Multiple Diseases Hematopoietic PDF

CHAPTER 13 Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System Box 13.2  Conditions Known or Suspected to Cause Secondary Platelet Dysfunction in Animals SECONDARY PLATELET HYPOFUNCTION Underlying Disease Uremia Antiplatelet antibodies (also cause immune-mediated thrombocytopenia) Infection...

CHAPTER 13 Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System Box 13.2  Conditions Known or Suspected to Cause Secondary Platelet Dysfunction in Animals SECONDARY PLATELET HYPOFUNCTION Underlying Disease Uremia Antiplatelet antibodies (also cause immune-mediated thrombocytopenia) Infection (BVDV, FeLV) Hyperglobulinemia Increased fibrinolytic products Hyperammonemia Snake envenomation Drugs or Other Exogenous Agents Platelet inhibitors NSAIDs—irreversible (aspirin) or reversible inhibition of cyclooxygenase Colloidal plasma expanders (e.g., hydroxyethyl starch) Other drugs and exogenous agents (many) SECONDARY PLATELET HYPERFUNCTION Underlying Disease Infection (heartworm and RMSF in dogs, FIP, pasteurellosis in cattle) Inflammation Neoplasia Taurine deficiency in cats Nephrotic syndrome BVDV, Bovine viral diarrhea virus; FeLV, feline leukemia virus; FIP, feline infectious peritonitis, NSAIDs, nonsteroidal antiinflammatory drugs; RMSF, Rocky Mountain spotted fever. Box 13.3  Portals of Entry into Bone Marrow Hematogenously Direct penetration (trauma) and cellular defenses. Of course, leukocytes themselves function as an essential part of inflammation and immune function, as discussed briefly in the section in this chapter on Granulopoiesis and Monocytopoiesis (Myelopoiesis) and in greater detail in Chapter 3, Inflammation and Healing, and Chapter 5, Diseases of Immunity. Biochemical steps in the glycolytic pathway or linked to it generate antioxidant molecules that enable erythrocytes to withstand oxidative insults throughout their many days in circulation. In addition to producing energy in the form of adenosine triphosphate (ATP), glycolysis generates NADH, which helps convert the oxidized, nonfunctional form of Hgb, known as MetHgb, back to its active, reduced state. Another antioxidant erythrocyte metabolic pathway, the pentose shunt or hexose monophosphate shunt, generates NADPH to help maintain glutathione in the reduced state. Diseases Affecting Multiple Species of Domestic Animals Aplastic Anemia (Aplastic Pancytopenia) Aplastic anemia, or more accurately aplastic pancytopenia, is a rare condition characterized by aplasia or severe hypoplasia of all hematopoietic lineages in the bone marrow with resulting cytopenias. The term aplastic anemia is a misnomer because affected cells are not limited to the erythroid lineage. Many of the conditions reported to cause aplastic anemia do so only rarely or idiosyncratically; more frequently, they cause other 829 hematologic or nonhematologic abnormalities. A partial list of reported causes of aplastic anemia in domestic animals includes the following: Chemical agents Antimicrobial agents (dogs, cats) Chemotherapeutic agents (dogs, cats) Phenylbutazone (horses, dogs) Bracken fern (cattle, sheep) Estrogen (dogs) Trichloroethylene (cattle, sheep) Aflatoxin B1 (horses, cattle, dogs, pigs) Infectious agents E  hrlichia (ehrlichiosis [dogs, cats]) Parvovirus (dogs, cats) FeLV (cats) Feline immunodeficiency virus (cats) Lentivirus (equine infectious anemia [horses]) Idiopathic (horses, cattle, dogs, cats) Most of these causes, especially the chemical agents, are directly cytotoxic to HSCs or progenitor cells, resulting in their destruction. However, another proposed mechanism is disruption of normal stem cell function because of mutation or perturbation of hematopoietic cells and/or their microenvironment. This pathogenesis is mostly recognized in retroviral infections. Aplastic anemia occurs in both acute and chronic forms. Most of the chemical causes result in acute disease. Grossly, affected animals may show signs of multisystemic infection and hemorrhage resulting from severe neutropenia and thrombocytopenia, respectively. Severe neutropenia typically develops within 1 week of an acute insult to the bone marrow, and severe thrombocytopenia occurs in the second week. This sequence is a result of the circulating life spans of each cell type; in health, neutrophils have a blood half-life of 5 to 10 hours, whereas platelets circulate for 5 to 10 days. The development of signs of anemia, such as pale mucous membranes, is more variable. The presence and severity of anemia depends on how rapidly the marrow recovers from the insult and the erythrocyte life span of the particular species. Microscopically, bone marrow is hypocellular with markedly reduced hematopoietic cells. Hematopoietic cells are replaced with adipose tissue, and there is a variable inflammatory