The expanding role of advanced nurse practitioners (ANPs) sees them at the forefront of patient consultation and management. The first article in this two-part series discussed history-taking in patients with suspected haematological disease (Milne, 2022). This article will examine the critical thinking required to aid in the diagnosis of the adult haematology patient and discuss regularly seen abnormalities within the blood. The aim is to ensure the most appropriate blood tests are performed and referral for specialist review is made promptly when necessary.
Haematological malignancy accounts for 44 160 expected cases a year, with approximately 10 100 new leukaemia cases diagnosed, making leukaemia the 12th most common cancer in the UK (Cancer Research UK, 2022). Not all deviations from normal values will be due to malignancy. The role of ANPs is to critically evaluate our findings, through analysis, interpretation, explanation, open-mindedness, and problem solving
Pathophysiology
The body produces blood cells by a process called haemopoiesis in the bone marrow, which is a spongy tissue found in the centre of the bones. Infants produce bone marrow in most of their skeleton but, as we reach adulthood, there is fatty replacement of the marrow. Due to these changes the main production in adults occurs in the long bones of the femurs, pelvis, ribs and sternum. Bone marrow production is vital to ensure adequate numbers of red blood cells, white blood cells and platelets. It responds to the ongoing need for blood cell production, such as increasing the circulating white cells to fight infections.
Haemopoiesis begins with a pluripotent stem cell that can develop into individual cell lineages. The stem cell may form a myeloid progenitor cell, which in turn can produce red cells, platelets, monocytes, neutrophils, eosinophils and basophils. Alternatively, it can form a lymphoid progenitor cell, which in turn can form B and T lymphocytes and natural killer cells (Figure 1).
Red blood cells
Human red blood cells (erythrocytes) are produced through erythropoiesis, developing from stem cells to mature red blood cells in approximately 21 to 25 days in the bone marrow. Erythropoiesis is regulated by the hormone erythropoietin. Approximately 90% of the hormone is made in the peritubular interstitial cells of the kidney and 10% is made elsewhere. There are no stores of erythropoietin within the body and its production is stimulated by oxygen levels within the kidney. Hypoxia will stimulate increased erythropoietin production, which in turn increases red cell production. The bone marrow requires other minerals for effective erythropoiesis, including iron, zinc and vitamins especially B12, folate, vitamins C, E, B6 and thiamine.
In a healthy individual the red cells circulate for approximately 120 days in the peripheral bloodstream before being broken down by the spleen. The iron contained in the haem of haemoglobin may be stored in the liver or spleen as ferritin or haemosiderin.
White blood cells
White blood cells, otherwise known as leucocytes, develop in the bone marrow from stem cells. They form a vital part of our immunity with cells involved in fighting illness and disease. Despite their important roles, they make up only approximately 1% of our blood and are stored in the blood and lymph tissue. Their lifespan is short therefore the bone marrow is constantly producing them. There are several types of white cells:
- Lymphocytes—these white blood cells include the following:
- B cells, known as B lymphocytes: these cells produce antibodies to aid the body in mounting a response to infection
- T cells, known as T lymphocytes: these cells help recognise and remove infection-causing cells
- Natural killer cells: these cells are responsible for attacking and killing viral cells and cancer cells
- Monocytes: these cells are present when the body is fighting chronic infections and help break down bacteria
- Granulocytes: there are three types of granulocyte cell. They have large cytoplasmic granules. They typically have a role in both innate and adaptive immune responses in the fight against viral and parasitic infections:
- Basophils: these white cells are typically present in increased numbers when an allergic reaction is present
- Eosinophils: these white cells are responsible for responding to parasitic infections
- Neutrophils: these white cells are vital for health and make up most white cells within the body. They are the body's first line of defence and are responsible for surrounding and destroying bacteria and fungi that may invade the body.
Platelets
Platelets are the smallest of the blood cells produced in the bone marrow. They derive from cells called megakaryocytes. Megakaryocyte production is regulated by the hormone thrombopoietin, which is produced in the liver and kidneys. Approximately 1011 platelets are produced by a person daily, with a lifespan of 7 to 10 days. They are part of the process required for haemostasis, the process of stopping bleeding at a site of damaged endothelium. By forming a platelet plug and activation of the clotting cascade, bleeding should be controlled.
