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Haematology for the practice nurse

Article  in  Practice Nurse · February 2019

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HOME CLINICAL A-Z CURRICULUM ESSENTIALS PRESCRIBING NURSE ADVANCED PRACTICE GUIDELINES

FEBRUARY 2019
Dr Mary Lowth
MA, MB, BChir, FRCGP
GP and medical educator

Haematology for the practice

nurse

An enormous number of acute and chronic conditions can

affect the structure and function of the cellular and protein
components of the blood. It is impossible to cover all of
haematology in one article, but this gives an overview of
primary conditions of the blood, focusing particularly on more
serious haematological disease

Many haematological conditions are relatively common, but can present so

insidiously, and with such non-specific symptoms that patients themselves
may not notice anything is wrong. The practice nurse therefore needs to be
both alert to unexplained abnormalities on blood tests, even mild ones on
routine tests, and aware of the possible significance of vague symptoms,
particularly those that persist.

COMPONENTS OF THE BLOOD

The main cell types in blood are:

Red blood cells

White blood cells
Platelets.

Most are produced in the bone marrow, although T and B lymphocytes are
also produced in the lymph nodes and spleen, and T cells in the thymus
gland. All blood cells originate from undifferentiated stem cells, which divide
first into immature red or white blood cells, or platelets, then divide further to
become the final, functional cell.

White blood cells, whose main role is to fight infection and ingest abnormal
cells, then last for a few hours to a few days. Platelets, whose role is in the
clotting mechanism, last about 10 days and red cells, whose main role is to
carry oxygen to tissues, about 120 days. The bone marrow produces more
white blood cells in response to infections and injuries, more red cells in
response to blood loss or lowered oxygen levels, and more platelets in
response to bleeding.
The haematological disorders discussed here are mainly those that affect
these cells and their production and function.

DISORDERS OF HAEMOGLOBIN AND RED CELLS

These include abnormalities of shape, production and destruction of red cells,

and abnormalities of the haemoglobin they carry.

Anaemia

This is the most common red cell disorder encountered in primary care.
Crucially, this is not a diagnosis but a red flag symptom that requires one.

Anaemia may result from blood loss or inadequate production of red cells or
haemoglobin. Unexplained anaemia is a red flag for serious disease,
particularly in older patients where it may be the presenting symptom of
cancer, particularly of the GI tract. This may be detected incidentally as a part
of a long-term medication review.

Mild anaemia is often asymptomatic, although more severe anaemia causes

tiredness, breathlessness and pallor, and sometimes jaundice. While rapid
blood loss causes acute symptoms, it is possible to become extremely
anaemic with relatively mild symptoms if the decline is slow and steady.
Haemoglobin levels as low as 4mg/dl have been reported in patients still
managing their normal daily lives.

Anaemia in women of menstrual age is commonly caused by menorrhagia,

but it is essential that even this common diagnosis is confirmed by supportive
history, examination and response to treatment.

Anaemia may also be haematological in origin, resulting from primary bone

marrow disorders causing impaired production, including aplastic anaemia,
myeloproliferative disorders and myelofibrosis. Causes of anaemia are listed
in Table 1.

Polycythaemia

Polycythaemia is an excess of red cells. It results from increased red cell

production, which may be caused by low oxygen levels (such as in chronic
lung disease or after time at altitude) or by abuse of erythropoetin.
Polycythaemia increases haematocrit, and the thicker blood may sludge in
small vessels, risking stroke.

Polycythaemia vera (PV) is a rare myeloproliferative disorder, mainly affecting

people aged over 40 years. It results from a bone marrow malignancy
affecting red cell precursors, resulting in the overproduction of red cells,
which may eventually crowd out other cell production.

Haemoglobinopathies

These are lifelong genetic disorders affecting the quantity or shape of the
haemoglobin molecule. Most common are thalassaemia, in which
haemoglobin is deficient, and sickle cell disease and trait, in which it is
misshapen.

Thalassaemia

Thalassaemia is most common in those of Mediterranean, South Asian,

Southeast Asian and Middle Eastern origin. Severe disease can be inherited
if both parents carry the trait, so antenatal screening is offered to all women
in the UK.

Thalassaemia major causes marked anaemia requiring frequent transfusions

and leading to bone problems, splenic enlargement, and iron overload
causing heart and liver disease. Splenectomy may be needed.

Minor thalassaemia (thalassaemia trait) is usually asymptomatic. It causes a

mild microcytic anaemia that resembles iron deficiency but does not respond
to iron. Its prime importance for the practice nurse lies in the need to suspect
it as a possible cause of anaemia, and to facilitate pre-conceptual counselling
and testing of those affected.

