Bone marrow depression is the most frequent clinical syndrome directly linked to the presence of Feline leukaemia virus (FeLV); it is the consequence of a primary viral infection of the haematopoietic stem cells or stromal cells, which constitute the supportive environment for haematopoietic cells. The most frequent form of alteration is marrow hypoplasia, which leads to peripheral cytopenia of one or more cell lines (erythroid, myeloid or megakaryocytic) (bicytopenia or pancytopenia). In FeLV-infected cats, regenerative anaemia is less frequent than non-regenerative anaemia and usually occurs in the presence of co-infections by Mycoplasma haemofelis or M. haemominutum, or an immune-mediated haemolytic anaemia. Immune-mediated haemolytic anaemia is present in around one third of FeLV-positive cats; in some cases it precedes the onset of another myeloproliferative disease or lymphoma. In addition, FeLV is a frequent cause of thrombocytopenia and granulocytopenia.
Both FeLV and Feline immunodeficiency virus] (FIV) are among the infectious diseases most commonly associated with neutropenia. FeLV infection leads to the destruction of haematopoietic stem cells and the lack of maturation of neutrophils, associated with an alteration of the microenvironment. When secondary, these infections are responsible for greater consumption of neutrophils. FIV infections may also be responsible for neutropenia although in these cases the neutropenia is usually mild and transient, and develops in the first weeks of the infection; the neutropenia seems to result from a lack of differentiation between monocytes and granulocytes.
Macrocytosis, and consequent anisocytosis, is present in most cats with anaemia resulting from FeLV infection; this abnormality may develop in both regenerative and non-regenerative cases of anaemia. Some FeLV-positive cats may have marked anisocytosis even in the presence of a normal mean corpuscular volume (MCV) and around 50% of FeLV-positive cats have macrocytosis even in the absence of anaemia; the finding of macrocytosis in an apparently healthy animal should always be an indication for performing a test for FeLV.
It has been suggested that macrocytosis could be indicative of a period of intense erythropoiesis before the onset of a hypoproliferative anaemia, but the real nature of the phenomenon is still unknown.
Retrovirus-mediated bone marrow hypoplasia
From a diagnostic point of view, in all forms of bone marrow hypoplasia there is a non-regenerative, normocytic, normochromic anaemia, without other significant morphological findings. The diagnosis can be made only from the clinical history and additional tests (e.g. detection of hepatorenal failure, assay of apparently suspicious physical compounds, serological examinations for infective diseases) or from a bone marrow examination which may show alterations of the marrow.
Feline leukaemia virus-mediated aplastic anaemia
Particular aplasticanaemias are associated with infectious diseases such as FIV and FeLV in the cat, and parvovirosis and ehrlichiosis in the dog. The diagnosis of anaemia is particularly complex in the presence of FeLV, as various pathogenic mechanisms may be involved. FeLV predisposes to chronic inflammation and the anaemia may, therefore, present the typical characteristics of this form of anaemia (see below: anaemia of chronic inflammatory disease); in some cases, however, the infection of marrow precursors leads to the appearance of a selective erythroid aplasia, without alterations in the white blood cell lineage or, even more rarely, to haemolytic types of anaemia characterized, therefore, by a regenerative, macrocytic, hypochromic picture.
Aplastic anaemia vera is a rare occurrence during FeLV infections, although it has been historically associated with FeLV subgroup C infections.1,2 This term usually defines a selective marrow depression affecting only red blood cells (pure red cell aplasiaor PRCA). This syndrome is characterized by hypocellular bone marrow with replacement of the totipotent tissue by fat.3,4,5 During FeLV, or also FIV, infections, more frequently the other cell lines are also involved (pancytopenia). PRCA is a severe and rare form of immune-mediated non-regenerative anaemia, and can be diagnosed only from a bone marrow examination. PRCA is characterized by a complete, or almost complete, absence of erythroid precursors in the bone marrow, with concomitant marrow plasmocytosis and lymphocytosis. The leucocyte and platelet counts are within the reference ranges.