Normal parameters for blood results
Table 1 shows the normal parameters for adult blood results. Following assessment of a patient, the interpretation of their blood results (high and low values) may hold vital answers to their potential diagnosis or may indicate further investigations are required.
Table 1. Normal parameters for blood results
| Blood component | Normal parameters |
|---|---|
| Haemoglobin | 130–180 g/litre (male)115–165 g/litre (female) |
| Haematocrit (HCT) | 0.37–0.47 litre/litre |
| Mean cell volume (MCV)* | 84–105 femtolitres |
| Reticulocytes | 50–150 x 109 |
| White blood cells (WBC) | 4.0–11.0 x 109 |
| Neutrophils | 1.8–7.5 x 109 |
| Lymphocytes | 1.0–4.0 x 109 |
| Monocytes | 0.2–0.8 x 109 |
| Eosinophils | 0–0.4 x 109 |
| Basophils | 0.0–0.1 x 109 |
| Platelets | 150–450 x 109 |
| Lactate dehydrogenase (LDH) | 120–246 units per litre |
| Serum ferritin | 22–322 micrograms per litre |
| Serum folate | >4.0 micrograms per litre |
| Serum vitamin B12 | 211–911 nanograms per litre |
| Iron saturation | 15.0–45% |
| Serum iron | 11–31 micromoles per litre |
| Transferrin | 2.15–3.65 g/litre |
Conditions linked to low blood counts
Anaemia
One of the most common presentations seen in practice is anaemia. Anaemia is defined as a haemoglobin (Hb) range two standard deviations below the normal range for age and sex. In males more than 15 years of age this would be a Hb below 130 g/litre (grams per litre). In non-pregnant females aged more than 15 years this would be a Hb below 120 g/litre (National Institute for Health and Care Excellence (NICE), 2021)
It is thought that anaemia affects 33% of the world population (Stoffel et al, 2020). Anaemia itself is not a diagnosis, but an abnormal clinical finding that requires an explanation for its cause. Investigations for anaemia may be more subjective depending on red cell size. The size of the red cell is the mean cell volume (MCV). A raised MCV is classified as macrocytic anaemia. A low MCV is defined as microcytic anaemia and normocytic anaemia may be a combination of both (Table 2)
Table 2. Examples of anaemia and possible causes
| Anaemia type | Possible cause |
|---|---|
| Macrocytic anaemia (elevated mean cell volume) | B12 deficiency/folate deficiencyHaemolysisLiver disease/alcohol abuse/medicationMyelomaMyelodysplastic syndromeHypothyroidism |
| Normocytic anaemia | Anaemia of chronic diseaseAcute bleedingAnaemia due to erythropoietin deficiencyMyeloma |
| Microcytic anaemia (reduced mean cell volume) | Iron deficiencyAnaemia of chronic diseaseThalassaemia trait/sickle cell |
Clinical assessment relies on obtaining a good history and this is important when investigating unexplained anaemia.
A history should focus on:
- Duration of symptoms: a sudden onset of dyspnoea or fatigue may suggest a more acute cause for the anaemia such as recent bleeding or haemolysis
- Specific questioning on blood loss. This should be concise and include systems-related questions such as whether the patient has experienced gastrointestinal tract issues, has recently donated blood or has gynaecological problems, including menorrhagia
- Family history: there may be hereditary reasons, for example, haemoglobin disorders such as thalassaemia or sickle cell disease, which can occur in some ethnic groups
- Drug history: this should include recreational and over-the-counter drugs
- Alcohol intake
- Dietary factors: a folate or iron deficiency, for example, may be caused by a vegan diet
- Chronic illnesses: these include rheumatic disorders, malignancy and chronic inflammatory disorders, which can suppress red cell production.
The cause may well be classified into: an intrinsic problem arising from the bone marrow or due to extrinsic factors outside the red blood cells, such as autoimmune disorders or the effects of medications.
Acute causes of anaemia may also be considered when examining the patient history. These include:
- Acute leukaemia
- Previous chemotherapy: the lowest blood cell counts occur 7 to 10 days following treatment
- Previous radiotherapy
- Acute haemorrhage
- Haemolytic anaemia
- Infection
- Inflammation.
