Quick tip: A high Hb is often not due to a primary haematological problem. 

An elevated Hb can be due to either a primary myeloproliferative neoplasm (e.g polycythaemia vera), or may be secondary to other conditions. Secondary causes are either due to hypoxia, or less commonly excess erythropoietin or endocrine disorders. It will often be identified as an incidental finding on a full blood count,  but may present with thrombosis, more often arterial than venous, or constitutional symptoms of hyperviscosity such as headaches, itching, blurred vision parasthesiae or chest pain. Haematocrit is probably a more reliable measure of polycythaemia than haemoglobin alone-this is the percentage of blood made up by red cells i.e 0.45 = 45% of centrifuged blood is red blood cells.

Common causes

• Secondary polycythaemia
  • Smoking
  • COPD/asthma
  • Fibrotic lung disease
  • Sleep apnoea
  • Steroid or testosterone use-either as therapy or by bodybuilders
  • Cyanotic heart disease
• Relative (measured decrease in plasma volume)/Apparent polycythaemia
  • Not a genuine polycythaemia, but a raised Hb due to relatively increased red cell mass i.e by decreased plasma volume 
  • Hypertension, alcohol excess, diuretics, dehydration
• Polycythaemia vera- one of the myeloproliferative neoplasms
• Erythropoietin excess (rare)
  • Renal cell or hepatocellular carcinoma
  • Cerebellar haemangioma
  • Wilms Tumour
• Endocrine (rare)
  • Cushing's syndrome
  • Conn's syndrome
• Inherited disorders of erythropoietin receptors

Workup

• History
  • Night sweats, lymphadenopathy, splenomegaly, headache, dizziness, itching induced by hot water/bathing
  • Most cases however are asymptomatic
• Repeat full blood count with blood film
  • Looking for Haemoglobin of over 165g/L in males and 160 g/L in females (Arber et al. Also check local ranges)
  • Haematocrit might be more useful; a repeated value of over 0.48 (48%) in females or 0.52 (52%) in males, is worth investigating further (BSH guideline)
  • Relative polycythaemia is uncommon but can occur in heavily diuresed patients where the level of haemoglobin is raised but only due to relative increased haemoglobin concentration due to decreased blood plasma volume. Other causes include hypertension, obesity and alcohol
  • There may also be elevated white cells or platelets in a myeloproliferative disorder
• Ferritin level
  • May be low in polycythaemia vera despite a high haematocrit but do not replace- risk of hyperviscosity and vascular events. The iron deficiency is ‘protecting’ the patient to a degree. Discuss with haematology.
• Erythropoietin level
  • Suppressed in primary polycythaemia
  • Elevated in conditions causing erythropoietin excess
• Assess thrombotic risk 
  • Higher risk patients may merit a more urgent referral to haematology services

Referral to haematology should be considered in patients with a persistently elevated haemoglobin in the absence of a respiratory cause (or if the Haematocrit is over 0.48 (48%) in females or 0.52 (52%) in males, discussion should be had with haematology).

If contacting a haematology on-call service before referring the patient consider asking if testing for JAK2 V617F mutation would be appropriate as this may improve efficiency of haematology outpatient review. This is an acquired mutation presented in around 95% of patients with polycythaemia vera.

An urgent referral should be sent in those presenting with thrombosis or symptoms of hyperviscosity for urgent venesection. Aspirin is recommended in primary polycythaemia but not secondary polycythaemia, after the appropriate risk assessment for risks and benefits of aspirin use. 

Secondary polycythaemia can be managed by venesection in certain cases although evidence is often weak (see BSH guideline).

