Immune-Mediated Thrombocytopenia-Current Approach
World Small Animal Veterinary Association World Congress Proceedings, 2003
Barbara Kohn, Prof. Dr. med. vet., DECVIM
Clinic for Small Animals, Free University of Berlin
Berlin, Germany

Thrombocytopenia is the most common acquired hemostatic disorder in dogs, and immune mediated thrombocytopenia (ITP) is the most common cause of severe thrombocytopenia. In one study 9% of 268 dogs with decreased platelet counts were diagnosed as having either primary ITP or Evans' syndrome (ITP and immune-mediated hemolytic anemia). ITP is a disease in which antibodies (mainly IgG) bound to the surface of platelets result in their premature destruction by macrophages in the spleen and liver. Target antigens for autoantibodies in human beings are epitopes within the glycoprotein (GP) IIb/IIIa or GP Ib/IX complex. GP IIb/IIIa (fibrinogen receptor) has been identified as a target antigen in the dog. Platelet life span studies in dogs with ITP have not been reported, but studies in humans with ITP showed a reduction of the lifespan from normally 7-10 days to minutes. ITP can be classified as primary or secondary based on underlying etiologies. ITP, in the absence of other identifiable disease, is referred to as primary ITP or idiopathic thrombocytopenic purpura (pITP). Antibodies are thought to be directed against normal host platelet-surface antigens (antiplatelet autoantibodies), and the cause of this antibody production is unknown. This is a diagnosis of exclusion of underlying diseases. In approximately 30% of the cases ITP and immune-mediated hemolytic anemia (IMHA) occur together in one animal (Evans` syndrome). In secondary ITP initiating factors are detected such as: infectious diseases (e.g., ehrlichiosis, babesiosis, leishmaniasis, leptospirosis, dirofilariasis, FeLV, FIV, FIP, and other viral or bacterial infections such as cystitis, prostatitis), neoplasia (e.g., lymphoma, hemangiosarcoma, mammary tumors), drugs (e.g., sulfonamides, vaccines, cephalosporins, phenobarbital), blood transfusions. ITP may be a component of Systemic lupus erythematosus (SLE).

Signalment

ITP is reported in dogs of all ages. In one study 80% of the pITP patients were younger than 6 years. Any breed of dog, including crossbreeds, can be affected. Several breeds, however, are predisposed such as Cocker Spaniels, Poodles, and Old English Sheepdogs and a genetic background is strongly suspected. Familial ITP is reported in humans and in families of Cocker Spaniels, Scottish Terriers, and others. Gender predilection to many autoimmune disease is recognized. ITP occurs in female dogs approximately twice as frequently as in male dogs depending on the study. In the cat only single case reports of feline ITP exists.

Typical clinical findings are surface bleedings (petechiae in skin and mucosa, ecchymosis, gingival bleeding, melena, epistaxis, scleral and retinal bleeding, hematochezia, hematemesis, hemorrhagic vaginal discharge, hyphema, hematuria), lethargy and pale mucous membranes. Spontaneous bleeding occurs with platelet counts < 30,000-40,000/µl. The degree of hemorrhage for any given platelet count is unpredictable, however, and dogs with ITP may have platelet counts < 20,000/µl without evidence of bleeding.

Anemia can be due to blood loss or due to immune-mediated hemolytic anemia (Evans' syndrome). Evans' syndrome accounts for approximately 30% of all cases of ITP, it is very rare in the cat. Other clinical findings are spleno- and/or hepatomegaly and fever. Neurologic deficits due to central nervous system bleeding are rare. A lymphadenopathy points to a secondary cause of ITP such as ehrlichiosis.