Another blood count to consider aiding a diagnosis is the platelet count. A reactive thrombocytosis (elevated platelet count) may be seen in iron deficiency anaemia although the mechanism by which iron deficiency leads to thrombocytosis is still unclear (Mhadgut et al, 2018).
Reticulocytes (immature red blood cells) are produced in the bone marrow. They mature into red blood cells within 1-2 days. The reticulocyte count may be indicative of bone marrow function or activity. Reticulocyte counts may be elevated as a response to blood loss or haemolytic anaemias, as the body tries to compensate for the reduction in circulating red blood cells. A reduced reticulocyte count in anaemia may suggest impaired bone marrow function due to conditions including myelodysplasia, aplastic anaemia, and myelofibrosis (Riley et al, 2001).
Iron deficiency anaemia
Symptoms of iron deficiency anaemia may develop with an initial gradual onset of symptoms that may include shortness of breath and fatigue, reduced exercise tolerance and light-headedness.
Iron deficiency anaemia is more commonly seen in pre-menopausal women due to menorrhagia. Iron deficiency in men and post-menopausal women should be further investigated due to the risk of occult gastrointestinal bleeding and malignancy. (NICE, 2021).
A review of blood results may confirm the diagnosis of iron deficiency anaemia. If there is a low haemoglobin level, there may be evidence of microcytosis (a mean corpuscular volume (MCV) of <80). Serum ferritin levels reliably correlate with total body iron stores. A serum ferritin of less than 30 micrograms/litre confirms a diagnosis of iron deficiency. It is important to remember that serum ferritin is an acute phase reactant protein, therefore interpretation of ferritin results may be difficult in the presence of infection or inflammation, malignancy, or liver disease. In chronic kidney disease and other inflammatory conditions, a ferritin level of 100 micrograms/litre or higher may still be indicative of iron deficiency and needs to be interpreted in addition to other results (NICE, 2021) (see Table 3).
Table 3. Common differences seen in iron studies comparing iron deficiency anaemia and anaemia of chronic disease
| Iron deficiency anaemia | Anaemia of chronic disease |
|---|---|
| ↑ Transferrin to catch available iron protein molecules | ↓ Transferrin |
| ↓ Serum iron | ↓ Serum iron |
| ↓ Serum saturation (due to not as much iron available) | ↓ Serum saturation |
| ↓ Ferritin | ↑ Ferritin due to inflammation of chronic disease (may also be raised due to acute inflammation) |
Treatments for iron deficiency
Iron supplementation
A person with iron deficiency will require iron supplementation. This comes in a variety of forms, including both oral and intravenous supplementation. Many people report that they are unable to tolerate iron supplementation. It is important to explore side effects and offer guidance.
Hepcidin regulates iron metabolism and is mainly produced by the liver. Oral iron supplementation induces an increase in serum hepcidin. High concentrations of hepcidin reduces iron absorption, therefore resulting in little, if any, iron being absorbed from supplements taken on consecutive days. This mechanism has been thought to have been responsible for poor treatment response. It could be suggested that reduced knowledge of this process has resulted in clinicians increasing doses of iron supplementation. Many patients report poor tolerance of oral iron preparations due to increasing side effects including nausea, abdominal pain and diarrhoea, which in turn lead to poor compliance, often exacerbated by increasing doses. Recent studies suggest iron absorption from oral supplements is at its highest if using an alternate once-daily dosing regimen. Studies also found greater compliance of treatment with alternate daily dosing as patients reported fewer side effects, including gastrointestinal disturbance (Stoffel et al, 2020).
Vitamin C enhances iron absorption as it captures non-haem iron, storing it in a form more readily absorbed by the body, therefore it is recommended that patients take daily vitamin C tablets or take their iron supplementation with a glass of orange juice. Education to avoid tea and coffee at the time they take their iron supplementation is important as tannins obstruct the absorption of the iron.
It is always important to remember that if iron deficiency is due to contributing factors for example menorrhagia, that referral to appropriate teams should be made to investigate and treat the cause, which could be fibroids, for example.
