Diseases of the spleen, bone marrow, thymus, and lymph nodes may involve all these organs concurrently or individually. The most important diseases are equine infectious anemia (EIA), lymphoma, strangles, Rhodococcus infection, and red maple toxicity. Two important congenital diseases, severe combined immunodeficiency disease (SCID) and neonatal isoerythrolysis, are also mentioned in Chapter 2, “Diseases of Foals and Juveniles.” Hyperplasia is a more common reaction than inflammation in lymph nodes, spleen, and bone marrow, and the gross lesions in each organ are usually subtle. Red bone marrow is more likely due to congestion than erythroid regeneration. Evaluation of blood is a common antemortem technique; bone marrow taken from ribs, sternum, or long bones is usually examined postmortem; and biopsy and/or fine-needle aspiration are usually reserved for peripheral lymph nodes. Regenerative anemia is not reflected in the peripheral blood as it is in other species; therefore do not expect to see increased reticulocytes, increased mean corpuscular volume (MCV), or decreased mean corpuscular hemoglobin concentration (MCHC).
I. Diseases of the bone marrow
1. Severe combined immunodeficiency disease
SCID is seen primarily in Arabian foals as an autosomal recessive trait. In such animals 25% may be carriers of a gene defect that blocks the development of B and T lymphocytes. The disorder is characterized by severe hypoplasia of primary and secondary lymphoid tissues. Occurrence of this inherited disease has declined in recent years due to selective breeding and genetic testing for the recessive carrier genes. SCID affects both T and B lymphocyte lineages. Opportunistic pathogens (viruses, adenovirus, bacteria, Cryptosporidium sp, Pneumocystis jiroveci [previously carinii], Candida sp.) take advantage of the animal’s compromised immune function. Colostral antibodies, if adequate, usually protect affected foals for the first 4–6 months of their lives, but when these antibodies are depleted, infectious diseases and death are inevitable. Additional examples of pathologic changes are discussed in Chapter 2, “Diseases of Foals and Juveniles.” Pathologic and clinicopathologic findings useful in the diagnosis of SCID include hypogammaglobulinemia, lymphopenia, and hypoplasia of lymphoid organs. By far the most common immunodeficiency in horses is failure of passive transfer of colostral antibodies. Without treatment these foals develop sepsis in joints, bones, lungs, and internal organs resulting in the foal’s death. Uncommon immune deficiencies in other breeds of horses include agammaglobulinemia, selective immunoglobulin M (IgM) deficiency, and the fell pony syndrome.
Figure 15.1. Arabian Foal. Head. Epiphora and Rhinorhea. SCID. The nostrils are partially occluded by discharge from bronchopneumonia, and there is evidence of ocular discharge from conjunctivitis.
Figure 15.2. Arabian Foal. Thymus. Lymphoid Hypoplasia. SCID. Because of severe hypoplasia, the thymus will be small and difficult to identify grossly. Microscopically, it is characterized by a paucity of lymphocytes in cortex and medulla. (H&E) (Courtesy Dr. L. Perryman, Colorado State University.)
2. Myeloid necrosis
Figure 15.3. Horse. Long Bone. Bone Marrow Necrosis. The marrow is of variable but also of multifocal brown discoloration. There was evidence of necrosis and inflammation in the bone marrow as well as intranuclear herpesvirus inclusions in multinucleate inflammatory giant cells. The myeloid necrosis, contributed to the horse’s pancytopenia. This was a case of gamma herpesvirus infection with PCR positive for EHV-2 and EHV-5. The horse also had evidence of multinodular pulmonary fibrosis. (Courtesy Dr. J. Roberts, National Zoo, Washington, DC.)
3. Myelodysplasia
Figure 15.4. Horse. Ribs and Sternum. Bone Marrow Hypercellularity. Cross section. The bone marrow of the ribs is abundant and diffusely red due to marked hypercellularity. This was a case of myeloproliferative disorder with hematologic findings of anemia and thrombocytopenia and clinical signs of disseminated hemorrhage. Microscopic evaluation of the bone marrow aspirate revealed megakaryocytic aplasia, dyserythropoiesis, and granulocytic hypoplasia with maturation arrest. The syndrome eventually leads to various forms of overt leukemia.