infiltrate of lymphocytes, plasma cells, and macrophages. In addition, there may be necrosis, hematopoietic cell apoptosis, and an increase in phagocytic macrophages. Fig. 13.21 shows bone marrow aspirates from a dog with pancytopenia from acute 5-fluorouracil toxicosis, before and during recovery. Congenital Disordersd Many inherited or presumably inherited disorders of blood cells have been recognized in domestic animals, including rare or sporadic cases and conditions that are of questionable clinical relevance. This section and the later sections covering species-specific disorders are not comprehensive but instead focus on the more common, wellcharacterized, or recently reported conditions. Erythropoietic Porphyrias. Porphyrias are a group of hereditary disorders in which porphyrins accumulate in the body because of defective heme synthesis. Inherited enzyme defects in Hgb synthesis have been identified in Holstein cattle, Siamese cats, and other cattle and cat breeds, resulting in bovine congenital erythropoietic porphyria and feline erythropoietic porphyria, respectively. dSee E-Table 1.2 for a list of potential, suspected, or known genetic diseases affecting bone marrow, blood cells, or the lymphatic/lymphoid system. 830 SECTION II Pathology of Organ Systems A than the R-type isoenzyme. The disease is reported in many dog breeds and fewer cat breeds (e.g., Abyssinian, Somali, and domestic shorthair). Erythrocyte PK deficiency results in decreased ATP production and shortened erythrocyte life spans. In dogs the hemolytic anemia is typically chronic, moderate to severe, extravascular, and strongly regenerative. With chronicity, hemolytic anemia causes enhanced intestinal absorption of iron and subsequent hemosiderosis, especially of the liver and bone marrow. Dogs typically die at 1 to 5 years of age of hemochromatosis-induced liver and bone marrow failure. However, cats with PK deficiency typically show no clinical signs, have milder anemia, and do not develop organ failure. Grossly, affected animals have lesions attributed to hemolytic anemia, including splenomegaly, pale mucous membranes, and rarely icterus. Dogs with end-stage disease have cirrhosis, myelofibrosis, and osteosclerosis. Dogs with PK deficiency do not necessarily have the same genetic defect, so mutation-specific DNA-based assays are required. In contrast, a single DNA-based test is available to detect the common mutation affecting Abyssinian, Somali, and domestic shorthair cats. Cytochrome-b5 Reductase Deficiency. Deficiency of cytochrome-b5 reductase (Cb5R, also known as methemoglobin reductase), the enzyme that catalyzes the reduction of MetHgb (Fe3+) to Hgb (Fe2+), has been recognized in many dog breeds and in domestic shorthair cats. It is probably an autosomal recessive trait. Affected animals may have cyanotic mucous membranes or exercise intolerance but usually lack anemia and clinical signs of disease. Life expectancies are normal. B Figure 13.21 Aplastic Anemia, Canine Bone Marrow Aspirates. A, Bone marrow aspirate from a dog 8 days after ingestion of a toxic dose of 5-fluorouracil shows stromal cells but a lack of developing blood cells. B, Bone marrow aspirate from the same dog 1 week later, after resumption of hematopoiesis. Inset, Higher magnification of Fig. 13.21, B, shows early- and late-stage erythroid and granulocytic precursors. Wright’s stain. (Courtesy Dr. M.M. Fry, College of Veterinary Medicine, University of Tennessee.) Accumulation of toxic porphyrins in erythrocytes causes hemolytic anemia, whereas accumulation of porphyrins in tissues and fluids produces discoloration, including red-brown teeth, bones, and urine (see Fig. 1.58). Because of the circulation of the photodynamic porphyrins in blood, these animals have lesions of photosensitization of the nonpigmented skin. All affected tissues, including erythrocytes, exhibit fluorescence with ultraviolet light. Histologically, animals may exhibit perivascular dermatitis, as well as multisystemic porphyrin deposition, hemosiderosis, EMH, and marrow erythroid hyperplasia. Cats may show evidence of renal disease, including hypercellular glomeruli, thickened glomerular and tubular basement membranes, and tubular epithelial lipidosis, degeneration, and necrosis. Other porphyrias have been diagnosed in cattle, pigs, and cats but are not known to cause hemolytic anemia. Pyruvate Kinase Deficiency. Pyruvate kinase (PK) deficiency is an inherited autosomal recessive condition resulting from a defective R-type PK isoenzyme that is normally present in high concentrations in mature erythrocytes. To compensate for this deficiency, there is persistence of the M2-type PK isoenzyme, which is less stable Glucose-6-Phosphate Dehydrogenase Deficiency. Deficiency of glucose-6-phosphate dehydrogenase (G6PD), the