Blood transfusion
A blood transfusion is a potential treatment for anaemia but will only provide a short-term response, depending on the cause. The decision to transfuse is a clinical decision based on comorbidities and symptoms. Current guidelines (NICE, 2015) recommend a restrictive transfusion strategy should be implemented in non-bleeding patients with anaemia. Transfusion for iron deficiency anaemia is not advocated unless the patient is experiencing severe symptoms of anaemia. NICE guidance recommends a pre-transfusion threshold of Hb70 g/litre and a post-transfusion level of 70-90 g/litre. This will be dependent on other comorbidities such as cardiac history, as such patients may require a higher pre-transfusion threshold to avoid symptomatic angina episodes.
Pancytopenia
Pancytopenia refers to a reduction in all three bone marrow cell lines: anaemia (reduction in red blood cells), leukopenia (reduction in white blood cells) and thrombocytopenia (reduction in platelets). Individuals may also present with bi-cytopenia (a reduction in only two cell lines). Pancytopenia may occur due to number of diseases, some of them life threatening, or it may be congenital. These can be categorised by process:
- Bone marrow infiltration: for example in haematological malignancies, including acute leukaemia, multiple myeloma, lymphoma, metastatic cancer, myelofibrosis, and infectious diseases, including malaria and fungal infections
- Blood cell destruction: for example disseminated intravascular coagulation, excessive blood cell destruction secondary to hypersplenism, sepsis, secondary to cytotoxic drugs
- Bone marrow aplasia: for example nutritional disorders such as folate deficiency, vitamin B12 deficiency, aplastic anaemia, medication, infectious diseases including parvovirus and HIV, alcohol excess and myelodysplasia
- Congenital: Fanconi anaemia, GATA-binding factor 2 (GATA 2) deficiency.
Initial evaluation of a patient with pancytopenia will include rapidity of onset, physical examination and drug history. Repeat blood tests including a peripheral blood smear, also known as a blood film, should be requested. This may reveal abnormalities not detected by automated laboratory tests.
Referral to a haematologist to aid diagnosis is appropriate unless cytopenias are due to a non-specialist cause, for example vitamin B12 or folate deficiency. A haematologist may perform a bone marrow biopsy if a primary bone marrow disorder is suspected.
Acute leukaemia
Acute leukaemia is a medical emergency. It is a malignant disease of the white blood cells that progresses aggressively due to uncontrolled proliferation of either the myeloid or lymphocyte stem cells. The leukaemia cells rapidly replace normal haematopoietic cells of the bone marrow. Presentation often includes fatigue, breathlessness, frequent infections, bruising and bleeding all secondary to anaemia and thrombocytopenia as the white cell count rises rapidly. Definitive diagnosis will require a bone marrow biopsy therefore urgent referral to a haematologist should be made if leukaemia is suspected.
Benign ethnic neutropenia
Neutropenia is defined as an absolute neutrophil count of <1.5 x 109. The severity of neutropenia is classified according to the neutrophil reading: mild is defined as 1.0-1.5 x 109, moderate neutropenia, 0.5-1.0 x 109 and severe neutropenia, <0.5 x 109.
Benign ethic neutropenia is an inherited cause for a neutrophil count of <1.5 x 109. It is more often associated with individuals with ethnicities of African, Middle Eastern or Caribbean descent. Despite a mild neutropenia they do not appear to be at increased risk of infections. The lower absolute neutrophil count is driven by a phenotype called Duffy, which is thought to have been an evolutionary response to protect from malaria. It is seen in 80-100% of those of sub-Saharan African ancestry (Merz and Achebe, 2021).
Benign ethnic neutropenia should be suspected in an individual who has persistent neutropenia with no evidence of recurrent infections, other cytopenias, splenomegaly, lymphadenopathy, or secondary causes of neutropenia. Usually, individuals with benign ethnic neutropenia are at no greater increased risk of infection and do not require intervention.
