Johanna L. Watson, Consulting Editor Johanna L. Watson • Debra Deem Morris Blood loss may be acute or chronic, and the clinical and laboratory manifestations are widely different because physiologic adaptation occurs in the chronic state. Common causes for acute blood loss include trauma (e.g., severe lacerations), surgical procedures (e.g., dehorning, castration), and erosion of the carotid artery by guttural pouch mycosis in horses. External hemorrhage is immediately obvious, but hemorrhage into a major body cavity may be occult (e.g., spontaneous rupture of the middle uterine artery, splenic rupture resulting from trauma or erosion of a major vessel by abscess, aneurysm, or neoplasia). Hemoperitoneum may induce signs of colic, and hemothorax is generally attended by dyspnea. Acute massive blood loss induces hypovolemic shock characterized by tachycardia, tachypnea, cold extremities, pale mucous membranes, muscle weakness, and eventual death resulting from cardiovascular collapse. Acute blood loss does not initially cause a change in the packed cell volume (PCV) or total plasma protein, although rapid mobilization of extracellular fluid to maintain circulating blood volume causes PCV and total plasma protein to decline within 12 to 24 hours. The severity of blood loss may be partially masked by splenic contraction, because shock causes activation of the sympathetic nervous system. Icterus is absent, and bone marrow erythroid hyperplasia is delayed by 3 to 4 days. Peripheral signs of erythroid regeneration in horses are limited to mild anisocytosis with a variable increase in mean corpuscular volume. Ruminants show erythrocyte polychromasia, basophilic stippling, Howell-Jolly bodies, and occasionally nucleated erythrocytes within 4 days of hemorrhage onset. Diagnosis of acute blood loss is based on clinical signs, evidence of recent hemorrhage, and anemia accompanied by hypoproteinemia. Hemoperitoneum and hemothorax may be suggested by ultrasound and abdominocentesis and thoracocentesis, respectively. Treatment of acute blood loss should initially be aimed at stopping the hemorrhage. External hemorrhage may be managed by pressure wraps or appropriately placed ligatures, but attempting to control internal hemorrhage when the patient is a poor risk for general anesthesia may be inadvisable, and the source of hemorrhage may not be found. Hypovolemic shock should be treated by prompt intravenous (IV) administration of 40 to 80 mL/kg of sodium-containing crystalloid solutions. Studies indicate that a small volume of hypertonic saline (2 to 4 mL/kg 7.2% sodium chloride) may temporarily reverse the pathophysiologic sequelae of severe hemorrhagic shock.1,2 The total volume of crystalloid solution required is usually much greater than the volume of blood lost, because crystalloid solutions distribute throughout the extracellular space. The clinical response to fluid administration should be evaluated in light of ongoing losses to determine the necessary replacement volume. If anemia becomes life threatening, whole blood transfusion must be considered. A PCV less than 20% in an animal with acute blood loss suggests depletion of erythrocyte reserves, and persistent reduction of the PCV over a period of 24 to 48 hours to 12% or less indicates the need for blood transfusion. A low but stable PCV (12% to 20%) does not necessitate transfusion, because transfusion should be reserved for instances in which oxygen delivery to the tissues is inadequate to support life. Blood transfusion can only be viewed as a temporary therapeutic procedure because even crossmatch-compatible allogeneic erythrocytes are removed from the circulation by the mononuclear phagocyte system (MPS) within 2 to 4 days of transfusion.3 Horses and cattle display a high degree of blood type polymorphism, and minor antigenic incompatibilities are only delineated by blood typing.4 Serum antibodies against nonhost erythrocyte antigens (erythrocyte alloantibodies) probably mediate the short lifespan of transfused erythrocytes. Compatibility testing is used to avert life-threatening antigen-antibody reactions caused by major blood group mismatching. The routine crossmatch involves incubating washed erythrocytes from donor (major) and recipient (minor) with serum from the other. Gross and microscopic examination for clumping demonstrates serum agglutinins in horses. Sensitized cattle erythrocytes do not become clumped in saline solution but do lyse in the presence of rabbit complement, so only a hemolytic crossmatch can be performed in this species. Not all equine erythrocyte alloantibodies act as agglutinins, and hemolysins must be detected by adding complement to the reaction mixture. Pooled rabbit serum must first be absorbed with equine erythrocytes to remove naturally occurring antibodies. The necessity for special handling and storage of rabbit serum makes hemolytic crossmatch procedures impractical for most veterinarians. These tests are best performed by veterinary hematology laboratories (e.g., Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis), which usually require serum and whole blood in sodium citrate or acid-citrate-dextrose (ACD) to crossmatch. The first transfusion of whole blood to a horse or ruminant not previously transfused or sensitized by immunization or pregnancy is usually well tolerated because natural alloantibodies are of low concentration and weak activity. After incompatible transfusions, alloantibodies develop rapidly, making subsequent transfusions more hazardous. Blood for transfusion should be collected aseptically into sterile containers containing sodium citrate (2.5% to 4%) or ACD solution and used immediately. The necessary dosage can only be estimated, but in most instances replacing 20% to 40% of the calculated blood loss is sufficient to maintain life until the bone marrow can respond. A drop in PCV from 36% to 12% in a 500-kg animal (8% body weight blood) represents a loss of 27 L of blood. In this case, 6 to 8 L of whole blood would be therapeutic and easily donated by another 500-kg individual. Blood warmed to 37° C (98.6° F) should be administered through an in-line filter to remove clots. After pretransfusion vital parameters have been recorded, 0.1 mL of blood/kg body weight is given over 5 to 10 minutes and the evaluation is repeated. If parameters and attitude are unchanged, the transfusion can be continued at a rate not to exceed 20 mL/kg/h. The recipient should be continuously monitored so the transfusion can be stopped if adverse reactions like tachypnea, dyspnea, restlessness, defecation, tachycardia, piloerection, muscle fasciculations, or sudden collapse occur. Although these signs may not indicate anaphylaxis, severe reactions should be treated with epinephrine (0.01 to 0.02 mL/kg, 1 : 1000). Mild signs may respond to a slowed transfusion rate or administration of corticosteroids or flunixin meglumine. Because it is often impossible to delineate the cause of transfusion reactions, the safest approach is to discontinue the blood and administer isotonic crystalloid solutions. The prognosis is good for most cases of acute blood loss if hypovolemic shock is quickly treated and bleeding stops. Normal bone marrow begins to replace lost cells within 5 days. Sequential PCV analysis will be necessary to determine whether blood loss is controlled. Examples of specific disorders follow. See Chapter 31 for an in-depth discussion of this and other respiratory diseases. Monica Aleman • Johanna L. Watson