Diagnosis and treatment of immune-mediated thrombocytopenia (Proceedings)

Immune-mediated thrombocytopenia (IMTP) is one of the more common immune-mediated diseases in small animal practice, especially in dogs. However, in surveys of thrombocytopenic dogs in the United States and Europe, IMTP is a relatively uncommon cause of thrombocytopenia compared to thrombocytopenia caused by inflammatory (including infectious) disease, neoplasia and miscellaneous causes. Cats can develop IMTP, but apparently with a frequency that is much less than that seen in dogs. This presentation will provide an overview of the pathogenesis, clinical features, diagnosis and treatment of IMTP. As used in these notes, IMTP refers to the idiopathic disease.

Pathogenesis

IMTP is usually an idiopathic immune-mediated disease with no known trigger or predisposing cause identified. At heart, IMTP is an example of a type II hypersensitivity reaction in which antibodies are formed against a platelet antigen. The attachment of antibody to the platelet directs the platelet's destruction by cells of the mononuclear phagocytic cell system, or possibly by complement-mediated destruction. The reasons why the immune system promotes antibody formation against platelet antigen are unknown, but in keeping with other hypotheses underlying the development of immune-mediated disease, possibilities include antigenic mimicry (a platelet antigen “looks” like a foreign antigen), loss of central or peripheral immune tolerance mechanisms, formation of haptens, or unmasking of a hidden antigen or alteration of a normal platelet protein in a manner that renders it immunogenic. Regardless of the primary cause, the manifestation is the same: low circulation platelet numbers, often profoundly low.

A key distinction between the pathogenesis of IMTP and other causes of thrombocytopenia, including some diseases that have been shown to provoke secondary immune-mediated platelet destruction (secondary IMTP), is that the diagnosis of idiopathic IMTP carries the assumption, or is supported by results of diagnostic testing  that a predisposing cause of thrombocytopenia can not be identified. This distinction is important because it carries diagnostic implications for the affected patient.

Mechanisms of thrombocytopenia

There are several general mechanisms that cause thrombocytopenia in dogs and cats, and exclusion of these mechanisms and their causes is a key component to the diagnosis of IMTP. In addition to platelet destruction, thrombocytopenia can result from decreased platelet production, increased platelet consumption, and less commonly, platelet loss and sequestration. 

Exclusion of causes of increased platelet consumption is an important element to the diagnosis of IMTP as this mechanism is a relatively common cause of thrombocytopenia.  The classical causes of consumptive thrombocytopenia are disseminated intravascular coagulation (DIC), and vasculitis. Large vessel thromobosis appears in some patients to be another cause of consumptive thrombocytopenia. The diagnosis of DIC is suspected in a thrombocytopenic patient that has prolonged PT and PTT, increases in products of fibrin degradation (d-dimers or fibrin degradation products [FDPs]), and an underlying disease process that increases the risk of DIC. Common categories of disease causing DIC include systemic inflammatory disease (which can be infectious or non-infectious), some neoplastic diseases, trauma, heat stroke, and severe hepatic disease. The existence of one of these in a thrombocytopenic patient should initially steer the clinician away from a diagnosis of IMTP.

Vasculitis can be a consequence of systemic inflammatory disease (again, either infectious or non-infectious), some tumors, and can also arise as an idiopathic disease in some patients. There are often other clues suggesting the existence of vasculitis as a cause of thrombocytopenia in the patient affected by the disorder. Deceased production of platelets typically is a reflection of a primary bone marrow disorder, such as that caused by some infectious disease (e.g. chronic ehrlichiosis), infiltrative disease (e.g. bone marrow lymphoma), or toxic disease (many drugs).

Clinical presentation

The history in patients with IMTP is often unspectacular. The development of clinical signs may occur acutely, or may take a more smoldering clinical course. Travel history in the candidate patient is important to assess the possibility of infectious disease (e.g. Ehrlichia canis) that can travel well in dogs.

The clinical presentation of patients with IMTP can be surprisingly variable, but some manifestation of spontaneous bleeding is the most common reason for presentation of the affected patient to the veterinary clinician. Bleeding can occur anywhere, in any organ or tissue, accounting in part for the variety in clinical presentation. In addition to petechial hemorrhages in skin, mucous membranes or sclera that are often noticed by owners, hematuria, hematemesis, melena or hematochezia, or ocular hemorrhage can be additional clinical signs provoking veterinary attention.

The physical examination of patients with IMTP can be also be variable. In addition to petechial hemorrhages, mucous membrane pallor is common if there has been enough hemorrhage (usually secondary to urinary tract or gastrointestinal tract bleeding) to cause anemia. Splenomegaly may be appreciated, and fever may or may not be present. Hemorrhage into the anterior chamber, or retinal hemorrhage, may be apparent during ocular examination. A rectal examination could suggest the presence of gastrointestinal tract bleeding if there is evidence of fresh blood, or melena, on the exam glove or thermometer. For patients with mucous membrane pallor, a rectal examination can be a quick assessment for the presence of gastrointestinal tract bleeding as the cause of anemia. Neurologic abnormalities are possible if there has been bleeding into the central nervous system.

Other physical examination findings that should be viewed with suspicion in the thrombocytopenic patient include heart murmurs, especially known new murmurs (endocarditis), peripheral edema or erythema (vasculitis), lymph node enlargement (neoplastic or infectious disease), or other masses (neoplasia). Such features should be carefully investigated to prevent erroneous diagnosis and treatment of IMTP.

