Abstract
An adult domestic short hair cat was presented in a critical condition with icterus. Various investigations demonstrated the presence of haemolytic anaemia and hepatic abnormalities, as well as significant coagulation defects. Systemic lupus erythematosus (SLE) was suggested as a possible cause.
Few reports of feline systemic lupus erythematosus (SLE) exist in the veterinary literature. Each emphasises the difficulty of diagnosing SLE based on the protean nature of the disease. Various organ involvement has been reported with cutaneous, neurological, articular, ocular, renal, vascular and haematological abnormalities (Heise et al 1973, Faircloth & Montgomery 1981, Gabbert 1983, Scott et al 1979, Prelaud 1992, Alexander et al 1996, Vitale & Irkhe 1997). This report describes coagulation defects as a probable sequel of SLE in a cat, which has not previously been documented in this species.
Case report
A 4-year-old female domestic shorthair cat was presented in an extremely debilitated state. The owners reported a 3-month history of ‘waxing and waning’ disease with inappetence, periods of vomiting and reluctance to move, and anorexia for the 10 days prior to presentation. The cat had received no veterinary treatment during the previous 2 years.
The cat was thin (1.9 kg) and was estimated to be 5% dehydrated. The rectal temperature was 37.8°C, and the cat remained unusually quiet on the examination table (the cat was known to be nervous and aggressive). There was both tachycardia and tachypnoea, and mucous membranes were pale and icteric. Manipulation of the hindlimbs and palpation of the spine elicited a clear pain response. Bilateral miosis was also present.
Blood samples were submitted for routine analysis. The cat was placed on intravenous fluids (lactated Ringers solution) and a nasooesophageal tube was placed to facilitate feeding (with Hills a/d diet).
A complete blood count (Table 1) revealed a regenerative anaemia, with marked reticulocytosis. The leucocyte count was normal, but there were nucleated erythrocytes, a thrombocytopenia, and numerous spherocytes seen on examination of the blood film. Serum biochemistry (Table 1) revealed an elevated ALT and total bilirubin, with a predominance of unconjugated bilirubin. The total proteins were also elevated with a polyclonal elevation of gamma globulins and normal albumin (Fig 1). Radiographs of the spine and pelvis were unremarkable.
Based on the haematological findings, a haemolytic anaemia was suspected. Screening serological tests for feline leukaemia virus (FeLV), feline immunodeficiency virus (FIV) and feline coronavirus infection (FCoV) were negative. A direct Coombs' test was also negative. An anti-nuclear antibody (ANA) test was strongly positive with a titre of 1/4096. The fluorescence was homogeneous and reticulated.
Haematology and plasma biochemistry results
Total proteins electrophoresis.
Hepatic ultrasonography revealed a diffuse increase in echogenicity with no portal lymphadenopathy or obvious neoplastic infiltrate and no abdominal effusion. With these findings, a liver biopsy was scheduled. Prior to this a coagulation profile was performed (Table 2), which revealed a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT). Fibrinogen concentration was normal, and fibrin degradation products (FDP) were absent. Due to the risks of haemorrhage, the owners declined to pursue the liver biopsy.
Coagulation profile results
Control plasma is a mixed plasma pool from 10 healthy cats; nd=not done; s=seconds.
The coagulopathy was investigated further, and a search was undertaken for a circulating anticoagulant (CA). The ‘aPTT prolongation’ method was used (Table 2), employing a kit (PTTA, with cephaline and kaolin, Stago). Using this, the aPTT measured 46 s (patient) against a control of 24 s. A mixed sample was then constituted comprising equal volumes of patient and control plasma. The aPTT should be close to the reference value if a quantitative defect (one or more factors) exists. The aPTT was 32 s in this case, but remained appreciably (33%) above the reference (control) value of 24 s (the aPTT is considered significantly elevated if it is more than 20% above the control value). Following this aPTT was measured using a kit less sensitive to CA (CK Prest, with cephaline and silica, Stago). Using this kit, there was no appreciable difference between the patient (17 s) and control (16.5 s) plasma samples. These results suggested the presence of a CA. Based on the presence of neuropathy or arthropathy (stiff gait, painful hindlimbs), haemolytic anaemia (regenerative anaemia with spherocytes and high indirect bilirubin), high ANA titre and the presence of CA, a tentative diagnosis of SLE was made.
We instituted treatment with ampicillin (Ampicat, Virbac) at 25 mg/kg tid, prednisolone (Hydrocortancyl, Roussel) 1 mg/kg bid, arginine (120 mg/day) and carnitine (40 mg/day) with continued feeding of Hills a/d diet. This treatment regime was continued for the first 20 days.
After 3 weeks, the cat's clinical condition had improved considerably. She was moving more easily, and was eating voluntarily with a gain in weight (2.4 kg). The mucous membranes were less icteric and less pale and the miosis had resolved. Repeat blood tests revealed that the anaemia had resolved (Hb: 6 g/dl), and the bilirubin had dropped to 5 mg/l and was composed of 100% unconjugated bilirubin. Re-examination 2 months later showed that the cat continued to do well. The prednisolone dose was then tapered to 1 mg/kg once every second day, and stopped in the third month. Three months after ceasing therapy, the cat was in good health and a repeat coagulation profile was normal.