Immune thrombocytopenia
The average lifespan of a platelet cell is between 7 and 10 days. These are tiny blood cells that help form clots to stop bleeding. Anyone presenting with spontaneous bruising or bleeding, or petechiae (flat discrete lesions that do not blanche) would require an urgent full blood count to assess their platelet count for evidence of thrombocytopenia (a reduced number of platelets). Immune thrombocytopenia (ITP) is defined as a platelet count of <100 x 109. Severity of bleeding risk increases when the platelet count is <20 x 109
ITP is an autoimmune condition causing the body's immune system to destroy platelets, although the mechanism is not completely understood. It is more prevalent in women than men, with the highest incidence considered to be in women aged 15 to 50 years (Hoffbrand and Moss, 2011).
People may often present with bruising, spontaneous epistaxis, bleeding gums or prolonged heavy menstrual bleeding. They may also present with small reddish dots under the skin (non-blanching) called a petechial rash. The onset is often sudden. A patient with ITP can relapse spontaneously.
ITP is a diagnosis of exclusion. If there are no other causes for the thrombocytopenia, for example lymphadenopathy, splenomegaly and medications, ITP should be considered.
Treatment would be under the care of a haematologist with an urgent referral via their emergency department unless they are already known to a haematology team. Chronic ITP patients will likely have contact numbers for their haematology team for an urgent review if relapse is suspected.
As well as reviewing low blood counts during the interpretation of results, on occasion there will be elevated readings. It is important to develop an understanding of the possible causes and implications for patient management.
Elevated haemoglobin (erythrocytosis)
Erythrocytosis is defined as haemoglobin >185 g/litre and/or haematocrit >0.52 g/litre in males and haemoglobin >165 g/litre and/or haematocrit >0.48 g/litre in females. Erythrocytosis may often be detected as an incidental finding during routine blood testing if a patient is asymptomatic. NICE (2020a) recommends repeating the blood test after 7 days to assess if the rise is transient. It may also be an incidental finding following a thrombotic event.
On occasion, patients present with symptoms of hyperviscosity. Hyperviscosity symptoms associated with erythrocytosis include headaches, itching, blurred vision, fatigue, chest and abdominal discomfort and shortness of breath are reported.
Erythrocytosis may be due to either a primary myeloproliferative neoplasm, for example polycythaemia vera or due to secondary causes, most commonly hypoxia.
Measurement of haematocrit (HCT) is often a more reliable indicator of polycythaemia. An erythropoietin level would also be recommended as erythropoietin will be suppressed in primary polycythaemia and elevated in cases causing erythropoietin excess such as hypoxia. Referral to the haematology team should be considered, especially if the patient has a high risk of thrombosis. Secondary polycythaemia does not always require treatment. When treatment is required it is usually low dose aspirin and venesections (removal of blood).
Common secondary causes of polycythaemia include:
- Smoking
- Chronic obstructive pulmonary disease/asthma
- Sleep apnoea
- Steroid or testosterone use.
In some cases, secondary polycythaemia can be reversed if the patient is counselled and provided with health education advice on the cause, for example smoking cessation advice.
Lymphocytosis
An elevated lymphocyte counts >4.0 x 109 are often an incidental finding and often not a cause for concern. Common causes of transient lymphocytosis include:
- Viral infections including Epstein-Barr virus, HIV, hepatitis, measles, mumps, cytomegaly virus and pertussis (whooping cough) Reasons for persistent lymphocytosis include:
- Malignancy including chronic lymphocytic leukaemia (CLL), lymphoproliferative disorders and non-Hodgkin's lymphoma (may have lymphadenopathy on examination)
- Acute lymphoblastic lymphoma
- Previous splenectomy
- Smoking.
The urgency for investigation would be guided by the patient's condition. Blood film may be requested and referral to haematology for further advice as appropriate.
Neutrophilia
An elevated neutrophil count is often related to an acute episode and is often reactive. It is often classified as higher than 7.7 x 109
Common causes of neutrophilia include:
- Bacterial infection (acute rise with quick return to normal as the infection is treated)
- Corticosteroid use
- Smoking—seen in approximately 22% of smokers (Stemmelin et al, 2004)
- Chronic myeloid leukaemia
- Chronic myelomonocytic leukaemia.
Thrombocytosis
Thrombocytosis refers to a platelet count of >450 x 109. This is a common finding, especially in hospital patients, as is often a reactive sign of acute illness. A prolonged elevation in platelet count without acute or chronic inflammatory processes may be due to other common causes including:
- Iron deficiency/blood loss
- Hyposplenism/post-splenectomy
- Essential thrombocythemia
- Less commonly, it may be due to underlying malignancy including polycythaemia vera.
