Acquired thrombocytopenia

Causes of thrombocytopenia fall into one or a combination of the following general mechanisms:
  • Decreased production of platelets in the marrow
  • Increased consumption of platelets in coagulation
  • Increased destruction of platelets by macrophages
  • Sequestration of platelets in the spleen or microvasculature
  • Acute, severe hemorrhage
Remember that platelet clumping in blood samples (as evident in peripheral blood smears) will artifactively decrease the platelet count (obtained by any method) and, in some instances, may result in a pseudothrombocytopenia. There have been rare reports in human patients (with isolated reported case in horses) of an EDTA-dependent pseudothrombocytopenia. This only occurs in blood collected into EDTA (not citrate or heparin) due to EDTA-induced unmasking of platelet antigens by EDTA with binding of antibodies and subsequent platelet aggregation. In these circumstances, platelet counts need to be determined from citrated or heparinized blood samples (although citrate is preferred as heparin can also produce platelet clumping).

  • Decreased platelet production

    Most causes of decreased platelet production are not just selective for megakaryocytes but affect the erythroid and myeloid (granulocyte) lines as well. Therefore, thrombocytopenia due to decreased production is usually accompanied by neutropenia and or/anemia without reticulocytosis. Remember that neutrophils survive in the circulation for approximately 12 hours, whereas platelets survive for up to 7-10 days. Therefore, thrombocytopenia and neutropenia may precede anemia in animals with these bone marrow conditions (as red cells have a much longer lifespan). Acquired causes of decreased bone marrow production of platelets include the following:

    1) Bone marrow aplasia or hypoplasia: Causes include drug toxicities (estrogen, griseofulvin, trimethoprim-sulfonamides, albendazole), bracken fern poisoning in cattle, infectious agents (Ehrlichia canis infection), and idiopathic (likely immune-mediated).
    2) Leukemia: An acute leukemia (acute myeloid leukemia or acute lymphoid leukemia) arising in the bone marrow wipes out the remaining hematopoietic cells. Animals may present with pancytopenia with or without circulating blasts. Some animals have a leukocytosis comprised only of leukemic blasts, with a concurrent neutropenia, thrombocytopenia and non-regenerative anemia.
    3) Infiltrative neoplasia: This is due to replacement of the bone marrow by extramedullary neoplasia, such as lymphoma. Metastatic carcinomas (breast, prostate) are a common tumor that metastasizes to the bone marrow in man, but not in animals.
    4) Ineffective hematopoiesis: Some animals with pancytopenia have a cellular marrow, but hematopoiesis is not effective, likely due to increased intramedullary cell death. Causes include neoplastic conditions (myelodysplastic syndromes in cats, histiocytic sarcoma in dogs), infectious agents (Ehrlichia canis) and immune-mediated disease.
    5) Necrosis: Necrosis of the bone marrow from ischemic, radiation or toxic injury or secondary to infectious agents can result in a pancytopenia. This is a very rare cause of pancytopenia in animals.

  • Increased platelet consumption

    Thrombocytopenia of variable severity is a fairly consistent finding in disseminated intravascular coagulation (DIC). Vasculitis, whether caused by infectious agents or immune complexes, can produce thrombocytopenia even without laboratory results indicative of DIC; the thrombocytopenia of Rocky Mountain spotted fever is thought to be due primarily to generalized endothelial damage.

  • Increased platelet destruction

    Immune-mediated destruction of platelets can occur as a clinical syndrome of idiopathic (primary) immune-mediated thrombocytopenia - called ITP or IMT - or as a component of other infectious, neoplastic or systemic immunologic diseases, such as systemic lupus erythrematosis (SLE). There is no routinely available, reliable method for detecting antiplatelet antibodies in animals at this time. The platelet factor 3 (PF3) release test widely mentioned in the veterinary literature is no longer available and never was a very reliable test. Detection of IgG on megakaryocytes of thrombocytopenic animals by direct immunofluorescence methods is considered as supportive evidence of antibodies with antiplatelet activity; this procedure is neither sensitive nor specific and is not a routinely offered test either. Newer procedures using flow cytometery to detect anti-platelet antibodies are now available at certain referral institutions. Antiplatelet antibodies confirm an immune-mediated pathogenesis for the thrombocytopenia, but do not distinguish between primary and secondary ITP. Positive results are seen in animals with infectious disorder (e.g. Ehrlichiosis in dogs), neoplasia and other immune-mediated disease (e.g. SLE). ITP is diagnosed most frequently in dogs but rare cases of ITP in cats and horses have been seen. Examination of a peripheral blood smear in animals with ITP show very few or no platelets in severe cases (as illustrated by the image on the right which is a smear from a dog with ITP).

