Immune-mediated thrombocytopenia and immune-mediated arthritis (Proceedings)

There are a number of causes of decreased platelets in dogs and cats, but whenever platelet counts fall acutely an immune-mediated disorder should be suspected. Bleeding disorders that occur as platelets drop can cause rapid deterioration and death. Early recognition and aggressive management is important with immune-mediated thrombocytopenia (IMT). Immune-mediated arthritis also has various underlying causes, but usually has a slower onset and is less likely to be severe or fatal. The following discussion briefly reviews etiology, clinical signs, diagnosis, and management of IMT and arthritis associated with immune system disorders. During the presentation, cases will be presented as time permits.

Immune-mediated thrombocytopenia

Pathophysiology

A similar mechanism to IMHA occurs in IMT, as IgG antibodies are directed against platelet membranes resulting in destruction (see previous Proceedings article on IMHA). Primary (idiopathic) disease is more common in dogs than secondary IMT. There is likely to be a genetic predisposition, as certain breeds are over-represented in studies including Cocker Spaniels, Old English Sheepdogs, Poodles, and Cavalier King Charles Spaniels. Young to middle age adults are most often affected, and females are slightly more likely than males to be diagnosed with primary IMT.

Thrombocytopenia and thrombocytopathia (abnormal platelet function) with an immune-mediated component also occurs secondary to other diseases. Among the reported causes are:

• Infections

     o Ehrlichiosis

     o Anaplasmosis

     o Rocky Mountain Spotted Fever

     o Hemobartonellosis

     o Babesiosis

     o Leptospirosis

     o Leishmaniasis

     o Heartworm disease

     o Histoplasmosis

     o Feline leukemia virus

     o Feline immunodeficiency virus

     o Feline infectious peritonitis

     o Toxoplasmosis

     o Cytauxzoonosis

• Drugs (hundreds of examples in human medicine)

     o Vaccines

     o Antibiotics

     o NSAIDs

     o Anticonvulsants

     o Chemotherapeutics

     o Heparin

     o Sedatives

     o Hormones

     o Diuretics

     o Cardiovascular drugs

     o Oral hypoglycemics

     o Methimazole, propylthiouracil

• Endocrinopathies

     o Diabetes mellitus

     o Hyperadrenocorticism

• Vasculitis, DIC

• Neoplasia (e.g. lymphoma)

• Chronic infectious or inflammatory disease (e.g. IBD)

• Myelophthisis

• Other immune-mediated disorders (e.g. IMHA, SLE)

Clinical signs

As with IMHA, the owner may only notice lethargy, weakness, and anorexia. On physical exam, pale mucous membranes and petechiae or ecchymoses are common. A careful inspection of the mucous membranes and skin may be needed (hair should be clipped if thick) to detect pinpoint hemorrhages. Bleeding such as epistaxis, melena, hematuria, hyphema, and neurologic signs is less common. The blood loss associated with platelet destruction may mimic IMHA or other causes of anemia. Splenomegaly and fever may be noted. Hematomas or bleeding into body cavities suggests rodenticide toxicosis or other causes or coagulopathy, not IMT.

Diagnostic testing

A low platelet count, typically less than 50,000/μL, is the most important finding. Platelet levels may drop to 10,000 or even be undetectable. Automated cell counters may not be accurate if the platelet count is very low or high. Blood smear examination is highly recommended. An estimate of the platelet count can be made by determining the average number of platelets in a high-power field (100X oil objective) and multiplying by 20,000. 8 or more platelets/hpf is normal. Anaplasma platys may be observed as stippled blue morulae within platelets. Large platelets (megathrombocytes), which indicate bone marrow regeneration, may be found on a blood smear. A regenerative anemia due to blood loss (no spherocytes) may be seen on routine bloodwork along with nonspecific findings of neutrophilia and decreased plasma proteins. Coagulation testing (prothrombin time, partial thromboplastin time, D-dimer test, fibrin degradation products, antithrombin) is typically normal.

