Platelet Disorders

This benign, inherited giant platelet disorder affects ~50% of dogs in the breed. It is characterized by thrombocytopenia with macrothrombocytes in 30% of cases and variable platelet aggregation in response to adenosine diphosphate, depending on the platelet count. No correlation has been found between macrothrombocytopenia and age, gender, neuter status, coat color, weight, or heart murmur status. The disorder is detected by a routine CBC. Affected dogs have normal coagulation protein activity.

This autosomal recessive disorder is characterized by 12-day cycles of cytopenia. All marrow stem cells are affected, but neutrophils are most affected because of their short half-life (usually <24 hr). Mild to severe thrombocytopenia can be seen, and excessive bleeding is a potential complication. The disorder is fatal; affected dogs usually die from fulminating infections before 6 mo of age. Even dogs that receive intensive antibiotic therapy usually die by 3 yr of age with amyloidosis (see Amyloidoses) secondary to chronic antigenic stimulation from recurrent infections. Treatment with recombinant granulocyte colony-stimulating factor has been temporarily successful in alleviating the neutropenic cycles until antibodies are produced against the noncanine proteins.

This disorder occurs when maternal antibodies are produced against a paternal antigen on fetal platelets. It has been reported in a 1-day-old Quarter horse foal. Immunoglobulins bound to the foal’s platelets were identified in the mare’s plasma, serum, and milk by indirect assays. The immunoglobulins were further shown to recognize platelets from the foal’s full brother, born 1 year earlier. This diagnosis should be considered for foals with severe thrombocytopenia when other causes can be excluded.

A group of lambs artificially reared and fed bovine colostrum had prolonged bleeding from puncture wounds from ear tag placement, subcutaneous bruising, weakness, and pale mucous membranes. All affected lambs died within 48 hr of birth. Thrombocytopenia was seen in whole blood, and platelets were markedly decreased on blood smears. The presence of antibodies directed against platelets was suspected because the cows from which colostrum was obtained had been used in a previous experiment in which they had been immunized against sheep blood.

This condition (also called idiopathic thrombocytopenia or idiopathic thrombocytopenic purpura is characterized by immune-mediated destruction of either circulating platelets or, less commonly, marrow megakaryocytes. It has been seen in dogs, horses, and rarely cats. Clinical signs include petechiae of the gingivae or skin and ecchymosis, melena, or epistaxis. Platelet concentration is usually <50,000/μL and often <10,000/μL at the time of diagnosis. Evaluation of megakaryocytes (by bone marrow aspiration) helps determine whether circulating platelets or marrow megakaryocytes are targeted by antibody. A test for platelet factor 3 released from damaged platelets has been unreliable or not readily available commercially. A megakaryocyte immunofluorescence assay that detects antibodies on megakaryocytes has been done, but an adequate bone marrow aspiration sample must be obtained. A direct test for the presence of antiplatelet antibodies—an ELISA that detects platelet-bound antibodies—has been reported to have good sensitivity (94%) but is not highly specific for primary immune-mediated thrombocytopenia. A negative test result likely excludes primary immune-mediated thrombocytopenia as the cause of thrombocytopenia; however, a positive test result could indicate either primary immune-mediated thrombocytopenia or secondary immune-mediated thrombocytopenia (eg, thrombocytopenia associated with autoimmune hemolytic anemia, lymphoproliferative diseases, systemic lupus erythematosus).

Affected animals should be kept at rest, and treatment is based on administration of corticosteroids, starting at a high dose and then tapering (as in the treatment of Hemolytic Anemia). Transfusion with fresh whole blood should be performed in animals with a PCV <15%; however, whole blood transfusion to replenish platelets is often futile with regard to normalization of primary hemostasis, because the platelets are removed from circulation within a couple of hours. Splenectomy should be reserved as a treatment for animals that have recurrent episodes of thrombocytopenia. Vincristine has been used to enhance the release of platelets from marrow megakaryocytes. It also coats platelets and has a cytotoxic effect on macrophages that ingest coated platelets. A single dose of vincristine at the time corticosteroids are started shortens the time to recovery of the platelet count.