Hemoperitoneum is accumulation of blood in the abdominal cavity and can be a life-threatening problem. In the horse, associated causes are trauma, postoperative abdominal hemorrhage, neoplasia, complications from pregnancy and foaling (utero-ovarian, middle uterine, and external iliac artery rupture), organ rupture, mesenteric injury, coagulopathies, ovarian hematoma, systemic amyloidosis, and idiopathic hemoperitoneum.5–11 The underlying cause is identified in the majority of cases (78%).11 Trauma (spleen and in mares, reproductive tract with associated vessels) and neoplasia are the most common causes of hemoperitoneum.7,11 A recent retrospective study of 67 horses with hemoperitoneum revealed that Thoroughbreds and Arabians were overrepresented breeds.11 Middle-aged and older horses (>13 years of age) and females may be overrepresented.10,11 The most common clinical signs include abdominal discomfort, lethargy, hypovolemic shock, pale mucous membranes, prolonged capillary refill time, tachycardia, and tachypnea.10,11 Other clinical signs are anorexia, reluctance to move, weakness, trembling, cool extremities, and abdominal distention.10 Clinicopathologic abnormalities include anemia, neutrophilia, lymphopenia, thrombocytopenia, hypoproteinemia, hypocalcemia, and azotemia.10 Abnormalities in clotting parameters may be observed, depending on the cause. Hemorrhagic abdominal effusion is characterized by high red blood cell (RBC) count (>2,400,000 RBC/µL), PCV (≥18%), and total protein (≥3.2 g/dL), with a normal to high leukocyte count.10 Central venous pressure and blood lactate concentration appear to be early indicators of hypovolemia due to acute blood loss.12 Fluid swirling and site of hemorrhage may be evident on abdominal ultrasound. Primary goals of therapy are treating hypovolemic shock, restoring perfusion and oxygen delivery to tissues, correcting fluid deficits, stopping further blood loss, and preventing complications. Blood transfusion should be considered if anemia becomes life threatening. The use of antifibrinolytic and procoagulant agents have been reported in the literature, but controlled studies on efficacy and safety in the horse with acute blood loss are lacking. Physical activity must be restricted in affected patients. The short-term outcome is strongly associated with the underlying cause.11 Horses with neoplasia, uterine artery rupture, mesenteric injury, or disseminated intravascular coagulation (DIC) have a greater risk of not surviving. The survival rate has been reported to range from 51% to 74%.10,11 Poor short-term outcome was significantly associated with high respiratory rate in one study.11 Prepartum hemorrhage appears to be associated with a poorer prognosis than postpartum hemorrhage (100% vs. 20% mortality, respectively).11 Hemothorax may occur secondary to trauma (including lung biopsy), neoplasia, and strenuous exercise (see Chapter 31).13 Hemothorax in neonatal foals may be the result of lacerated lungs and vessels from fractured ribs (see Chapter 20).14 Exercise-induced pulmonary hemorrhage (EIPH) has not been identified as a major cause of blood loss. EIPH is associated with high-intensity exercise in horses. An estimated 14% to 75% of racehorses examined by endoscopy have EIPH.15 Based on bronchoalveolar lavage analysis, a study suggested that 100% of horses performing strenuous exercise have EIPH.16 EIPH has been reported in various breeds. A recent study reported that the frequency of EIPH is associated with race type, distance, gender, and age. In one study, epistaxis was more common in females, older horses (vs. <2 years of age), following steeplechase races (vs. flat races), and at shorter distances (≤1600 m long).17 Recurrence rate in that study was reported to be 4.64%. The pathophysiology of EIPH is not completely known. For a complete description of this disorder, see Chapter 31. Johanna L. Watson • Debra Deem Morris A number of diseases can result in chronic loss of blood that is insidious until clinical signs of anemia develop. Physiologic adaptation to gradually developing tissue hypoxia generally masks signs of anemia until the PCV is less than 15%. Causes for chronic blood loss include bleeding gastrointestinal (GI) lesions, certain renal diseases, hemostatic dysfunction, bloodsucking external parasites, and haemonchosis (especially in goats and sheep). GI hemorrhage is usually caused by neoplasia (especially gastric squamous cell carcinoma in horses and abomasal lymphoma in cattle), parasitism, or mucosal ulceration (e.g., abomasal ulcers in cattle and nonsteroidal antiinflammatory drug [NSAID] toxicity in horses). Significant hemorrhage may occur in ruminants heavily infested with Haemonchus contortus shortly after they are treated with an anthelmintic. Generally, GI hemorrhage is best detected by chemical determination of fecal occult blood, because melena rarely occurs in horses, and bleeding abomasal ulcers cannot be excluded in cattle when melena is absent. Because of the low specificity of tests for fecal occult blood, the diagnosis of chronic GI blood loss is usually supported by strong clinical suspicion and ruling out other sources of hemorrhage. Although both renal calculi and renal papillary necrosis due to NSAID therapy cause hematuria, anemia rarely results. Renal neoplasia and congenital renal vascular anomalies are rare causes of chronic blood loss anemia. Other causes of blood loss include idiopathic hematuria and idiopathic recurrent hematuria of Arabian horses. Disorders of hemostasis can cause internal or external hemorrhage that leads to anemia if enough blood is lost. Qualitative or quantitative abnormalities of blood vessels, platelets, or coagulation factors result in hemostatic dysfunction (see next section). Loss of erythrocyte iron secondary to chronic severe blood loss may result in iron deficiency anemia. Hypoferremia or reduced serum ferritin develops with increased total iron-binding capacity and reduction in marrow iron. The key to managing chronic blood loss is determining the primary cause; treatment of the anemia per se is rarely indicated. Iron deficiency may be alleviated by oral (PO) supplementation with ferrous sulfate, although good-quality forages contain more than adequate amounts of iron. Parenteral iron supplementation as iron dextran should be avoided because it has been associated with anaphylactoid reactions in large animals. Examples of specific disorders follow. Monica Aleman • Johanna L. Watson Gastric ulceration is also known as equine gastric ulceration syndrome (EGUS). Although EGUS is not an important cause of blood loss, it has a high prevalence among adult horses. Thoroughbred racehorses have the greatest prevalence (range, 82% to 93%), followed by endurance horses (67%), show horses (58%), hospitalized horses (49%), and geriatric patients with abdominal pain (18%).18–22 Gastric ulcers were found in 66.6% of pregnant and 75.9% of nonpregnant mares on a Thoroughbred breeding farm.23 Clinical signs may include poor hair coat, decreased appetite, poor performance, nervous disposition, abdominal pain, teeth grinding, and salivation among others. Proposed causes of gastric ulceration include exercise, transportation, grazing deprivation, alternating periods of feeding and fasting, diets with high-concentrate content, and confinement. For a complete description of gastric ulceration see Chapter 32. Right dorsal colitis (RDC) is an enteropathy associated with NSAID administration, most