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They are generally diseases of middle or older age and have features in common, including a potential for transforming to acute leukaemia.

Myelofibrosis may arise de novo or result from progression of polycythaemia vera or essential thrombocythaemia.

Treatment of polycythaemia vera and essential thrombocythaemia can greatly influence prognosis, hence the importance of diagnosing these rare disorders early.

They need to be distinguished from other types of polycythaemia (secondary polycythaemia, apparent polycythaemia) and other causes of a raised platelet count (secondary or reactive thrombocytosis), whose prognosis and treatment are different.

Polycythaemia

An elevation in packed cell volume (PCV), rather than a raised haemoglobin concentration, defines polycythaemia.

A raised packed cell volume (>0.51 in males, >0.48 in females) needs to be confirmed on a specimen taken without prolonged venous stasis (tourniquet).

Patients with a persistently raised packed cell volume should be referred to a haematologist for measurement of red cell mass by radionuclide labelling of the red cells.

Red cell mass is best expressed as the percentage difference between the measured value and that predicted from the patient’s height and weight (derived from tables).

Red cell mass measurements more than 25% above the predicted value constitute true or absolute polycythaemia, which can be classified into aetiological categories.

When the packed cell volume is raised but the red cell mass is not, the condition is known as apparent or relative polycythaemia and is secondary to a reduction in plasma volume.

Polycythaemia vera

Presentation can be incidental but is classically associated with a history of occlusive vascular lesions (stroke, transient ischaemic attack, ischaemic digits), headache, mental clouding, facial redness, itching, abnormal bleeding, or gout.

Initial laboratory investigations A raised white cell count (>10X109/l neutrophils) or a raised platelet count (>400Xl09/l) suggest primary polycythaemia, especially if both are raised in the absence of an obvious cause, such as infection or carcinoma.

Serum ferritin concentration should be determined as iron deficiency may mask a raised packed cell volume, resulting in a missed diagnosis.

Specialist investigations Red cell mass should be determined to confirm absolute polycythaemia, and secondary polycythaemia should be excluded.

Most patients with primary polycythaemia have a low serum erythropoietin concentration.

If the spleen is not palpable then splenic sizing (ultrasonography) should be performed to look for enlargement.

Bone marrow cytogenetic analysis may reveal an acquired chromosomal abnormality which would favour a primary marrow disorder such as polycythaemia vera.

Erythroid colony growth from blood or bone marrow in the absence of added erythropoietin culture from peripheral blood would support the diagnosis.

No single pathognomonic test exists and the diagnosis is best made using a diagnostic algorithm (opposite).

Treatment Traditional treatment using the marrow suppressant effect of radioactive phosphorus (32P) has been superseded because of the additional risk of inducing malignancies such as acute leukaemia in later life.

Repeated venesection to maintain the packed cell volume at <0.45 has become the mainstay of treatment.

At this volume the risk of thrombotic episodes is much reduced.

Venesection has to be frequent at first but is eventually needed only every 6-10 weeks in most patients.

If thrombocytosis is present, concurrent therapy to maintain the platelet count to <400X109/l is necessary. Hydroxyurea (0.5-1.5 g daily) is recommended for this purpose and is not thought to have a pronounced leukaemogenic potential.

Some use interferon α in preference to hydroxyurea in younger patients, as this drug is not thought to increase the long term risk of leukaemic transformation.

Low dose intermittent oral busulphan may be a convenient alternative in elderly people.

Anagrelide is a new agent that can specifically reduce the platelet count and may be useful in conjunction with treatment to control the packed cell volume (see under Essential thrombocythaemia).

Progression Long survival (>10 years) of the treated patient has revealed a 20% incidence of transformation to myelofibrosis and about 5% to acute leukaemia.

The incidence of leukaemia is further increased in those who have transformed to myelofibrosis and those treated with 32P or multiple cytotoxic agents.

Secondary polycythaemia

Many causes of secondary polycythaemia have been identified, the commonest being hypoxaemia (arterial saturation <92%) and renal lesions.

In recent years the abuse of drugs such as erythropoietin and anabolic steroids should also be considered in the right context. Investigations are designed to determine the underlying disorder to which the polycythaemia is secondary.

Treatment is aimed at removing the underlying cause when practicable.

In hypoxaemia, in which the risk of vascular occlusion is much less pronounced than in polycythaemia vera, venesection is usually undertaken only in those with a very high packed cell volume.

At this level the harmful effects of increased viscosity no longer outweigh the oxygen carrying benefits of a raised packed cell volume.

Reduction to a packed cell volume of 0.50-0.52 may result in an improvement of cardiopulmonary function.

In practice the symptoms experienced by individual patients often decide the target packed cell volume.

In polycythaemia associated with renal lesions or other tumours, the packed cell volume should generally be reduced to <0.45.

Apparent polycythaemia

In apparent or relative polycythaemia red cell mass is not increased and the raised packed cell volume is secondary to a decrease in the volume of plasma.

An association exists with smoking, alcohol excess, obesity, diuretics, and hypertension.

The need for treatment is uncertain.

Lowering the packed cell volume by venesection is undertaken only in patients who have a significantly increased risk of vascular complications for other reasons.

On follow up one-third of patients revert spontaneously to a normal packed cell volume.

Essential thrombocythaemia

Like polycythaemia vera and idiopathic myelofibrosis, essential thrombocythaemia is one of the group of clonal conditions known as the myeloproliferative disorders.

