Platelet Disorders in Animals
Disorders of platelets can be divided into acquired or congenital thrombocytopenias and acquired or congenital functional disorders (thrombocytopathias), with acquired thrombocytopenia being the most common.
Hereditary macrothrombocytopenia is a benign, inherited giant platelet disorder that affects ~50% of Cavalier King Charles Spaniels. 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.
Cyclic hematopoiesis is an autosomal recessive disorder 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 hours). Mild to severe thrombocytopenia can be seen, and excessive bleeding is a potential complication. The disorder is fatal; affected Gray Collies usually die from fulminating infections before 6 months of age. Even dogs that receive intensive antibiotic therapy usually die by 3 years of age with amyloidosis 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. Collie breeders have successfully minimized the occurrence of this condition, and it exists now mostly in laboratory settings for study of hematopoiesis.
Fetal and neonatal alloimmune thrombocytopenia is a rare disorder that 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 developed severe thrombocytopenia with prolonged bleeding from puncture wounds from ear tag placement, subcutaneous bruising, weakness, and pale mucous membranes. All affected lambs died within 48 hours of birth. 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.
Acquired thrombocytopenias are reported frequently in dogs and cats, less often in horses, and rarely in other species. Numerous causes have been identified, most involving immune-mediated destruction of platelets.
Primary immune-mediated thrombocytopenia (ITP), (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. Middle-aged female or spayed female dogs, especially Cocker Spaniels, are over-represented. Clinical signs include petechiae of the gingivae or skin and ecchymosis, melena, or epistaxis. Platelet counts are usually <30,000/μL and often <10,000/μL at the time of diagnosis. If bleeding occurs at a platelet count >30,000, an additional coagulation abnormality may be present.
A variety of tests have been developed in an attempt to prove the presence of anti-platelet antibodies, but none has shown dependable sensitivity and specificity. Currently, a clinical diagnosis of ITP is usually made by excluding other causes of thrombocytopenia. A bone marrow aspirate can help determine whether megakaryocytes have been targeted by antibody, but it is rarely needed, because treatment and prognosis are similar whether or not megakaryocytes are decreased.
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. A single injection of vincristine (0.01-0.02 mg/kg) when starting treatment has been shown to shorten the time to recovery of the platelet count. Transfusion with fresh whole blood should be performed in animals with clinical signs related to anemia; however, whole blood or even platelet transfusions to replenish platelets are often futile with regard to normalization of primary hemostasis, because the platelets are removed rapidly from circulation. Splenectomy should be reserved as a treatment for animals that have recurrent episodes of thrombocytopenia. The platelet count should be monitored as steroids are decreased because relapses may occur. Any drugs that interfere with coagulation should be avoided. Some animals may develop adverse effects from prolonged corticosteroids, and other immunosuppressive drugs might be required.
Anaplasma platys, A phagocytophilum, or Ehrlichia canis infections, spread by ticks, cause mild to severe thrombocytopenia in dogs. A platys infection usually is characterized by mild, often cyclic thrombocytopenia in the acute stages of disease. Chronic infections often have constant mild to moderate thrombocytopenia. Morulae (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. 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 leukopenia and sometimes hyperglobulinemia (monoclonal or polyclonal). A phagocytophilum infection has been documented in a wide variety of domestic and wild animals. It is characterized by bleeding, fever, lethargy, and a reluctance to move. Changes in blood parameters include thrombocytopenia and lymphopenia. Morulae may be seen in granulocytes.
Treatment for these infections is doxycycline. Chronic E canis infections may not respond well, although some dogs can survive without clinical signs despite subnormal RBC, WBC, and platelet counts, especially in endemic areas.
Hemangiosarcoma, lymphoma, and carcinomas may be associated with consumptive thrombocytopenia due to DIC. 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.
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, 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. Studies have failed to confirm an association between recent vaccination and development of ITP, although it might occur rarely.
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.
Congenital disorders of platelet function affect platelet adhesion, aggregation, or secretion. They can be either intrinsic or extrinsic to platelets. Testing of intrinsic platelet function requires careful handling of samples and specialized equipment that is not routinely available in diagnostic laboratories; therefore, the incidence of intrinsic functional defects in platelets is not known accurately. However, if a coagulopathy exists (especially with petechiae or mucosal bleeding) with normal coagulation screening, platelet count, and von Willebrand factor, then a platelet function disorder should be suspected.
There is no specific treatment for any of the intrinsic platelet function disorders. In instances of severe hemorrhaging, fresh, platelet-rich plasma can be administered. Whole blood may be administered if the affected animal is anemic.
Von Willebrand Disease, caused by a defective or deficient von Willebrand factor (vWF, or formerly 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. Many affected dogs are asymptomatic.
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 and mediates platelet adhesion to subendothelial surfaces—the first step in clot formation. Clinical signs are most commonly mucosal bleeding, usually without evidence of petechiae or bruising seen postoperatively in some affected animals. Von Willebrand disease should be suspected in animals with clinical signs of a platelet disorder and normal coagulation screening tests (APTT and PT) and adequate platelet counts, long buccal mucosa bleeding time, and prolonged PFA-100 closure times. Buccal mucosal bleeding time is a good screening test in dogs with signs of a platelet disorder and a normal platelet count. 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 frozen plasma, or fresh whole blood effectively alleviates a bleeding episode. Type 1 von Willebrand disease may respond to treatment with desmopressin acetate, which causes release of high-molecular-weight multimers from the endothelium. Desmopressin may also be used in these dogs before surgery to minimize bleeding complications. The dose is 1 mcg/kg SC given 30 minutes before surgery.
Concomitant hemostatic abnormalities may exacerbate von Willebrand disease. 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.
Chédiak-Higashi syndrome is an autosomal recessive disorder 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.
Canine thrombopathia has been described in Basset Hounds. 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 platelet counts and vWF should be suspected of having thrombopathia. Specific diagnosis of canine thrombopathia requires specialized platelet function testing.
Bovine thrombopathia is an autosomally inherited platelet function defect 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 may cause thrombocytopenia in cattle.
Glanzmann thrombasthenia, previously thrombasthenic thrombopathia, is an autosomally transmitted disorder that 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.
Several diseases have been associated with acquired platelet function disorders. Hyperglobulinemia associated with multiple myeloma induces a platelet membrane defect resulting in impaired hemostatic function. In uremia associated with any form of renal disease, platelet adhesion and aggregation are decreased.
Numerous drugs can impair platelet function. Drugs reported to block platelet receptor binding or to change platelet membrane charge or permeability include furosemide, penicillin, carbenicillin, lidocaine, phentolamine, and chlorpromazine. Drugs that inhibit transduction of messages received at the platelet surface include caffeine, theophylline, dipyridamole, and papavarine. Drugs that inhibit execution of platelet responses (aggregation, secretion, or thromboxane production) include aspirin, indomethacin, phenylbutazone, ticlopidine, pentobarbital, and sulfinpyrazone. Clinical bleeding problems may not be caused by drug-induced impairment of platelet function unless another disorder associated with a hemostatic defect is also present.
Clinical signs of platelet disorders include petechiae, ecchymoses, mucosal bleeding, continued oozing of blood after injury or surgery
Thrombocytopenia is much more common than thrombopathia, with immune-mediated thrombocytopenia the most common cause of severe thrombocytopenia in dogs.
Von Willebrand disease is the most common cause of an abnormal buccal mucosal bleeding time in the presence of a normal platelet count.