Sickle cell disease

In sickle cell disease abnormal haemoglobin affects the shape of red cells,
which causes them to collapse in low oxygen levels, usually in small blood
vessels. It mainly affects people of African, Caribbean, Middle Eastern,
Eastern Mediterranean and Asian ethnicity. The full disease is inherited from
both patients, and causes anaemia and very painful sickling episodes.

Patients with sickle cell trait have only one faulty gene and are usually
asymptomatic, with mild anaemia that does not respond to iron therapy.

Red cell abnormalities

Several uncommon inherited conditions affect red cell shape; the best known
is hereditary spherocytosis (HS), in which the red cells are spherical rather
than disc-shaped, and red cell life span is significantly reduced. HS typically
causes splenomegaly, which may necessitate splenectomy, and can cause
anaemia and jaundice.

DISORDERS OF PLATELETS AND CLOTTING MECHANISMS

The clotting mechanism of the blood has several elements and abnormalities
of any may leading to problems with bleeding or clotting. These include
fragile blood vessels (caused by some diseases such as amyloidosis), altered
platelet number or function, and problems with the cascade of proteins
(clotting factors) that lead to clot formation.

Clotting factor disorders

Clotting factors are made in the liver. Hereditary deficiencies include:

Haemophilia – factor VIII deficiency

Christmas Disease – factor IX deficiency
von Willebrand’s disease – deficiency of a protein which helps activate
Factor VIII.

Impaired clotting can also result from severe liver disease, vitamin K
deficiency and from an autoimmune attack on clotting factors, preventing their
function.

Clotting factor deficiencies can lead to heavy or unusual bleeding, typically

after tissue injury or surgery, and bleeding into joints. Treatment is usually by
replacement of the factors involved, although this has in the past led to the
iatrogenic infection of patients with HIV and hepatitis C through use of
pooled, contaminated blood products.

Thrombophilia is an increased tendency to form blood clots. Mutations of

some clotting factors increase clotting tendencies. The Factor V Leiden
mutation causes an increased tendency to thrombosis during pregnancy or
when taking oestrogen. Inherited deficiencies of the natural anticoagulants
protein S, protein C and antithrombin also increase the risk of thrombosis.
The risk is then compounded in hypercoagulable states such as pregnancy
and after surgery.

PLATELET DISORDERS

Low platelet levels

Thrombocytopenia (low platelet count) results from decreased platelet

production or increased destruction. Very low platelet levels typically lead to
increased or prolonged bleeding from mucous membranes such as the nose
and gums. More severe deficiency can produce deeper, life-threatening
bleeds. Normal platelet levels are 150,000-450,000 per dl. There is a lot of
spare capacity, but levels less than 10,000 put patients at severe risk.

Production failure may occur in myeloproliferative disorders and

haematological malignancies, in myelodysplasia and in aplastic anaemia, in
which functional marrow is lost or replaced by abnormal tissue. It may also
occur as a medication side effect, or after exposure to some chemicals.

Increased platelet breakdown is often autoimmune, and can occur in the

presence of other autoimmune diseases or alone, when it is called idiopathic
thrombocytopaenia purpura (ITP). ITP is the most common cause of platelet
deficiency in children.

Some bacterial infections, including meningococcus, can cause destruction of

platelets. Drugs, including heparin, quinine, and anticonvulsants, can cause
platelet breakdown.

Raised platelet levels

Thrombocythaemia (raised platelet levels) can be a transient response to

infection. Essential thrombocythaemia (ET) is a myeloproliferative disorder
similar to polycythaemia vera, but in which the platelet cell line proliferates.
The excess platelets may cause thrombosis, and can also collect in the
spleen, leading to splenomegaly. ET can be a precursor to acute myeloid
leukaemia, and a cause of myelofibrosis.

Table 2 summarises the symptoms of thrombocytopaenia and

thrombocythaemia.

DISORDERS OF WHITE CELLS AND BONE MARROW

White cells include neutrophils, lymphocytes (B and T types), monocytes,

eosinophils and basophils. We normally produce around a billion a day.
Leukopaenia

Deficiency of white cells, leukopenia, increases susceptibility to infection.

Examples of the many conditions that cause white cell production to fall are
given in Table 3.

