POLYCYTHAEMIAPolycythaemia (or erythrocytosis) is defined as an increasein haemoglobin, PCV and red cell count. PCV is a more reliableindicator of polycythaemia than is Hb, which may bedisproportionately low in iron deficiency. Polycythaemia canbe divided into absolute erythrocytosis where there is a trueincrease in red cell volume, or relative erythrocytosis wherethe red cell volume is normal but there is a decrease in theplasma volumeAbsolute erythrocytosis is due to primary polycythaemia(PV) or secondary polycythaemia. Secondary polycythaemiais due to either an appropriate increase in red cells inresponse to anoxia, or an inappropriate increase associatedwith tumours, such as a renal carcinoma.

• Primary polycythaemia:polycythaemia vera (PV)PV is a clonal stem cell disorder in which there is an alterationin the pluripotent progenitor cell leading to excessive prolif-PrimaryPolycythaemia veraMutations in erythropoietinreceptorHigh-oxygen-affinityhaemoglobinsSecondaryDue to an appropriateincrease inerythropoietin:High altitudeLung diseaseCardiovascular disease(right-to-left shunt)Heavy smokingIncreased affinity ofhaemoglobin, e.g.familial polycythaemiaRelative:Stress or spuriouspolycythaemiaDehydrationBurns

Due to an inappropriate

increase in erythropoietin:

Renal disease–renal cell

carcinoma, Wilms’ tumour

Hepatocellular carcinoma

Adrenal tumours

Cerebellar haemangioblastoma

Massive uterine fibroma

eration of erythroid, myeloid and megakaryocytic progenitorcells. Over 95% of patients with PV have acquired mutationsof the gene Janus Kinase 2 (JAK2). There is a V617F mutationwhich causes the substitution of phenylalanine for valine atposition 617. JAK2 is a cytoplasmic tyrosine kinase thattransduces signals, especially those triggered by haematopoieticgrowth factors such as erythropoietin, in normal andneoplastic cells. The significance of the discovery is twofold:

first of immediate significance is the clinical utility of thedetection of JAK2 mutations for the diagnosis of PV andsecond is the prospect of the development of new treatmentsfor the myeloproliferative disorders based on targetingJAK2 activity.

Clinical featuresThe onset is insidious. It usually presents in patients agedover 60 years with tiredness, depression, vertigo, tinnitus

andvisual disturbance. It should be noted that these symptomsare also common in the normal population over the age of60 and consequently PV is easily missed. These features,together with hypertension, angina, intermittent claudicationand a tendency to bleed, are suggestive of PV.Severe itching after a hot bath or when the patient iswarm is common. Gout due to increased cell turnover maybe a feature, and peptic ulceration occurs in a minority ofpatients. Thrombosis and haemorrhage are the major

complicationsof PV.

The patient is usually plethoric and has a deep duskycyanosis. Injection of the conjunctivae is commonly seen.The spleen is palpable in 70% and is useful in

distinguishingPV from secondary polycythaemia. The liver is enlarged in50% of patients.

Diagnosisshows the revised WHO criteria for diagnosis inadults. The measurement of red cell and plasma volume arenot necessary. There may be a raised serum uric acid, leucocytealkaline phosphatase and a raised serum vitamin B12and vitamin B12 binding protein (transcobalamin 1

Course and managementTreatment is designed to maintain a normal blood count andto prevent the complications of the disease, particularlythromboses and haemorrhage. Treatment is aimed at keepingthe PCV below 0.45 L/L and the platelet count below 400 ×109/L. There are three types of specific treatment

Venesection. The removal of 400–500 mL weekly willsuccessfully relieve many of the symptoms of PV. Irondeficiency limits erythropoiesis. Venesection is oftenused as the sole treatment and other therapy isreserved to control the thrombocytosis. The aim is tomaintain a packed cell volume (PVC) of < 0.45 L/L.

■Chemotherapy. Continuous or intermittent treatmentwith hydroxycarbamide (hydroxyurea) is used frequentlybecause of the ease of controlling thrombocytosis andgeneral safety in comparison to the alkylating agentssuch as busulfan, which carry an increased risk of acuteleukaemia. Low-dose intermittent busulfan may be moreconvenient for elderly people, and this must be weighedagainst the potential risk of long-term complications.