A persisting platelet count >600X109/l is the central diagnostic feature, but other causes of a raised platelet count need to be excluded before a diagnosis of essential thrombocythaemia can be made.

Laboratory investigations

Investigations may reveal other causes of raised platelet count. Apart from a full blood count and blood film they should also include erythrocyte sedimentation rate, serum C reactive protein and serum ferritin, bone marrow aspirate, trephine, and cytogenetic analysis.

Although the latter is generally normal in essential thrombocythaemia, certain abnormalities may favour a diagnosis of myelodysplasia or iron deficient (masked) polycythaemia vera and it is important to exclude the presence of a Philadelphia chromosome, which would indicate a diagnosis of chronic myeloid leukaemia.

Presentation and prognosis

Thirty to fifty per cent of patients with essential thrombocythaemia have microvascular occlusive events: for example, burning pain in extremities (erythromelalgia) or digital ischaemia, major vascular occlusive events, or haemorrhage at presentation.

These are most pronounced in elderly people, in whom the risk of cerebrovascular accident, myocardial infarction, or other vascular occlusion is high if left untreated.

Patients with pre-existing vascular disease will also be at higher risk of such complications.

The risk in young patients is lower, though major life threatening events have been described.

Transformation to myelofibrosis or acute leukaemia may occur in the long term in a minority of patients.

Treatment and survival

All patients should receive daily low dose aspirin, unless contraindicated because of bleeding or peptic ulceration.

This reduces the risk of vascular occlusion but may increase the risk of haemorrhage, particularly at very high platelet counts.

Reduction of the platelet count by cytotoxic agents (daily hydroxyurea, or intermittent low dose busulphan in elderly people) reduces the incidence of vascular complications and appreciably improves survival in older patients (from about three years in untreated patients to 10 years or more in treated patients).

The newer drug anagrelide is used increasingly in view of its specificity to the platelet lineage (it selectively inhibits megakaryocyte differentiation) and because of an expectation that it will not increase the long term risk of leukaemic transformation. Interferon α has also been used and is particularly useful in pregnancy.

The Medical Research Council “Primary Thrombocythaemia 1” trial is currently comparing the use of hydroxyurea and anagrelide in patients with essential thrombocythaemia and a high risk of thrombosis.

Idiopathic myelofibrosis

The main features are bone marrow fibrosis, extramedullary haemopoiesis (production of blood cells within organs other than the bone marrow), splenomegaly, and leucoerythroblastic blood picture (immature red and white cells in the peripheral blood).

Good evidence exists that the fibroblast proliferation is secondary (reactive) and not part of the clonal process.

In some patients, the fibrosis is accompanied by new bone formation (osteomyelosclerosis). Idiopathic myelofibrosis needs to be distinguished from causes of secondary myelofibrosis (see below).

Presentation

Idiopathic myelofibrosis may have been present for many years before diagnosis.

Patients could have had previous undiagnosed primary polycythaemia or thrombocythaemia.

The absence of palpable splenomegaly is rare.

The main presenting features are abdominal mass (splenomegaly), weight loss (hypermetabolic state), anaemia, fatigue, and bleeding.

Fevers and night sweats may be present and are associated with a worse outcome.

Laboratory investigations

A leucoerythroblastic blood picture is characteristic but not diagnostic of idiopathic myelofibrosis as it can occur in cases of marrow infiltration (eg by malignancy, amyloidosis, tuberculosis, osteopetrosis) severe sepsis, severe haemolysis, after administration of haemopoietic growth factors as well as in various types of chronic leukaemia.

The blood count is variable. In the initial “proliferative phase” red cell production may be normal or even increased. About half of presenting patients may have a raised white cell count or platelet count (absence of the Philadelphia chromosome will distinguish from chronic myeloid leukaemia).

As the bone marrow becomes more fibrotic, the classic “cytopenic phase” supervenes.

Progression and management

The median survival of 2-4 years may be much longer in patients who are asymptomatic at presentation.

More recently it has been shown that the presence of anaemia, a very high or low white cell count, the presence of bone marrow chromosomal abnormalities and an advanced patient age are all associated with worse prognosis. Bone marrow transplantation from a matched sibling or unrelated donor should be offered to young patients with poor prognostic features.

This is the only curative treatment modality for myelofibrosis, but in view of its toxicity it cannot be performed in the majority of patients with this disorder, who are over 50 years old at diagnosis.

Supportive blood transfusion may be needed for anaemic patients.

Cytotoxic agents may be useful in the proliferative phase, particularly if the platelet count is raised.

More recently antifibrotic and antiangiogenic agents such as thalidomide have been used to inhibit progression of fibrosis but success has been limited and there is no convincing evidence that such treatment improves survival.

Androgenic steroids such as danazol and oxymethalone can improve the haemoglobin in a proportion of anaemic patients.

Splenectomy may improve the quality of life (though not the prognosis) by reducing the need for transfusions or the pain sometimes associated with a very enlarged spleen.

Operative morbidity and mortality can be high and are usually secondary to haemorrhage, making preoperative correction of coagulation abnormalities imperative.

Low dose irradiation of the spleen may be helpful in frail patients.

Death can be due to haemorrhage, infection or transformation to acute leukaemia.

Portal hypertension with varices, iron overload from blood transfusion, and compression of vital structures by extramedullary haemopoietic masses may also contribute to morbidity.