Leukocytosis

Increased production of white cells is a normal response to infection or injury,

and can also be caused by some drugs, including steroids. Neutrophils and
leucocytes are most commonly affected. However, increased white blood cell
production is also caused by leukaemias; when white counts are extremely
high acute neoplastic processes are a likely cause. Extremely high levels of
neutrophils (> 100,000 per microlitre) can cause hyperviscosity severe
enough to cause breathing difficulty and acute stroke. Causes of leucocytosis
are given in Table 4.

HAEMATOLOGICAL MALIGNANCIES

The diagnosis of haematological malignancy represents perhaps the greatest

challenge for the practice nurse, and the greatest opportunity for success.
Diagnostic delay is common in haematological cancer.1 Prior to diagnosis,
patients often have multiple primary care consultations without their condition
being identified, although only about a third are asymptomatic at diagnosis.1

Diagnostic delay can increase complications and decrease treatment

success, and there is an urgent need to improve diagnostic efficiency. This is
not an easy area. Symptoms are non-specific and may creep on so quietly
that patients don’t think to mention them, or may put them down to their age
or fitness. Tiredness and pain are particularly common, although
lymphadenopathy (in lymphoma) and bleeding and bruising (in acute
leukaemia) may occur and are important, specific clues. Night sweats, weight
loss and unexplained anaemia are also common and should always raise
concerns – as should any persisting symptoms which do not resolve as
expected.

Leukaemia

Leukaemias are cancers of the haematogenous tissues that produce

immature, white blood cells, sometimes in high enough numbers to make the
blood appear white (hence the name). Lymphocytic leukaemias affect
lymphocytes (B cells or T cells) while myeloid leukaemias affects the myeloid
line (which normally produces neutrophils, monocytes, eosinophils, red cells
and platelets), producing immature cells called myeloblasts.

Leukaemias can be acute, with highly abnormal blood test results and many
immature cells visible on peripheral blood films. They can also be chronic and
insidious, with blood tests little altered and symptoms vague and non-specific.
The symptoms of leukaemia are shown in Box 1. Previous radiotherapy and
some types of chemotherapy increase the risk of all leukaemias.

There are four main types of leukaemia:

Acute lymphocytic leukaemia (ALL) – the most common type of cancer

in children, and prognosis with treatment is good. Adults tend to do less
well with treatment. ALL is more common in those who have had a
sibling with ALL
Acute myeloid leukaemia (AML) – more common in people over 65
years of age, but prognosis is, again, better in children. People with
some genetic disorders, such as Down syndrome, have an increased
risk of AML and ALL
Chronic lymphocytic leukaemia (CLL) – relatively common in older
adults and may be present as a chronic disease for many years. CLL is
more common in patients of white ethnicity
 Chronic myelogenous leukaemia (CML) – uncommon and typically
affects older adults. Most cases result from chromosome changes in
marrow precursors, resulting in an abnormal chromosome 22 (the
Philadelphia chromosome). Men are more likely to develop AML and
CML. Exposure to certain chemicals, such as benzene, increases the
risk of myeloid leukaemias.

Treatment depends on which cell is proliferating, and on whether the

leukaemia is acute or chronic. Treatments may include chemotherapy,
targeted therapies such as monoclonal antibodies, Chimeric Antigen
Receptors Cell Therapy (CAR-T), other drug therapies and bone marrow
transplant.

Treatment of acute leukaemias is approached in phases, which may include:

Induction (to eliminate most abnormal cells)

Consolidation (to destroy remaining abnormal cells)
Maintenance (to prevent recurrence), and
Prevention (in ALL preventative treatment is given to the central
nervous system to prevent malignant cells from taking refuge there.)

Treatment of chronic leukaemias depends on the level and nature of

abnormal cells. Early stage CLL usually requires only monitoring, although
progressive disease treatment may involve any of the therapies used for
acute leukaemia. CML, however, benefits from early treatment at diagnosis.

LYMPHOMA

Lymphomas are cancers of the lymphatic system, which includes the lymph
nodes, spleen, thymus and bone marrow. They are more common with
greater age, particularly in men. Some infections, including HIV and Epstein
Barr Virus, increase the risk of lymphoma, as does prolonged use of
immunosuppressant drugs. Lymphomas are most often solid tumours that
often present with a large painless lymph node, typically in the neck. They
may not always cause blood tests to be deranged.

There are many types of lymphoma, but the most common types are
Hodgkin’s lymphoma and Non-Hodgkins lymphoma. These differ in cell type;
in Hodgkin’s lymphoma a specific type of abnormal cell called a Reed-
Sternberg cell is present. Lymphoma is common in patients over 55, but
Hodgkin’s Lymphoma also occurs relatively commonly in younger adults.
Typical symptoms of lymphoma are shown in Box 2.