rate-controlling enzyme of the pentose phosphate pathway (PPP), has been reported in an American saddlebred colt, its dam, and one male dog. The PPP is an antioxidative pathway that generates NADPH, which maintains glutathione in its reduced form (GSH). Therefore, in animals with G6PD deficiency, oxidants are not scavenged, and erythrocyte oxidative injury occurs. The colt with G6PD deficiency had severe oxidative hemolytic anemia with eccentrocytes on blood smear evaluation. However, the colt’s dam only had eccentrocytes and showed no hematologic signs of disease. Leukocyte Adhesion Deficiency. Leukocyte adhesion deficiency (LAD) is a fatal autosomal recessive defect of leukocyte integrins, in particular the β2 chain (also known as cluster of differentiation [CD] 18 [CD18]). Disease has been recognized in Holstein cattle (known as bovine leukocyte adhesion deficiency [BLAD]) and Irish setter dogs (known as canine leukocyte adhesion deficiency [CLAD]) (see Chapter 3, Inflammation and Healing). Without normal expression of this adhesion molecule, leukocytes have severely impaired abilities to migrate from the blood into tissues. As a result, animals with leukocyte adhesion deficiency have marked neutrophilia with nonsuppurative multisystemic infections. Blood neutrophils often have nuclei with greater than five nuclear segments, termed hypersegmented neutrophils, resulting from neutrophil aging within blood vessels (Fig. 13.22). These animals are highly susceptible to infections and usually die at a young age. Pelger-Huët Anomaly. Pelger-Huët anomaly (PHA) is a condition of hyposegmented granulocytes resulting from a lamin B receptor mutation. It has been described in dogs, cats, horses, and rabbits, especially in certain breeds. In Australian shepherd dogs the mode of inheritance is autosomal dominant with incomplete penetrance. Most cases of PHA are the heterozygous form and of CHAPTER 13 Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System 831 von Willebrand Disease Information on this topic is available at www.expertconsult.com. Hereditary Coagulation Factor Deficiencies Information on this topic is available at www.expertconsult.com. Hereditary γ-Glutamyl Carboxylase Defect Information on this topic is available at www.expertconsult.com. Toxicoses Figure 13.22 Leukocyte Adhesion Deficiency, Canine Blood Smear. Neutrophils in animals with leukocyte adhesion deficiency cannot migrate into the tissues, resulting in marked neutrophilia and morphologic signs of aging, such as nuclear hypersegmentation (arrow). Wright-Giemsa stain. (Courtesy Dr. K.M. Boes and Dr. K. Zimmerman, College of Veterinary Medicine, Virginia Polytechnic Institute and State University.) A B Figure 13.23 Pelger-Huët Anomaly, Feline Blood Smears. Eosinophil (A) and neutrophil (B) have hyposegmented nuclei with mature, condensed chromatin. Wright’s stain. (Courtesy Dr. M.M. Fry, College of Veterinary Medicine, University of Tennessee.) no clinical significance. However, skeletal abnormalities, stillbirths, and/or early mortality may accompany PHA in rabbits and cats, especially homozygotes. In PHA the nuclei of neutrophils, eosinophils, and basophils fail to segment, resulting in band-shaped, beanshaped, or round nuclei. Although the nuclear shape is similar to that of an inflammatory left shift, healthy animals with PHA do not have clinical signs or other laboratory findings indicating inflammation. For example, neutrophils in healthy animals with PHA have mature (clumped) chromatin and do not show signs of toxicity (Fig. 13.23). An acquired, reversible condition mimicking PHA, known as pseudo–Pelger-Huët anomaly, is occasionally noted in animals with infectious disease, neoplasia, or drug administration. Chédiak-Higashi Syndrome Information on this topic is available at www.expertconsult.com. Glanzmann Thrombasthenia Information on this topic is available at www.expertconsult.com. CalDAG-GEFI Thrombopathia Information on this topic is available at www.expertconsult.com. Oxidative Agents. A variety of oxidative toxins cause hemolytic anemia and/or MetHgb in domestic species. More common or well-characterized oxidants are listed here: Horses—Acer rubrum (red maple) Ruminants—Brassica spp. (cabbage, kale, and rape), copper Dogs—Acetaminophen, propofol, zinc Cats—Acetaminophen, propofol, propylene glycol All species—Allium spp. (chives, garlic, and onions) To horses, red maple leaves and bark are toxic, especially wilted or dried leaves. The toxic principle is believed to be gallic acid. Plants that contain high concentrations of nitrates, such as cabbage, kale, and rape, may cause oxidative injury to erythrocytes; cattle are more susceptible than sheep and goats. However, sheep are more prone to copper toxicosis relative to other ruminants. The condition occurs in