    Primary ITP usually presents as a clinical syndrome of acute onset small vessel type bleeding in a dog without signs of severe systemic illness. The degree of anemia is variable and depends on the amount of blood lost through hemorrhage and the presence of concurrent immune-mediated destruction of red cells (hemolytic anemia). The diagnosis of ITP is based on finding thrombocytopenia, normal coagulation test results, exclusion of other diseases, and favorable response to immunosuppressive therapy. Bone marrow aspiration is generally not indicated in the initial work-up of a patient with ITP; results show normal erythroid and granulocytic lines and, in most cases, normal to increased numbers of megakaryocytes. Rare dogs with ITP have no or few megakaryocytes in marrow; such patients are considered to have immune-mediated destruction of megakaryocytes as well. These dogs are thought to respond more poorly to immunosuppressive therapy than dogs with megakaryocytic hyperplasia. Platelet destruction in some animals can be quickly controlled with fairly mild immunosuppression (corticosteroids alone) but in others prolonged treatment with cytotoxic drugs (azathioprine and/or vincristine in combination with corticosteroids) is necessary to increase the platelet count. Dogs in the latter category need intense supportive care to manage the side effects of the immunosuppressive drugs and the loss of blood. Since the spleen is a major site of platelet destruction, splenectomy is done in rare cases refractory to control by drugs. Because ITP can be a part of more generalized immune-mediated disease, clinical signs, physical findings, history, and laboratory results should be evaluated for evidence of abnormalities of other organs, particularly skin, joints, and kidneys, that may lead to recognition of SLE.

    Secondary ITP occurs with infectious diseases, neoplasia and drugs. Immune-mediated destruction of platelets is one of several possible mechanisms by which infectious diseases can cause thrombocytopenia. Thrombocytopenia is seen in some viral infections and may occur within 7-10 days of vaccination with modified-live viruses (especially canine distemper virus). This post-vaccinal thrombocytopenia is generally mild (platelet counts rarely decrease < 100,000/Ál), with the most severe decreases seen in puppies. Immune-mediated destruction is partly responsible for the thrombocytopenia of canine ehrlichiosis (E. canis) and infectious canine cyclic thrombocytopenia (E. platys). The severe thrombocytopenia in some cows with BVD appears to be due in part to antibody-mediated destruction. Babesia, a protozoan erythroparasite, can cause thrombocytopenia.

    Many drugs have been reported to cause ITP in human patients and therefore are potential causes of thrombocytopenia in animals. In general, if an animal with the clinical syndrome of ITP is receiving drugs, these should be discontinued if at all possible and reintroduced with caution when a normal platelet count is restored.
    Petechiae and gingival hemorrhage in a Doberman with primary ITP
    Documented cases of drug-related ITP in animals are few but include gold compounds, PTU (propylthiouracil, an anti-
    thyroid drug), sulfonamides, and penicillin.

    Immune-mediated thrombocytopenia is associated with neoplastic diseases in some animals. Neoplasms such as lymphoma and a variety of benign and malignant solid tumors have been implicated in some cases.

    Immune-mediated thrombocytopenia due to blood transfusions (so-called post-transfusion purpura) is a rare condition in human patients characterized by a severe thrombocytopenia 1 to 2 weeks after blood or blood product transfusion. This has been reported in a dog with hemophilia A. The dog developed a severe thrombocytopenia (platelet count < 10,000/Ál), on 2 occasions after being transfused (the first occurred 8 days after a second blood transfusion; the second, 5 days after cryoprecipitate infusions). On both occasions, the platelet counts normalized within 4 to 6 days of corticosteroid therapy (but the dog may have recovered spontaneously without treatment).

    Neonatal thrombocytopenic purpura has been recognized in pigs, mules and one Quarterhorse foal. In pigs, agglutinating antibodies against sire and piglet platelets have been documented in the dam. The piglets are generally born healthy, then develop thrombocytopenia after 5 to 9 days, with the nadir occurring at 10 to 13 days. Thrombocytopenia is due to increased platelet destruction and decreased platelet production. Clinical signs of cutaneous hemorrhage are seen. Death may result at 2 to 3 weeks of age. Surviving piglets appear clinically and hematologically normal by 16 weeks of age. Severe thrombocytopenia was discovered in a 1 day old Quarterhorse foal presenting for weakness and failure to suckle. His dam's serum contained antibodies that bound to his and a full brother's platelets.

  • Increased platelet sequestration

    Excessive platelet pooling in spleens enlarged due to a variety of reasons may cause thrombocytopenia. Thrombocytopenia in animals with bacteremia or endotoxemia is due in part to sequestration of damaged platelets in organs such as lung, liver and spleen. However, animals with these diseases are likely to have DIC as well, which contributes to the thrombocytopenia by consumption in coagulation.Severe, acute hemorrhage due to trauma or deficiency of coagulation factors can result in mild to moderate thrombocytopenia (usually not < 50,000/Ál).

  • Acute severe hemorrhage

    Severe, acute hemorrhage due to trauma or deficiency of coagulation factors can result in mild to moderate thrombocytopenia (usually not < 50,000/Ál).

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