Links:   BMJ     NICE CKS     BSH Guideline
Specific references;

• Arber et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016 127:2391-2405

Quick Tip; Mean corpuscular volume is an average reading of red cell size, therefore a 'normal' MCV could be a combination of a micro- and macrocytic process 

Anaemia investigations involve determining whether it is an intrinsic problem with the bone marrow or due to an extrinsic cause. This process can be made easier by classifying the anaemia by red cell size; 

Macrocytic 

• B12/Folate deficiency 
• Reticulocytosis (immature red cells)/Haemolysis 
• Alcohol abuse/liver disease/medications (alcohol directly toxic to red cells) 
• Myelodysplastic syndrome 
• Myeloma 

Normocytic 

• Anaemia of chronic disease 
• Mixed iron deficiency and macrocytosis 
• Renal anaemia (Erythropoietin deficiency) 
• Acute bleeding 
• Myeloma 
• Sickle cell anaemia 

Microcytic 

• Iron deficiency 
• Thalassaemia trait or syndrome 

Workup 

• Thorough history including 
  • Medication history (especially for myelosuppressive medications) 
  • Any history of bleeding, including gastrointestinal tract 
  • Alcohol history  
• Blood film, reticulocyte count and hypochromia percentage 
  • For morphology of red cells to aid diagnosis 
• Haemoglobinopathy screen if microcytic and from at-risk ethnic group  
• B12/Folate levels 
• TSH 
• Ferritin (see below) 
• If haemolysis suspected test; 
  • LDH (Raised), Haptoglobins (Decreased), Reticulocytes (Raised), DAT screen (positive in immune- note false positives common), Direct and indirect bilirubin 
• Serum electrophoresis 
  • To identify whether a condition causing a paraprotein (like myeloma) is causing the anaemia 
• OGD+- Colonoscopy if clinically indicated (through gastroenterology) 
• If renal disease present consider EPO level after discussion with renal physicians (often not tested for as it is assumed to be deficient in chronic kidney disease) 

Refer to haematology if concerned about underlying haematological or bone marrow problem such as a raised paraprotein which may indicate myeloma (see Paraprotein and Light chains sections), or myelodysplasia (macrocytosis in the absence of other obvious causes, especially if other cell lines affected e.g low platelets/ white blood cells) 

Notes

Iron replacement strategies 

Research into iron replacement strategies (currently in non-anaemic, iron deficient women but theory likely to be applicable to anaemic patients) shows that alternate day, once daily oral iron dosing optimises absorption and reduces side effects.  

BD/TDS dosing regimens cause significant homeostatic hepcidin rises which actually inhibits subsequent iron absorption from the gut. The ‘spare’/unabsorbed iron is then responsible for many of the GI side effects. Alternate day dosing or once daily dosing allows time for hepcidin to drop again after first dose, and thus allow absorption of subsequent doses. 

Although not definitive, this appears to be the future for oral iron replacement. Consider this if patients have previously been intolerant of traditional regimen oral iron replacement before referring for IV iron-much cheaper and less (& reversible) significant side-effects than IV iron (skin staining etc). 

B12/folate replacement strategies (Adapted from NICE CKS B12 deficiency guidance)

• B12: If no neurological involvement; Hydroxocobalamin 1mg IM alternate days for 2 weeks, followed by maintenance of 3 monthly injections if not malabsorption-related or 6 monthly if malabsorption-related (BNF/NICE). If neurological involvement; Hydroxocobalamin 1mg on alternate days until no further improvement then 1mg every 2 months (BNF). If felt to be dietary, good sources of B12 include red meat, salmon, milk, cheese and eggs (not an exhaustive list) 
• Folate; Folic acid 5mg once daily for 3-4 months or longer if the underlying cause continues (e.g haemolysis). Dietary sources include broccoli, Brussels sprouts, asparagus, peas, chickpeas, and brown rice. 
• If deficient in both, B12 MUST BE REPLACED FIRST, as replacement of folate first can cause catastrophic neurological injury (subacute combined degeneration of the cord) due to rapid consumption of remaining B12 

Iron studies interpretation

Tests for a patient's iron status can be confusing. Those most commonly used are; 

• Ferritin; Useful in the absence of inflammation, but as an acute phase protein ferritin can be raised in acute and chronic inflammation or malignancy despite deplete iron stores. 
• Soluble transferrin receptor; Increased in iron deficiency as a response to iron deficiency in cells, but is not affected by inflammation therefore can be useful in cases of acute/chronic inflammation (test not yet available in all hospitals). 
• Iron binding capacity; Increased in iron deficiency and bleeding. Decreased in iron overload disorders, anaemia of chronic disease and thalassaemia.
• % Transferrin saturation; Increased in iron overload disorders. Decreased in iron deficiency states.
• Serum iron; Not commonly tested as does not quantify iron stores reliably due to diurnal fluctuations in levels and sensitivity to dietary iron intake at the time of testing. If low, is however suggestive of iron deficiency. 
• Mean reticulocyte haemoglobin; Mean reticulocyte Hb content of <29 pg can support the diagnosis of iron deficiency if initial tests are inconclusive. Can be particularly useful in assessing iron deficiency in patients with CKD. 
• % Hypochromic red cells; A value for %HRC of >5% suggests iron deficiency.  