4. Immune-mediated thrombocytopenia
Immune-mediated thrombocytopenia (ITP) The disorder is either primary, resulting from autoantibodies directed against bone marrow megakaryocyte or circulating platelet membrane antigens, or secondary to a variety of infectious agents, neoplasms, and/or drug administration that typically provide circulating haptens to adhere to megakaryocyte or platelet membranes and induce an immune-mediated destruction. Antibodies are usually directed against platelets and not megakaryocytes, and only platelets are decreased in the peripheral blood. There is no simple and accurate test for ITP. If platelet counts remain low and disseminated intravascular coagulation (DIC) is ruled out, then ITP is a likely cause. Numerous megakaryocytes, especially if they are regenerative with active thrombocytopenia in a horse that does not have DIC, are most likely due to ITP. Petechiae and thrombocytopenia are seen in a few horses postinfection with S. equi. The syndrome is referred to as purpura hemorrhagica, and the thrombocytopenia is most likely due to immune-mediated mechanisms. Clinical signs of severe thrombocytopenia include epistaxis and petechiae in the skin and oral, nasal, and vaginal mucous membranes. Thrombocytopenia is defined as a platelet count less than 90,000/μL in affected horses; however, most horses with immune-mediated thrombocytopenia have counts of less than 20,000/μL. Bleeding is not usually due to thrombocytopenia unless the counts are 10,000/μL or less. The most common causes of thrombocytopenia are DIC and poor venipuncture technique, such that tissue thromboplastin has been released. Thrombocytopenia due to tickborne diseases is common in dogs, suspected in horses but rarely proven. Snap tests used in dogs are used in horses. Positivity implies antibodies are present, and exposure occurred, but not that the disease is present or that antigen is present.
Figure 15.5. Horse. Bone Marrow. Hypercellularity. Immune-Mediated Thrombocytopenia. There are only a few areas of active bone marrow left. Most has been displaced by adipose tissue. Megakaryocytes are absent microscopically, and therefore the antibodies were most likely directed against megakaryocytes. All other cell lines were unaffected.
Figure 15.6. Horse. Head. Midsagittal Section. Turbinate Hemorrhage. Immune-Mediated Thrombocytopenia. The turbinates are reddened by severe acute hemorrhage.
Figure 15.7. Horse. Head. Frontal Bones. Acute Dermal Hemorrhage. Immune-Mediated Thrombocytopenia. The skin over the nose and frontal bones is characterized by petechiae and hemorrhage.
5. Neoplasia
The primary tumors involving the bone marrow of horses include stage 5 lymphoma and acute lymphoid leukemia. Other tumors such as multiple myeloma (plasma cell tumor of the marrow) have been seen in horses, but these are rare.
Figure 15.8. Horse. Long Bone. Bone Marrow. Acute Lymphocytic Leukemia. Lymphoid leukemia is diagnosed when the tumor begins in the marrow and may spread to liver, spleen, and other peripheral tissues. Most of the marrow has been displaced by an off-white multifocal to coalescing neoplastic tissue.
Figure 15.9. Horse. Long Bone. Bone Marrow. Myeloma. The cut surface of long bone has a discrete circular gray region that was diagnosed as myeloma. This is a rare tumor in horses. It is associated with marked hyperproteinemia and monoclonal gammopathy. (Courtesy P. Stromberg, Ohio State University.)
6. Bone marrow biopsy
Sampling bone marrow in the horse, ante- or postmortem, is done infrequently. If only one cell line is abnormally decreased or increased, the etiology is usually outside of the bone marrow, and therefore examination of marrow elements is not needed once the cause is established. When two or more hematopoietic cell lines are affected, then examination of the bone marrow is indicated and may help establish the cause. Bone marrow examination is warranted for any of the following: (1) two or more hematopoietic cell lines are decreased, (2) leukemia is suspected, and/or (3) there is an unexplained decrease or increase in hematopoietic cells.
II. Diseases of circulating blood cells
1. Immune-mediated hemolytic anemia
a. Isoerythrolysis of the newborn
This condition affecting red blood cells is described in Chapter 2, “Diseases of Foals and Juveniles.”
b. Autoimmune hemolytic anemia
This condition is better referred to as immune-mediated hemolytic anemia (IMHA) because the cause is only rarely due to autoantibodies directed against red blood cell antigens. Most cases have antibodies and/or complement nonspecifically attached to the surface of red blood cells often due to a hapten that has altered the red blood cell antigens in such a way that they are considered foreign to the immune system, or the antibody is directed against an antigen attached to the red blood cells. The hapten is usually not known, but some known causes are penicillin, Clostridium perfringens myositis of the cervical region, and red blood cell parasites. In most cases the hemolysis is extravascular due to phagocytosis of red blood cells coated with IgG by macrophages in the spleen and liver. Therefore, the urine and kidneys are not discolored red brown. Intravascular hemolysis is usually associated with IgM and complement attachment. With either mechanism there often is moderate to severe anemia and prominent hepatosplenomegaly.
Autoagglutination is uncommon but diagnostic when present. Spherocytosis is difficult to recognize in the horse because central pallor of red blood cells is not a normal feature. Coombs positivity is associated with IMHA but is also seen in other diseases. A positive Coombs test means there is antibody and/or complement attached to red blood cells. However, this can happen nonspecifically; it does not guarantee IMHA is present, and it does not differentiate autoimmune from immune-mediated unless direct and indirect tests are performed. The Coombs test, like any test, can also be falsely negative for several reasons and IMHA is present.
Figure 15.10. Horse. Blood Smear. IMHA. Blood is agglutinating spontaneously on a glass slide, to right; normal to left.