Repeat platelet count is recommended for a patient in approximately 3-4 months. If there are no contributing factors as discussed above and there is a persistently elevated platelet count of >450 x 109, a referral to the haematology team is recommended, for further investigations into possible diagnosis of myeloproliferative disorder.
COVID-19
As demands on health services change, there is a need to constantly update our knowledge, something that is particularly important during a pandemic.
With the emergence of COVID-19 in late 2019, little was known about the disease and its long-term manifestations. COVID-19 is caused by a beta coronavirus which is transmitted via droplets and contaminated surfaces. As yet, research continues to enable us to fully understand the pathogenesis, but it is now known that SARS-CoV-2 cells bind to host cells via a receptor, angiotensin converting enzyme (ACE 2) which is expressed across many human cell types, including the endothelium of blood vessels (Agbuduwe and Basu, 2020). Case reports are reporting a host of haematological side effects. The most reported blood count abnormality is lymphopenia, which occurs in 35-83% of patients (Agbuduwe and Basu, 2020).
Other haematological manifestations of COVID-19 include:
- Lymphopenia
- Neutrophilia
- Mild thrombocytopenia
- Elevated lactate dehydrogenase (LDH)
- Elevated ferritin.
As yet, there is still a lot to be learnt about the full pathophysiology associated with COVID-19, although it has become apparent that thrombotic complications are common without predisposing risk factors. Recent data from France suggests that a pulmonary embolism was diagnosed in approximately 23% of patients with severe COVID-19 infection. (Grillet et al, 2020).
It has also been suggested that the thrombotic effect may be multifactorial, with direct endothelial damage from SARS–CoV-2 or immune cells (Varga et al, 2020), inflammatory cytokine-induced activation of the clotting cascade and an increase in acute phase pro-coagulants such as factor VIII and fibrinogen.
Prevention and early diagnosis of venous thromboembolism (VTE) are paramount. Current recommendations for anticoagulation recommend pharmacological VTE prophylaxis for both hospital- and community-treated patients with COVID-19 pneumonia (NICE, 2020b).
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a new syndrome that appeared more prevalent with people who had received certain brands of the COVID-19 vaccine. Most individuals present with thrombosis. It is now thought that this is due to an antibody that in turn leads to platelet activation. As a result, there is significant stimulation of the coagulation system and clinically significant thromboembolic complications (Warkentin and Cuker, 2022). Sites of thrombosis associated with VITT include deep vein thrombosis, pulmonary embolism and more unusual sites including the splenic, mesenteric and portal veins. Arterial thrombosis leading to ischaemic stroke has also been recorded (Warkentin and Cuker 2022).
VITT is potentially life threatening. Treatment would include intravenous immunoglobulins, anticoagulation, therapeutic plasma exchange and possible platelet transfusion.
As health professionals, it remains important to encourage vaccination within our patient populations, with appropriate education of potential side effects. The risk of COVID-19-related thrombosis complications continues to carry a much higher risk than the very rare complication of VITT (Warkentin and Cuker, 2022).
Conclusion
The critical analysis of blood results requires consideration of many factors, including duration of symptoms and speed of onset. Many diagnoses may be multifactorial but require careful assessment and good history taking. Structured evaluation of the blood results in combination with critical evaluation of the history is essential as derangement of blood results may have a primary haematological diagnosis but may often be secondary to other underlying comorbidities.
With the emergence of COVID-19 and its effects on the blood there may yet be more side effects to be discovered, leading to body system complications.
KEY POINTS
- Many benign haematological conditions are responsible for deranged blood results
- Cases of haematological malignancy are increasing. It is an important consideration of a differential diagnosis, as early intervention saves lives
- Anaemia is a symptom, requiring investigation of the cause
- NICE provides guidance on patient management
CPD reflective questions
- What factors would you consider when assessing a patient with anaemia to aid your differentials of possible causes?
- When would it be appropriate to refer a patient to the haematology team for review?
- In what ways could you change your practice regarding educating patients taking iron supplementation?