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SPLENOMEGALY
Management
• Unless the patient has angina, heart failure or evidence of cerebral hypoxia,
transfusion is not necessary and oral iron supplementation (ferrous sulphate
200 mg 8-hourly for 3–6 mths) is appropriate, together with treatment
of the underlying cause. The Hb should rise by 10 g/l every 7–10 days.
THALASSAEMIAS
Beta-thalassaemia
• Failure to synthesise beta chains is the most common type of
thalassaemia and most frequently occurs in the Mediterranean area.
• Heterozygotes: Have beta-thalassaemia minor, a condition in which there
is usually mild anaemia and little or no clinical disability. The anaemia has a
microcytic hypochromic pattern, but individuals are not iron-deficient.
• Homozygotes: Have beta-thalassaemia major and either are unable to
synthesise HbA or at best produce very little. After the first 4 mths of life,
they develop a profound hypochromic anaemia. Levels of HbF (α2γ2)
are raised.
• Intermediate grades of severity also occur.
• Management of beta-thalassaemia major is as follows:
• • Blood transfusions to maintain the Hb level >100 g/l.
• • Daily folic acid should be prescribed.
• • Repeated transfusions can lead to iron overload, which is treated
with the iron-chelating drug desferrioxamine.
• • Splenectomy is indicated for splenomegaly.
• • Cure is now a possibility for selected children, with allogeneic bone
marrow transplantation.
Alpha-thalassaemia
• Reduced or absent alpha-chain synthesis is common in
Southeast Asia. There are two alpha gene loci on chromosome 16
and therefore four alpha genes.
• • If one is deleted, there is no clinical effect.
• • If two are deleted, there may be a mild microcytic
hypochromic anaemia.
• • If three are deleted, the patient has haemoglobin H
disease; treatment is similar to that for beta-thalassaemia of
intermediate severity.
• • If all four alpha genes are deleted, the baby is stillborn (hydrops
fetalis).
SICKLE-CELL ANAEMIA
• The normal Hb molecule is comprised of two alpha and two non-alpha
globin polypeptide chains, each containing a haemoglobin group.
Haemoglobin A (HbA-α2β2) is the predominant form in adults. Sickle-cell
disease results from a single glutamic acid to valine substitution at
position 6 of the beta globin chain. It is inherited as an autosomal recessive
trait.
• Homozygotes: Only produce abnormal beta chains that make haemoglobin S
(HbS, termed SS), resulting in the clinical syndrome of sickle-cell disease.
• Heterozygotes: Produce a mixture of normal and abnormal beta chains
that make normal HbA and HbS (termed AS), and this results in the clinically
asymptomatic sickle trait.
• Individuals with sickle-cell trait are relatively resistant to the lethal
effects of falciparum malaria, which explains the high incidence of the
sickle gene in equatorial Africa where falciparum malaria is endemic.
Clinical features
• When HbS is deoxygenated, the Hb molecules polymerise and the red cell membrane
becomes distorted, producing characteristic sickle-shaped cells. Sickling is precipitated
by hypoxia, dehydration and infection. Sickled cells have a shortened survival and
plug vessels in the microcirculation. This results in a number of acute syndromes
termed ‘crises’ and chronic organ damage.
• Vasoocclusive crisis: Plugging of small vessels in the bone results in avascular
necrosis, producing acute severe bone pain. Commonly affected sites include the femur,
humerus, ribs, pelvis and vertebrae. Vaso-occlusion in the spleen can give rise to
recurrent splenic infarction and adults may have no functional spleen. Occlusion at
other sites can result in cerebro-vascular accidents and proliferative retinopathy.
• Sickle chest syndrome: This may follow on from a vaso-occlusive crisis and is the most
common cause of death in adult sickle disease. Bone marrow infarction results in
fat emboli to the lungs, which cause sickling and infarction, leading to ventilatory failure.
• Sequestration crisis: Thrombosis of the venous outflow from an organ causes loss
of function and acute painful enlargement. Massive splenic enlargement may result
in severe anaemia and circulatory collapse. Sequestration in the liver leads to severe
pain due to capsular stretching.
• Aplastic crisis: Infection with human erythrovirus 19 results in severe red cell
aplasia, producing a very low Hb.
Investigations
• • Patients with sickle-cell disease have a compensated anaemia (usually
60–80 g/l) with a reticulocytosis.
• • Blood film shows sickle cells.
• • Hb electrophoresis demonstrates a predominance of HbS with absent HbA.
COAGULATION DISORDERS
• Coagulation factor disorders can arise from defi ciency
of a single factor (usually congenital, e.g. haemophilia
A) or of multiple factors (often acquired, e.g. liver
disease).