animals that have chronically accumulated large amounts of copper in the liver through the diet. The copper is then acutely released during conditions of stress, such as shipping or starvation. Continuous rate infusions of the anesthetic propofol may cause oxidative hemolytic anemia in dogs and cats, but single or multiple single doses are not expected to cause clinical hemolysis. Zinc toxicosis has been identified in a wide range of animals; however, it is most common in dogs because of their indiscriminate eating habits. Common sources include pennies, batteries, paints, creams, automotive parts, screws, nuts, and coating on galvanized metals. Propylene glycol is an odorless, slightly sweet solvent and moistening agent in many foods, drugs, and tobacco products. Although it is “generally recognized as safe” for animal foods other than for cats by the Food and Drug Administration, it has been banned from cat food since 1996. Grossly and microscopically, animals show varying signs of oxidative hemolysis and/or MetHgb, as previously presented in the section discussing anemias (see Bone Marrow and Blood Cells, Dysfunction/Responses to Injury, Blood Cells, Abnormal Concentrations of Blood Cells, Anemia). In sheep with copper toxicosis, hemoglobinuric nephrosis, frequently described as gunmetal-colored kidneys with port wine–colored urine, is a classic postmortem lesion. Snake Envenomation. Hemolytic anemia from snake envenomation has been reported in horses, dogs, and cats. It is most commonly reported with viper and pit viper envenomations, including those from rattlesnakes. Hemolysins within viper venom directly injure erythrocytes, causing intravascular hemolysis. Other mechanisms of hemolysis include the action of phospholipase A2 on erythrocyte membranes and erythrocyte mechanical fragmentation resulting from intravascular coagulation and vasculitis. Nonhemolytic lesions depend on the venom’s additional components and may include hemorrhage, paralysis, and/or tissue edema, inflammation, and necrosis. On blood smear evaluation, animals with snake envenomation may have ghost cells, spherocytes, and/or echinocytes (see Figs. 13.13 and 13.15). CHAPTER 13 Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive defect in the lysosomal trafficking regulator (LYST) protein. The syndrome has been identified in Hereford, Brangus, and Japanese black cattle, Persian cats, and several nondomestic species. The defective LYST protein results in granule fusion in multiple cell types, including granulocytes, platelets, and melanocytes, as well as abnormal cell function. Individuals with CHS have severely impaired cellular innate immunity because of neutropenia, impaired leukocyte chemotaxis, and impaired killing by granulocytes and cytotoxic lymphocytes. Platelets lack the dense granules that normally contain key bioactive molecules involved in hemostasis, including platelet agonists, such as ADP and serotonin. In vitro platelet aggregation is severely impaired. As a result, animals with CHS exhibit oculocutaneous albinism (resulting from altered distribution of melanin granules) and are prone to infection and bleeding. Blood smear evaluation reveals granulocytes with large cytoplasmic granules. Glanzmann thrombasthenia (GT) is an inherited platelet function defect caused by a mutated αIIb subunit of the integrin αIIbβ3 (also known as glycoprotein IIb-IIIa [GPIIb-IIIa]). The disorder has been recognized in Great Pyrenees and otterhound dogs and several horse breeds, including a quarter horse, a standardbred, a thoroughbred-cross, a Peruvian Paso mare, and an Oldenburg filly. The αIIbβ3 molecule has multiple functions but is best known as a fibrinogen receptor that is essential for normal platelet aggregation. Bleeding tendencies vary widely between affected individuals but mainly occur on mucosal surfaces. The condition is characterized by an in vitro lack of response to all platelet agonists and severely impaired clot retraction (i.e., whole blood samples without anticoagulant often fail to clot). Molecular testing is available to detect diseased or carrier states in dogs and horses. Calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI) is a molecule within the signaling pathway that results in platelet activation in response to platelet agonists. Mutated CalDAG-GEFI has been documented in basset hound, Eskimo spitz, and Landseer dogs and Simmental cattle. All reported mutations have a bleeding tendency. In vitro platelet aggregation responses to platelet agonists, such as ADP, collagen, and thrombin, are absent or impaired. von Willebrand disease (vWD) is the most common canine hereditary bleeding disorder and has also been described in many other domestic species. The disease actually refers to a group of inherited conditions characterized by a