■Low dose aspirin 100 mg daily with the abovetreatments is used for patients with recurrent thromboticepisodes .

■Anagrelide inhibits megakaryocyte differentiation and isuseful for thrombolysis

General treatmentRadioactive 32P is only given to patients over 70 yearsbecause of the increased risk of transformation to acuteleukaemia. Allopurinol is given to block uric acid production.The pruritus is lessened by avoiding very hot baths. H1-

receptor antagonists have largely proved unsuccessful inrelieving distressing pruritus, but H2-receptor antagonistssuch as cimetidine are occasionally effective.

Surgery. Polycythaemia should be controlled beforesurgery. Patients with uncontrolled PV have a high operativerisk; 75% of patients have severe haemorrhage followingsurgery and 30% of these patients die. In an emergency,

reduction of the haematocrit by venesection and appropriatefluid replacement must be carried out

PrognosisPV develops into myelofibrosis in 30% of cases and intoacute myeloblastic leukaemia in 5% as part of the naturalhistory of the disease

Secondary polycythaemiasMany high-oxygen affinity haemoglobin mutants (HOAHM)have been described which lead to increased oxygen affinitybut decreased oxygen delivery to the tissues, resultingin compensatory polycythaemia. A congenital autosomalrecessive disorder (Chuvasch polycythaemia) is due to adefect in the oxygen-sensing erythropoietin productionpathway caused by a mutation of the von Hippel–Lindau

)VHL (gene, resulting in an increased production oferythropoietin.

Essential thrombocythaemia (ET)Essential thrombocythaemia (ET) is a myeloproliferative disorderclosely related to PV. Patients have normal Hb levelsand WBC but elevated platelet counts. At diagnosis theplatelet count will usually be > 600 × 109/L, and may be ashigh as 2000 × 109/L or rarely even higher. ET presents eithersymptomatically with thromboembolic or less commonlybleeding problems or incidentally (e.g. at a routine medicalcheck).The diagnosis of ET is not straightforward as there is noglobal gold standard test. The JAK2 mutation tests (see PV)are useful in that the gene is mutated in about half of all casesof ET, confirming a myeloproliferative disorder. For theremaining 50% of patient with a normal JAK2 gene, clinicalassessment and observation over a period of time arerequired. As a generalization a person with a very high plateletcount (> 1000 × 109/L) who is clinically normal with goodhealth will most likely prove to have ET. In a patient with alower platelet count, e.g. 600 × 109/L, and in poor health thediagnosis can be more difficult. Other disorders which maygive rise to reactive high platelet counts include autoimmunerheumatic disorders and malignancy. Individuals who havebeen splenectomized (for any reason, including trauma)sometimes have high platelet counts

MYELOFIBROSIS (MYELOSCLEROSIS)The terms myelosclerosis and myelofibrosis are interchangeable.There is clonal proliferation of stem cells and myeloidmetaplasia in the liver, spleen and other organs. Increasedfibrosis in the bone marrow is caused by hyperplasia ofabnormal megakaryocytes which release fibroblast-stimulatingfactors such as platelet-derived growth factor. In about

25% of cases there is a preceding history of PV and 50%have the JAK2 mutation seen in PV

Clinical featuresThe disease presents insidiously with lethargy, weaknessand weight loss. Patients often complain of a ‘fullness’ in theupper abdomen due to splenomegaly. Severe pain related torespiration may indicate perisplenitis secondary to splenicinfarction, and bone pain and attacks of gout can complicatethe illness. Bruising and bleeding occur because of thrombocytopeniaor abnormal platelet function. Other physicalsigns include anaemia, fever and massive splenomegaly (forother causes

Investigations ■Anaemia with leucoerythroblastic features is present

Poikilocytes and red cells withcharacteristic tear-drop forms are seen. The WBC countmay be over 100 × 109/L, and the differential WBCcount may be very similar to that seen in chronicmyeloid leukaemia (CML); later leucopenia may develop.

■The platelet count may be very high, but in laterstages, thrombocytopenia occurs.

■Bone marrow aspiration is often unsuccessful and thisgives a clue to the presence of the condition. A bonemarrow trephine is necessary to show the markedlyincreased fibrosis. Increased numbers ofmegakaryocytes may be seen.