commonly phenylbutazone.24,25 Other factors that may predispose to RDC are infection, immune-mediated response, genetics, and stress; pathogenesis is unknown. NSAIDs act by inhibiting cyclooxygenase (more inhibition of constitutively expressed COX-1 than inducible COX-2 expression during states of inflammation), which will cause inhibition of prostaglandin E production, resulting in hypoxic or ischemic GI mucosal damage and delayed mucosal healing.25 Ponies and young performance horses appear to be predisposed. Clinical signs include inappetence, lethargy, intermittent or episodic colic, diarrhea, and weight loss. Clinicopathologic abnormalities may include mild anemia, moderate to severe hypoproteinemia with hypoalbuminemia, hypocalcemia, and in some cases azotemia. Although mild anemia is seen in most cases, horses occasionally present with severe anemia and hematochezia. RDC often develops over a period of days or a few weeks. The complete discussion of diagnosis and treatment is included in Chapter 32. Johanna L. Watson • Debra Deem Morris The basis for understanding the pathogenesis and manifestations of hemostatic disorders is a thorough understanding of the normal physiologic mechanism of hemostasis. Hemostasis can be viewed as two interrelated components—coagulation and fibrinolysis (both with their respective inhibitors)—which function to arrest bleeding from a damaged blood vessel and maintain nutrient blood flow. Coagulation is mediated by blood vessels, platelets, and blood procoagulant proteins. When a blood vessel is damaged, vasoconstriction occurs, followed by rapid adherence of platelets to subendothelial collagen. Platelet adhesion causes membrane conformational changes that trigger aggregation, contraction, and granule secretion (the basic platelet reaction). Platelet phospholipoprotein (platelet factor 3) provides the necessary surface to catalyze interactions among the activated coagulation proteins that result in thrombin formation. Coagulant proteins are localized to this hemostatic plug because the platelet surface protects them from plasma anticoagulants. Through an incompletely understood mechanism, platelets also prevent spontaneous hemorrhage into the skin and mucous membranes by maintaining vascular integrity. Procoagulant proteins circulate in the blood as precursor forms (zymogens) that must be altered during coagulation to become active. Numerous communications exist between the traditional extrinsic and intrinsic pathways, although initiating mechanisms remain distinct.26 The extrinsic system is initiated when lipoprotein tissue factor (TF) gains access to the bloodstream. TF is widely distributed in most tissues, including endothelial cells and monocytes, and it may be increased or secreted in response to numerous pathologic stimuli like bacterial endotoxin. Intrinsic coagulation is initiated when blood is exposed to a negatively charged surface (e.g., activated platelets). Because of reciprocal activation between factor XII and prekallikrein, the intrinsic coagulation pathway stimulates formation of numerous inflammatory mediators such as kinins and complement. Both coagulation pathways culminate in the formation of activated factor X (Xa) by which thrombin is generated. In addition to catalyzing the conversion of fibrinogen to fibrin, thrombin promotes platelet aggregation, enhances cofactor activities of factors V and VIII, and activates factor XIII and protein C.27 Mechanisms to localize coagulation to the site of vascular injury are critical to protect against generalized thrombosis.28 Plasma anticoagulant proteins include the serpins, which inhibit activated coagulation factors, and the protein C system, which is directed against cofactors V and VIII.29 Antithrombin III (AT III), the main physiologic inhibitor of thrombin and Xa, normally provides 70% of the anticoagulant activity of plasma. Although not absolutely necessary, heparin accelerates AT III action by 2000-fold.30 Activated protein C destroys factors V and VIII, ultimately limiting its own activation, which depends on thrombin and endothelial cofactor, thrombomodulin. Protein S enhances the anticoagulant ability of protein C. The fibrinolytic system is activated at the same time as coagulation and functions to prevent tissue ischemia by limiting the extent of fibrin clot formation. Plasmin, primarily responsible for degradation of fibrin, exists in the plasma as the zymogen plasminogen. Plasminogen has a high affinity for fibrin, as does tissue plasminogen activator (tPA); because clots contain the necessary components to allow lysis from within, systemic plasmin formation is avoided. α2-Antiplasmin (α2-AP), the main physiologic inhibitor of plasmin, competes with the binding of plasminogen to fibrin, and the clot contains equal amounts of both glycoproteins. Because of this molar balance between α2-AP and plasminogen, a normal blood clot does not lyse spontaneously, despite fixation of tPA. Physiologic plasminogen activator inhibitors (PAIs) are found in plasma, platelets, and endothelial cells; platelet-derived PAI protects a blood clot against premature lysis. Clot lysis is initiated if additional tPA is taken up from the surrounding tissues, and stasis upstream from the occluded vessel is a potent stimulus for release of endothelial tPA. Conversion of plasminogen to plasmin allows partial digestion of fibrin and exposure of additional plasminogen binding sites. When this additional plasminogen is converted to plasmin, the inhibitory effect of α2-AP is overcome, and clot lysis is accelerated. Plasmin hydrolyzes fibrinogen and fibrin with equal affinity, as well as numerous other procoagulants, and it can activate complement and kininogen. The physiologic actions of plasmin are limited to the fibrin clot by the affinity between the latter and plasminogen and the presence of α2-AP in blood. Because of multiple interactions between the coagulation and fibrinolytic systems, the most important factor that determines the rate of fibrinolysis is the rate of fibrin formation.31 Jeffrey W. Norris The presentation of patients with reductions in protein levels or activity associated with the traditional coagulation pathways may range from asymptomatic to severe prolongation of bleeding subsequent to trauma, including that associated with diagnostic procedures, surgery, and parturition. Other signs of pathologic hemorrhage associated with coagulation factor deficiency include subcutaneous hematomas, hemarthroses, epistaxis, melena, or hematuria. Several coagulation factor deficiencies have been described in domestic herd animals. Prekallikrein, or Fletcher factor, deficiency has been described in both Miniature1 and Belgian horses.2 Conversion of prekallikrein to kallikrein is traditionally thought of as initiating the intrinsic pathway of coagulation through activation of factor XII. Recent studies have demonstrated that prekallikrein and factor XII are critical factors in thrombosis but not hemostasis.3,4 This subtle role of prekallikrein in the coagulation system is consistent with observations that many patients with prekallikrein deficiency are asymptomatic, but bleeding in response to trauma (e.g., surgery) is possible.2 The inheritance pattern of this deficiency and the causal mutation have not been determined. The second step of the intrinsic pathway of coagulation is activation of factor XI by activated factor XII. Factor XI deficiencies have been reported in Holstein,5 Holstein-Friesian,6 and