quantitative or qualitative deficiency of vWF. This factor is a multimeric glycoprotein that is stored in platelet α-granules and endothelial cells and circulates as a complex with coagulation factor VIII. Its primary functions are to stabilize factor VIII and mediate platelet binding to other platelets and subendothelial collagen. Although not technically a platelet disorder, vWD is often classified as such because it results in a loss of normal platelet function. Different types of vWD vary in terms of mode of inheritance and severity of clinical disease. Type I vWD is characterized by low plasma vWF concentration but normal multimeric proportions and a mild to moderate clinical bleeding tendency; it has been reported in many dog breeds. Type II vWD is characterized by low vWF concentration, absence of large multimers, and a moderate to severe bleeding tendency; it has been reported in German short-haired pointer and German wirehaired pointer dogs. Type III vWD is characterized by absence of vWF and a severe bleeding tendency; familial and sporadic cases have been reported in numerous dog breeds. The buccal mucosal bleeding time is prolonged with vWD, often with adequate concentrations of platelets 831.e1 and normal prothrombin time (PT) and partial thromboplastin time (PTT). However, PTT may be mildly prolonged because vWF stabilizes factor VIII, and deficiency of vWF results in enhanced factor VIII degradation. Grossly, affected animals exhibit bleeding tendencies, especially in the form of gingival bleeding, epistaxis, and hematuria or at sites of injections, venipuncture, or surgery. Inherited coagulation factor deficiencies have been documented in most domestic species, including deficiencies of prekallikrein and factors I, II, VII, VIII, IX, X, XI, and XII. Of these disorders, hereditary coagulation factor VIII (hemophilia A) and factor IX (hemophilia B) deficiencies are most common. Hemophilia A has been recognized in horses, cattle, dogs, and cats, and hemophilia B occurs in dogs and cats. Both disorders have an X-linked recessive mode of inheritance, meaning that clinical disease is more common in males. Affected males have variable tendencies to bleed, depending on the severity of the deficiency, exposure to trauma, and size and activity level of the affected individual. Carrier females are usually asymptomatic. Laboratory tests often reveal adequate platelets, normal PTs, and prolonged PTTs. Hereditary defects in γ-glutamyl carboxylase, the enzyme required for normal carboxylation of vitamin K–dependent coagulation factors, have been recognized in a flock of Rambouillet sheep and two Devon rex cats from the same litter. The genetic defect is not known in cats, but in sheep it is an autosomal recessive trait that results in a premature stop codon and truncated γ-glutamyl carboxylase. In sheep there is increased lamb mortality with excessive bleeding during parturition, especially through the umbilicus or into subcutaneous tissues. 832 SECTION II Pathology of Organ Systems Avitaminosis K Information on this topic is available at www.expertconsult.com. Nutritional and Metabolic Disorders Severe malnutrition is probably a cause of nonregenerative anemia in all species attributable to combined deficiencies of molecular building blocks, energy, and essential cofactors. By far the most commonly recognized specific deficiency that results in anemia is iron deficiency. Other specific nutritional deficiencies causing anemia in animals are uncommon or rare. Acquired cobalamin (vitamin B12) and folate deficiencies are recognized as causes of anemia in human beings but are rare in animals. Iron Deficiency Anemia. Iron deficiency is usually not a primary nutritional deficiency but rather occurs secondary to depletion of iron stores via chronic blood loss. The most common route of loss is through the gastrointestinal tract (e.g., neoplasia in older animals or hookworm infection in puppies). Chronic blood loss may also be caused by marked ectoparasitism (e.g., pediculosis in cattle or massive flea burden in kittens and puppies), neoplasia in locations other than the gastrointestinal tract (e.g., cutaneous hemangiosarcoma), coagulation disorders, and repeated phlebotomy of blood donor animals. Rapidly growing nursing animals may be iron deficient when compared with adults because milk is an iron-poor diet. In most cases this has little clinical significance (and in fact is normal). An important exception is piglets with no access to iron, which may cause anemia, failure to thrive, and increased mortality. Neonatal piglets are routinely given parenteral iron for this reason. Copper deficiency can cause iron deficiency in ruminants and may occur because of copper-deficient forage or impaired usage of copper by high dietary molybdenum or sulfate. It