Waldenstrom’s macroglobulinemia is a rare subtype in which excessive,

large, non-functional immunoglobulins are produced by the abnormal cells.
Symptoms resemble those of other lymphomas, but with additional effects of
hyperviscosity, which can cause peripheral numbness and tingling,
headache, altered vision, confusion and stroke.

Treatment of lymphoma depends on the stage and type of the disease, and
may involve chemotherapy, radiotherapy, other drug agents and bone marrow
transplant. New targeted therapies are currently undergoing clinical trials.

Myelofibrosis

Myelofibrosis is a condition that can result from leukaemias or

myeloproliferative disorders, in which the bone marrow is first disrupted then
eventually replaced by scar tissue. It can be asymptomatic for years.
Eventual symptoms resemble those of chronic leukaemias.

Myeloma and MGUS

Multiple myeloma is a cancer of plasma cells, which are fully matured B-

lymphocytes. These proliferate and produce abnormal monoclonal proteins,
often of one single type, which can damage other organs, particularly the
kidneys.

Myeloma is an uncommon cancer seen almost exclusively in patients over 60

years old. It often has a slow course, over years, but once symptomatic,
tends to cause bone and kidney symptoms, including bone pain, pathological
fractures and kidney stones. The abnormal proteins can cause acute renal
impairment. Calcium levels are often raised and cause nausea, constipation,
thirst and confusion. Other symptoms resemble those of leukaemias, with
fatigue very common, and frequent infections resulting from the replacement
of healthy bone marrow components.
Myeloma is usually preceded by an asymptomatic and relatively common
condition called Monoclonal Gammopathy of Undetermined Significance
(MGUS). About 1 in 100 people with MGUS will develop myeloma each year.

Myeloma is more common in men, in patients of black ethnicity and in those

with a close family history of the disease. It is one of the important causes of
an unexplained, very raised ESR.

Myeloma is diagnosed on bone marrow testing, and may be treated with

targeted therapies, biological or chemotherapy agents, steroids, radiotherapy
and, sometimes, bone marrow transplant.

STAYING ALERT FOR HAEMATOLOGICAL MALIGNANCY

Red flag symptoms

Haematological malignancies become more common with increasing age, but

are also among the more common childhood cancers. While many cause
non-specific symptoms that can creep on so slowly that patients don’t think
them significant, it is the role of health professionals to try to explain all
symptoms. If our explanations don’t work, because symptoms do not resolve
as expected, we need to investigate further.

Table 5 lists the NICE red flag and other symptoms of haematological
malignancy.2 These generally merit urgent, sometimes immediate
investigation. In children this may mean urgent admission.

RESEARCH AND NEW DEVELOPMENTS

Haematological malignancy is a busy area for pharmacological research.

There are ongoing trials of treatments for leukaemias, particularly CLL, and in
monoclonal antibody therapies for myeloma.

One treatment that received much attention recently is CAR-T, (marketed as

Kymriah),3 which modifies a patient’s own immune cells; T-cells are primed
by the therapy to recognise and destroy cancer cells. CAR-T therapy is risky
but can be curative where other treatments have failed. It is a one-time,
hospital-administered treatment. In September NICE approved it for B-cell
acute lymphoblastic leukaemia (ALL) in young people up to age 25 years, in
one of the fastest funding approvals in the history of the NHS.3 CAR-T has
been described as a game-changer and is also used for some adult B cell
lymphomas.

SUMMARY

Haematological disease is a wide subject area and symptoms are often

vague or non-specific. The onset of symptoms can be insidious and patients
may feel they are not worth mentioning. As health professionals our role is to
find an explanation for those symptoms that people present with, but we also
owe it to our patients to investigate further if those symptoms fail to resolve
as we expect.

REFERENCES

1. Howell DA, Smith AG, Jack A, et al. Time-to-diagnosis and symptoms of

myeloma, lymphomas and leukaemias: a report from the Haematological
Malignancy Research Network. BMC Hematology. 2013;13(1):9.
doi:10.1186/2052-1839-13-9

2. NICE Guideline NG12: Suspected Cancer: Recognition and Referral, June

2015. https://www.nice.org.uk/guidance/ng12/chapter/1-Recommendations-
organised-by-site-of-cancer#haematological-cancers

3. NICE Technology Appraisal 554: Tisagenlecleucel for treating relapsed or

refractory B-cell acute lymphoblastic leukaemia in people aged up to 25
years, Dec 2018. www.nice.org.uk

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