Immune Mediated Thrombocytopaenia

Also known as: ITP — Idiopathic Thrombocytopaenic Purpura — Evan’s Syndrome

Introduction

Immune-mediated thrombocytopaenia (ITP) occurs due to an autoimmune response directed against circulating platelets or megakaryocytes in the bone marrow. The destruction of cells is mediated by antibodies, making ITP a form of type II hypersensitivity. The antibodies bind to surface recptors on the platelets and act as a foundation for the assembly of serum complement components or as opsonins, promoting the uptake and destruction of platelets by cells of the monocyte-phagocyte system (MPS). The destruction of platelets usually results in severe thrombocytopaenia and, if the blood level of platelets fall below approximately 50x10^9/l, the affected animal is at risk of mucosal haemorrhages.

ITP may be primary (with no apparent underlying cause) or secondary to another disease process; infections, neoplasia, other automimmune diseases, transfusion reactions and drug reactions (particularly antibiotics) are underlying conditions that can cause a secondary ITP . ITP that occurs concurrently with immune-mediated haemolytic anaemia (IMHA) is known as Evan’s syndrome.

Signalment

Primary ITP has been reported in cats but it is much more common in dogs. Breeds of dog at particular risk of ITP are similar to those that also suffer from IMHA, namely Old English Sheepdogs, Cocker Spaniels and Poodles.

Diagnosis

Clinical Signs

Most affected animals will present with some form of bleeding disorder and it is important to differentiate disorders of primary haemostasis (such as ITP and thrombocytopathia) from those of secondary haemostasis (such as Haemophilia A and B). Disorders of primary haemostasis are usually less severe than those of secondary haemostasis as, if the platelets are absent or non-functional, bleeding is often still prevented by the formation of a stable fibrin clot. Common features of a disease of primary haemostasis include:

• Petechial haemorrhages of the mucous membranes and skin
• Bleeding from mucous membranes, producing melaena, haematochezia, haematuria, haemoptysis and haematemesis.
• Haemorrhage into the retina or brain may produce blindness or neurological signs, respectively.

Affected animals may also show other, less specific signs:

• Lethargy, anorexia and weakness.
• Pyrexia
• Lymphadenopathy
• Hepatosplenomegaly due to the fact that most destruction of platelets occurs in the MPS of the liver and spleen.

Laboratory Tests

Haematological analysis of a blood sample will show thrombocytopaenia, often with extremely low platelet counts (e.g. 1-5x10^9/l). There may be a reactive neutrophilia and other features of a stress leucogram. Examination of a blood smear may show evidence of microthrombocytes (small platelets that have been partially phagocytosed by cells of the MPS, similar to spherocytes in IMHA) or immature macrothrombocytes (a sign of bone marrow platelet regeneration). The patient may be anaemic in cases of Evan’s syndrome or if significant haemorrhage has occurred.

Other Tests

Definitive diagnosis relies on the detection of serum anti-platelet antibodies but this test is not widely available.

Other tests may also be used to exclude potential infectious causes of thrombocytopaenia such as Ehrlichia platys and Anaplasma phagocytophilum.

Faecal occult blood tests represent an unreliable way of detecting gastro-intestinal haemorrhage in cases of mild melaena. The animal must be deprived of meat, bismuth subsalicylate and ferrous sulphate for 3 days before the faecal samples are taken for analysis.

Bone Marrow aspirates are not diagnostic for this condition.

Diagnostic Imaging

Imaging is not required to make a diagnosis of ITP but it may be used to rule out underlying causes of the disease. The major features of abdominal ultrasonography and radiography in affected animals will be hepatosplenomegaly.

Treatment

Stabilisation

Severely thrombocytopaenic animals or those suffering from neurological signs may require transfusions with whole blood. The platelets transferred in this process have only a very short half-life in the recipient and this technique is therefore of little use in the majority of patients where the immune response is not controlled.

Immunosuppressive Therapy

The ultimate goal of the therapeutic regime is to control the autoimmune response to prevent further destruction of platelets. The bone marrow stem cells will then be able to replace the platelets that have been lost in the disease. A variety of drugs have been used in the treatment of ITP but those in widespread use include:

• Corticosteroids including prednisolone and dexamethasone act to suppress cell- and antibody-mediated responses. These drugs act quickly, are frequently effective and are widely available, making them the most commonly used drugs in the management of ITP.
• Adjunctive immunosuppressive therapy may be provided with ciclosporin, azathioprine or cyclophosphamide. Ketaconazole and Cyclosporin can be used synergistically to reduce the dose of Cyclosporin/Ciclosporin used because of Ketaconazole's ability to inhibit the enzyme cytochrome P450.
• A recent prospective study indicated that human immunoglobulin may produce a significantly better outcome in cases of ITP. This product is thought to act by occupying sites (Fc receptors) on cells of the MPS that are usually used to recognise opsonised platelets and mediate phagocytosis. Although it seems to be highly effective, this product is extremely expensive and is perhaps best indicated in actively bleeding or refractory cases.
• Vincristine is occasionally used in cases of severe thrombocytopaenia as it is thought to cause the release of platelets from the bone marrow. The immature platelets released however are not completely functional. It also reduces macrophage function by inhibiting the assembly of microtubules necessary for phagocytosis.
• Splenectomy may be performed in cases refractory to medical management to remove the cells responsible for the phagocytosis of platelets. Whilst this can be considered in cases that have frequent relapses, the hepatic mononuclear phagocytic system can also destroy platelets so splenectomy does not always ameliorate symptoms.

Prognosis

Similarly to IMHA, mortality is most likely in the initial stages of the disease and the mortality rate is approximately 30% in this period. Beyond this, the majority of animals recover well although they usually require tapered immunosuppressive treatment for roughly six months to completely control the disease. Initial responses to treatment are relatively quick, so if no increase in platelet number is seen within 1 week of initiating treatment, investigate further for an underlying cause which requires treatment.

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References

Ettinger, S.J, Feldman, E.C. (2005) Textbook of Veterinary Internal Medicine (6th edition, volume 2) Elsevier Saunders Company

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