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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
Inherited Haemolytic Anaemias 213
Emergency Box 5.2 Management of an acute painful
sickle cell crisis in opioid-naïve adults
• Analgesia
• Morphine 0.1 mg/kg intravenously (i.v.)/subcutaneously (s.c.) every 20
minutes until paincontrolled, then 0.05–0.1 mg/kg i.v./s.c./orally (p.o.)
every 2–4 hours. Consider patient-controlled analgesia (PCA).
• Give adjuvant non-opioid analgesia: paracetamol, ibuprofen, diclofenac.
• Prescribe laxatives routinely and other adjuvants as necessary:
• Laxatives: lactulose 10 mL twice daily, senna two to four tablets daily
• Antipruritics: hydroxyzine 25 mg twice daily
• Antiemetics: cyclizine 50 mg three times daily
• Anxiolytic: haloperidol 1–3 mg p.o./intramuscularly (i.m.) as required
• Antibiotics: e.g. cefotaxime and clarithromycin in acute chest syndrome.
• Oxygen, 60% by face mask if arterial oxygen saturation <95%
• Rehydration, encourage oral fluids 60 mL/kg/24 hours. Give i.v. or
nasogastric fluids if insufficient intake orally
• Investigations: Daily full blood count, reticulocyte count, urea and
electrolytes in all patients. In others, depending on clinical circumstances:
liver biochemistry, blood and urine cultures, chest X-ray, arterial blood
gases (if saturations <95%), ultrasound of abdomen
• Monitor pain, sedation, vital signs, respiratory rate and oxygen saturations
every 30 minutes until the pain is controlled and stable and then every
2 hours
• Examine daily: the respiratory system for the acute chest syndrome,
andthe abdomen for increase in liver or spleen size which may indicate
asequestration crisis
Hydroxycarbamide (hydroxyurea) raises the concentration of fetal Hb and
is used in some patients with recurrent painful crises. BMT from a HLAmatched sibling is used in some patients with severe disease.
Sickle cell trait
In the heterozygous state, Hb AS, the blood count and film are normal. There
are usually no symptoms unless there are extreme circumstances leading to
hypoxia, such as flying in a non-pressurized aircraft.
Metabolic red cell disorders
A number of red cell enzyme deficiencies may produce haemolytic anaemia,
the most common of which is glucose-6-phosphate dehydrogenase (G6PD)
deficiency.
214 Haematological disease
Glucose-6-phosphate dehydrogenase deficiency
G6PD is a vital enzyme in the hexose monophosphate shunt, which maintains glutathione in the reduced state. Glutathione protects against oxidant
injury in the red cell. G6PD deficiency is a common heterogeneous X-linked
trait found predominantly in African, Mediterranean and Middle Eastern
populations.
G6PD deficiency causes neonatal jaundice, chronic haemolytic anaemia
and acute haemolysis precipitated by the ingestion of fava beans and a
number of common drugs such as quinine, sulphonamides, quinolones
and nitrofurantoin. Diagnosis is by direct measurement of enzyme levels in
the red cell. Treatment involves the avoidance of precipitating factors, and
transfusion if necessary.
ACQUIRED HAEMOLYTIC ANAEMIA
Autoimmune haemolytic anaemia
This acquired disorder is due to destruction of red blood cells by autoantibodies directed against antigens on the patient’s red blood cells.
Autoimmune haemolytic anaemia (AIHA) is divided into ‘warm’ (65%),
‘cold’ (30%) and ‘mixed’ (5%) types, depending on whether the antibody attaches better to the red cells at body temperature or at lower
temperatures (Table 5.11). Immunoglobulin (Ig) G or IgM antibodies
attach to the red cell, resulting in extravascular haemolysis through
sequestration in the spleen, or in intravascular haemolysis through
activation of complement. The autoimmune haemolytic anaemias are
diagnosed on the basis of a positive direct antiglobulin (Coombs’) test.
The red blood cells of the patient are reacted with antiserum or monoclonal antibodies prepared against the various immunoglobulins and
the third component of complement (C3d). If either autoantibodies or
complement are present on the red cell surface, agglutination of red cells
will be detected.