There is no reliable test to confirm IMT. A bone marrow aspirate typically has normal to increased megakaryocytes. The platelet factor 3 test to detect anti-platelet antibodies has limited sensitivity and specificity. Flow cytometry for platelet-associated antibody levels (IgG) may be available. Neither of these tests differentiates between primary and secondary IMT. In general, IMT is diagnosed by excluding other causes and observing response to immunosuppressive therapy.

Therapy

Research studies investigating this disorder in animals are limited. Corticosteroids and azathioprine are used in the same dose and duration as in IMHA (see previous Proceedings). Vincristine increases platelet counts temporarily and a single dose of 0.02 mg/kg IV is indicated when starting other treatments. Vincristine may be repeated after one week if needed. Many clinicians treat suspected IMT with doxycycline in case of rickettsial disease at a dose of 5-10 mg/kg once or twice a day.

Other drugs are anecdotally reported to be helpful if prednisone and azathioprine fail or if side effects are severe. Cyclosporine, danazol, mycophenolate, and leflunomide are possible options. Human intravenous immunoglobulin (hIVIG) was reported in a retrospective study of 5 dogs with severe primary IMT. Four of the 5 dogs responded positively with a rapid recovery of platelet counts and shorter hospital stay. More studies are needed, but hIVIG is currently expensive ($500 or higher depending on dose).

If possible, any previous drugs are discontinued, as the IMT may be due to an adverse drug reaction. Because the main risk for the patient is bleeding, packed red cell transfusions may be helpful. Gentle handling of the patient is important (limit injections, use pressure bandages, avoid drugs that affect coagulation). Platelet transfusions are possible but the lifespan of transfused platelets is thought to be minutes to hours instead of the normal 7-10 days. Thromboembolism and DIC are not common with IMT unless Evan's Syndrome is present (concurrent IMHA and IMT). The prognosis for IMT is somewhat better than for IMHA but 30% mortality is reported and relapses may occur. Owners should be committed to long-term therapy and frequent rechecks of platelet counts and other diagnostics.

Case presentation

Immune-mediated arthritis

The etiology of immune-based arthropathies is unknown, but clinically these disorders can be divided into erosive and nonerosive, based on bony changes seen on radiographs. Rheumatoid arthritis is an example of erosive, and occurs in any breed of dog (very rare in cats). Erosive polyarthritis has been reported in young Greyhounds. Periosteal proliferative polyarthritis is common in cats but rare in dogs, and is characterized by periosteal new bone formation along with erosion. The major nonerosive form is systemic lupus erythematosus. Other causes of nonerosive arthritis include idiopathic polyarthritis, chronic infectious disease, and polyarthritis/meningitis syndrome.

The onset of swollen, painful joints tends to be acute, with smaller joints (carpus, hock) affected. Fever, lethargy, and enlarged lymph nodes may be present. Diagnosis involves ruling out infectious causes of arthritis such as bacterial (including Lyme disease), rickettsial (RMSF or ehrlichiosis), viral (e.g. calici), or rare findings such as fungal, mycoplasmal, or protozoal. Immune-mediated nonerosive arthritis is one of the causes of fever of unknown origin.

Radiographs are helpful, although changes may not be apparent for weeks after onset. Arthrocentesis (ideally two or more joints) and aspiration of synovial fluid for analysis is indicated. Elevated white cell counts, primarily neutrophils, are seen with immune-mediated polyarthritis. A rheumatoid factor test (antibody response against IgG) may be positive but false negatives are possible and positive results occur with other diseases. Significant increases in C-reactive protein have been reported.

The treatment for noninfectious immune-mediated arthropathies involves immunosuppression with corticosteroids and other drugs such as azathioprine, cyclophosphamide, methotrexate, leflunomide, and gold salts. Supportive care for joint disease may include weight loss, glucosamine/chondroitin supplements, fish oil or enriched diets, glycosaminoglycans. Acupuncture or other alternative therapies can be considered.