Anaplasma platys, A phagocytophilum, or Ehrlichia canis infections cause mild to severe thrombocytopenia in dogs. A platys infection (see Ehrlichiosis and Related Infections) usually is characterized by mild, often cyclic thrombocytopenia in the acute stages of disease. Chronic infections often have constant mild to moderate thrombocytopenia. Morula (single to multiple, round to oval basophilic inclusions) can sometimes be identified in platelets of infected dogs. The thrombocytopenia is seldom severe enough to result in clinical bleeding tendencies. Ticks are the likely vectors. E canis infections are characterized by variable alterations in total WBC count, PCV, and platelet count. In acute infections, there is usually thrombocytopenia and possibly anemia or leukopenia. In chronic infections, there may or may not be thrombocytopenia or anemia; however, there is often leukocytosis and sometimes hyperglobulinemia (monoclonal or polyclonal). Infected dogs may have epistaxis, melena, gingival bleeding, retinal hemorrhage, hematoma formation, and prolonged bleeding after venipuncture or surgery.

A phagocytophilum infection has been documented in a wide variety of domestic and wild animals. It is characterized by fever, lethargy, and a reluctance to move. Changes in blood parameters include thrombocytopenia and lymphopenia accompanied by increased serum alkaline phosphatase and hypoalbuminemia.

Hemangiosarcoma, lymphoma, and adenocarcinoma may be associated with consumptive thrombocytopenia due to disseminated intravascular coagulation. Immunologic and inflammatory mechanisms cause increased platelet consumption and decreased platelet survival. However, bleeding tendencies without thrombocytopenia occasionally exist. Altered platelet function due to an acquired membrane defect has been associated with hyperglobulinemia. Vasculitis also may contribute to the hemostatic disorder.

Dogs vaccinated repeatedly with modified-live adenovirus and paramyxovirus vaccines may develop thrombocytopenia 3–10 days after repeat vaccination. The thrombocytopenia is usually transient and may be sufficiently mild that a bleeding tendency will not be evident unless superimposed on another platelet or coagulation disorder. Studies have failed to confirm an association between recent vaccination and development of idiopathic thrombocytopenic purpura; however, it might still occur rarely.

Thrombocytopenia associated with administration of certain drugs has been reported in dogs, cats, and horses. One mechanism is marrow suppression of megakaryocytes or generalized marrow stem cell suppression (after administration of estrogen, chloramphenicol, phenylbutazone, diphenylhydantoin, and sulfonamides). Another mechanism is increased platelet destruction and consumption (after administration of sulfisoxazole, aspirin, diphenylhydantoin, acetaminophen, ristocetin, levamisole, methicillin, and penicillin). Drug reactions are idiosyncratic and therefore unpredictable. Platelets usually return to normal shortly after the drug is discontinued. Drug-induced bone marrow suppression may be prolonged. The chemotherapy drug lomustine has sometimes caused prolonged thrombocytopenia that persists after the drug is stopped.

Quantitative platelet disorders have been reported in liver disease with or without coagulation protein deficiencies. In two studies of cats with thrombocytopenia, 29%–50% had infectious diseases, including feline leukemia, feline infectious peritonitis, panleukopenia, or toxoplasmosis. The mechanism of thrombocytopenia has not been identified in many cases. Feline leukemia virus replicates and accumulates in megakaryocytes and platelets; aplasia or hypoplasia of marrow stem cells, immune destruction of infected platelets, or extravascular sequestration of platelets within lymphoid tissues may contribute to thrombocytopenia in this disease.

This disorder, caused by a defective or deficient von Willebrand factor (vWF, also called Factor VIII-related antigen), is the most common inherited bleeding disorder in dogs (reported in nearly all breeds and in mixed breeds). It has also been reported in cats, rabbits, cattle, horses, and pigs. It is relatively frequent (10%–70% prevalence) in several breeds of dogs: Doberman Pinschers, German Shepherds, Golden Retrievers, Miniature Schnauzers, Pembroke Welsh Corgis, Shetland Sheepdogs, Basset Hounds, Scottish Terriers, Standard Poodles, and Standard Manchester Terriers. Canine von Willebrand disease is classified into three subtypes based on clinical severity, plasma vWF concentration, and vWF multimer composition. Type 1 is the most common form and is characterized by mild to moderate clinical signs, low vWF concentration, and a normal multimer distribution. Type 2 is characterized by moderate to severe clinical signs, low vWF concentration, and a loss of high-molecular-weight multimers. Type 3, seen most often in Shetland Sheepdogs and Scottish Terriers, is a severe disorder characterized by total absence of vWF. Two modes of inheritance are known. In the less common autosomal recessive pattern of inheritance, homozygosity is usually fatal, and heterozygosity results in asymptomatic carriers. In the more common inheritance pattern of autosomal dominant with incomplete penetrance, homozygotes and heterozygotes can have variable bleeding tendencies. Affected animals may have gingival bleeding, epistaxis, and hematuria. Some puppies may bleed excessively only after injection, venipuncture, or surgery, such as tail docking, ear cropping, and dewclaw removal.