‘Warm’ autoimmune haemolytic anaemia
Clinical features
This anaemia occurs at all ages in both sexes, with a variable clinical picture
ranging from mild haemolysis to life-threatening anaemia. It may be primary
or secondary (see Table 5.11).
Investigation
There is evidence of haemolysis (p. 204–205) and direct Coombs’ test is
positive.
Acquired Haemolytic Anaemia 215
Table 5.11 Features of autoimmune haemolytic anaemia
Warm Cold
Temperature at which
antibody attaches best to
red cell
Type of antibody
Direct Coombs’ test
Primary condition
Secondary causes
CLL, chronic lymphocytic leukaemia; IgG, immunoglobulin G; IgM, immunoglobulin M; SLE,
systemic lupus erythematosus, NSAIDs; non-steroidal anti-inflammatory drugs.
37°C
IgG
Strongly positive
Idiopathic
Lymphomas
CLL
Autoimmune
disorders, e.g. SLE
Carcinomas
Many drugs, e.g.
NSAIDs, penicillins
Lower than 37°C
IgM
Positive
Idiopathic
Lymphomas
Infections, e.g.
Mycoplasma
pneumoniae
Infectious
mononucleosis
Paroxysmal cold
Haemoglobinuria
Management
High-dose steroids (e.g. prednisolone 1 mg/kg daily) induce remission in
80% of cases. Splenectomy or rituximab can be useful in those failing to
respond to steroids.
‘Cold’ autoimmune haemolytic anaemia
Clinical features
IgM antibodies (cold agglutinins) attach to red cells in the cold peripheral parts
of the body and cause agglutination and complement-mediated intravascular
haemolysis. After certain infections (e.g. Mycoplasma, Epstein–Barr virus),
there is increased synthesis of cold agglutinins (normally produced in insignificant amounts) and transient haemolysis. A chronic idiopathic form occurs in
elderly people, with recurrent haemolysis and peripheral cyanosis.
Investigation
There is evidence of haemolysis (p. 204-5), and direct Coombs’ test is positive. Examination of a peripheral blood film at room temperature shows red
cell agglutination, which is reversible on warming the sample.
216 Haematological disease
Management
Treatment is usually that of the underlying condition and avoiding exposure
to cold.
Drug-induced haemolysis
Two types of mechanisms have been identified:
• In the most common form, the drug may associate with structures on the
red cell membrane and thus be part of the antigen in a haptenic reaction.
There is severe complement-mediated intravascular haemolysis which
resolves quickly after drug withdrawal.
• The drug may induce a subtle alteration of one component of the red cell
membrane, rendering it antigenic. There is extravascular haemolysis and
a protracted clinical course.
The mechanisms for drug-induced haemolytic anaemia probably also
apply to drug-induced thrombocytopenia and neutropenia.
Non-immune haemolytic anaemia
Paroxysmal nocturnal haemoglobinuria
There is an inability to produce the glycosylphosphatidylinositol (GPI) anchor,
which tethers several proteins to the cell membrane. Deficiency of two of
these proteins, CD59 (membrane inhibitor of reactive lysis) and CD55 (decayaccelerating factor), renders the red cell exquisitely sensitive to the haemolytic
action of complement. The clinical manifestations of this rare disease include
intravascular haemolysis, venous thrombosis and bone marrow aplasia.
Haemoglobinuria typically manifests as dark urine at night and in the morning
on waking. Haemolysis may be precipitated by infection, iron therapy or surgery.
Paroxysmal nocturnal haemoglobinuria should be considered in any patient
with chronic or episodic haemolysis. Diagnosis is made by demonstrating deficiency of the GPI-anchored proteins on haemopoietic cells by flow cytometry.
Treatment is supportive (e.g. with blood transfusions) and with eculizumab, a
monoclonal antibody that binds to the C5 component of complement, prevents
its activation and reduces haemolysis. BMT has been successful in selected
patients. Progression to myelodysplasia and acute leukaemia may occur.
Mechanical haemolytic anaemia
Red cells may be injured by physical trauma in the circulation. Examples of
this form of haemolysis include:
• Leaking prosthetic heart valves: damage to red cells in their passage
through the heart
• March haemoglobinuria: damage to red cells in the feet from prolonged
marching
• Microangiopathic haemolysis: fragmentation of red cells in abnormal
microcirculation caused by malignant hypertension, haemolytic-uraemic
syndrome or disseminated intravascular coagulation (DIC).
