Myeloproliferative Disorders Flashcards
What are myeloproliferative disorders
In these disorders, there is uncontrolled clonal proliferation of one or more of the cell lines in the bone marrow, namely erythroid, myeloid and megakaryocyte lines. Myeloprolifera-tive disorders include polycythemia vera (PV), essential thrombocythaemia (ET), myelofibrosis (all of which have a JAK-2 molecular lesion) and chronic myeloid leukaemia (CML) (a genetic BCR-ABL lesion). These disorders are grouped together as there can be transition from one disease to another; e.g. PV can lead to myelofibrosis. They may also transform to acute myeloblastic leukaemia. The non-leukaemic myeloproliferative disorders (PV, ET and myelofi-brosis) will be discussed in this section.
Mention the myeloproliferative disorders
Polycythemia
Essential thrombocythaemia
Myelofibrosis
Chronic myeloid leukaemia
What is polycythemia
Polvcvthaemia (or ervthroctosis) is defined as an increase in haemoglobin, PCV and red cell count. PCV is a more reliable indicator of polycythemia than is Hb, which may be disproportionately low in iron deficiency. Polycythemia can be divided into absolute erythrocytosis where there is a true increase in red cell volume, or relative erythrocytosis where the red cell volume is normal but there is a decrease in the plasma volume (Fig. 8.6).
Absolute erythrocytosis is due to primary polycythemia
(PV) or secondary polycythaemia. Secondary polycythaemia is due to either an appropriate increase in red cells in response to anoxia, or an inappropriate increase associated with tumours, such as a renal carcinoma.
What is polycythemia vera
PV is a clonal stem cell disorder in which there is an alteration in the pluripotent progenitor cell leading to excessive proliferation of erythroid, myeloid and megakaryocytic progenitor cells. Over 95% of patients with PV have acquired mutations of the gene Janus Kinase 2 (JAK2). There is a V617F mutation which causes the substitution of phenylalanine for valine at position 617. JAK2 is a cytoplasmic tyrosine kinase that transduces signals, especially those triggered by haemat-opoietic growth factors such as erythropoietin, in normal and neoplastic cells. The significance of the discovery is two-fold: first of immediate significance is the clinical utility of the detection of JAK2 mutations for the diagnosis of PV and second is the prospect of the development of new treatments for the myeloproliferative disorders based on targeting JAK2 activity.
What are some clinical features of polycythemia vera
The onset is insidious. It usually presents in patients aged over 60 years with tiredness, depression, vertigo, tinnitus and visual disturbance. It should be noted that these symptoms are also common in the normal population over the age of 60 and consequently, PV is easily missed. These features, together with hypertension, angina, intermittent claudication and a tendency to bleed, are suggestive of PV.
Severe itching after a hot bath or when the patient is warm is common. Gout due to increased cell turnover may be a feature, and peptic ulceration occurs in a minority of patients.
Thrombosis and hemorrhage are the major complications of PV.
The patient is usually plethoric and has a deep dusky cyanosis. Injection of the conjunctivae is commonly seen.
The spleen is palpable in 70% and is useful in distinguishing
PV from secondary polycythaemia. The liver is enlarged in 50% of patients.
How is polycythemia vera diagnosed
The measurement of red cell and plasma volume is not necessary. There may be a raised serum uric acid, leucocyte alkaline phosphatase and a raised serum vitamin B12 and vitamin B12 binding protein (transcobalamin 1).
What is the course of polycythemia vera and how is it managed
Treatment is designed to maintain a normal blood count and to prevent the complications of the disease, particularly thromboses and haemorrhage. Treatment is aimed at keeping the PCV below 0.45 L/L and the platelet count below 400×10°L. There are three types of specific treatment:
• Venesection. The removal of 400-500 mL weekly will successfully relieve many of the symptoms of PV. Iron deficiency limits erythropoiesis. Venesection is often used as the sole treatment and other therapy is reserved to control the thrombocytosis. The aim is to maintain a packed cell volume (PVC) of <0.45 L/L.
Chemotherapy. Continuous or intermittent treatment with hydroxycarbamide (hydroxyurea) is used frequently because of the ease of controlling thrombocytosis and general safety in comparison to the alkylating agents such as busulfan, which carry an increased risk of acute leukaemia. Low-dose intermittent busulfan may be more convenient for elderly people, and this must be weighed against the potential risk of long-term complications.
• Low-dose aspirin 100 mg daily with the above treatments is used for patients with recurrent thrombotic episodes.
• Anagrelide inhibits megakaryocyte differentiation and is useful for thrombolysis.
What is the general treatment for polycythemia vera
Radioactive 32P is only given to patients over 70 years because of the increased risk of transformation to acute leukaemia. Allopurinol is given to block uric acid production.
