Hemostasis is a complex interaction between platelets, blood vessels and the coagulation cascade. The goal of hemostasis is to form a clot. Effective primary hemostasis depends on adequate platelet numbers, adequate platelet function, vessel wall integrity, and von Willebrand factor. Bleeding disorders related to primary hemostasis are mainly related to platelets and rarely to vessels. Platelet disorders may be quantitative (thrombocytopenia) or qualitative (thrombopathia). Thrombocytopenia is the most common primary hemostatic defect.
In cats, decreased platelet counts are a common laboratory finding. However, this is often a so-called pseudothrombocytopenia (incorrect low platelet values) which can occur with automated counting of platelets. It is related to the tendency for feline platelets to aggregate and the size of some of the platelets that in this species can be similar to the size of red blood cells. Therefore, manual counting (e.g., using Thrombo Plus®-tubes, Sarstedt and a Neubauer counting chamber) or slide evaluation must always be done to confirm whether the thrombocytopenia is real or artifactual. For blood sampling it is advisable to collect the initial 1-2 ml of blood for clinical chemistry. The following blood is then collected in K-EDTA tubes for hematological evaluation. The EDTA- tubes should be carefully checked for small blood clots and the counting of thrombocytes should be completed within 30 minutes, if possible. Studies have shown that estimation of platelet numbers on stained blood smears is reliable over a wide range of platelet counts in cats. Each platelet per oil immersion field represents a circulating platelet count of approximately 20,000/µl. Obvious platelet clumps in the blood smear, however, prevent accurate determination of the platelet number per oil immersion field.
A reduced production, increased destruction or increased utilization of platelets, sequestration in the spleen, or a combination of these pathomechanisms can cause thrombocytopenia.
Clinical studies evaluating the causes for thrombocytopenia in cats are infrequently found in the literature.
The prevalence of feline thrombocytopenia (< 200,000 platelets/µl) at North Carolina State University from 1985 to 1990 was 1.2% (41/3300). Cats were divided into six categories based on clinical diagnoses: 29% had infectious disease (e.g., FeLV, FIV, FIP), 20% had neoplasia (e.g., leukemia, lymphoma, hemangiosarcoma), 7% had cardiac disease, 2% had primary immune-mediated disease, 22% had multiple diseases (e.g., FeLV, lymphoma, leukemia), and 20% had disorders of unknown etiology. The mean platelet count for all thrombocytopenic cats was 52,000/µl with a range of 1000-190,000/µl.
No significant differences were found between groups with respect to platelet count. Disseminated intravascular coagulopathy was diagnosed in 12% of the cats.
In a study performed at the Clinic for Small Animals, FU Berlin, the following diagnoses were established in 63 cats with thrombocytopenia (platelet counts 10,000-179,000/µl, median 83,000): 17 cats had viral infections (7 FIP, 3 FeLV, 4 FIV, 3 feline rhinitis), 16 had aseptic inflammation (4 fat necrosis, 4 trauma, 2 pancreatitis, 2 FLUTD, 2 hepatitis, 1 nasal polyp, 1 gastric ulcer), 10 had neoplasia (6 lymphoma, 2 leukemia, 1 fibrosarcoma, 1 hemangiosarcoma), 6 had bacterial infections (2 pneumonia, 1 cystitis, 1 pyelonephritis, 1 abscess, 1 pyometra), 3 had bone marrow disease (aplasia), 3 immune-mediated disease (1 immune-mediated hemolytic anemia, 1 primary immune-mediated thrombocytopenia, 1 Evans' syndrome), 4 cats had other diseases (1 renal failure, 1 hyperthyroidism/ cardiomyopathy, 2 hepatopathy), and 4 were random findings (routine check-up).
Other reasons for feline thrombocytopenia mentioned in the literature are drugs, e.g., propylthiouracil, methimazole, griseofulvin, albendazole, chloramphenicol, cytotoxic drugs (doxorubicin, carboplatin, azathioprine, etc.) and infections with parvovirus, Ehrlichia risticii, Anaplasma phagocytophilum, Babesia felis, Mycoplasma spp., Cytauxzoon felis, Histoplasma capsulatum.
Based on these data one of the main causes of thrombocytopenia in cats are viral infections. The mechanisms associated with thrombocytopenia during a viral infection may be multifactorial and vary with the agent. Virus induced thrombocytopenia may be caused by inhabiting precursor cells, thus reducing megakaryocytopoiesis, direct platelet damage or lysis by the virus itself, removal of platelets by the mononuclear phagocytic system, or by disseminated intravascular coagulation (DIC). Immune-mediated destruction of the platelets can be a contributing factor.
Inflammatory diseases are another important cause for decreased platelet counts in cats. In inflammatory disease states interactions of platelets with altered or damaged endothelial surfaces cause extensive platelet activation, clumping, and removal of platelets by the mononuclear phagocytic system. Platelet destruction in bacterial infections can occur as a result of platelet adherence or aggregation to activated monocytes or neutrophils. Exotoxins may directly damage platelets and contribute to thrombocytopenia. Immune-mediated destruction might contribute to thrombocytopenia in different infectious diseases.
In neoplastic disease there is a wide variety of pathomechanisms that may cause thrombocytopenia: Platelets may be sequestered in the spleen, liver, or the tumor as such; consumption of platelets may be increased (e.g., due to DIC); they may be destroyed by immune reactions, and production may be reduced due to bone marrow involvement.
