Introduction

Introduction:

The haematopoietic system comprises the bone marrow and the bone marrow derived cells, and the lymphoreticular tissues: the thymus, spleen and lymph nodes.

Bone Marrow:

The bone marrow is the predominant site of haematopoiesis. Any disturbance of the normal function of the bone marrow can result in impaired haematopoiesis and manifest as anaemia, and/or thrombocytopenia and/or leukopenia.

Disorders of erythropoiesis:

The hormone erythropoietin (EPO), produced by the kidney is the main growth factor stimulating erythropoiesis. Tissue oxygenation is the basic regulator of EPO release with EPO being released in response to hypoxia. Hypoxia can be due to:

• low environmental oxygen – high altitudes

• decreased RBC – anaemia

• decrease oxygen uptake – lung disease, chronic heart failure

Under times of increased oxygen demand, the bone marrow may release RBC precursors into the peripheral blood. Reticulocytes can increase from normal levels of 1% up to 30-50% of total RBC, nucleated RBC may increase from 0% to 5-20% of total RBC.

It is important to remember that horses do not release reticulocytes into the peripheral blood despite severe anaemia. To measure a regenerative response in a horse requires serial PCV assessment over a period of weeks or bone marrow evaluation.

Anaemia: the decreased ability of blood to supply tissues with adequate oxygen for proper metabolic function.

Anaemia is characterised by:

• Decreased haemoglobin,

• Packed cell volume (haematocrit), or

• Decreased total erythrocyte count.

Anaemia is a clinical manifestation of an underlying disease process, NOT a diagnosis.

Classification of anaemia:

Regenerative versus non-regenerative - An assessment of bone marrow function. A regenerative anaemia has adequate bone marrow function. A non-regenerative anaemia indicates that there is a problem with bone marrow production of RBCs

Morphology - based on RBC size & haemoglobin concentration:

• Microcytic, normocytic or macrocytic

• Hypochromic or normochromic. Hyperchromic changes are usually lab errors

Three basic causes of anaemia:

• Red blood cell loss (regenerative) - eg coagulopathy, epistaxis, trauma

• Red blood cell destruction (regenerative) - eg immune-mediated disease, toxins

• Decreased/ineffective production (non-regenerative) - eg anaemia of inflammatory disease, neoplasia

Erythrocytosis - an increase in packed cell volume

Approximate synonym = ‘polycythaemia'. Polycythaemia can also imply erythrocytosis accompanied by leukocytosis and thrombocytosis.

Classification of erythrocytosis:

• Relative erythrocytosis – most common, total number of RBCs in body is normal. Increased PCV due to dehydration and haemoconcentration. Also in excitable individuals following catecholamine-induced splenic contraction

• Absolute erythrocytosis – true increase in number of RBCs in body

Absolute erythrocytosis:

• Primary - neoplastic proliferation of erythrocytes. Very rare in animals, similar to well defined human disease polycythaemia vera.

• Secondary:

1. Appropriate – in response to hypoxaemia

2. Inappropriate - eg EPO doping – racehorses, cyclists; renal neoplasia – EPO production (rare); paraneoplastic syndrome – EPO-like hormones.
   

Disorders of thrombopoiesis:

Platelets play a critical role in haemostasis with the formation of platelet plugs

Thrombocytosis: usually a reactive change and is thus transient and mild - eg in response to haemorrhage there is often a “rebound” thrombocytosis; following splenectomy; feature of chronic iron deficiency anaemia; acute or chronic infections/inflammatory conditions etc.

Erythropoietin has some ability to enhance platelet production. In circumstances when EPO is increased there will be enhanced RBC production and platelet production and this can lead to a thrombocytosis.

Thrombocytopenia:

Two mechanisms -

1. premature destruction or

2. decreased production

Premature destruction:

• Auto-immune thrombocytopenia - similar pathogenesis as AIHA. The co-occurrence of immune mediate thrombocytopenia and immune mediate haemolytic anaemia is called Evan's syndrome. May be a component of SLE syndrome.

• Infectious causes eg dogs – Ehrlicia platys – infects platelets and causes cyclic thrombocytopenia

• Disseminated Intravascular Coagulation

Decreased production:

• drug and chemical toxicities - common causes: oestrogens, phenylbutazone and thiazide diuretics.

• general bone marrow suppression by drugs will usually result in decreased WBC count before they reduce platelets due the the longer life span of platelets.