Discussion
Systematic lupus erythematosus is a rare immune-mediated disorder of unknown origin. It has been described in humans, dogs, cats, rats and mice (Scott et al 1983, Faircloth & Montgomery 1981, Gorman & Werner 1986, Pedersen & Barlough 1991). It is characterised by a pattern of multi-organ involvement and an increased activity of humoral-mediated immunity leading to the presence of a great variety of antibodies directed against ‘self’ and ‘non-self’ antigens (Scott et al 1983, Gorman & Werner 1986). This results in the deposition of immune complexes on the basement membrane of vessels (Scott et al 1983, Pedersen & Barlough) leading to inflammation. Type III hypersensitivity is the main form of inflammation seen. The presence of ANA directed against nuclear material (DNA, RNA, nucleoproteins and histone proteins) is the most common feature of the disease (Scott et al 1983, Pedersen & Barlough 1991, Aucoin et al 1988) despite the occasional presence of antibodies directed against cytoplasmic components (e.g. mitochondria, reticulum and ribosomes) which has been demonstrated in humans and dogs (Alexander et al 1996). The aetiology of SLE remains unknown but appears to be multifactorial. Genetic and viral (retroviral) factors are suspected as well as T-suppressor lymphocyte hyporeactivity (Scott et al 1983, Pedersen & Barlough 1991). Ultraviolet light and some medicines can promote SLE or modulate the occurrence of disease (Scott et al 1983, Faircloth & Montgomery 1981, Alexander et al 1996, Monestier et al 1995). Systematic lupus erthematosus can be fulminant or exhibit a chronic pattern in which acute phases and remissions alternate. Feline SLE is rare (Scott et al 1983, Heise et al 1973, Faircloth & Montgomery 1981, Gabbert 1983, Scott et al 1979, Pedersen & Barlough 1991, Kalaher & Scott 1991, Prelaud 1992, Alexander et al 1996, Vitale & Irkhe 1997). Numerous signs have been reported including synovitis, dermatitis, glomerulonephritis, neuropathia, serositis, anaemia thrombocytopenia and leucopenia. Diagnosis is difficult due to the protean nature of the disease and the fact that a positive ANA tire is not pathognomonic of the disease—some healthy cats have naturally-occurring low titres of ANA. A positive ANA test may also be present at the beginning of diseases such as FeLV, FIV, feline infectious peritonitis, cholangiohepatitis and following drug administration (Pedersen & Scott 1991, Kalaher & Scott 1991, Prelaud 1992). Heise et al described the first case of feline SLE in 1973. Since then anecdotal cases have been reported. Pedersen & Barlough (1991) reported a series of 11 cases of feline SLE seen between 1979 and 1990. These cats showed fever (2/11), neurological or behavioural signs (6/11), hyperaesthesia (2/11), adenitis (3/11), erosive or exudative polyarthritis (6/11), conjunctivitis (2/11), dermatitis (4/11), lingual or palatine ulceration (2/11), renal damage (8/11), regenerative anaemia with a positive or negative Coomb's test (2/11), neutropenia (4/11), lymphopenia (4/11) and leucopenia (5/11). There was no sex or breed predisposition and the cats were between 2 and 11 years of age. None of the cats tested positive for FeLV or FIV, whereas two tested positive for feline syncitium-forming virus.
In this case we demonstrated coagulation abnormalities and the presence of circulating anticoagulant in a cat with probable SLE. These features have not previously been reported in feline SLE (Stone et al 1994). Circulating anticoagulants are antibodies directed against the phospholipid exposed sites involved in the formation of the prothrombin activation complex. This complex is composed of calcium ion, factor Xa, factor V, and phospholipids. Alteration of the complex induces a qualitative disorder of the common pathway leading to prolongation of both PT and aPTT (O'Keefe & Couto 1988, Triplett 1996, Scotto et al 1995). The presence of CA sometimes results in thrombocytopenia. Suggested mechanisms include alteration of the platelet membrane by the CA fixed on the surface, or autoaggregation (Triplett 1995, 1996). In humans, 21–65% of SLE patients have CA (Scotto et al 1995). Despite its name indicating anticoagulant properties (CA was first discovered in patients with bleeding tendencies), most patients are presented with limb or pulmonary arterial or venous thrombosis. In humans, the presence of CA is not persistent, and is usually only present for a few months. In our case, no clinical signs could be definitively related to the presence of CA, although neurological/behavioural signs could potentially have been caused by cerebral microthrombosis (presence of CA and possibly platelet aggregates). In contrast, CA is the best explanation for the prolonged PT and aPTT. Severe hepatopathy with extensive parenchymal damage may impair the synthesis of proteins, including coagulation factors, leading to a prolongation of coagulation times. However, although the disease had been present for in excess of 3 weeks (longer than the half-life of albumin), serum albumin levels were normal suggesting end-stage liver disease was probably not the cause of the coagulopathy. We therefore sought another explanation for this finding, and discovered the existence of an apparent CA. Searching for a CA appears to be a rational approach when confronted with unexplained alterations in coagulation profiles in cats suspected of having SLE.