Specific references  

Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Stoffel NU et al. Lancet Haematol. 2017 Nov;4(11):e524-e533. doi: 10.1016/S2352-3026(17)30182-5 

Guideline for the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children. Br J Haematol. A British Society for Haematology Good Practice Paper. Fletcher A, et al. 2022 Feb;196(3):523-529. doi: 10.1111/bjh.17900. Epub 2021 Oct 24. PMID: 34693519.

Links:  BMJ    B12 and Folate deficiency investigations 

Quick Tip; If a patient is B12 and folate deficient, B12 MUST be replaced before folate as the surge in red cell production if folate is given first can causes a dramatic consumption of remaining B12 and risk of subacute combined degeneration of the cord

An increased mean corpuscular volume is seen due to abnormal DNA production, conditions which increase the proportion of immature cells in the circulation, or when red cells are exposed to toxic substances. 

Common causes

• B12 or folate deficiency
  • The deficiency of either causes abnormal DNA synthesis and subsequent large red cells. B12 deficiency specifically can cause diffuse neurological complications such as loss of proprioception and reflexes, ataxia, depression & psychosis
  • Causes of B12 deficiency include pernicious anaemia, gastrectomy, atrophic gastritis, terminal ileal disease (Crohn's/resection/tuberculosis), bacterial overgrowth, chronic pancreatitis, drugs (colchicine, phenytoin, metformin, alcohol, proton pump inhibitors)
  • Causes of folic acid deficiency are include poor dietary intake, malabsorption and alcohol abuse.
• Reticulocytosis
  • Any condition causing an increased number of immature red cells in the circulation can raise the MCV as these cells, reticulocytes, are larger than mature red cells
  • Causes for reticulocytosis include haemolysis or marrow stress, such as sepsis or trauma
• Toxins affecting red cells
  • Alcohol and chemotherapy agents are directly toxic to red cells and can increase their size
• Myelodysplasia
  • Myelodysplasia can cause a macrocytosis as the bone marrow becomes more dysplastic and red cell production becomes more abnormal. This should be suspected in patients with a blood film with dysplastic features or other cytopenias. Usually older patients. 
• Pregnancy
• Liver disease
• Myeloma
• Hypothyroidism

Workup

• History and examination including assessment of diet (vegans more prone to B12 deficiency), alcohol intake and medication history
• Repeat full blood count
• Blood film
  • Looking for features of B12/folate deficiency (hypersegmented neutrophils, oval macrocytes), haemolysis or dysplastic features
• B12 and folate levels
  • If deficient then replace. If both B12 and folate deficient, B12 must be replaced first due to risk of subacute combined degeneration of the cord if folate is replaced first
  • B12: If no neurological involvement; Hydroxocobalamin 1mg IM alternate days for 2 weeks, followed by maintenance of 3 monthly injections if not malabsorption-related or 6 monthly if malabsorption-related (BNF/NICE). If neurological involvement; Hydroxocobalamin 1mg on alternate days until no further improvement then 1mg every 2 months (BNF). If felt to be dietary, good sources of B12 include red meat, salmon, milk, cheese and eggs (not an exhaustive list).
    • Investigate the cause of B12 deficiency (causes most commonly gastroenterological) - see BSH reference
  • Folate; Folic acid 5mg once daily for 3-4 months or longer if the underlying cause continues (e.g haemolysis). Dietary sources include broccoli, Brussels sprouts, asparagus, peas, chickpeas, and brown rice.
• If haemolysis suspected complete a haemolysis screen;
  • LDH (Raised), Haptoglobins (Decreased), Reticulocytes (Raised), DAT screen (positive), bilirubin (increased)
• Serum electrophoresis
• TSH
• A bone marrow biopsy would be considered if dysplastic features were present on the blood film or there were significant cytopenias (alcohol can suppress the marrow causing cytopenias, as well as causing macrocytosis)

It is possible to get falsely 'normal' B12 assays even with B12 deficiency – if strong clinical suspicion, consider discussion with biochemistry lab/haematology as other investigations may be appropriate.  

