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The distinction between the various classical MPNs can be challenging, as

highlighted by the continuum of disease and the transitional entities as described in 1.1.5. The dynamic nature of haematopoiesis described in 1.2, coupled with the varied, non-malignant causes of increased erythroid/megakaryocytic and fibroblast activity also contribute to the difficulties in the accurate diagnosis of classical MPNs.

1.3.1 Essential thrombocythaemia

A peripheral blood thrombocytosis is the sine qua non of ET with thrombocytosis defined as demonstrating a platelet count greater than 450 x 109/L in adults (Schafer, 2004). This increase in platelets may be classed as a primary thrombocytosis, due to an underlying abnormality in haematopoiesis processes, or as secondary (also

referred to as ‘reactive’) thrombocytosis, when the increase can be attributed to an external cause (Buss et al., 1994).

The body’s requirement for platelets can be increased under a range of

circumstances, some examples of which are shown in Error! Reference source not f

ound.. This includes circumstances in which there is an increased requirement for

platelets, for example during blood loss following injury or surgery. Inflammatory mediators such as interleukin-6 can cause stimulate platelet production (Burmester et al., 2005; Kaser et al., 2001; Wolber et al., 2001), under circumstances where an increase in platelet production is not necessarily required (secondary increase).

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Increased platelet requirement Secondary increase Tissue damage/vascular injury Infection

Post-operative Inflammation

Haemorrhage Iron deficiency

Malignancy Therapy related

Table 1-2. Causes of reactive thrombocytosis (Harrison et al., 2010).

Thrombocytosis is often first identified as an incidental finding following a routine blood count. The most common cause of a raised platelet count would be a reactive thrombocytosis which is typically transient in nature and resolves without causing clinical complications or requiring intervention (Griesshammer et al., 1999). If platelet counts are assessed at only a single time point, it is impossible to determine whether the thrombocytosis was due to a reactive process.

Primary thrombocytosis is rarer and is most frequently attributable to ET. Complications within this group are more prevalent, with data suggesting that approximately 20% of patients present have symptomatic disease, presenting with features such as headaches, visual disturbances or thromboembolytic events (Brodmann et al., 2000). Differentiating between primary and secondary

thrombocytosis has a significant impact on patient management. The identification of underlying reactive causes should be pursued alongside the confirmation of persistence of thrombocytosis. In cases where no reactive cause is identified, evidence of malignant causes should be sought (Harrison et al., 2010).

Symptomatically, ET can be difficult to diagnose. The symptoms associated with ET are primarily related to vascular occlusive events, which can also occur as a result of many other conditions (Rumbaut and Thiagarajan, 2010). Major thrombotic events affecting cerebrovascular, cardiac, pulmonary, hepatic or splenic circulation may be fatal (Sagripanti et al., 1996). Vascular occlusions within the micro-vessels are also common, causing a wide range of symptoms including pain and

discolouration of the fingers and toes, headaches and visual dysfunction, which occur as a result of the transient suspension of blood flow (Frewin and Dowson, 2012).

1.3.2 Polycythaemia Vera

Polycythaemia is defined as an elevated haemoglobin (>185g/L in adult males and 165g/L in adult females). This may be classed as a true or apparent polycythaemia on the basis of whether the patient has an increased red cell mass (McMullin et al., 2005). Apparent polycythaemia occurs when plasma volume is decreased; this may be seen in individuals with increased alcohol intake (Biswas et al., 2003). True polycythaemia can be further separated according to whether the cause is primary and secondary (see Figure 1-5). Secondary polycythaemia occurs as a result of hypoxia or in some hereditary conditions (as shown in Table 1-3).

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Congenital Acquired

High oxygen-affinity haemoglobin variant

Cardiac disease

2,3-biphosphoglycerate mutase deficiency

Chronic lung disease

Erythropoietin receptor-mediated Carbon monoxide poisoning Chuvash erythrocytosis (vhl mutation) Smoker's erythrocytosis

End-stage renal disease Hepatocellular carcinoma Renal cell cancer

Table 1-3. Example of causes of secondary polycythaemia (adapted from McMullin et al., 2005b).

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Figure 1-5. Differential diagnosis of polycythaemia. Patients presenting with increased haemoglobulin and/or haematocrit levels can be separated according to the presence or absence of increased red cell mass, allowing those with apparent polycythaemia to be identified. Where true polycythaemia is present, this can be further discriminated into primary polycythaemia (PV) and secondary polycythaemia.

Increased Haemoglobin and

Haematocrit

Increased Red Cell

Mass True Polycythamia

Primary

Secondary

Increased EPO

Inherited Normal Red Cell Mass

Decreased Plasma Volume

Apparent Polycythaemia

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EPO production is stimulated by low tissue oxygen levels. Hypoxia can arise in a wide range of conditions, as shown in Table 1-3, giving rise to increased levels of EPO and subsequently an increase in red cell mass (Lee and Percy, 2011).

Polycythaemia may be asymptomatic, and only be identified as an incidental finding following a routine blood count. However, prolonged polycythaemia is associated with a range of symptoms including (Koopmans et al., 2012; Radia and Geyer, 2015);

o Fatigue

o Pruritis (Itching)

o Erythromelalgia (burning sensation in extremities) o Headaches

o Dizziness

o Reddening of skin o Splenomegaly o Thrombosis

The symptoms associated with PV are primarily related to the thickening of

peripheral blood and occlusive events which result from hyperviscosity (Emanuel et al., 2012; Geyer et al., 2014; Mesa et al., 2007). Similarly to patients with ET, major thrombotic events affecting cerebrovascular, cardiac, pulmonary, hepatic (Budd-Chiari) or splenic circulation can occur and may be fatal. (Sagripanti et al., 1996). Complications arising from PV are common, with data suggesting that approximately 30-40% of patients present with symptomatic disease and splenomegaly (Geyer et al., 2014).

1.3.3 Primary myelofibrosis

The presentation of PMF is highly variable, as PMF can arise as a de novo condition, or as a progression/transformation of an existing PV/ET (Bose and Verstovsek, 2016). Additionally, de novo PMF can present in both the prefibrotic stage of disease as well as in its overt form (Tefferi, 2018). As a result of these varying aetiologies patients may present with features ranging from hyper-cellularity (polycythaemia, leucocytosis, thrombocytosis) through to pancytopenia (anaemia, leucopoenia, and thrombocytopenia) and hepato-splenomegaly attributable to extramedullary haematopoiesis (Guglielmelli et al., 2017). Overt PMF is associated with a more severe clinical presentation than is reported in pre-fibrotic PMF (Rumi et al., 2018). The severity of symptoms may be contributed to the increasing hepato/splenomegaly; and can include portal hypertension, pain, and splenic

infarction, as well as progressive bone marrow failure due to the increasing areas of fibrosis within the marrow (Guglielmelli et al., 2017).