• other toxins – uraemia, bacterial and fungal toxins

Platelet functional disorders:

Decreased platelet function:

• von Willebrands disease - deficiency of vW factor. vWF is produced and secreted by endothelial cells. Exposure of vWF to subendothelium promotes a conformational change. vWf promotes platelet-platelet and collagen-platelet interaction. vWD is the most common canine hereditary bleeding disorder

• Platelet adhesion is impaired in uraemia.

• Non-steroidal antiinflammatory drugs (NSAIDs) interfere with cyclooxygenase (COX) function, inhibiting production of Thromboxane A2 by platelets. Aspirin irreversibly inhibits COX activity. Non-aspirin NSAIDs inhibit COX in a reversible fashion and so platelet dysfunction with these drugs is only transient. With the increased use of COX-2 specific NSAIDs the inhibition of platelet function is less of a concern as platelets contain COX-1.

Enhanced platelet function:

Some Definitions:

Lymphoma: proliferation of malignant lymphoid cells that primarily affects lymph nodes or solid visceral organs (eg liver, spleen)

Leukaemia: malignant diseases of haematopoietic tissues characterised by replacement of normal bone marrow with an abnormal clonal proliferation of blood cells.

Leukaemias:

• Often, but not always, see increased numbers of neoplastic cells in peripheral blood.

• Often infiltrate tissues such as spleen, lymph nodes, liver…

• Leukaemia subdivided into lymphoproliferative and myeloproliferative

Myeloproliferative disorders:

• General term for diseases characterised by medullary and extramedullary proliferation of one or more blood cell lineages, excluding lymphoid cells.

• Includes but not limited to myeloid leukaemias

• Generally associated with:

  • expansion of marrow spaces with red, firm marrow at the expense of fat

  • a meaty enlarged spleen

  • variable lymphadenopathy

  • diffuse infiltration of neoplastic cells into the liver which becomes swollen and pale

Leukaemias (myeloid and lymphoid) are classified as acute or chronic. This denotes the clinical course of disease and also suggests the degree of cell immaturity observed.

Acute leukemia:

Rapid progression – maximum of 1-2 months from disease onset to death/euthanasia without treatment
Malignant cells are generally undifferentiated/poorly differentiated

Chronic leukemia:

Slow progression – disease course is measured in years
Malignant cells generally show a high degree of differentiation allowing easier classification

Myelodysplastic syndromes:

• A diverse group of disorders characterised by refractory cytopenias – anaemia, leukopenia and/or thrombocytopenia, accompanied by dysplastic changes in the marrow in one or more cell lines.

• Changes indicate ineffective blood cell production which in animals generally results in bone marrow failure.

• It is believed that myelodysplastic disorders are a prodromal stage which will evolve into leukaemias.

• the bone marrow is usually hypercellular

• most often occur in dogs and cats
  

Thymus:

The thymus is composed of epithelial cells that make up a scaffold which lymphoid precursors will colonise.The thymus is the site of T-lymphocyte production. Lymphoid precursors leave the bone marrow and enter the thymus where they undergo maturation into naive T-lymphocytes. The T-lymphocyte produced in the thymus play very important immune regulatory functions as well as being responsible from detecting foreign antigens in the context of MHC.

In most species, the thymus reaches maximal development about the time of puberty. The thymus normally regresses during adult life and this regression can be accelerated during severe or chronic illness.The thymus never completely disappears and continues to be the site of T lymphocyte production throughout life.

A failure in thymic development or function can lead to an immunodeficent state. There may be failure of lymphoid precursors to reach the thymus or there may be a failure of thymic development of T-lymphocytes. It is also possible for a combined failure of B and T lymphocyte production to occur. In this condition of severe combined immunodeficient (SCID) the affected animal is extremely susceptible to a wide range of infectious agents and the condition is usually fatal early in life.

Thymic neoplasia:

It is important to remember that the thymus is composed of an epithelial component and a lymphoid component and as such there is potential for neoplastic transformation of either cell type. Neoplasia of the epithelial component of the thymus is referred to as Thymoma and neoplasia of the lymphoid component is referred to as thymic lymphoma.

Spleen:

the spleen is the major secondary lymphoid organ and is the largest mass of lymphoid tissue in the body.

It is important to be able to differentiate the various nodular changes that occur in the spleen. In particular nodular hyperplasia, haemagiosarcoma, haemangioma and haematoma need to be distinguished and the only reliable way to do this is by histological examination.

Lymph nodes:

The lymph nodes are involved in immune surveillance and are frequently the site of antibody production. Lymph nodes are often the site of infection and are frequently involved in metastatic neoplasia.

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