Referral to haematology is recommended if haemolysis, dysplasia or myeloma are identified on the bloods and blood film, or if other cytopenias are present (thrombocytopenia/ leukopenia). 

Links:  BMJ Best Practice (subscription required)     NICE CKS B12 and Folate deficiency investigations     BSH B12/folate deficiency guidance

Quick tip; Microcytic anaemia in the UK is most commonly caused by iron deficiency

The differential for microcytic anaemia is quite limited. The most important causes are;

• Iron deficiency anaemia (uncommonly due to dietary deficiency, more often from bleeding or malabsorption)
• Anaemia of chronic disease (more often normocytic however)
• Thalassaemia or thalassaemia trait
• Hookworm very common in low and middle income countries, uncommon in UK practice
• Lead poisoning (rare)
• Congenital sideroblastic anaemia (very rare)

Workup;

• Repeat full blood count with blood film (comments of microcytosis, hypochromia and pencil cells/rod poikilocytes would support iron deficiency particularly)
• Ferritin (with soluble transferrin receptor if available and history of acute/chronic inflammation- see 'Low Haemoglobin' module)
• Serum B12 and folate
• Haemoglobinopathy screen in patients of family background at risk of haemoglobinopathy (these patients will have a high/normal RBC whereas iron deficient patients will have low RBC, and often a very low MCH).
  • Note; Alpha thalassaemia trait will not be detected on a haemoglobinopathy screen but is not clinically relevant unless at risk of alpha zero (aa/--) which is seen in east Asian populations. This is because if a patient's partner is also a possible carrier of alpha zero any child would be at risk of Hb Barts --/-- (incompatible with life)

If no evidence of thalassaemia, referral to gastroenterology should be considered because primary haematological causes for microcytosis are so rare. Identification of a source of malabsorption or bleeding is the priority. If associated with changes in bowel habit or an older patient particularly, consider 2 week wait referral. 

Iron replacement strategies

Research into iron replacement strategies (only currently in non-anaemic, iron deficient women so far but likely to be applicable to anaemic patients) shows that alternate day, once daily oral iron dosing allows time for hepcidin to drop again after first dose (it rises after iron absorbed). Daily dosing, and especially split dosing causes hepcidin rises which blocks further absorption from the gut. The ‘spare’/unabsorbed iron is then responsible for many of the GI side effects. Although not definitive, this appears to be the future for oral iron replacement. Consider this if patients have previously been intolerant of traditional regimen oral iron replacement before referring for IV iron-much cheaper and less (& reversible) significant side-effects than IV iron (skin staining etc).

https://link.springer.com/article/10.1007%2Fs12185-017-2373-3 

Links; NICE CKS

Quick Tip; Although a B12 level above the reference range has an association with cancer, there is no guidance about a suggested investigative pathways

B12 levels above the reference range are not an uncommon finding in those who are not on B12 supplementation. A Danish population cohort study (n=333,667) found that the incidence of B12 levels above the reference range was 6%. 

A raised B12 level (without supplementation) has been associated with increased cancer incidence. An increasing level of B12 seems to correlate with increasing cancer incidence but this appears to be lost from 1 year after the initial measurement. The 3 commonest cancers were myeloid haematological malignancy, liver malignancy and myeloma (although the myeloma association was not seen in another study (Jammal et al.)). Many of the commonest solid organ cancers represented the remaining associated malignancies. 

Standardised cancer incidence ratio with different baseline B12 levels. Adapted from Arendt JF, Pedersen L et al (2013).

Cancer however is not the only cause of raised B12, with other causes including liver disease, alcoholism, interstitial renal disease, autoimmune and infectious disease (Arendt, Jammal).