Japanese Black cattle.7 The deficiency has been reported in Canada,5 Britain,6 the United States,8 Poland,9 Turkey,10 and Japan.7 Factor XI deficiency in cattle is transmitted as an autosomal recessive trait.11 Most cases result from a 76–base pair (bp) insertional mutation in exon 12 of the F11 gene,8 but a 15-bp insertional mutation in exon 9 of the F11 gene has also been identified in a group of Japanese Black cattle.7 Estimates of the prevalence of the former mutant gene allele are approximately 1.2%,8,12 but the latter mutant allele may have a prevalence as high as 23.1% in Japanese Black cattle.13 Cattle with factor XI deficiency may be asymptomatic or present with a range of signs that includes prolonged bleeding, reduced resistance to infection (particularly mastitis, metritis, and pneumonia),11,14 and an increased prevalence of repeat breeding, possibly due to a slower estrus cycle.15 Distribution of this deficiency within a family group is best determined by genetic analysis because there is poor segregation in factor XI plasma levels between normal and heterozygous cattle.16 Factor VIII deficiency, or hemophilia A, has been reported in a range of breeds, including Quarter Horses,17 Japanese Brown cattle,18 and Hereford cattle.19 Congenital factor VIII deficiency is X-linked and recessive, with clinical disease occurring predominantly in males, although homozygous females or heterozygous females with X inactivation may also be affected. A leucine-to-histidine mutation leading to the deficiency was recently found in the F8 gene of Japanese Brown cattle.20 Factor VIII levels of 5% or less are considered to be moderate to severe hemophilia and may predispose patients to spontaneous hemorrhage; a less severe deficiency may lead to excessive hemorrhage only after trauma. Factor VIII is stabilized in circulation via non-covalent association with von Willebrand factor, which also promotes platelet-endothelial adhesion at sites of vascular injury. Deficiency of von Willebrand factor has been reported in a Quarter Horse filly that had hemorrhage from mucosal surfaces following trauma.21 A combined deficiency of the vitamin K–dependent coagulation factors (factors II, VII, IX, and X) was reported in a family of Rambouillet sheep.22 Signs included excessive subcutaneous bleeding and bleeding from the umbilicus in newborn lambs following parturition. Evidence that (1) affected lambs were consistently produced by a single sire in the flock and (2) failure to identify a known vitamin K antagonist in affected lambs was consistent with an inherited disorder. Breeding data from the study supported an autosomal recessive mode of transmission. The molecular defect underlying this coagulopathy is unknown, but mutations leading to altered vitamin K metabolism or γ-glutamyl carboxylase function are possible. A second combined deficiency with moderate decreases of factors VIII, IX, and XI was reported in an Arabian colt.23 Factors VII and prothrombin were also moderately reduced in this colt, but no abnormalities were apparent in plasma from the sire, mare, or other half-siblings, raising the possibility of an acquired coagulopathy. Additional differential diagnoses for coagulation factor deficiencies include DIC, warfarin toxicosis (horses), moldy sweet clover toxicosis, and acute hepatic disease. The heritable clotting factor deficiencies involve proteins in the intrinsic pathway, and prolonged activated partial thromboplastin time (APTT) is the primary hemostatic abnormality. However, multifactor defects in the vitamin K–dependent coagulation factors (e.g., that described in Rambouillet sheep22) and acquired coagulation factor deficiencies also involve proteins in the extrinsic or common pathways of coagulation, which will cause a trend toward prolongation of both the prothrombin time (PT) and APTT. Except as noted for factor XI deficiency in cattle, the definitive diagnosis of heritable clotting factor deficiencies is based on specific quantitative assays of those factors. Heritable clotting factor deficiency is treated by replacing the factors through the administration of fresh plasma. Specific clotting factor concentrates are not commercially available for large animals, and development of such products is unlikely because of the rarity of these disorders. The expense of therapy and potential for complications makes the long-term prognosis poor for horses with hemophilia A or animals with multiple congenital coagulation factor defects. Cattle with factor XI deficiency apparently have a normal lifespan but may require treatment for secondary diseases like infection, owing to their increased susceptibility. Jeffrey W. Norris • Monica Aleman Glanzmann thrombasthenia is a rare, inherited platelet defect caused by either a quantitative or qualitative change in the platelet glycoprotein complex IIb-IIIa (integrin αIIbβ3). This complex is made from two subunits encoded by separate genes that must both be expressed to form stable, functional heterodimers on the platelet surface. This complex is the receptor that binds fibrinogen and mediates platelet aggregation. Glanzmann thrombasthenia has been documented in humans and dogs.1,2 Of the six reports of thrombasthenia in the horse,3–7 four have been confirmed to be Glanzmann thrombasthenia by genetic analysis. Interestingly, mutations associated with Glanzmann thrombasthenia in horses have only been found in the αIIb subunit. An 18-month-old Oldenburg filly was shown to be homozygous for a G-to-C mutation of codon 72 in exon 2 that causes an arginine-to-proline substitution.8 A similar G-to-C mutation, also causing an arginine-to-proline substitution, was identified at codon 41 in exon 2 of both a 7-year-old Thoroughbred cross gelding that was homozygous for the mutation, and a 4-year-old Quarter Horse mare that was heterozygous.9 Both arginine-to-proline mutations occur in a single highly conserved portion of the αIIb gene and are expected to destabilize the protein structure, leading to an absence of the complex on platelet surfaces.9 Further analysis of the Quarter Horse mare revealed a 10-bp deletion in the second αIIb allele that spanned the distal (5′) exon 11 splice site and likely led to decay of the mRNA transcribed from the allele.10 This deletion was also identified in a 17-year-old Peruvian Paso that was homozygous for the mutation.7 The prominent clinical sign of Glannzman thrombasthenia in the horse is chronic intermittent epistaxis unrelated to exercise. Other signs include petechial and ecchymotic hemorrhages in the nasopharynx. Conclusive diagnosis usually requires nonstandard testing procedures. Clinical biochemistry may indicate mild anemia in the face of normal platelet count, activated coagulation time, partial thromboplastin time (PTT), PT, thrombin time, fibrin degradation products, and plasma concentration of von Willebrand factor. However, gingival bleeding time is prolonged (>60 minutes, control horses <2 minutes), clot retraction is markedly reduced, and platelet aggregation in response to various agonists as measured by aggregometry is markedly impaired. Closure time measured using a PFA-100 analyzer with collagen/ADP cartridges is markedly prolonged.6 Also, the amplitude of thromboelastograph (TEG) tracings may be reduced, consistent with weakened tensile strength of kaolin- or tissue factor–induced clots.6 Flow cytometric studies using CD41/CD61 monoclonal antibodies have revealed a reduction in αIIbβ3 integrin on platelet surfaces.5 