Diagnostic considerations

The laboratory data base in patients with IMTP usually shows moderate to profound thrombocytopenia, with platelet counts below 40,000/ul common. Spontaneous bleeding typically does not occur until platelet counts are below this level, so the patient with spontaneous bleeding at higher patient counts should be viewed as potentially having another process, such as abnormal platelet function, factor deficiency or vasculitis, contributing to bleeding. Anemia can be present secondary to hemorrhage, or potentially from concurrent immune-mediated hemolytic anemia (IMHA); the anemia of hemorrhage is usually regenerative if present for several days, while the anemia of IMHA can be regenerative or poorly-regenerative. Hypoproteinemia would support hemorrhage as a contributor to anemia. Hypoalbuminemia in patients with peripheral edema would raise suspicion for vasculitis as the cause of thrombocytopenia. Patients with gastrointestinal tract hemorrhage may have increases in BUN discordant to creatinine (i.e. increased BUN with normal creatinine). Other findings on a biochemical profile are possible and non-specific, but could be viewed as potential clues to the existence of causes of thrombocytopenia other than IMTP. Results of a urinalysis are often unhelpful unless there has been urinary tract bleeding, in which case hematuria is expected.

To exclude platelet consumption as a cause of thrombocytopenia, PT and PTT, and d-dimers or FDPs can be performed. In patients with IMTP, PT and PTT should be normal, and d-dimers or FDPs should be normal or be present in low concentrations.

Under ideal circumstances, the abdomen and thorax of patients suspected of having IMTP should be imaged to exclude occult neoplasia or infections as a possible cause of thrombocytopenia. Abdominal ultrasound can reveal lesions within the parenchyma of the liver and spleen that could contribute to thrombocytopenia, and ultrasound-guided aspirates can be performed during the examination period. If abdominal ultrasonography is not available, plain radiographs will suffice as they can still give information about enlargement or irregularities of the liver, spleen or intra-abdominal lymph nodes. Patients with IMTP should not have evidence of occult infections or tumors.

Patients living in areas where infectious diseases notorious for causing thrombocytopenia exist can be tested by serologic assays. Important infectious disease considerations include Rocky Mountain spotted fever (RMSF) and ehrlichiosis, babesiosis, and anaplasmosis, and salmon-poisoning disease in the Pacific Northwest. Cats with unknown retroviral status should be tested for feline leukemia and feline immunodeficiency viruses.

Once other mechanisms or other causes of thrombocytopenia have been excluded to the extent possible, the diagnosis of IMTP is often established by default. While assays that detect anti-platelet antibody have been described, these assays generally are not yet considered specific for the diagnosis of IMTP as other diseases (e.g. rickettsial infections for one example) have been associated with the appearance of antiplatelet antibody.

Treatment of IMTP

Patients with IMTP need to be treated with immunosuppressive drugs. There have been no studies that establish the best treatment approach, so protocols are largely established by personal experience and the experience of others. The author's approach is to administer prednisone 1 mg/kg PO q12h in conjunction with azathioprine 1-2 mg/kg PO q24h for 14 days, then every other day. Prednisone is typically given at this initial daily dose for at least 2-3 weeks; I like to see acceptable platelet counts for about 2 weeks before considering a dose reduction. Prednisone doses are dropped about 20% every 2-3 weeks assuming platelet counts remain acceptable, which requires obtaining platelet counts before each dose reduction. It is not unusual for these patients to experience thrombocytosis, which may be attributed in part to glucocorticoid administration. Other immunosuppressive drugs, such as cyclosporine A, or leflunomide, can be used if patients can't tolerate other drugs, or owners can't tolerate side effects.

Some clinicians prefer to give a dose of vincristine (0.02 mg/kg IV once) as part of the initial treatment approach. Vincristine can help increase peripheral platelet numbers, and one retrospective study suggests that dogs with IMTP treated with vincristine leave the hospital sooner than patients not treated with vincristine. The author will give vincristine to patients with bleeding and severe thrombocytopenia. A disadvantage to use of vincristine in such patients is the need to limit exposure of hospital staff and owners to chemotherapy residues.

Additional medications that have been used in the treatment of IMTP in dogs include leflunomide, and human intravenous immune globulin. The author does not use these as first line treatment of IMTP, but views them as alternatives when other immunosuppressive drugs can't be given.

Other supportive care may be needed in the IMTP patient. Clinical signs secondary to hemorrhage may require administration of blood products (whole blood, packed red blood cells and plasma). Fluids may also be needed for short-term support if patients are not drinking on their own. One other trick that the author learned many years ago from Dr. Leah Cohn is that oral administration of a diagnostic dose of barium sulfate can help ameliorate gastrointestinal tract bleeding in IMTP patients.

Prognosis

Patients with IMTP tend to respond favorably to immunosuppressive therapy, and the mortality rate associated with the disease is reportedly low. The presence of concurrent IMTP and IMHA is generally associated with a worse prognosis than is IMTP alone. In one recent study, 84% of dogs with IMTP survived to discharge, with a relapse rate of approximately 10% in the dogs that could be followed after discharge. This particular paper suggested that the presence of increased BUN and melena were negative prognostic indicators, but the author has seen many of such dogs survive to discharge and beyond. Also, in the author's experience, patients that die from IMTP tend to have central nervous system bleeds that cause acute death or prompt euthanasia. The author has also had two patients in his career that developed urethral obstructions secondary to large blood clots in the urinary bladder as a result of thrombocytopenic induced bleeding.

References and suggested reading (additional references available on request)

Botsch V, et al. Retrospective study of 871 dogs with thrombocytopenia. Veterinary Record 2009; 164:647-651.

Grindem CB, et al. Epidemiologic survey of thrombocytopenia in dogs: a report on 987 cases. Veterinary

Clinical Pathology 1991; 20:38-43.

O'Marra SK, et al. Treatment and predictors of outcome in dogs with immune-mediated thrombocytopenia. J Am Vet Med Assoc 2011;238:346–352.

Rozanski EA, et al. Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. J Am Vet Med Assoc 2002;220:477-481.