The pruritus is lessened by avoiding very hot baths. H1-receptor antagonists have largely proved unsuccessful in relieving distressing pruritus, but H2-receptor antagonists such as cimetidine are occasionally effective.
Surgery. Polycythemia should be controlled before surgery. Patients with uncontrolled PV have a high operative risk; 75% of patients have severe haemorrhage following surgery and 30% of these patients die. In an emergency, reduction of the hematocrit by venesection and appropriate fluid replacement must be carried out.
What is the prognosis for polycythemia vera
PV develops into myelofibrosis in 30% of cases and into acute myeloblastic leukaemia in 5% as part of the natural history of the disease.
What are secondary polycythemias
Many high-oxygen affinity haemoglobin mutants (HOAHM) have been described which lead to increased oxygen affinity but decreased oxygen delivery to the tissues, resulting in compensatory polycythemia. A congenital autosomal recessive disorder (Chuvasch polycythaemia) is due to a defect in the oxygen-sensing erythropoietin production pathway caused by a mutation of the von Hippel-Lindau (VHL) gene, resulting in an increased production of erythropoietin.
The causes of secondary polycythemias are shown in
Table 8.15.
Serum erythropoietin (EPO) levels are normal or raised in secondary polycythemia. Rarely the discovery of a high EPO level may be the clue to the presence of an EPO secreting tumour.
The treatment is that of the precipitating factor; e.g. renal or posterior fossa tumours need to be resected. The commonest cause is heavy smoking, which can produce as much as 10% carboxyhaemoglobin and this can produce poly-cythaemia because of a reduction in the oxygen-carrying capacity of the blood. Heavy smokers also often have respiratory disease.
Complications of secondary polycythemia are similar to those seen in PV, including thrombosis, haemorrhage and cardiac failure, but the complications due to myeloprolifera-tive disease such as progression to myelofibrosis or acute leukaemia do not develop. Venesection may be symptomati-cally helpful in the hypoxic patient, particularly if the PCV is above 0.55 L/L.
What is ‘relative’ or ‘apparent’ polycythemia (Gaisböck’s syndrome)
This condition was originally thought to be stress-induced.
The red cell volume is normal, but as the result of a decreased plasma volume, there is a relative polycythaemia. ‘Relative’ polycythemia is more common than PV and occurs in middle-aged men, particularly in smokers who are obese and hypertensive. The condition may present with cardiovascular problems such as myocardial or cerebral ischaemia. For this reason, it may be justifiable to venesect the patient. Smoking should be stopped.
What is essential thrombocythemia
Essential thrombocythaemia (ET) is a myeloproliferative disorder closely related to PV. Patients have normal Hb levels and WBC but elevated platelet counts. At diagnosis the platelet count will usually be >600×10%L, and may be as high as 2000 × 10%L or rarely even higher. ET presents either symptomatically with thromboembolic or less commonly bleeding problems or incidentally (e.g. at a routine medical check).
The diagnosis of ET is not straightforward as there is no global gold standard test. The JAK2 mutation tests (see PV are useful in that the gene is mutated in about half of all cases of ET, confirming a myeloproliferative disorder. For the remaining 50% of patient with a normal JAK2 gene, clinical assessment and observation over a period of time are required. As a generalization a person with a very high platelet count (>1000×10 L) who is clinically normal with good health will most likely prove to have ET. In a patient with a lower platelet count, e.g. 600×10%L, and in poor health the diagnosis can be more difficult. Other disorders which may give rise to reactive high platelet counts include autoimmune rheumatic disorders and malignancy. Individuals who have been splenectomized (for any reason, including trauma) sometimes have high platelet counts.
What is the treatment for essential thrombocythemia
Treatment is with hydroxycarbamide (hydroxyurea), anagre-lide or busulfan to control the platelet count to less than 400×10%L.
a-Interferon is also effective; it is administered by subcutaneous injection. ET may eventually transform into PV, myelofibrosis or acute leukaemia, but the disease may not progress for many years.
What is myelofibrosis
Myelofibrosis is a very debilitating chronic myeloproliferative neoplasm. It may be primary or develop late in the course of essential thrombocythaemia or polycythemia vera. There is clonal proliferation of stem cells and myeloid metaplasia in the liver, spleen and other organs. Increased fibrosis in the bone marrow is caused by hyperplasia of abnormal meg-akaryocytes which release fibroblast-stimulating factors such as platelet-derived growth factor.
What are some clinical features of myelofibrosis
The disease presents insidiously with lethargy, weakness and weight loss. Patients often complain of a ‘fullness’ in the upper abdomen due to splenomegaly. Severe pain related to respiration may indicate perisplenitis secondary to splenic infarction, and bone pain and attacks of gout can complicate the illness. Bruising and bleeding occur because of thrombocytopenia or abnormal platelet function. Other physical signs include anemia, fever and massive splenomegaly (for other causes, see p. 406).