■The Philadelphia chromosome is absent; this helps todistinguish myelofibrosis from most cases of CML.

■The leucocyte alkaline phosphatase (LAP) score isnormal or high.

■A high serum urate is present. ■Low serum folate levels may occur owing to the

increased haemopoietic activity.

Differential diagnosisThe major diagnostic difficulty is the differentiation of myelofibrosisfrom CML as in both conditions there may be markedsplenomegaly and a raised WBC count with many granulocyteprecursors seen in the peripheral blood. The main distinguishingfeatures are the appearance of the bone marrowand the absence of the Philadelphia chromosome inmyelofibrosis.Fibrosis of the marrow, often with a leucoerythroblasticanaemia, can also occur secondarily to leukaemia or lymphoma,tuberculosis or malignant infiltration with metastaticcarcinoma, or to irradiation.

TreatmentThis consists of general supportive measures such as bloodtransfusion, folic acid, analgesics and allopurinol. Drugs suchas hydroxycarbamide (hydroxyurea) and busulfan are usedto reduce metabolic activity and high WBC count and plateletlevels. Chemotherapy and radiotherapy are used to reducesplenic size. If the spleen becomes very large and painfuland transfusion requirements are high, it may be advisableto perform splenectomy. Splenectomy may also result inrelief of severe thrombocytopenia.

PrognosisPatients may survive for 10 years or more; median survivalis 3 years. Death may occur in 10–20% of cases from transformationto acute myeloblastic leukaemia. The mostcommon causes of death are cardiovascular disease, infectionand gastrointestinal bleeding.

MYELODYSPLASIA (MDS)Myelodysplasia (MDS) describes a group of acquired bonemarrow disorders that are due to a defect in stem cells. Theyare characterized by increasing bone marrow failure withquantitative and qualitative abnormalities of all three myeloidcell lines (red cells, granulocyte/monocytes and platelets).The natural history of MDS is variable, but there is a highmorbidity and mortality owing to bone marrow failure, andtransformation into acute myeloblastic leukaemia occurs inabout 30% of cases

Clinical and laboratory featuresMDS occurs mainly in the elderly, and presents with symptomsof anaemia, infection or bleeding due to pancytopenia.Serial blood counts show evidence of increasing bonemarrow failure with anaemia, neutropenia, monocytosis andthrombocytopenia, either alone or in combination. By contrast,in chronic myelomonocytic leukaemias (CMML), monocytes

are > 1 × 109/L and the WBC count may be > 100× 109/L.

The bone marrow usually shows increased cellularitydespite the pancytopenia. Dyserythropoiesis is present, andgranulocyte precursors and megakaryocytes also haveabnormal morphology. Ring sideroblasts are present in alltypes. In refractory anaemia with excess blasts (RAEB) andrefractory anaemia with excess blasts in transformation

)RAEB-t ,(the number of blasts in the bone marrow isincreased, and the prognosis is worse than in those typeswith a low number of blast cells (< 5%).

ManagementPatients with < 5% blasts in the bone marrow are usuallymanaged conservatively with red cell and platelet transfusionsand antibiotics for infections, as they are needed.

Haemopoieticgrowth factors (e.g. erythropoietin, G-CSF) may beuseful in some patients.Patients with > 5% blasts have a less favourable prognosis,and a number of treatment options are available:

Supportive care only is suitable for elderly patients withother medical problems.■ ‘Gentle’ chemotherapy (low-dose or single-agent, e.g.azacytidine) may be useful in patients with high WBCcounts.■ Intensive chemotherapy schedules used for acutemyeloblastic leukaemia may be tried inpatients under the age of 60, but the remission rate isless, and prolonged pancytopenia may occur owing topoor haemopoietic regeneration because of the defectin stem cells.■ Lenalidomide (a thalidomide analogue) has beenproven to be remarkably successful in the treatment ofearly stage myelodysplasia with a chromosome 5qdeletion (the 5q– syndrome). Avoid use in women ofchild-bearing age.■ Bone marrow transplantation offers the hope of curein the small proportion of MDS patients who are underthe age of 50 and who have an HLA-identical sibling oran unrelated HLA-matched donor