Currently, no treatment is available. Superficial cauterization of bleeding sites in nasal mucosa using silver nitrate swabs and a CO2 laser has been attempted but provided only temporary hemostasis.7 Clients have been advised to be observant for signs of bleeding requiring supportive care; regular monitoring for anemia is recommended.7 Severe intermittent bleeding was reported in a 2-year-old Thoroughbred filly subsequent to minor insults.11 Platelet concentration, PT, PTT, antithrombin III, and the coagulation factors (von Willebrand, VIII, IX, XI, and XII) were unremarkable. Several integral platelet membrane glycoproteins involved in aggregation and clotting, including GPIb, GPVI, and αIIbβ3, were present on platelets from this filly. The filly’s template bleeding time was over 120 minutes, compared to 5.5 minutes in control horses. Platelet-rich plasma aggregated normally in response to a range of agonists (ADP, thromboxane A2) but was prolonged in response to thrombin and collagen.12 Consistent with the reduced aggregation in response to thrombin, fibrinogen binding to platelets from the filly was markedly decreased in comparison to control platelets.12 Platelets from this filly also had reduced prothrombinase activity, which reflects decreased thrombin activation and catalysis of fibrinogen polymerization. Reduced fibrinogen binding and prolongation of the template bleeding time was also observed in one of two offspring from the affected mare. In a screen of 444 randomly selected horses from a single breeding facility, a normal distribution of fibrinogen binding was established for equine platelets, and 0.7% of the population was found to have reduced levels of fibrinogen binding (67.6% to 83.4% reduction) that were comparable to the affected mare and offspring.13 Unlike Glanzmann thrombasthenia, in which platelets lack the ability to bind fibrinogen entirely, the αIIbβ3 integrin on platelets from horses with this bleeding diathesis functions normally. Therefore, acute bleeding in established cases has been managed by stabilization of clotting through inhibition of fibrinolysis using ε-aminocaproic acid. Monica Aleman • Johanna L. Watson Acquired defects of hemostasis may be divided into those involving blood vessels, platelets, and coagulation factors, although some diseases affect more than one component. Vasculitis is a clinicopathologic process that involves inflammation and necrosis of blood vessel walls, regardless of size, location, or cause.1 Vasculitis in large animals is generally a secondary manifestation of a primary infectious, toxic, or neoplastic disorder and has characteristics of hypersensitivity vasculitis in humans. The predominant involvement of small vessels in the skin (e.g., venules, arterioles) is the hallmark of hypersensitivity vasculitis. Clinical manifestations of vasculitis include demarcated areas of dermal or subcutaneous edema that may progress to skin infarction, necrosis, and exudation.2 Hyperemia, petechial and ecchymotic hemorrhages, and ulceration of mucous membranes are common. Although the skin and mucous membranes are predominantly involved, hemorrhage and necrosis may occur in any organ system, resulting in conditions like lameness, colic, dyspnea, and ataxia. Subclinical renal disease is not uncommon. Vasculitis is often attended by a number of adverse sequelae such as cellulitis, thrombophlebitis, laminitis, and pneumonia. Characterized vasculitis syndromes with predominant cutaneous involvement include equine purpura hemorrhagica (EPH), equine viral arteritis (EVA), equine infectious anemia (EIA), and equine granulocytic ehrlichiosis (EGE). There are also a number of vasculitis syndromes in horses for which cause, pathogenesis, and clinical course are poorly defined.3,4 Vasculitis is apparently uncommon in ruminants but may accompany certain septicemic diseases (e.g., malignant catarrhal fever of cattle, bluetongue of sheep).5 Hematologic and serum biochemical findings in vasculitis are determined by the underlying disease, length of illness, organ involvement, and secondary complications. Chronic inflammation may be attended by neutrophilia, mild anemia, hyperglobulinemia, and hyperfibrinogenemia. Some horses with EPH develop a moderate anemia (PCV 20% to 25%) that is thought to be caused by increased erythrocyte destruction.6 The platelet count is generally normal. Muscle damage may be reflected by increased serum concentrations of creatine phosphokinase (CPK) and aspartate aminotransferase (AST). The creatinine may be elevated, and urinalysis may rarely show trace hematuria or proteinuria if there is glomerulonephritis. Definitive diagnosis of vasculitis is made by demonstration of the characteristic histopathology of involved vessels. Full-thickness punch biopsies (at least 6 mm in diameter) of skin in an affected area should be obtained and preserved in 10% formalin and Michel’s transport medium. Multiple biopsies from different sites may be necessary to reach the diagnosis. The most common inflammatory pattern is neutrophilic infiltration of venules in the dermis and subcutaneous tissue, with nuclear debris in and around involved vessels (leukocytoclasis) and fibrinoid necrosis. Immunofluorescence on biopsies preserved in Michel’s medium may reveal immune complexes. Considerable evidence suggests that most vasculitis syndromes are mediated by immunologic mechanisms—that is, a hypersensitivity reaction to a microbe, drug, toxin, or protein.1 In some instances an exogenous stimulus cannot be identified, and an autoimmune pathogenesis is suspected. Immune complex deposition in vessel walls, with subsequent complement activation and chemoattractant production, seems to be the major pathogenic mechanism. Infiltrating neutrophils and macrophages release proteolytic enzymes that cause vessel wall necrosis with subsequent edema, hemorrhage, and infarction of supplied tissues. Size and physiochemical properties of immune complexes, blood flow turbulence in sites of vessel bifurcation, and hydrostatic forces in dependent areas account for preferential formation of lesions in certain disease states and anatomic locations. Horses and cattle with idiopathic vasculitis may have incomplete response to therapy with an unpredictable poor prognosis.5,6 Equine Purpura Hemorrhagica. Purpura hemorrhagica (PH) is a noncontagious disease of horses characterized by vasculitis leading to extensive edema and hemorrhage of the mucosa and subcutaneous tissue. The disease has been recognized as a sequela to infection with or exposure to Streptococcus equi, Streptococcus zooepidemicus, Rhodococcus equi, Corynebacterium pseudotuberculosis, and others, and vaccination against S. equi.2,7 Young to middle-aged horses are commonly affected (mean, 8.4 years of age; range, 6 months to 19 years).7 Clinical signs usually develop acutely within 2 to 4 weeks of a respiratory infection.8 Predominant signs are well-demarcated subcutaneous edema of all four limbs, lethargy, anorexia, hemorrhages on mucous membranes, fever, and tachycardia. Other signs are tachypnea, reluctance to move, serum exudation from the skin, colic, and epistaxis. The predominant laboratory abnormalities include anemia, neutrophilia, hyperproteinemia, hyperfibrinogenemia, hyperglobulinemia, and elevated muscle enzymes. Thrombocytopenia is rarely detected in horses with PH. Skin biopsy shows evidence of acute leukocytoclastic or non-leukocytoclastic vasculitis with necrosis of blood vessels. The lesions