vWF circulates as a complex with coagulation Factor VIII (also called Factor VIII-coagulant) and mediates platelet adhesion to subendothelial surfaces—the first step in clot formation. Defective or deficient vWF mimics disorders caused by thrombocytopenia or intrinsic platelet defects. Von Willebrand disease should be suspected in animals with clinical signs of a bleeding disorder that have normal results on coagulation screening tests (APTT and PT) and adequate platelet concentrations, long buccal mucosa bleeding time, and prolonged platelet function analysis closure times. Quantitative tests of vWF are diagnostic. Diagnosis is confirmed by identifying low vWF concentration in plasma or via DNA screening. Occasionally, affected animals may have decreased Factor VIII-coagulant and therefore have prolonged APTT and activated clotting time (ACT). Drugs known to interfere with normal platelet function should be avoided in animals with suspected disease. Transfusion of cryoprecipitate, fresh plasma, or fresh whole blood effectively alleviates a bleeding episode. Type 1 von Willebrand disease may respond to treatment with desmopressin acetate, which causes Weibel-Palade release (high-molecular-weight multimers) from the endothelium through an unknown method of action. Desmopressin may also be used in these dogs before surgery to minimize bleeding complications.

Concomitant hemostatic abnormalities may exacerbate von Willebrand disease. Hypothyroidism (see Hypothyroidism) previously had been thought to be associated with von Willebrand disease; both conditions are prevalent in many of the same breeds of dogs, eg, Doberman Pinschers and Golden Retrievers. In one study, administration of thyroid supplementation to hypothyroid dogs without deficiency of vWF did not increase vWF activity; in fact, in most of the tested dogs, vWF activity actually decreased. Therefore, administration of levothyroxine as a treatment of von Willebrand disease cannot be recommended and may even exacerbate the disease.

This autosomal recessive disorder is characterized by abnormal granule formation in leukocytes, melanocytes, and platelets (see Morphologic Abnormalities). The defect appears to be in microtubule formation; therefore, granules, which are abnormally large but reduced in number, are evident in numerous types of cells. Diluted coat color results from the defect in the melanocytes. Leukocytes may have decreased functional ability to phagocytize and kill organisms (an inconsistent finding in animals), and platelets have decreased aggregation and release reactions. Platelets are almost devoid of dense granules and have markedly decreased storage quantities of adenosine diphosphate and serotonin. Prolonged bleeding in affected blue smoke Persian cats occurs after venipuncture or surgery. The syndrome has been diagnosed in mink, cattle, and beige mice with similar bleeding tendencies.

This disorder has been described in Basset Hounds. Affected dogs have epistaxis, petechiation, and gingival bleeding. Results of studies suggest that inheritance is autosomal with variable penetrance. Platelets have abnormal fibrinogen receptor exposure and impaired dense granule release. Basset Hounds with mucosal bleeding and petechiation and normal concentrations of platelets and vWF should be suspected of having thrombopathia. Specific diagnosis of this disorder requires specialized platelet function testing. Results of the clot retraction test are usually normal.

This autosomally inherited platelet function defect is seen in Simmental cattle. Bleeding can be mild to severe in affected cattle and is exacerbated by trauma or surgery. Platelets have impaired aggregation responses. Bovine viral diarrhea virus (see Bovine Viral Diarrhea and Mucosal Disease Complex) may cause thrombocytopenia in cattle.

This autosomally transmitted disorder, previously thrombasthenic thrombopathia, has been diagnosed in Otterhounds and Great Pyrenees dogs, and in Thoroughbred-cross, Quarter horse, and Oldenburg filly horses. Affected animals have prolonged bleeding times and form hematomas at sites of venipuncture or injury. Numerous (30%–80% of all platelets), bizarre, giant platelets are seen on blood smears. Due to a decreased synthesis of either glycoprotein IIb or IIIa, the membrane receptor glycoprotein IIb-IIIa is reduced or lacking on the surface of platelets. All affected animals to date have had a defect in IIb synthesis.

Blood from affected animals does not have normal clot retraction, and the platelets do not aggregate normally after stimulation with adenosine diphosphate, collagen, or thrombin.