Myeloproliferative Disorders 217
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. Myeloproliferative disorders include polycythaemia vera, essential
thrombocythaemia, myelofibrosis and chronic myeloid leukaemia. These
disorders are grouped together as there can be transition from one disease
to another; for example, polycythaemia vera can lead to myelofibrosis. They
occur principally in middle-aged and elderly people and are often characterized by genetic lesions in the JAK-2 (Janus kinase 2), CALR (calreticulin) or the
MPL (thrombopoietin receptor) genes. They differ from the acute leukaemias
(also clonal proliferation of a single cell line), where the cells also do not differentiate normally but where there is progressive accumulation of immature
cells. Myeloproliferative disorders can also transform into acute leukaemia.
Polycythaemia
Polycythaemia is defined as an increase in Hb, PCV and RCC. These measurements are all concentrations and are therefore directly dependent on plasma
volume as well as red blood cell mass. The production of red cells by the bone
marrow is normally regulated by the hormone erythropoietin, which is produced
in the kidney. The stimulus for erythropoietin production is tissue hypoxia.
In absolute polycythaemia there is an increase in the red cell mass.
Primary polycythaemia is due to an acquired or inherited mutation leading
to an abnormality within red blood progenitors. It includes polycythaemia
vera and rare familial variants. Secondary polycythaemia is caused by an
erythropoietin response to chronic hypoxia or by an erythropoietin-secreting
tumour (Fig. 5.4).
Relative or apparent polycythaemia (Gaisböck’s syndrome) occurs in
middle-aged obese men and is associated with smoking, increased alcohol
intake and hypertension. The PCV is normal but plasma volume is decreased.
Polycythaemia vera
Polycythaemia vera (PV) arises from a single haemopoietic progenitor cell and
leads to excessive proliferation of red cells and a variable increase in platelets and myeloid cells. JAK-2 mutations, present in over 95% of patients, lead
to constitutive activation of its tyrosine kinase activity, which plays a pivotal
role in cell proliferation and survival.
Clinical features
Symptoms and signs are the result of hypervolaemia and hyperviscosity.
Typical symptoms include headache, vertigo, tinnitus, visual disturbance,
angina pectoris, intermittent claudication, pruritus and venous thrombosis.
Physical signs include a plethoric complexion and hepatosplenomegaly as
218 Haematological disease
Polycythaemia
Absolute Relative
Primary
Polycythaemia
vera
Mutations in
erythropoietin
receptor
High oxygen
affinity
haemoglobins
Fig. 5.4 The causes of polycythaemia.
Secondary
Inappropriate increase
in erythropoietin
Tumours (renal, liver
and cerebellar)
Apparent
polycythaemia
Appropriate increase
in erythropoietin
Lung disease
Heavy smoking
Congenital cyanotic
cardiac disease
(right-to-left shunt)
High altitude
Dehydration
a result of extramedullary haemopoiesis. Splenomegaly, if present, reliably
distinguishes polycythaemia vera from secondary polycythaemia. There is
an increased risk of haemorrhage as a result of friable haemostatic plugs,
and an increased risk of gout caused by increased cell turnover and uric acid
production. The onset is insidious and PV is increasingly detected on routine
blood tests conducted for another reason.
Investigations
• A blood count showing raised white cell and platelet counts is suggestive
of PV as opposed to other causes of polycythaemia.
• In the presence of a gain of function mutation in JAK-2, the diagnosis is
confirmed if the haematocrit is raised (> 0.52 in men; > 0.48 in women)
or the red cell mass is raised 25% predicted.
Management
• There is no cure, and treatment is given to maintain a normal blood
count and to prevent the complications of the disease, particularly
thrombosis and haemorrhage. Regular venesection (e.g. 3-monthly) to
maintain PCV <0.45 L/L may be all that is needed in many patients.
• Chemotherapy. Hydroxycarbamide (hydroxyurea) and busulfan are used
to reduce the platelet count. Subcutaneous α-interferon injections are
also effective.
Myeloproliferative Disorders 219
• Low-dose aspirin with the above treatments is used for patients with
recurrent thrombotic episodes.
