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Evidence-based management of ITP (Proceedings)

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Nov 01, 2010

Dogs with immune-mediated thrombocytopenia (ITP) usually present with platelet counts low enough to be considered life-threatening, although overt signs of bleeding are uncommon. Owners usually only note anorexia or lethargy, although in some cases epistaxis, cutaneous bruising/petecchiae/echymoses, or oral bleeding may be noted. Very rarely patients will present with complications that require immediate intervention such as pleural effusion. As a specialist, the most common reason for referral to me of ITP patients is inadequate or no response to appropriate immunosuppression. As with IMHA, this often is due to unfamiliarity with some of the treatment options beyond glucocorticoids, or a difficult-to-diagnose underlying disease. This presentation will briefly review the more common causes of secondary ITP and the diagnostic tests which I routinely consider prior to instituting therapy, and then discuss in-depth treatment options for dogs with this disease.

ITP: DIAGNOSTIC WORK-UP

Primary versus Secondary causes of ITP

Development of anti-platelet antibodies may be idiopathic (primary ITP), or may occur secondary to a number of infectious or neoplastic diseases, or certain drugs. The diseases listed below can cause thrombocytopenia through other mechanisms, without the presence of anti-platelet antibodies. Differentiation can be difficult, as there are no widely available tests which allow detection of anti-platelet antibodies. An anti-megakaryocyte antibody test is available through some specialty laboratories, but this must be performed on bone marrow aspirate samples. As a very general rule primary ITP results in much lower peripheral platelet counts than ITP secondary to concurrent diseases. Primary ITP dogs usually present with platelet counts less than 20,000; dogs with secondary ITP often have platelet counts higher than this. However clinicians should remember that these are general rules only—I have seen many cases of secondary ITP (particularly with RMSF or neoplastic diseases) where the peripheral platelet count is very low, in the 'primary ITP' range. Intense history-taking and physical examination are required in every case, as well as screening tests to ensure that there are no concurrent diseases. Diseases which are definitely associated with thrombocytopenia include:

Increased consumption:

     • Acute severe hemorrhage (e.g. gastrointestinal bleeding, rodenticide toxicity)

     • DIC

     • Vasculitis (e.g. sepsis/endotoxemia; tick-borne diseases)

Sequestration

     • Portal hypertension

     • Splenomegaly (barbiturate or acepromazine overdose; hypersplenism, splenic infarction)

     • Splenic torsion

Decreased production

     • Myelophthisis (bone marrow infiltration by tumors)

     • Estrogen excess (Sertoli cell tumor; iatrogenic)

     • Myelofibrosis

     • Infections: Ehrlichia sp., Leishmania infantum; Histoplasma capsulatum; FeLV

Increased destruction (Immune-mediated thrombocytopenia)

     • Drugs: sulfonamides, other antibiotics, anti-thyroidal drugs

     • Recent vaccination?

     • Neoplasia: lymphoma, malignant histiocytosis

     • Infectious diseases: Ehrlichia sp., Babesia sp.; RMSF; Bartonella sp.?,

     • Other autoimmune diseases: SLE

Diagnostic testing

Most patients with ITP that present to first-line practitioners are relatively stable. Although immunosuppression in most cases is appropriate and often rapidly leads to normalization of platelet count, diagnostic testing to determine if there are concurrent diseases causing secondary ITP or thrombocytopenia by non-immune-mediated mechanisms is always recommended first. If the history or physical examination reveal any clinical signs or findings that do not fit with a 'classic' case of ITP then these should be pursued as appropriate. Unlike dogs with hemolytic anemia, I am less willing to institute immunosuppressive therapy without thorough diagnostic testing, because it is much more common for me to find secondary causes of thrombocytopenia than anemia. Additionally, primary ITP is often much more difficult to treat than IMHA, and thus finding any cause of secondary disease is very much to the patient's advantage.

I always perform a full minimum database—complete blood count, full serum chemistry panel, and urinalysis. I only recommend a urine culture if the urinalysis suggests an infection may be present. Thoracic and abdominal radiographs and abdominal ultrasound are ideal. I consider a fundic examination to be part of a normal physical examination; evidence of vasculitis (suggesting rickettsial disease or hematologic malignancies), granulomas (fungal lesions), or neoplastic cells (particularly lymphoma) may be detected. Careful palpation of lymph nodes is done multiple times, and if there is any hint of lymphadenopathy, I aspirate and at a minimum look at the slide myself. If in the appropriate geographic region, I submit serum for tick-borne disease titers, and start doxycycline therapy while waiting for results.

The final diagnostic test I perform in every case of ITP is a bone marrow aspirate. Severe thrombocytopenia is not considered a contraindication for bone marrow aspiration, as bleeding is limited by the bone itself, and severe bleeding from this site does not endanger the patient's life. As with IMHA, lymphoma is a common cause of secondary ITP, and this disease must be diagnosed prior to instituting immunosuppression. All the drugs used to treat ITP, particularly glucocorticoids, result in lysis of lymphocytes; therefore treatment may put these dogs into remission. Although this may be an apparent advantage, prednisone alone is not the optimal therapy for lymphoma—dogs with lymphoma treated with prednisone alone have a median survival of only 3 months, as opposed to longer survival rates with combination chemotherapy. Additionally administration of prednisone prior to the diagnosis of lymphoma worsens long-term prognosis, as glucocorticoids induce multi-drug resistance against many chemotherapeutics. That being said, the bone marrow aspiration does not provide information which influences diagnosis or case outcome in the vast majority of dogs with thrombocytopenia.