In cats primary or secondary immune-mediated thrombocytopenia have rarely been described or characterized. ITP occurs as a primary or idiopathic (pITP) and as a secondary (sITP) form In sITP, infections, other immune-mediated diseases (e.g., systemic Lupus erythematosus), drugs, neoplasias, blood transfusions, or vaccination may trigger an increased production of antibodies which may adhere to or cross react with platelet receptors causing an increased destruction of platelets by the mononuclear phagocytic system. The diagnosis of a primary ITP in cats is based as in other species on the exclusion of underlying diseases, the presence of a mostly severe thrombocytopenia, the response to immunosuppressive therapy, and the presence of platelet-bound antibodies (PBA). For cats, little information is available on the application of direct or indirect methods to detect platelet-bound or anti-megakaryocytic antibodies to evaluate immunological factors in the pathogenesis of thrombocytopenia. Recently we have described flow cytometry for evaluation of PBA in cats.
The advantage of flow cytometry over other methodologies is the small amount of blood required and even in severely thrombocytopenic animals enough platelets can be recovered for reliable evaluation. Little denaturation of antigens and antibodies on the platelet membrane occurs as there is minimal sample handling and manipulation.
Platelet-bound antibodies may be antiplatelet auto-antibodies, but could also represent 'secondary' antibodies. The latter include immune complexes, which are bound to platelet Fc receptors, antibodies against platelet antigens, which are formed by modification of the antigen (e.g., caused by disease), or antibodies which bind to antigens, which were adsorbed by the surface of thrombocytes (e.g., tumor antigens, drug metabolites).
Direct PBA testing was performed in 42 thrombocytopenic cats (platelet counts 60,000-179,000/µl, median 56,000/µl). Of these 42 cats, 19 had positive PBA test results, 17 of which were considered to have secondary immune-mediated thrombocytopenia (sITP). Underlying diseases included fat necroses (4), FIP (3), FeLV (2) or FIV (2) infections, lymphoma (2), leukemia (1), hepatitis (1), pyelonephritis (1), or hyperthyroidism/cardiomyopathy (1). In 2 cats, no underlying disease was found suggesting a primary immune-mediated thrombocytopenia (pITP). The PBA test was negative in 23 cats diagnosed with varying underlying diseases and in 47 healthy control cats with platelet values within the reference range. These data suggested that immune-mediated destruction of platelets might be an important pathologic mechanism for feline thrombocytopenia caused by various underlying diseases.
In humans and small animals, spontaneous bleeding occurs rarely at platelet values > 20-30,000/µl if they do not suffer from thrombocytopathia or a coagulopathy in addition. In a study 7 out of 63 cats with thrombocytopenia displayed spontaneous bleeding. Platelet counts in these bleeding cats ranged from 10,000-57,000/µl, median 34,000/µl. 13 of 63 cats had platelet counts < 30,000/µl, 10 of these 13 cats displayed no clinical signs of hemorrhage. The 7 bleeding cats exhibited mainly surface bleeding: bleeding of the gums (4), petechiation (4), epistaxis (1), retinal and scleral hemorrhage (1). Two cats had hematomas, and one cat had abdominal bleeding. The diagnoses in these 7 cats were FIV (3), primary ITP (1), Evans' syndrome (1), leukemia (1), megakaryocytic/erythrocytic aplasia of unknown cause (1). Of the 7 cats suffering from spontaneous bleeding examined in our study, 5 resulted PBA test positive; 3 of 5 had platelet counts > 30,000/µl. It was shown in humans that PBA may alter the shape, volume, and morphology of thrombocytes, which may interfere with their function.
In another study, 9 out of 41 cats showed spontaneous hemorrhage. Bleeding was related to platelet values below 30,000/µl, and occurred in cats suffering from neoplasia (n = 5), infections with FeLV (2), pITP (1), or associated to an Eisenmenger's syndrome (1).
If bleeding occurs or not is not only dependent of the number of platelets but also of their age and functionality and of the vascular integrity. Cats might be able to tolerate very low platelet counts without showing spontaneous bleeding. This could be explained by thrombocytes of cats being activated more easily than those of dogs. Feline platelets are stimulated more readily by aggregation inductors, such as collagen or thrombin, than those of dogs. Activation of thrombocytes results in the release of serotonin. It was shown that dense-granules of cats contain 3 or 1.5 times the amount of serotonin compared to dense-granules of humans or dogs, respectively. Serotonin is a potent vasoconstrictor and induces primary aggregation of platelets. In addition, serotonin will potentiate the aggregation effect of other agonists.
Therapeutic approach in cats with thrombocytopenia depends on the underlying disease. Patients with severe thrombocytopenia should always be closely monitored for critical bleeding. Transfusion of platelets is most beneficial in thrombocytopenia caused by decreased platelet production, where the platelet life span is normal. It is less beneficial with increased consumption and sequestration and least beneficial in ITP, where transfused platelets may be rapidly destroyed. A review of transfusions at the author's clinic revealed that of 91 transfused cats four were transfused because of blood loss due to severe thrombocytopenia (Evans' syndrome, ITP, FIV infection, leukemia). In cats with acute hemorrhage due to thrombocytopenia or if surgery is necessary transfusions with fresh whole blood are recommended. If fresh whole blood is used, a rule of thumb is to transfuse 10 ml/kg, although resources may dictate a smaller dose. This amount will raise the recipient platelet count by a maximum of approx. 10,000/µl.
References
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