• Anagrelide inhibits megakaryocyte differentiation and is useful for
thrombocytosis.
• Ruxolitinib is a JAK-2 inhibitor more widely used in myelofibrosis but
which may have a role in patients with severe symptoms such as
pruritus or splenomegaly.
• Allopurinol is given to decrease uric acid levels.
Secondary polycythaemia
Secondary polycythaemia presents with similar clinical features to primary polycythaemia, although the white cell and platelet counts are usually normal and
the spleen is not enlarged. In patients with tumours the primary disease must be
treated to lower the level of erythropoietin. In hypoxic patients, oxygen therapy
(p. 507) may reduce the Hb, and a small-volume phlebotomy (400 mL) may
help those with severe symptoms. Smokers should be advised to stop smoking.
Essential thrombocythaemia
Patients have normal Hb levels and white cell count but elevated platelet
count. Platelet size and function are abnormal, and presentation may be
with thrombosis (or, less commonly, bleeding). Differential diagnosis is from
secondary causes of a raised platelet count and other myeloproliferative
disorders (Table 5.12). In general, an otherwise well person with a platelet
count of >1000 × 109/L will have essential thrombocythaemia. The JAK-2
gene is mutated in about half of all cases. For the remaining 50% of patients,
mutations are usually present in CALR or MPL, removing the need for a bone
marrow biopsy. Hydroxycarbamide (hydroxyurea), busulfan, anagrelide or
interferon alfa are used to reduce platelet production. Due to the thrombotic
risk, aspirin should be given to all patients.
Table 5.12 Differential diagnosis of a raised platelet count
Reactive thrombocytosis
Autoimmune rheumatic disorders
Chronic infections
Inflammatory bowel disease
Malignancy
Haemorrhage
Surgery
Splenectomy and functional hyposplenism
Primary thrombocythaemia
Polycythaemia vera
Myelofibrosis
Myelodysplasia
220 Haematological disease
Myelofibrosis (myelosclerosis)
Myelofibrosis is characterized by haemopoietic stem cell proliferation
associated with marrow fibrosis (abnormal megakaryocyte precursors
release fibroblast-stimulating factors, such as platelet-derived growth factor).
Clinical features
There is an insidious onset of weakness, weight loss and lethargy. Bleeding
occurs in the thrombocytopenic patient. There is hepatomegaly and massive
splenomegaly caused by extramedullary haemopoiesis (p. 221). The most
common causes of death are transformation to acute myeloid leukaemia,
progression of myelofibrosis, cardiovascular disease and infection.
Investigations
• Blood count shows anaemia. The white cell and platelet counts are high
initially, but fall with disease progression as a result of marrow fibrosis.
• Blood film examination shows a leucoerythroblastic picture (immature
red cells caused by marrow infiltration) and ‘teardrop’-shaped red cells.
• Bone marrow is usually unobtainable by aspiration (‘dry tap’); trephine
biopsy shows increased fibrosis.
• The Philadelphia chromosome is absent; this and the bone marrow
appearance helps to distinguish myelofibrosis from chronic myeloid
leukaemia, which may present similarly.
• JAK-2 mutation is present in approximately 60% of the cases and a
CALR mutation in 25%.
Management
• Transfusions are given for anaemia and allopurinol to decrease serum
uric acid levels.
• Historically, symptomatic splenomegaly was managed using
hydroxycarbamide, busulfan, radiotherapy or splenectomy. However,
splenectomy is associated with significant morbidity and mortality in
myelofibrosis and the other treatments are largely ineffective.
• A promising development is the targeted therapy with JAK inhibitors.
Ruxolitinib results in substantial spleen reduction, improved life
expectancy and reduction in symptoms.
• Allogeneic stem cell transplantation may offer hope of a cure for younger
patients.
Myelodysplasia
Myelodysplasia is a group of acquired bone marrow disorders caused by a
defect in stem cells. There is progressive bone marrow failure, which may
evolve into acute myeloid leukaemia. The myelodysplastic syndromes are
predominantly diseases of the elderly, and may be diagnosed on a routine full
The Spleen 221
blood count or when patients present with anaemia, infection or bleeding due
to pancytopenia. The diagnosis is made on the basis of characteristic blood
film and bone marrow appearances. The paradox of peripheral pancytopenia
and a hypercellular bone marrow reflects premature cell loss by apoptosis.