Figure 15.11. Blood Smear. IMHA. Light microscopic agglutination is evidenced by red blood cells adhered together in irregularly sized and organized clusters or morulae (left). Rouleaux is common in the horse and differentiated from agglutination by red blood cells arranged in a linear fashion, like a stack of coins (right). It does not mean a specific disease is present because it can be seen in normal horses and horses with increased serum protein.
2. Infections
Infectious agents targeting equine red blood cells are Trypanosoma sp. (T. evansi), protozoa (Babesia sp.), bacteria (Clostridium perfringens), or viruses (equine lentivirus). Babesia equi or B. caballi are the causative agents for equine piroplasmosis. Equine lentivirus is the etiology of equine infectious anemia (EIA). Trypanosomiasis is exotic to the Northern Hemisphere and involves Trypanosoma evansi (Surra) as it affects circulating blood cells.
a. Equine infectious anemia
EIA is considered one of the most important infectious diseases of equines. The agent has a worldwide distribution; however, the prevalence of EIA has largely declined in North America due primarily to the rigorous testing required for selling or trading horses or moving them across state lines. EIA is caused by an arthropod-borne lentivirus of the family Retroviridae that induces a cyclic immune-mediated hemolytic anemia with disseminated petechial hemorrhage and edema. The virus absorbs to erythrocytes leading to hemolysis. Hemolysis occurs both extravascularly and intravascularly. Some aspects of anemia are due to the immune response (IgM, IgG, complement activation) causing lysis of erythrocytes. Tissue macrophages, typically those in the spleen, account for most of virus replication. The virus replicates less than 1% in circulating monocytes. Despite the low viral burden in circulating monocytes, hematophagous flies, particularly the horsefly (genus Tabanus), are responsible for transmission of the disease. Mechanical transmission by blood-contaminated grooming equipment, shared syringes, and needles and nasogastric tubes is also possible. Vertical transmission of the virus occurs transplacentally, leading to abortion. Foals may be born with or without antibody. If the mare is positive, the foal serum should be checked before colostrum intake to determine if no antibodies are present in foal as the virus did not cross the placenta. The official test for EIA diagnosis is the agar gel immunodiffusion test performed in certified diagnostic laboratories. STAT test now is available. EIA is a reportable disease.
Three different clinical forms of EIA are distinguished: acute, subacute, and chronic.
i. Acute form of EIA.
This form is characterized by fever, icterus, and anemia within a week of infection and frequently results in a high mortality rate. There is a decrease in the number of red blood cells, white blood cells (marked lymphopenia), and platelets. Dependent edema and petechial hemorrhages are common gross findings together with splenomegaly, hepatomegaly, and lymphadenopathy. Extensive necrosis of lymphocytes and renal tubular necrosis are typical microscopic findings. The microscopic liver lesions of focal infiltrations of lymphocytes are indicators of an immune response to viral antigens.
ii. Subacute form of EIA.
In this form of the disease, pathologic lesions are similar to the acute form, but survival is possible. Hyperplasia of lymphocytes should be expected.
iii. Chronic form of EIA.
The chronic form is encountered most frequently. It leads to generalized activation of the resident phagocytic system in several organs. Horses are typically emaciated and have an enlarged spleen and liver due to monocyte-macrophage (“reticuloendothelial”) hyperplasia. There also is liver hemosiderosis. Viral antigen-antibody-C3 form circulating immune-complexes that may deposit in glomeruli causing a progressive glomerulonephritis and eventual renal failure. Neurologic leukoencephalitis occurs occasionally in horses infected with EIA.
Asymptomatic carrier, with positive AGID test but no clinical signs, is probably the most common way the disease is encountered today.
Figure 15.12. Horse. Spleen. Splenomegaly and Lymphadenomegaly. Chronic EIA. Spleen with lienal vein thrombosis. There is hilus lymphadenomegaly due to hemosiderosis and lymphoid hyperplasia. (Courtesy Dr. J. King, Cornell University.)
Figure 15.13. Horse. Spleen. Splenomegaly. Chronic EIA. “Blackberry jam” appearance due to hyperemia, hemosiderosis, and lymphoid hyperplasia. (Courtesy Dr. Cho, Louisiana State University, Noah’s Arkive, University of Georgia.)
Figure 15.14. Horse. Liver. Hepatomegaly and Lymphadenomegaly. Chronic EIA. Hepatomegaly, discoloration, and lymphadenomegaly due to hepatitis, hemosiderosis, and lymphoid hyperplasia. (Courtesy Dr. J, King, Cornell University.)
Figure 15.15. Horse. Liver. Multifocal Intrahepatic Lymphocytic Aggregates. Chronic EIA. A microscopic hall mark for EIA infection are clusters of lymphocytes within liver sinusoids. (H&E) (Courtesy Dr. J. King, Cornell University.)
Figure 15.16. Horse. Kidney. Membranoproliferative Glomerulitis. Chronic EIA. Immune-complex glomerulopathy characterized by thickening of Bowman capsule and capillary loops (proliferative glomerulitis). (H&E) (Courtesy Dr. J. King, Cornell University.)
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