Urs Giger, Dr. med. vet., MS, FVH, DACVIM, DECVIM (Internal Medicine), ECVCP (Clinical Pathology)
Charlotte Newton Sheppard, Professor of Medicine, School of Veterinary Medicine, University of Pennsylvania
Philadelphia, PA, USA
Thrombocytopenia, a common cause of surface hemorrhage in dogs, can result from impaired thrombopoiesis, increased platelet destruction and consumption, and sequestration of platelets (splenomegaly). Reduced platelet production may be isolated or associated with an overall decreased hematopoiesis due to many drug reactions (estrogens, chemotherapeutics, azathioprine), infections (Ehrlichia spp.), and myelophthisis (leukemia, myeloma, myelofibrosis) but remains often idiopathic (immune-mediated?). Accelerated platelet destruction is commonly associated with immune-mediated thrombocytopenia (IMT), but enhanced platelet consumption may also be observed with neoplasia, vasculitis and disseminated intravascular coagulation (DIC). IMT can be divided into primary, also known as idiopathic thrombocytopenia purpura (ITP), and secondary forms triggered by infections (Ehrlichia, Rickettsia, and Babesia spp., vaccines), drugs, and cancer. Anticoagulant rodenticide poisoning can also be associated with mild to moderate thrombocytopenia. However, acute and chronic blood loss is not resulting in any significant consumptive thrombocytopenia unless there is concomitantly a vasculopathy or DIC present. Because thrombocytopenia occurs rarely in cats and is generally associated with drug exposure (griseofulvin, methimazole, propylthiouracil), viral infections, or malignant diseases, it will not be further discussed here.
A diagnosis of thrombocytopenia is made by a platelet estimated on a blood smear or complete blood cell count, but any thrombocytopenia must be verified by a review of a blood smear. Spurious thrombocytopenia may due to instrument limitations; e.g., megaplatelets in Cavalier King Charles and platelet aggregates with many illnesses and collection techniques; also Greyhounds have generally a mild thrombocytopenia. Classic signs of thrombocytopenia include petechiation, ecchymosis, epistaxis, and gastrointestinal blood loss. The most severe thrombocytopenias, seen with IMT/ITP, often cause only mild hemorrhage. Following a careful history, a search for an underlying cause is warranted to identify an infection (blood smear, serology, PCR) or cancer (also involving lymph nodes and spleen). Bone marrow examination is safe, but may rarely reveal a specific cause on initial presentation. A diagnosis of ITP is mostly based upon excluding other causes of thrombocytopenia, but platelet-associated antibodies can also be determined to support an immune mechanism for thrombocytopenia.
Therapy of thrombocytopenia is mostly dependent on the underlying cause and severity of clinical signs of bleeding rather than the actual platelet count. It is well appreciated that despite the severe thrombocytopenia due to ITP these animals may be at lesser bleeding risk than the ones with myelosuppressive disorders. Hence therapy of thrombocytopenia involves treatment of the underlying disease, withdrawal of any potential triggering agents, supportive care, and emergency control of bleeding and correction of severe anemia.
Platelet transfusions are very rarely indicated and restricted to serious uncontrolled bleeding into the brain or other critical sites. Platelet can only be transfused from freshly collected blood kept for <12 hours at room temperature, albeit there are efforts made to provide frozen or even artificial platelets. In ITP transfused platelets are thought to have an extremely short survival of minutes to hours rather than normal 7-10 days. Nevertheless, in patients with life-threatening bleeding into nervous or cardiopulmonary system, platelet rich plasma or concentrate transfusions may be considered. In clinical practice thrombocytopenic seriously bleeding patients may be the ones that could benefit more from a fresh whole blood transfusion to provide platelet and red blood cell support. At 1 hour post transfusion the anticipated platelet rise per transfusion is only modest (20,000/ul per 10ml fresh whole blood/kg transfusion. In most cases packed red cells and stored blood may be sufficient to correct the anemia. Prior to any transfusion the patient should be blood typed and DEA 1.1 compatible blood and if previously transfused cross-match compatible blood should be transfused. In case the thrombocytopenia is combined with a coagulopathy, supplementation of coagulation factors in the form of fresh frozen plasma may be considered.
As any drug may potentially trigger thrombocytopenia all drugs should be withdrawn except the ones absolutely required treating a life-threatening condition (e.g., phenobarbital for active seizures); a change in class of drugs may also be helpful. Since infections are common causes of thrombocytopenia and screens for infectious diseases may not be back for days (except SNAP tests), thrombocytopenic dogs are often empirically treated with antimicrobials. Most commonly doxycycline at 10mg/kg BID for 2 weeks is being used, however in certain geographic areas other antimicrobials may also be indicated; for instance babesiosis may cause severe thrombocytopenia before the hemolytic disease is recognized, and sepsis associated thrombocytopenia requires intense parenteral antibiotic administration. Furthermore, cancer associated thrombocytopenia is best corrected by treating the cancer.
In cases of ITP immunosuppressive therapy is used to inhibit platelet phagocytosis by macrophages and platelet-antibody production. Glucocorticosteroids are still the first and main immunosuppressive agents; they impair platelet destruction by blocking macrophages, interfere with platelet-antibody interactions, hamper any inflammatory response, and finally inhibit anti-platelet antibody production. While most clinicians start off with prednisone at a dose of 2mg/kg PO BID, dexamethasone at 0.2mg/kg can be administered IV daily in cases with gastrointestinal signs. Any steroids may induce serious side effects including gastrointestinal ulcers, thromboembolism iatrogenic hyperadrenocorticism, and bacterial infections. There is no evidence that dexamethasone is superior to prednisone if used at the equivalent dose (dexamethasone is 6-8 times more potent than prednisone); however, some clinicians are hesitant to use the high prednisone dose. In fact a high initial steroid pulse dose has been suggested to be effected but may also be associated with more serious side effects. Interestingly there is one additional immunosuppressive agent that is considered highly effective and relatively safe in the initial management of severe acute ITP. Vincristine at a dose of 0.02mg/kg (0.5mg m2 body surface) strictly IV once (may be repeated after a week) has been shown to accelerate the platelet count rise, when used in combination with prednisone. Potential mechanisms of action of vincristine include binding of tubulin and inhibition of macrophages. Other immunosuppressive agents may be considered if prednisone ± vincristine fail or intolerable side effects occur. These may include cyclosporine, danazol, azathioprine, and intravenous human immunoglobulin; none of these drugs have been approved or shown to be efficacious and safe in any clinical studies in dogs. In addition new immunosuppressive agents are being introduced such as mycophenolate and leflunomide. Finally, splenectomy may be considered in refractory or relapsing cases of ITP, but no data is available in dogs.
The prognosis depends on the underlying cause and type of hemorrhage on presentation. In ITP the bleeding is often less pronounced despite most severe thrombocytopenia. In uncomplicated cases of ITP a response is generally expected within days with platelet counts rising above the critical level of 40,000/μl, where bleeding would not be expected. Hence as soon as the platelet count rises >40,000/μl, the immunosuppressive therapy can be slowly tapered. In secondary forms of IMT the thrombocytopenia often resolves within 2 weeks if the trigger can be removed. In conclusion, thrombocytopenias in dogs can be associated with many different diseases and are highly rewarding to treat.