For diagnostic confirmation of pITP all secondary causes of ITP have to be excluded by history, hematology and clinical chemistry, urinalysis, different infectious disease titers (e.g., ehrlichiosis, babesiosis, FeLV, FIV), and radiography and sonography of thorax and abdomen. Dogs with ITP usually have marked thrombocytopenia (platelets < 40,000/µl) upon presentation. Examination of a peripheral blood smear is helpful to assess the presence of thrombocytopenia, although a platelet count is necessary to quantify its severity. Megathrombocytes and microthrombocytes may be seen due to active thrombopoiesis or fragmentation of platelets, respectively. Parameters of secondary hemostasis (prothrombin time, partial thromboplastin time) are in the normal range. A variety of assays to detect antiplatelet antibodies in dogs have been developed. However, only the detection of platelet-surface-bound antibodies (direct assays) by flow cytometry (or ELISA) is a useful test with good sensitivity. In dogs pretreated with steroids, the test might show "false negative" results. A positive test result in dogs with thrombocytopenia implicates an immune pathogenesis, but the test cannot differentiate between primary or secondary ITP. Platelet-surface-bound antibodies could be "true" antiplatelet autoantibodies against an antigen of the platelet membrane, immune complexes bound to platelet Fc receptors, antibodies bound to foreign antigens (e.g., tumor antigens, microbial antigens) adsorbed to the platelet surface, or a non-specific binding of IgG to platelets. A direct antiglobulin test (Coombs test) or antinuclear antibody titers are indicated if immunehemolytic anemia or Systemic lupus erythematosus is suspected. Bone marrow evaluation is only indicated in equivocal cases and if there is no response to therapy. Thrombocytopenia is not a contraindication to bone marrow aspiration. In canine ITP megakaryocyte numbers are usually normal to increased, but decreased numbers have been reported and may be associated with a poor prognosis.

Treatment

Cage rest and minimization of trauma are important, and subcutaneous or intramuscular injections or infusions are contraindicated. If severe hemorrhage occurs, platelets--either by fresh whole blood or platelet-rich plasma have to be administered. The effect of blood transfusions on platelet numbers is minimal, since the platelets administered are as rapidly destroyed as those of the patient. Platelet transfusions, however, may stop life-threatening hemorrhage. Especially gastrointestinal bleeding is dangerous since large amounts of blood can be rapidly lost. Therefore, the hematocrit has to be controlled in bleeding patients several times a day. Hypovolemia should be treated by administration of crystalloid or colloidal infusions, and anemia by transfusion of packed red blood cells or preferably fresh whole blood. Because of the potential of underlying occult infection and the predisposition to infection from immunoderegulation associated with ITP and immunosuppressive therapy, antibiotic therapy is generally indicated. If ehrlichiosis is suspected doxycycline is the antibiotic of choice. Removal of the triggering agent or treatment of the underlying condition can bring the ITP under control. Non-essential drugs, particularly those implicated to cause an immune reaction, should immediately be withdrawn. In many cases the platelet counts rise after successful therapy of the underlying diseases. However, in certain cases (e.g., with ehrlichiosis) immunosuppressive therapy is required to increase platelet counts.

Prednisolone (1-1.5 mg/kg BID initially) is the immunosuppressive therapy of choice for ITP. Alternatively, oral or parenteral dexamethasone at an equipotent dose of 0.6 mg/kg daily can be used initially, but is not proven to be more effective. Glucocorticoids interfere with the expression and function of macrophage Fc receptors and thereby immediately impair macrophage destruction of antibody-coated platelets. They also increase capillary resistance to hemorrhage by different mechanisms. Glucocorticoid reduction of antibody production occurs after weeks of treatment by decreasing the rate of lymphocyte division as well as by altering the type distribution of T lymphocytes in circulation. The reduction of T cells leaves fewer available to serve as helper cells to B cells, and by decreasing lymphocyte division, there are fewer B cells to produce antibodies.

A response reflected by an increased platelet count can be expected within 2-11 (mean 4) days. As glucocorticosteroid therapy is associated with well-known side effects, the initial dose will then be tapered by reducing the amount by one-fourth every 2 weeks, finally switching to alternate day therapy. Because of the potential of gastrointestinal ulceration by steroids, gastrointestinal protectants such as sucralfate and/or H2-receptor-antagonists may be considered. Tapering of the immunosuppressive drugs should always occur slowly over months. Platelet counts are initially controlled daily, then every few days and if the platelet counts are stable and in the normal range, every 2-3 weeks.

Other immunosuppressive therapy is warranted when prednisone fails, only controls the disease at persistently high doses, or causes unacceptable side effects. Other agents are generally used together with prednisone. Most of these agents are not effective in the acute management of ITP, but may have a place in the long-term control of refractory and relapsing cases.