CONGENITAL BLEEDING DISORDERS
HAEMOPHILIA A
• Haemophilia A is the most common congenital coagulation disorder.
It affects 1 : 10 000 individuals and is characterised by a reduction
in factor VIII. The factor VIII gene is located on the X chromosome.
Haemophilia A is inherited as an X-linked recessive disorder and patients
are therefore male. All daughters of haemophiliacs are carriers. If a
carrier has a son, he will have a 50% chance of having haemophilia,
and a daughter will have a 50% chance of being a carrier.
Clinical features and investigations
• The diagnosis is normally made after the age of 6 mths, when
babies become more mobile and first experience bruising or
haemarthrosis. The features of haemophilia A are related to the plasma
factor VIII level (Box 14.10). Individuals with severe haemophilia
experience recurrent haemarthroses in large joints, which over time
lead to secondary osteoarthrosis. Although joints and muscles are the
most common sites for haemorrhage, bleeding can occur at almost
any site. Intracranial haemorrhage is often fatal.
Management
• • Bleeding episodes should be treated early with i.v. factor VIII concentrate.
• • Freeze-dried factor VIII concentrates can be stored at 4°C in domestic
refrigerators, and many patients are therefore able to treat themselves at
home.
• • The concentrates are prepared from blood donor plasma which has been
screened for hepatitis B, C and HIV, and has undergone a viral inactivation process
during manufacture.
• • Factor VIII concentrates prepared by recombinant technology are also now
widely available and, although more expensive, are perceived as being safer
than those derived from plasma.
• • In individuals with mild haemophilia A, i.v. or intranasal desmopressin can be
used to increase factor VIII levels. This is often sufficient to treat a mild bleed or
cover minor surgery such as dental extraction.
Complications of therapy
• Before 1985 concentrates were not virally inactivated. As a result, many
patients treated became infected with hepatitis B, hepatitis C and HIV. All potential
recipients of pooled blood products should therefore be offered hepatitis A
and B immunisation. There is also now concern that the infectious agent which
causes variant CJD might be transmissible via blood and blood products.
• The other serious consequence of factor VIII infusion is the development of
anti-factor VIII antibodies, which arise in about 20–30% of severe
haemophiliacs. Such antibodies rapidly neutralise therapeutic infusions,
making treatment relatively ineffective. Infusion of factor VIIa may stop
bleeding.
ACUTE LEUKAEMIA
• Acute leukaemias occur at all ages, but ALL has a peak incidence in child-
hood. AML occurs mainly in middle and old age. In acute leukaemia there is
proliferation of primitive stem cells leading to an accumulation of blast cells
in the bone marrow, taking up marrow space at the expense of the
normal haematopoietic elements. Eventually, this proliferation spills into
the blood. The clinical features are usually those of bone marrow
failure (anaemia, bleeding or infection).
Investigations
• • FBC usually shows anaemia and thrombocytopenia. The leucocyte count
varies from as low as 1 × 109/1 to as high as 500 × 109/1 or more. •
The appearance of blast cells on the blood fi lm is usually diagnostic.
• • Bone marrow aspiration is the most valuable investigation and provides material for
cytology, cytogenetics and immunological phenotyping. The marrow is typically
hypercellular, with replacement of normal elements by leukaemic blast cells in varying
degrees. The presence of Auer rods in the cytoplasm of blast cells indicates
myeloblastic leukaemia.
Management
• Specific treatment for acute leukaemia is aggressive, has a number of side-effects, and
may not be appropriate for very elderly patients or for those with significant
comorbidity. In these patients supportive treatment only should be considered.
Specific therapy
• Before embarking on specific therapy, any underlying infection should be treated.
Anaemia and thrombocytopenia should be corrected with red cell and platelet
transfusions. The aim of treatment is to destroy the leukaemic clone of cells without
destroying the residual normal stem cell compartment. There are three phases:
• Remission induction: The bulk of the tumour is destroyed by combination
chemotherapy. The patient goes through a period of severe bone marrow
hypoplasia, requiring intensive support and inpatient care.
• Remission consolidation: Residual disease is attacked by several courses of
chemotherapy during the consolidation phase. This again results in periods of
marrow hypoplasia. In some patients this phase may include a stem cell
transplant.
• Remission maintenance: If the patient is still in remission after the
consolidation phase for ALL, a period of maintenance therapy is given,
consisting of a repeating cycle of drug administration. This is usually given on an
outpatient basis. This maintenance phase is not of benefit in most patients
with AML. In ALL, prophylactic cranial irradiation and intrathecal chemotherapy are
used to ensure therapy penetrates the CNS.