are marked dermal and subcutaneous hemorrhage, protein-rich edema, and multifocal areas of dermal infarction. Small arteries and capillaries are swollen and infiltrated by degenerate or nondegenerate neutrophils. Hyaline thrombi may be observed.7 Immune complexes have been demonstrated to be primarily composed of immunoglobulin (Ig)M or IgA and streptococcal M protein and may be present in capillaries and small blood vessels of horses with PH, leading to a type III hypersensitivity reaction.9 Deposition of immune complexes in vessel walls and subsequent complement activation may result in cell death. Extensive hemorrhages in the dermis, subcutis, skeletal muscles, lungs, kidneys, spleen, intestinal walls, and blood vessels have been observed in postmortem examination. Horses with infarctive PH can present with colic, lameness, muscle swelling, and stiffness.10 Extensive GI infarction results in severe colic signs. Significant findings in these horses include leukocytoclastic vasculitis and necrosis of various tissues, neutrophilia with a left shift, hypoalbuminemia, and high serum creatine kinase.10 Treatment should aim to address the primary cause if identified, reduce the immune and inflammatory response, initiate antimicrobial therapy in cases of active infection or prevent infection if indicated, provide supportive care, and prevent complications. Horses with known streptococcal infection should receive penicillin (22,000 IU/kg of intramuscular [IM] procaine penicillin G twice daily, or IV potassium penicillin G q6h) or other antibiotic with excellent efficacy against streptococcal organisms for at least 2 weeks. Hydrotherapy, limb bandages, and light exercise (hand walk) have been helpful in reducing limb edema. Fluids administered IV or via nasogastric tube may be necessary for animals that become severely lethargic and fail to drink or those that develop dysphagia from laryngeal edema. Stridor and dyspnea may indicate the need for tracheostomy. Prolonged treatment with corticosteroids (2 to 4 weeks) has resulted in favorable outcome and low relapse rate. However, some horses may require a longer course of therapy than 4 weeks. Depending on severity of clinical signs, proposed dosages are 0.04 to 0.2 mg/kg of dexamethasone (IV, IM, or PO) once (morning) or twice a day, or 0.5 to 1 mg/kg of prednisolone PO once (morning) or twice a day (0.05 to 1 mg/kg), with gradual reduction of the dosage.7 It has been suggested that antimicrobials be used throughout the course of corticosteroid therapy to reduce the occurrence of secondary sepsis.2 Outcomes will depend on early detection, early aggressive treatment, and extent of organ involvement. Skin sloughing, laminitis, cellulitis, pneumonia, and diarrhea are common and may significantly prolong convalescence. The prognosis is fair with early aggressive therapy and supportive care; a recent retrospective study of 53 horses with purpura hemorrhagica reported a mortality rate of 7.5%.7 Equine Viral Arteritis. Equine viral arteritis (EVA) is an infectious disease characterized by panvasculitis, edema, hemorrhage, and abortion in pregnant mares. EVA is caused by an enveloped, spherical, positive-stranded RNA virus with a diameter of 50 to 70 nm. Equine arteritis virus (EAV) is a nonarthropod-borne virus classified as a member of the new order Nidovirales within the family Arteriviridae.11 EAV was first isolated from fetal lung collected during an epizootic of abortion in Bucyrus, Ohio.12 Clinical signs may be absent or may develop 1 to 10 days after infection and include pyrexia, lethargy, anorexia, limb edema, stiffness, rhinorrhea, epiphora, conjunctivitis, rhinitis, and abortion. Edema of several regions can be observed, including periorbital, supraorbital, ventrum, mammary gland, scrotum, and limbs.13 Other signs include urticarial rash, abortion, respiratory signs, ataxia, mucosal eruptions, submaxillary lymphadenopathy, and intermandibular and shoulder edema. EAV can present as epidemic abortion, with occasional fatalities in foals and adults. With natural exposure, abortion rate varies widely (<10% to >60%) and can occur from 3 to 10 months of gestation.14 Infected mares do not become EAV carriers or chronic shedders and do not appear to have fertility problems. Laboratory abnormalities are variable and not diagnostic for EVA. Experimentally infected mature horses had a consistent leukopenia due to neutropenia and lymphopenia.15 After infection, EAV can be localized in macrophages and lymph nodes within 24 and 48 hours, respectively. Various tissues are affected, but blood vessels are the principal target of EAV. Within vessels, EAV localizes in endothelium, medial myocytes, and pericytes. The virus causes vasculitis with fibrinoid necrosis of the tunica media, abundant vascular and perivascular lymphocytic and lesser granulocytic infiltration with karyorrhexis, loss of endothelium, and formation of large fibrinocellular stratified thrombi.13 Body cavity effusion is common. The virus is mainly transmitted through aerosols from respiratory, urinary, or reproductive tract secretions of acutely infected animals. The other route of transmission is via semen from shedding stallions; the virus remains viable in fresh, chilled, and frozen semen.14 Horizontal transmission via fomites is possible.16 Natural EAV exposure results in long-term immunity to the disease. Mares and geldings eliminate virus within 60 days, but 30% to 60% of acutely infected stallions will become persistently infected, temporarily or permanently shedding virus in semen.13 The virus is maintained in the accessory organs of the male reproductive tract (ampullae, vasa deferentia).14 Seroprevalence for EAV is very common in the Standardbred and warmblood breeds and, more recently, EAV infection has been established within some Quarter Horse populations.17 Laboratory diagnosis of EVA can be based on virus isolation, viral nucleic acid detection (polymerase chain reaction [PCR] assay), or serology. In the case of serology, a fourfold or more increase in serum neutralizing antibodies between acute and convalescent samples (3 weeks apart) is required for diagnosis. Stallions with positive titers of 1 : 4 should be tested for persistent infection by virus isolation from sperm-rich ejaculate.14 Viral isolation and PCR can be attempted from respiratory secretions or fetal and placental tissues. Semen can be tested for viral shedding by culture, isolation, or PCR. Identification of carrier stallions is crucial in preventing dissemination of EAV. A modified live vaccine is commercially available (Arvac [Fort Dodge Animal Health, Livestock Division, Overland Park, Kan.]). Vaccination will result in development of a serum titer that will be detected on EVA testing and cannot be distinguished from active infection. Horses vaccinated for the first time should have serum submitted to a U.S. Department of Agriculture (USDA)-approved laboratory to confirm seronegative status. After vaccination, these animals should be isolated because they may temporarily shed the modified virus. Equine Infectious Anemia. See section on hemolytic anemia. John E. Madigan • Johanna L. Watson Definition and Etiology Equine granulocytic ehrlichiosis (EGE) was first reported in the late 1960s in the foothills of Northern California.1 The disease is caused by Anaplasma phagocytophila. This organism was formerly known as Ehrlichia equi, but it was reclassified in the Anaplasma genus based on genetic analysis.2 Recently, the