Jennifer A. Neel,     Raleigh, North Carolina

Adam J. Birkenheuer,     Raleigh, North Carolina

Carol B. Grindem,     Raleigh, North Carolina

Mechanisms of Thrombocytopenia

Thrombocytopenia occurs by one of four general mechanisms: decreased production, increased consumption/destruction, sequestration, and excessive loss. Often more than one mechanism occurs in any single disease or disorder. Decreased production is seen with suppression or destruction of megakaryocytes caused by immune-mediated disease, drugs, infectious agents, whole body irradiation, and myelophthisic disorders. Increased consumption or destruction is a common cause of thrombocytopenia in dogs and cats; etiologies include primary or secondary immune-mediated disease, drugs, toxins, disseminated intravascular coagulation (DIC) (vascular damage, septicemia, endotoxemia, massive tissue necrosis/damage, or release of procoagulant substances), disseminated neoplasia, and infectious diseases. Thrombocytopenia resulting from sequestration or abnormal distribution of platelets can be caused by splenic congestion/splenomegaly, hepatomegaly, neoplasia, severe hypothermia in dogs, and experimentally induced endotoxemia. Marked thrombocytopenia is not typically noted, and the effect is often transient. Excessive loss can occur with massive blood loss and is observed in some cases of hemorrhage associated with rodenticide toxicity, but often platelet counts are normal to increased in these patients. This chapter focuses on causes and treatment of immune-mediated and infectious thrombocytopenia.

Immune-Mediated Thrombocytopenia

Immune-mediated thrombocytopenia (IMTP) can be primary, secondary, vaccine induced, or posttransfusion. Primary, or idiopathic, IMTP is reported most commonly in dogs but has also been reported in cats. This is a disease of exclusion; other potential causes of secondary IMTP must be eliminated before a diagnosis of primary IMTP can be made. Acquired amegakaryocytic thrombocytopenia is a rare form of either primary or secondary immune-mediated disease resulting from autoantibodies directed toward megakaryocytes and has been reported in both dogs and cats (Thomas, 2010).

Secondary IMTP occurs when antibody targets nonself antigens adsorbed onto the surface of platelets or when immune complexes become bound to platelet surfaces. Underlying mechanisms include systemic autoimmune diseases (systemic lupus erythematosus), neoplasia, infectious agents, and drugs; occasionally, however, additional causes are identified or suspected, such as pemphigus, juvenile-onset polyarthritis syndrome in Akitas, and possibly canine inflammatory bowel disease (Scott and Jutkowitz, 2010). Thrombocytopenia associated with neoplasia is often multifactorial, with secondary immune-mediated destruction representing one potential component. Lymphoma in dogs has been associated most commonly with secondary IMTP, but it can occur with any neoplasm. In one study 10% of dogs with neoplasia had concurrent thrombocytopenia, and of this group 61% did not have identifiable factors known to cause secondary IMTP (Grindem et al, 1994). As with neoplasia, thrombocytopenia in infectious diseases is often multifactorial and can include a secondary immune-mediated component. Antiplatelet antibodies have been detected in various infectious diseases, including Ehrlichia canis infections and Rocky Mountain spotted fever (RMSF). Drugs are rarely reported to cause a true primary IMTP; more typically it is secondary in nature. With this mechanism the drug acts as a hapten, allowing immune-mediated targeting of the platelets. A few drugs are capable of causing a secondary immune-mediated reaction without a history of prior exposure (e.g., heparin in horses), but most occur following extended use or prior exposure. Several documented cases involving trimethoprim sulfonamide/sulfamethoxazole have been reported in dogs, but it could potentially be caused by any number of drugs. Vaccine-induced thrombocytopenia has been reported in dogs following immunization with modified live vaccines (canine distemper). Typically thrombocytopenia is mild and develops within 3 to 10 days after vaccination, but marked thrombocytopenia can occur. Posttransfusional thrombocytopenia has been reported occasionally in dogs.

Infectious Etiologies Associated with Thrombocytopenia

Table 61-1 lists infectious agents associated with thrombocytopenia in dogs and cats (Greene, 2012). Thrombocytopenia associated with infectious causes is often multifactorial, involving increased consumption, destruction, vasculitis, or sequestration; in many cases the pathogenesis is incompletely understood. As mentioned previously, a number of agents are associated with secondary IMTP. Some are known to cause bone marrow suppression, including feline leukemia virus (FeLV) infection, feline immunodeficiency virus (FIV) infection, feline panleukopenia (parvovirus), canine parvovirus, and chronic monocytic ehrlichiosis (E. canis, Ehrlichia chaffeensis). FeLV and FIV are of particular importance in feline thrombocytopenia. Viral diseases (FeLV, FIV, and feline infectious peritonitis [FIP]) are a major cause of or contributing factor to the development of thrombocytopenia in cats (Jordan, Grindem, and Breitschwerdt, 1993; Thomas, 2010).

DIC is commonly seen in gram-negative sepsis, infectious canine hepatitis (ICH), leptospirosis, salmonellosis, babesiosis (virulent strains), canine and feline parvovirus, cytauxzoonosis, and plague. Vascular damage occurs in endotoxemia, septicemia, heartworm disease, FIP, ICH, RMSF, and bartonellosis. Platelet sequestration within the spleen, liver, or lungs is noted in endotoxemia; plague; salmonellosis; babesiosis; cytauxzoonosis; and hemolytic crisis secondary to babesiosis, hemotropic mycoplasmosis (formerly hemobartonellosis), or cytauxzoonosis. Etiologic agents vary with geographic location and may be limited by the vector, intermediate host, or environmental requirements of the organism.

The degree of thrombocytopenia can vary. Although thrombocytopenia is most severe in IMTP and overwhelming sepsis (counts of less than 50,000/µl and often fewer than 10,000/µl), it can be moderate to severe in canine monocytic ehrlichiosis. In one report on prevalence of E. canis infection in thrombocytopenic dogs in an endemic region, infection was found in 63.1% of dogs with a platelet count of less than 100,000/µl but in only 21% of dogs with platelet counts between 100,000 and 200,000/µl; nonthrombocytopenic dogs had an infection rate of 1.4% (Bulla et al, 2004). Severe, cyclic thrombocytopenia is also seen with thrombocytotropic ehrlichiosis, but dogs are not systemically sick; clinically ill dogs with this disease should be evaluated for concurrent tick-borne diseases such as monocytic ehrlichiosis.

Tests used to diagnose infectious diseases include serology, polymerase chain reaction (PCR), antigen detection in fluids or tissues, cytology, blood smear evaluation, culture, virus isolation, electron microscopy, and histopathology (see Table 61-1; Greene, 2012).