Supportive therapy
• Aggressive chemotherapy involves periods of bone marrow failure and
requires adequate supportive care. The following problems are common:
• Anaemia: This is treated with red cell transfusion to maintain Hb >100 g/l.
• Bleeding: Thrombocytopenic bleeding requires platelet transfusions.
Prophylactic platelet transfusion should be given to maintain the platelet
count>10× 109/l. Coagulation abnormalities should be treated appropri-ately,
usually with fresh frozen plasma.
• Infection: Fever (>38°C) lasting over 1 hr in a significantly neutropenic patient
(neutrophil count <1.0× 109/l) indicates possible septicaemia and constitutes a
medical emergency. I.V. broad-spectrum antibiotic therapy is essential. Empirical
therapy is given with a combination of an aminoglycoside (e.g. gentamicin) and
a broad-spectrum penicillin (e.g. piperacillin/tazobactam). This combination is
synergistic and bactericidal.
• The organisms most commonly associated with severe neutropenia are
skin-based Gram-positive bacteria such as Staphylococcus aureus and
Staph. epidermidis which gain entry via cannulae and central lines, and
Gram-negative bacteria from the gut.
• Metabolic problems: Continuous monitoring of renal and hepatic function is
necessary. Renal toxicity occurs with some antibiotics (e.g. amino-glycosides)
and antifungal agents (amphotericin). Cellular breakdown during induction
therapy increases uric acid production, which may cause renal failure;
allopurinol and i.v. hydration are given as prophylaxis; renal failure;
allopurinol and i.v. hydration are given as prophylaxis against this.
Prognosis
• • Without treatment the median survival of patients with acute
leukaemia is about 5 wks.
• • Around 80% of adult patients <60 yrs of age achieve remission with
specific therapy. Remission rates are lower for older patients. However, the
relapse rate continues to be high.
• • The introduction of the drug ATRA (all transretinoic acid) for acute
promyelocytic leukaemia has greatly reduced the death rate from bleeding.
Bone marrow and peripheral blood stem cell transplantation
• Haematological indications for bone marrow transplantation
(BMT) include:
• • Leukaemias (AML, ALL, CML).
• • Myeloma.
• • Myelodysplastic syndrome.
• • Non-Hodgkin lymphoma.
• • Severe aplastic anaemia.
• • Myelofibrosis.
• • Severe immune deficiency syndromes.
CHRONIC MYELOID LEUKAEMIA (CML)
• CML is a myeloproliferative stem cell disorder resulting in proliferation of all
haematopoietic lineages but predominantly the granulocytic series. Cell maturation
proceeds fairly normally. The peak incidence is at the age of 55 yrs. Around 95%
of patients with CML have a chromosome abnormality (Philadelphia chromosome,
Ph), a shortened chromosome 22 formed by reciprocal translocation with
chromosome 9. A resulting chimeric gene (BCR ABL) codes for a protein with
tyrosine kinase activity, which plays a causative role in the disease, influencing
cellular proliferation and differentiation.
Clinical features
• The disease has three phases:
• • A chronic phase, in which the disease is responsive to treatment and is
easily controlled, typically lasting 3–5 yrs.
• • An accelerated phase, in which disease control becomes more difficult.
• • Blast crisis, in which the disease transforms into an acute leukaemia (usually
AML), which is relatively refractory to treatment.
• Common symptoms include tiredness, weight loss, breathlessness and
abdominal pain. About 25% of patients are asymptomatic at diagnosis.
Splenomegaly is characteristic and may be massive; hepatomegaly occurs in 50% of
cases.
Investigations
• • FBC usually shows a normocytic, normochromic anaemia.
• • Leucocyte count is usually raised (average 220 × 109), but the range of
values is wide.
• • Platelets may be low, normal or elevated.
• • Neutrophils are the predominant cell type on the blood film, although
the full range of granulocyte precursors is seen.
• • The number of circulating blasts increases dramatically as the disease
enters blast transformation.
• • Chromosome analysis of bone marrow reveals the Ph chromosome.
Management
• Imatinib: This specifically inhibits BCR ABL tyrosine kinase activity and
reduces white cell proliferation. It is first-line therapy in chronic phase
CML, producing a complete response in almost 80% of patients. It is also
useful for patients presenting in accelerated phase or blast crisis. Alternative
agents such as hydroxycarbamide and alpha interferon are less effective.
• Allogeneic BMT: This can provide a cure for younger patients in the
chronic phase who are Imatinib resistant.
• Treatment of blast crisis: Blast crisis is the main cause of death
in patients with CML. It is treated as acute leukaemia but
responds poorly, and supportive therapy alone may be appropriate in
elderly patients.