There is one controlled study showing the benefit of vincristine in patients with severe ITP. Administration of combined vincristine and prednisone was associated with more rapid increase in platelet numbers (4.9 vs 6.8 days) (dosage: 0.02 mg/kg or 0.5 mg/m2 strictly IV). Several other immunosuppressive or immunomodulating drugs can be used in conjunction with prednisone. Cyclosporine, an expensive but potent immunosuppressive agent, may be tried (2.5 mg/kg BID orally initially). Since different formulations might have different absorptions, blood concentrations should be regularly monitored if possible. The microemulsified formulation has better absorption than other formulations. Other drugs with unproven effects are danazole (5-10 mg/kg 2x/d orally), azathioprine (initially 2 mg/kg SID orally) or intravenous human immunoglobulin (0.5-1g/kg IV, once). Splenectomy may be considered in ITP patients failing prednisone and other immunosuppressive therapy. The response to splenectomy is insufficiently documented in dogs, however.

The prognosis of secondary ITP is good if the underlying disease can be treated. In general, ITP cases, with or without IMHA, have a favourable prognosis with intensive therapy including blood products if needed. Decreased megakaryocyte numbers may be associated with a poorer prognosis. It has been reported in former studies that approximately 30% of dogs with ITP die or are euthanized during the initial episode of thrombocytopenia or due to recurrence of disease. Evans' cases might have an even worse prognosis. In our patients the mortality rate for dogs with pITP and Evans' was below 10%. The risk of recurrence of disease (decreasing platelet counts) is approx. 40% either during treatment or after withdrawal of drugs. Relapses may be controlled by the same treatment as initially used, but a more gradual tapering regime may be necessary, leaving the animal on an alternating daily regimen of prednisone therapy for a period of months or possibly for the rest of its life.

References

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2.  Jackson, M.L. und S.A. Kruth (1985): Immune-mediated hemolytic anemia and thrombocytopenia in the dog: A retrospective study of 55 cases diagnosed from 1969 through 1983 at the Western College of Veterinary Medicine. Can. Vet. J. 26, 245-250

3.  Jans, H.E., J. Armstrong und G.S. Price (1990): Therapy of immune mediated thrombocytopenia. J. Vet. Intern. Med. 4, 4-7

4.  Kohn, B., U. Giger (2001): Anämien, Polyzythämien, Gerinnungsstörungen. In: Suter P.F. und H.G. Niemand (Hrsg.): Praktikum der Hundeklinik, 9. Auflage, Blackwell Wissenschafts-Verlag, Berlin, 623-665

5.  Kohn, B., R. Engelbrecht, U. Giger, W. Leibold (2000): Platelet-bound antibodies in dogs with thrombocytopenia and change with treatment. J. Vet. Intern. Med. 14, 361

6.  Kohn, B., R. Engelbrecht, W. Leibold, U. Giger (2000): Clinical findings, diagnostics and treatment results in primary and secondary immune-mediated thrombocytopenia in the dog. Kleintierpraxis 45 (12), 893-907

7.  Kohn, B., T. Linden, W. Leibold, U. Giger (2001): Platelet-bound antibodies in cats with thrombocytopenia. 11. ESVIM Congress, Dublin

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9.  Ruiz de Gopegui, W.J., B.F. Feldman (2000): Platelets and von Willebrand's Disease. In: Ettinger, S.J., E.C. Feldman (Hrsg.): Textbook of Veterinary Internal Medicine.W.B. Saunders, Philadelphia, 1817-1828

10. Shulman, N.R. und D.M. Reid (1994): Platelet Immunology. In Colman, R.W., J. Hirsh, V.J. Marder und E.W. Salzman (Hrsg.): Hemostasis and Thrombosis, Basic Principles and Clinical Practice. 3. Ausgabe. J. B. Lippincott Company, Philadelphia, 414-468

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Speaker Information
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Barbara Kohn, Prof. Dr. med. vet., DECVIM
Clinic for Small Animals, Free University of Berlin
Berlin, Germany


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