agents of human granulocytic ehrlichiosis (HGE), Ehrlichia phagocytophila and E. equi, were grouped into a single species and named A. phagocytophila.2 These organisms are identical based on 16S rRNA gene sequences, and they have similar morphology, host cell tropism, and indirect fluorescent antibody (IFA) response.3 The organism is found within vacuoles (1.5 to 5 µm in diameter) in the cytoplasm of infected granulocytes, primarily neutrophils and eosinophils. These vacuoles or inclusion bodies are pleomorphic and contain one or more coccobacillus or large granular aggregates called morulae. The organisms are visible under light microscopy as deep blue to pale blue gray with Giemsa or Wright-Leishman stains. Epidemiology Since the disease was first reported in California,4 cases have been diagnosed in Colorado, Connecticut,5 Florida, Illinois, Minnesota, New Jersey, New York, Oregon, Washington, Wisconsin, Canada, Brazil, northern Europe, and Israel. Equine cases occur during late fall, winter, and spring. There is no apparent gender or age predilection, but the disease appears to be less severe in younger horses. Persistent, chronic, or latent infections or carrier status have not been demonstrated and are unlikely to occur, since the presence of A. phagocytophila is limited to the acute phase. Therefore, it is also unlikely that infected horses could serve as reservoirs. The disease is not contagious but could be readily transmitted through the administration of infected blood. The vectors of granulocytic ehrlichiosis are Ixodes pacificus in California, Ixodes scapularis in the eastern and midwestern United States, and Ixodes ricinus in Europe.6–9 Potential or proposed reservoirs are white-footed mice, chipmunks, white-tailed deer, dusky-footed wood rats, cervids, lizards, and birds.9 Pathogenesis The pathogenesis of the disease is unknown. Entry of the organism occurs after inoculation from a biting tick and is presumed to be spread via blood and/or lymph. The organism has cell tropism toward neutrophils and eosinophils, where it replicates within vacuoles, forming characteristic morulae. Presumed cytolysis, induction of inflammation, cell sequestration, consumption, or destruction result in the observed clinical signs and pancytopenia.10 Cell- and humoral-mediated immune responses develop in affected animals. Antibody titers peak at 19 to 81 days after the onset of clinical signs, and immunity likely persists for a long period of time (>2 years).11 Clinical Signs Clinical signs include reluctance to move, fever ranging from 39.4° to 41.3° C (102.9° to 106.3° F), mild to moderate tachycardia (50 to 60 beats/min [bpm]), lethargy, decreased appetite, limb edema, petechiation, icterus, weakness, ataxia, and recumbency (reported in one case). Secondary trauma may result from falling in severely ataxic horses. These clinical signs appear to be less profound in younger horses. The incubation period after natural infection is believed to be less than 14 days. The prepatent period after experimental exposure to infected ticks or inoculation with infected blood is 8 to 12 days and 3 to 10 days, respectively. The disease is self-limiting and nonfatal provided no complications develop. However, affected horses may be predisposed to secondary bacterial, fungal, and viral infections.1 Abortions and laminitis have not been reported in affected horses. Clinical Pathology Laboratory alterations include anemia, leukopenia characterized by granulocytopenia and lymphopenia, and thrombocytopenia. Morulae may be observed within the cytoplasm of neutrophils and eosinophils during the acute phase of the infection. Diagnosis Definitive diagnosis is based on the presence of characteristic morulae (minimum of 3) within the cytoplasm of neutrophils and eosinophils, or positive PCR assay for A. phagocytophila in peripheral blood (buffy coat).12 Morulae may be observed in less than 1% of cells in the initial stages of the infection, rising to 20% to 50% of cells a few days later. A fourfold or greater increase in IFA titer of paired samples confirms recent exposure.13 Pathologic Findings Petechiae and ecchymosis of subcutaneous tissues, and edema of the ventral abdomen, limbs, and prepuce are characteristic in infected animals. Proliferative and necrotizing vasculitis, thromboses, and perivascular cuffing in subcutaneous tissue, fascia, kidneys, heart, brain, lungs, ovaries, and testes have been reported.1,10 Treatment, Prognosis, and Prevention The treatment of choice is IV administration of oxytetracycline at 7 mg/kg, or oral administration of doxycycline at 20 mg/kg of body weight once a day for 5 to 7 days. Prompt response to treatment is seen within the first 24 hours. Supportive therapy may be necessary in some cases. The disease can be self-limiting in 2 to 3 weeks if untreated. Prognosis is excellent provided no secondary complications develop. At present, prevention is limited to tick control. Johanna L. Watson • Debra Deem Morris Thrombocytopenia (platelet count < 100,000/µL) can result from one or more of three basic mechanisms: (1) decreased or ineffective platelet production; (2) abnormal sequestration (usually in the spleen); or (3) shortened platelet survival (consumption or destruction). Thrombocytopenia causes a hemorrhagic diathesis characterized by multiple sites of small vessel bleeding. Petechial hemorrhages with or without ecchymotic hemorrhages are generally found on the oral, nasal, or vaginal mucous membranes, as well as on the nictitans and sclera. Epistaxis, melena, hyphema, or microscopic hematuria may occur, but spontaneous hemorrhage is unusual unless the platelet count is less than 10,000/µL. Prolonged bleeding from wounds, injections, or surgical procedures and the propensity to form hematomas after minor trauma are quite common when the platelet count drops below 40,000/µL. The platelet count below which bleeding occurs varies among individuals and seems to be determined by concurrent diseases. The interaction of blood platelets with a discontinuous vascular surface constitutes the basis for primary hemostasis. In addition, platelets provide the phospholipoprotein surface necessary to catalyze interactions among the activated coagulation proteins that culminate in fibrin formation. The platelet surface also protects activated clotting factors from destruction by plasma anticoagulants, thereby localizing coagulation to the hemostatic plug. Platelets maintain vascular integrity through mechanisms involving immunoreceptor tyrosine activating motif (ITAM) signaling and prevent spontaneous hemorrhage into the skin and mucous membranes. Severe thrombocytopenia produces prolonged bleeding time and abnormal clot retraction without affecting clotting times or plasma fibrinogen. Persistent life-threatening hemorrhage caused by thrombocytopenia may be treated with a transfusion of compatible fresh whole blood or, preferably, platelet-rich plasma. The latter may be produced by centrifugation thrombocytopheresis1 or by centrifugation of freshly collected blood, 3 to 5 minutes at 250 g.2 Blood or plasma must be used immediately, and contact with glass must be prevented to avoid platelet adhesion and activation. Platelet transfusion is a very transient life-saving measure, and the ultimate prognosis for thrombocytopenia depends on the cause. Decreased production of platelets may occur secondary to replacement of the normal marrow architecture by neoplastic or inflammatory tissue (myelophthisic