concurrent diseases found in this case, we concluded that she suffered from primary IMHA and IMTP, also known as Evan’s syndrome, a very rare syndrome in cats. A recent retrospective study showed that higher lymphocytes and globulins are positive prognostic factors, while old age and high bilirubin are negative prognostic indicators. So Jasmine did have all positive prognostic indicators!
What was the treatment given and what alternatives did we have?
Treatment consisted in a blood transfusion, immuno-suppressive doses of steroids and doxycycline.
Blood transfusion is never treated lightly, especially in cats.
The first consideration is risk associated with the transfusion. Cats have naturally occurring allo-antibodies and can have life-threatening reactions when transfused un-matched blood. Transfusion reactions can also occur in match-transfusions. The second potential complication of a blood transfusion is volume overloading. A condition to which cats are particularly prone especially when anaemia is due to hemolysis as these animals are often already volume over-loaded due to compensatory mechanisms. Packed red blood cells are not available for cats and we use whole blood.
The second consideration is availability of blood products for cats. We do not have access to a cat blood bank and do not store blood for cats, we rely on a list of blood donors.
The decision to transfuse a cat or not is always based on a risk-benefit assessment and on clinical presentation and appreciation of whether the patient can cope with his anaemia or not rather than on numbers.
Unless contra-indicated, steroids are the first line of treatment for immune mediated diseases, due to their rapidity of action, good efficacy, availability and low cost. In cases where we want a steroid sparing drug or when no response is observed to the steroids, we would add-in another drug. Cats can not receive azathioprine, due to its potential myelotoxicity. In cats, we typically use cyclosporine due to the user friendly liquid formulation. Mycophenolic acid can also be used but we have no experience in cats and it has to be re-compounded. Chlorambucil has also been described for the management of IMHA in cats.
We used doxycycline in this case as PCRs for Mycoplasma spp. were not available when treatment was started. Given the non-regenerative nature of the anaemia, infectious anaemia was anyway unlikely and in retrospect we do think that antibiotics were not needed in this case.
We did not use platelet anti-aggregants in this case given the bleeding tendency observed. Later in the course of treatment, these were not added because, once past the acute disease phase, the risk of thrombosis is reduced and owner compliance can be affected when two many drugs are prescribed. Thrombosis is the main complication of IMHA and IMTP and risk is even higher when both diseases are present. Clopidogrel and aspirin are the most commonly used drugs. Clopidogrel is thought to be more effective.
Acknowledgement: We would like to thank the Priory Veterinary Group practice for referring this very interesting case.