is believed that copper deficiency impairs production of ceruloplasmin, a copper-containing enzyme involved in gastrointestinal iron absorption. Iron deficiency causes anemia by impaired Hgb synthesis. Iron is an essential component of Hgb, and when it is absent, Hgb synthesis is depressed. Because erythrocyte maturation is dependent upon obtaining a critical Hgb concentration, maturing erythroid precursors undergo additional cell divisions during iron-deficient states. These additional cell divisions result in small erythrocytes, termed microcytes (see Fig. 13.15, G). However, erythrocytes with low Hgb concentrations are produced when microcyte formation can no longer compensate for iron deficiency. The classic hematologic picture with iron deficiency anemia is microcytic (i.e., decreased MCV), hypochromic (i.e., decreased MCHC) anemia. Microcytes and hypochromasia (see Fig. 13.15, G) may also be discernible on blood smear examination as erythrocytes that are abnormally small and paler-staining, respectively. Early iron deficiency anemia is poorly regenerative, whereas continued hemorrhage and iron loss cause nonregenerative anemia. Additional hematologic changes may include evidence of erythrocyte mechanical fragmentation (e.g., schistocytes) and reactive thrombocytosis. Hypophosphatemic Hemolytic Anemia. Marked hypophosphatemia is recognized as a cause of intravascular hemolytic anemia in postparturient dairy cows and diabetic animals receiving insulin therapy. In postparturient cows, hypophosphatemia results from increased loss of phosphorus in their milk. Insulin therapy may cause hypophosphatemia by shifting phosphorus from the extracellular space to the intracellular space. In either case, marked hypophosphatemia (e.g., 1 mg/dL in cows, or ≤1.5 mg/dL in cats) is thought to decrease erythrocyte production of ATP, leading to inadequate energy required for maintenance of membrane and cytoskeletal integrity. An accompanying decrease in reducing capacity and increase in MetHgb concentration have also been noted in experimental studies of hypophosphatemic hemolytic anemia in dairy cattle, suggesting that oxidative mechanisms may also contribute to anemia. Affected animals are anemic and hemoglobinuric. Gross postmortem findings include pallor, decreased viscosity of the blood, and lesions arising from the underlying metabolic derangement (e.g., discolored pale yellow and swollen liver resulting from hepatic lipidosis). Renal tubular necrosis and Hgb pigment within the tubules is evident microscopically. Infectious Diseases This section covers infectious agents within the same genus that are recognized to cause disease in multiple species of domestic animals. Other infectious agents with more limited host specificity (e.g., cytauxzoonosis in cats, feline and equine retroviruses) are covered in later sections on species-specific diseases. Throughout both sections, diseases are organized by taxonomy (protozoal, bacterial and rickettsial, and viral). In addition to the images of infectious agents affecting blood cells shown in the sections that follow, also see E-Fig. 4.4 for additional images of the agents that cause these diseases. Babesiosis (Piroplasmosis). Babesia spp. and Theileria spp., presented in the next section, are members of the order Piroplasmida, and are generally referenced as piroplasms. These organisms are morphologically similar but have different life cycles; Babesia spp. are primarily erythrocytic parasites, whereas Theileria spp. sequentially parasitize leukocytes and then erythrocytes. Both are protozoan parasites spread by ticks, but other modes of transmission are possible (e.g., biting flies, transplacental transfer, and blood transfusions). Evidence is accumulating that dog fighting also transmits Babesia gibsoni infection. Babesia organisms are typically classified as large (2 to 4 μm) or small (60% of nucleated cells). The diagnosis may be supported by flow cytometric detection of immunoglobulin bound to neutrophils but is most often made on the basis of exclusion of other causes of neutropenia and response to immunosuppressive therapy. Immune-Mediated Thrombocytopenia. IMTP is a condition characterized by immune-mediated destruction of platelets. It is a fairly common condition in dogs and is less frequent in horses and cats. The disease is usually idiopathic but may be secondary to infection (e.g., equine infectious anemia and ehrlichiosis), drug administration (e.g., cephalosporins and sulfonamides), neoplasia, and other immune-mediated diseases. When IMTP occurs together with IMHA, the condition is called Evans syndrome. The thrombocytopenia is often severe (e.g., 100,000/μL Increased plasma cells in bone marrow Osteolysis Monoclonal gammopathy Light chain (Bence Jones) proteinuria Commitment to myeloid lineage