disease) or bone marrow aplasia. Both conditions are characterized by peripheral pancytopenia of variable severity and are extremely unusual in large animals. Myelophthisic disease with thrombocytopenia has been described in horses with various forms of myelogenous neoplasia3–5 and eosinophilic myeloproliferative disorder.6 Hypoplastic anemia with leukopenia and thrombocytopenia has been reported in horses and cattle and is discussed later in the chapter in the section on aplastic anemia. Shortened platelet lifespan is by far the most common cause of thrombocytopenia in large animals. Increased platelet consumption accompanies DIC (discussed in the next section) and rare cases of vasculitis. Immune-mediated mechanisms result in platelet destruction. Immune-mediated thrombocytopenia (IMTP) may be primary (idiopathic) or secondary to drug administration, infections, neoplasia, or other immunologic disorders.2 This disease is most common in horses and has been reported secondary to EIA,7 lymphoma,8 and autoimmune hemolytic anemia.9 The clinical signs of IMTP include mucosal hemorrhages and the propensity to bleed from small blood vessels. Horses with idiopathic IMTP are usually bright, afebrile, and without overt hemorrhage despite severely reduced platelet numbers. Thrombocytopenia in a horse with obvious primary disease should prompt a thorough hemostatic workup to rule out DIC. Alloimmune thrombocytopenia of neonates has been recognized as a spontaneous disease of human infants, piglets, foals, and possibly mule foals.10 Clinical signs include depression, loss of suckle, a bleeding tendency, blood loss, and rapidly developing anemia due to a profound thrombocytopenia. The condition occurs in multiparous dams, and immunoglobulins from the mare, found in her plasma, serum, and milk, bind to the foal’s platelets. Alloimmune thrombocytopenia should be considered in neonates with severe thrombocytopenia when other causes can be excluded, and platelet antibody assays should be used to support this diagnosis. Differential considerations include neonatal sepsis, neonatal maladjustment syndrome, and neonatal isoerythrolysis. Laboratory findings of IMTP include severe thrombocytopenia (<40,000/µL), prolonged bleeding time, and abnormal clot retraction with normal thrombin time (TT), PT, APTT, and plasma fibrinogen. Fibrin(ogen) degradation products (FDPs) may be mildly increased, and anemia accompanied by hypoproteinemia develops if there is ongoing blood loss. In most cases of IMTP and other causes for shortened platelet lifespan, megakaryocytic hyperplasia is evident on examination of bone marrow aspirates or biopsies. Megakaryocytic destruction by the immunologic process could induce megakaryocytic hypoplasia, although this is apparently rare in horses. The definitive diagnosis of IMTP requires demonstration of increased quantities of platelet-associated IgG or C3 or antiplatelet activity in the serum. Flow cytometric methods to detect platelet surface–associated IgG (PSAIgG) have been adapted for horses.11 Without PSAIgG testing, the diagnosis of IMTP must be based on small-vessel hemorrhagic diathesis and severe thrombocytopenia in a horse with normal coagulation times and no other evidence of DIC. Response to therapy (see next section) supports the diagnosis. A tentative diagnosis of IMTP in the horse should prompt a thorough search for an underlying disorder, especially lymphoma. Platelet destruction in IMTP is apparently mediated by antibodies coating the platelet surface that cause premature platelet removal from circulation by the mononuclear phagocyte system (MPS).12 In primary IMTP the platelet-associated Ig is directed against a membrane antigen, is usually of the IgG class, is produced in the spleen, fixes complement, and can be absorbed from serum by platelets from a normal individual of the same species. Autoantibodies may attach to megakaryocytes, but the latter are not necessarily destroyed because they do not circulate through the spleen or liver. In secondary IMTP the Ig bound to the platelet surface is part of an immune complex composed of antibody directed against a drug, microbe, or neoplastic antigen that is nonspecifically attached to the platelet Fc receptor. For secondary IMTP to be perpetuated, the foreign antigen must be constantly replenished or difficult to excrete. Drug-induced IMTP generally subsides within a few days of drug discontinuation, although thrombocytopenia secondary to chrysotherapy (gold therapy) may persist for weeks to years. Because gold is occasionally used to treat pemphigus foliaceus in horses, thrombocytopenia should be considered as a potential side effect. The spleen is the major site of platelet phagocytosis because (1) much antiplatelet antibody is secreted locally, (2) more than 30% of circulating platelets are normally stored there, and (3) the stagnant splenic blood flow allows sensitized platelets to pass slowly through a dense network of phagocytic cells. The mean cell life of circulating platelets and the platelet count are inversely proportional to the quantity of platelet-associated IgG. When any unexplained case of thrombocytopenia is treated, all current medication should be stopped. If a drug is absolutely necessary, it must be replaced by the chemically most dissimilar substitute. Drug-induced IMTP usually responds within 14 days of drug withdrawal. Most animals with suspected IMTP improve when treated with corticosteroids. Although their precise mechanisms of action are speculative, corticosteroids improve capillary integrity, impair clearance by the MPS, decrease the number and avidity of macrophage Fc receptors, impair antiplatelet antibody production, impede platelet-antibody interactions, and increase thrombocytopoiesis. Dexamethasone (0.04 to 0.2 mg/kg IV or IM) given once daily generally results in an elevation in the platelet count within 4 to 7 days. Once the platelet count is greater than 100,000/µL, the dose of dexamethasone can be reduced by 10% to 20% daily while the platelet count is monitored for a relapse. Occasionally, animals with IMTP are refractory to dexamethasone, in which case prednisolone (0.5-1 mg/kg IM twice daily) may be tried. Treatment with corticosteroids can usually be discontinued after a period of 10 to 21 days, provided the platelet count has been normal for at least 5 days. Most horses with IMTP have a favorable prognosis, and the disease resolves within 14 to 21 days. This suggests that many cases may be secondary, yet the initiating cause is rarely found. Chronic or recurrent IMTP requiring prolonged corticosteroid therapy has been reported.13 Alternative treatment modalities for IMTP are largely unproven in horses, because most cases are responsive to corticosteroids.14–16
Diseases of the Hematopoietic and Hemolymphatic Systems
Diseases Associated with Blood Loss or Hemostatic Dysfunction
Acute Blood Loss
Diagnosis
Treatment
Guttural Pouch Mycosis
Hemoperitoneum in Horses
Hemothorax
Exercise-Induced Pulmonary Hemorrhage
Chronic Blood Loss
Gastric Ulceration
Right Dorsal Colitis
Hemostatic Dysfunction
Basic Physiology of Normal Hemostasis
Inherited Coagulation Disorders
Thrombasthenia in Horses
Glanzmann Thrombasthenia.
Heritable Bleeding Diathesis (Other Than Glanzmann Thrombasthenia).
Acquired Hemostatic Disorders
Vasculitis.
Anaplasma Phagocytophila Infection in Horses
Thrombocytopenia
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Diseases of the Hematopoietic and Hemolymphatic Systems
Chapter 37