Supportive treatment (red cell and platelet transfusions) is given to
elderly patients with symptomatic disease. For younger patients, intensive
chemotherapy (as used for acute myeloblastic leukaemia) or allogeneic BMT
is used. Lenalidomide (a thalidomide analogue) is used in the treatment of
early-stage disease.
THE SPLEEN
The spleen, situated in the left hypochondrium, is the largest lymphoid
organ in the body. Its main functions are phagocytosis of old red blood cells,
immunological defence and to act as a ‘pool’ of blood from which cells may
be rapidly mobilized. Pluripotent stem cells are present in the spleen and
proliferate in severe haematological stress (extramedullary haemopoiesis),
e.g. haemolytic anaemia.
Splenomegaly
Causes of splenomegaly are given in Table 5.13. The spleen is only palpable
once it has almost doubled in size. Splenomegaly may cause hypersplenism,
which results in pancytopenia, increased plasma volume and haemolysis.
Splenectomy is performed mainly for:
Table 5.13 Causes of splenomegaly
Massive (extending into
right iliac fossa)
Chronic myeloid leukaemia Lymphoma
Myelofibrosis Leukaemia
Infection: Chronic malaria Myeloproliferative disorders
Kala-azar Haemolytic anaemia
Gaucher’s disease (rarely) Acute infection e.g. endocarditis, EBV
EBV, Epstein–Barr virus.
Moderate
Chronic infection e.g. tuberculosis, brucellosis
Parasitic infection e.g. malaria, schistosomiasis
Inflammation e.g. rheumatoid arthritis,
sarcoidosis, systemic lupus erythematosus
Storage diseases, e.g. Gaucher’s
Portal hypertension
Amyloidosis
222 Haematological disease
• Trauma
• Idiopathic thrombocytopenic purpura
• Haemolytic anaemias
• Hypersplenism.
Complications after splenectomy are an increased platelet count
(thrombophilia) in the short term and overwhelming infection in the long
term, particularly with Streptococcus pneumoniae, H. influenzae and the
meningococci. Pneumococcal, Haemophilus, meningococcal group C and
influenza vaccination is given before elective splenectomy. Meningococcal
polysaccharide vaccine is given for travellers to Africa and Saudi Arabia.
In addition, the patient is given lifelong penicillin V 500 mg twice daily or
erythromycin if they are allergic to penicillin.
BLOOD TRANSFUSION
The components of whole blood are prepared by differential centrifugation of
blood collected from volunteer donors.
• Blood components, such as red cell and platelet concentrates, fresh
frozen plasma (FFP) and cryoprecipitate, are prepared from single
donors.
• Blood components such as coagulation factor concentrates, albumin and
immunoglobulin are prepared using plasma from many donors as the
starting material.
Whole blood is rarely used, even for acute blood loss. Use of the required
component is a more effective use of a scarce resource.
Red cell concentrates. The plasma is removed from whole blood and
replaced with an additive solution. Storage is at 4°C with a shelf-life of 35
days and transfusion should be completed within 4 hours of removal from
cold storage. Red cell concentrates are used for acute bleeds in combination
with crystalloid or colloid and correction of anaemia. Transfusion of red cells
in addition to colloid is usually only necessary when >30% (>1500 mL in
an adult) of circulating volume has been lost. This degree of blood loss is
manifest by reduced systolic and diastolic blood pressure, pulse rate >120/
min, slow capillary refill and respiratory rate >20/min. The patient will be
pale and may be anxious. Transfusion may be required for lesser degrees
of blood loss that are superimposed on a pre-existing anaemia or reduced
cardiorespiratory reserve capacity. Transfusion of red cells is rarely necessary
for correction of chronic anaemia (where the underlying cause should be
treated) unless the anaemia is severe and life-threatening.
Platelet concentrates are stored at between +20°C and +24°C. Cold
storage causes irreversible platelet aggregation. Platelets are used to treat or
prevent bleeding in patients with severe thrombocytopenia. They are not used
in stable chronic thrombocytopenia without bleeding. For platelet transfusion,
the ABO and RhD group of the patient must be known and the same bedside
checks and monitoring procedures as for red cell transfusion must be used.