There are actually numerous causes of aplastic anaemia:6-9 various chemical substances and drugs (benzene, arsenic compounds, oestrogens, DDT, folic acid antagonists, sulphamides, phenylbutazone, lead, methimazole, griseofulvin), systemic diseases (chronic inflammation, infections, neoplasms, kidney or liver failure) and primary bone marrow diseases (osteomyelitis, leukaemias) may induce a selective bone marrow depression involving only erythrocytes.
In a trial carried out in 2005,10in which 13 cases of feline aplastic anaemia confirmed by bone marrow examination were assessed, only two subjects were positive for FeLV; the salient point, then confirmed by other studies, was that only young subjects (1-2 years old) had the association of FeLV–anaemia. The conclusion of the study was that in any case aplastic anaemia is rarely associated with retroviral infections and is more frequently a consequence of chronic renal failure.
Anaemia of chronic inflammatory disease
A special type of aplastic anaemia is that found during inflammatory processes, in which the defence mechanisms of the organism tend to sequester iron, which could be used by bacteria for their metabolic activities. Consequently, during the inflammatory process there is a state of sideropenia, but with increased serum ferritin. In such cases there is activation of systemic erythrophagocytosis by macrophages, with a decrease in the production of erythropoietin. From a diagnostic point of view, in cases of anaemia of chronic inflammatory disease, apart from the typical signs of inflammation (leucocytosis, increase of acute-phase proteins], etc.), there should also be a non-regenerative, normocytic, normochromic anaemia, associated with the above mentioned iron and ferritin alterations and a decrease in circulating erythropoietin. In these cases the marrow shows a selective depression of the eythroid cell line (with an increase in iron detectable by staining with Prussian blue) and, frequently, myeloid hyperplasia with possible signs of erythrophagocytosis. Chronic inflammatory forms are particularly frequent, both as a consequence of non-specific inflammatory processes as well as during specific disorders such as feline infectious peritonitis and FIV and FeLV infections. In such cases the findings, as mentioned above, are non-regenerative, normocytic normochromic anaemia, associated with neutrophilic leucocytosis and lymphocytopenia (leucopenia may be contemporaneously present only during FIV and/or FeLV infections).
Finally, aplastic anaemia can occur in subjects with leukaemia, caused by the neoplastic cells replacing erythropoietic bone marrow. In such cases, together with the usual non-regenerative, normocytic, normochromic anaemia, there is leucocytosis with circulating neoplastic elements. Bone marrow examination is indispensable in order to classify not only the anaemia correctly, but also the type of leukaemia.
References
- Brunning RB(1989) Bone marrow. In: Rosai,A(ed), Ackerman’s Surgical Pathology. St. Louis: C.V. Mosby, pp. 1251e1303.
- Dornsife RE, Gasper PE, Mullins JI, Hoover EA (1989) In vitro erythrocytopathic activity of an aplastic anemiainducing feline retrovirus. Experimental Hematology 17, 138e144.
- Lewis HB, Rebar AH (1979) Bone Marrow Evaluation in Veterinary Practice. St. Louis, MO: Ralston Purina Co.
- Miura A, Endo K, Sugawara T, Kameoka J, Watanabe N, Meguro K, Fukuhara O, Stao I, Suzuki C, Yoshinaga K (1991) T cell-mediated inhibition of erythropoiesis in aplastic anemia: the possible role of IFN-g and TNF-a. British Journal of Haematology 78, 442e449.
- Nissen C (1991) The pathophysiology of aplastic anemia. Seminars in Hematology 28, 313e318.
- Peterson ME, Kintzer PP, Hurvitz AI (1988) Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2, 150e157.
- Rottmann JB, English RV, Breitschwerdt EB, Duncan DE (1991) Bone marrow hypoplasia in a cat treated with griseofulvin. Journal of the American Veterinary Medical Association 198, 429e431.
- Weiss DJ. Aplastic anemia in cats e clinicopathological features and associated disease conditions 1996-2004. Journal of Feline Medicine and Surgery (2006) 8, 203-206
- Weiss DJ (2000) Aplastic anemia. In: Feldman BF, Zinkl JG, Jain NC (eds), Schalm’s Veterinary Hematology (5th edn). Town Lippincott Williams & Wilkins, pp. 212e215.
- Weiss DJ, Evanson OA (2000) A retrospective study of feline pancytopenia. Comparative Haematology International 10, 50e55.