Download polycythaemia

POLYCYTHAEMIA
Polycythaemia (or erythrocytosis) is defined as an increase
in haemoglobin, PCV and red cell count. PCV is a more reliable
indicator of polycythaemia than is Hb, which may be
disproportionately low in iron deficiency. Polycythaemia 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
Absolute erythrocytosis is due to primary polycythaemia
(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.
• Primary polycythaemia:
polycythaemia vera (PV)
PV is a clonal stem cell disorder in which there is an alteration
in the pluripotent progenitor cell leading to excessive prolifPrimary
Polycythaemia vera
Mutations in erythropoietin
receptor
High-oxygen-affinity
haemoglobins
Secondary
Due to an appropriate
increase in
erythropoietin:
High altitude
Lung disease
Cardiovascular disease
(right-to-left shunt)
Heavy smoking
Increased affinity of
haemoglobin, e.g.
familial polycythaemia
Relative:
Stress or spurious
polycythaemia
Dehydration
Burns
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 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
haematopoietic
growth factors such as erythropoietin, in normal and
neoplastic cells. The significance of the discovery is twofold:
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.
Clinical features
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 haemorrhage 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.
Diagnosis
shows the revised WHO criteria for diagnosis in
adults. The measurement of red cell and plasma volume are
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
Course and management
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 ×
109/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
General treatment
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. H1receptor antagonists have largely proved unsuccessful in
relieving distressing pruritus, but H2-receptor antagonists
such as cimetidine are occasionally effective.
Surgery. Polycythaemia 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 haematocrit by venesection and appropriate
fluid replacement must be carried out
Prognosis
PV develops into myelofibrosis in 30% of cases and into
acute myeloblastic leukaemia in 5% as part of the natural
history of the disease
Secondary polycythaemias
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 polycythaemia. 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.
Essential thrombocythaemia (ET)
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 × 109/L, and may be as
high as 2000 × 109/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 × 109/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 × 109/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
MYELOFIBROSIS (MYELOSCLEROSIS)
The terms myelosclerosis and myelofibrosis are interchangeable.
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 megakaryocytes which release fibroblast-stimulating
factors 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 features
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 anaemia, fever and massive splenomegaly (for
other causes
Investigations
■ Anaemia with leucoerythroblastic features is present
Poikilocytes and red cells with
characteristic tear-drop forms are seen. The WBC count
may be over 100 × 109/L, and the differential WBC
count may be very similar to that seen in chronic
myeloid leukaemia (CML); later leucopenia may develop.
■ The platelet count may be very high, but in later
stages, thrombocytopenia occurs.
■ Bone marrow aspiration is often unsuccessful and this
gives a clue to the presence of the condition. A bone
marrow trephine is necessary to show the markedly
increased fibrosis. Increased numbers of
megakaryocytes may be seen.
■ The Philadelphia chromosome is absent; this helps to
distinguish myelofibrosis from most cases of CML.
■ The leucocyte alkaline phosphatase (LAP) score is
normal or high.
■ A high serum urate is present.
■ Low serum folate levels may occur owing to the
increased haemopoietic activity.
Differential diagnosis
The major diagnostic difficulty is the differentiation of myelofibrosis
from CML as in both conditions there may be marked
splenomegaly and a raised WBC count with many granulocyte
precursors seen in the peripheral blood. The main distinguishing
features are the appearance of the bone marrow
and the absence of the Philadelphia chromosome in
myelofibrosis.
Fibrosis of the marrow, often with a leucoerythroblastic
anaemia, can also occur secondarily to leukaemia or lymphoma,
tuberculosis or malignant infiltration with metastatic
carcinoma, or to irradiation.
Treatment
This consists of general supportive measures such as blood
transfusion, folic acid, analgesics and allopurinol. Drugs such
as hydroxycarbamide (hydroxyurea) and busulfan are used
to reduce metabolic activity and high WBC count and platelet
levels. Chemotherapy and radiotherapy are used to reduce
splenic size. If the spleen becomes very large and painfuland transfusion
requirements are high, it may be advisable
to perform splenectomy. Splenectomy may also result in
relief of severe thrombocytopenia.
Prognosis
Patients may survive for 10 years or more; median survival
is 3 years. Death may occur in 10–20% of cases from transformation
to acute myeloblastic leukaemia. The most
common causes of death are cardiovascular disease, infection
and gastrointestinal bleeding.
MYELODYSPLASIA (MDS)
Myelodysplasia (MDS) describes a group of acquired bone
marrow disorders that are due to a defect in stem cells. They
are characterized by increasing bone marrow failure with
quantitative and qualitative abnormalities of all three myeloid
cell lines (red cells, granulocyte/monocytes and platelets).
The natural history of MDS is variable, but there is a high
morbidity and mortality owing to bone marrow failure, and
transformation into acute myeloblastic leukaemia occurs in
about 30% of cases
Clinical and laboratory features
MDS occurs mainly in the elderly, and presents with symptoms
of anaemia, infection or bleeding due to pancytopenia.
Serial blood counts show evidence of increasing bone
marrow failure with anaemia, neutropenia, monocytosis and
thrombocytopenia, 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 cellularity
despite the pancytopenia. Dyserythropoiesis is present, and
granulocyte precursors and megakaryocytes also have
abnormal morphology. Ring sideroblasts are present in all
types. In refractory anaemia with excess blasts (RAEB) and
refractory anaemia with excess blasts in transformation
(RAEB-t), the number of blasts in the bone marrow is
increased, and the prognosis is worse than in those types
with a low number of blast cells (< 5%).
Management
Patients with < 5% blasts in the bone marrow are usually
managed conservatively with red cell and platelet transfusions
and antibiotics for infections, as they are needed.
Haemopoietic
growth factors (e.g. erythropoietin, G-CSF) may be
useful 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 with
other medical problems.
■ ‘Gentle’ chemotherapy (low-dose or single-agent, e.g.
azacytidine) may be useful in patients with high WBC
counts.
■ Intensive chemotherapy schedules used for acute
myeloblastic leukaemia may be tried in
patients under the age of 60, but the remission rate is
less, and prolonged pancytopenia may occur owing to
poor haemopoietic regeneration because of the defect
in stem cells.
■ Lenalidomide (a thalidomide analogue) has been
proven to be remarkably successful in the treatment of
early stage myelodysplasia with a chromosome 5q
deletion (the 5q– syndrome). Avoid use in women of
child-bearing age.
■ Bone marrow transplantation offers the hope of cure
in the small proportion of MDS patients who are under
the age of 50 and who have an HLA-identical sibling or
an unrelated HLA-matched donor