Due to the relatively low cancer incidence with even high B12 levels it is hard to create an investigative/management pathway. If an incidental raised B12 is found, it seems reasonable to undertake the following;

• History and examination for liver disease and alcohol intake, any features of autoimmune or autoinflammatory disease and any risk factors for infectious disease. 
• An up to date full blood count, liver function tests and renal function. Serum electrophoresis may be beneficial in older patients but the myeloma association is conflicted in the data.
• Whether to repeat a FBC at a 3-6 month interval is of unclear benefit.
• An ultrasound of the abdomen could be considered if any features suggested liver disease/malignancy.

Refs;

• Arendt JF, Nexo E. Unexpected high plasma cobalamin: proposal for a diagnostic strategy. Clin Chem Lab Med. 2013;51(3):489–496.
• Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study. Arendt JF, Pedersen L, Nexo E, Sørensen HT J Natl Cancer Inst. 2013;105(23):1799. Epub 2013 Nov 18.
• High plasma concentration of vitamin B12: an indicator of hepatic diseases or tumors. Jammal et al. Rev Med Interne. 2013;34(6):337

Quick Tip; An acutely raised high platelet count is most commonly reactive due to infection or bleeding and often needs only observation

Thrombocytosis is a common finding in hospital inpatients as a reactive feature to acute illness. Persistent or significantly raised platelet counts (>450 x 10⁹/L), especially in the absence of an inflammatory trigger, should be referred for investigation for a possible underlying myeloproliferative disorder (essential thrombocythaemia, polycythaemia vera or myelofibrosis).

Common causes;

• Reactive thrombocytosis to acute or chronic inflammation
• Essential thrombocythaemia (or part of other myeloproliferative disorder such as polycythaemia vera)
• Iron deficiency
• Hyposplenism/post-splenectomy
• Less common, but significant - underlying malignancy. See NICE CKS reference below for advice regarding the role of X-ray in patients over 40 with thrombocytosis to investigate for lung cancer

Workup of chronic thrombocytosis

• Thorough history to identify any underlying autoimmune/inflammatory disorder, chronic infection or suspicion of malignancy
• Examination including for hepatosplenomegaly
• Repeat full blood count with blood film (at 3-4 month interval if not grossly elevated, and patient well with no other risk factors for arterial or venous thrombosis)
• Ferritin level (iron deficiency anaemia can cause thrombocytosis)
• ESR and CRP to investigate for inflammatory cause

If on repeat an elevated count is persistent and no other trigger is obvious, refer to haematology.

If significantly elevated (>600 x 10⁹/L) or the patient has an increased risk of thrombosis (history of acute coronary syndrome, venous thromboembolism or cerebrovascular disease) or is aged over 60, consider referring more urgently to haematology services/ seek on-call haematology advice as these features all increase the thrombosis risk

Essential thrombocythemia/myeloproliferative disorder

• Suspect in the absence of an obvious acute problem such as sepsis or trauma, and if underlying inflammatory condition or autoimmune conditions are ruled out. Suspicion should also be raised if haemoglobin or white cell counts are also above the reference range. This will often present over months rather than days as seen in response to sepsis/trauma.
• If this appears the most likely diagnosis, ask local haematology services about testing for JAK2/MPL/CALR in community/hospital at the time of referral (these are mutations commonly seen in myeloproliferative neoplasms) as this will expedite patient care if that result is available at the time of coming to clinic.

Reactive thrombocytosis

• This can occur in the context of infection, inflammation, bleeding (acute or chronic), malignancy or trauma
• The most significant acute elevations are seen post-op, and can present with platelet counts over 1000 x10^9. 
• Reactive thrombocytosis itself is not thought to be associated with increased thrombosis risk, rather that those patients with a reactive thrombocytosis will often have significant risk factors for thromboembolic disease. Aspirin therapy in small trials has not shown any benefit in decreasing thrombotic events. [See refs]. The only caveat to this is after splenectomy when there is some evidence that aspirin may protect patients with a significantly raised count in the immediate period post-splenectomy - discuss these cases with haematology.
• Acute, significant (usually over 1000 x10^9) reactive thrombocytosis is complicated further by the fact that severely elevated platelet counts can lead to a bleeding phenotype as von Willebrand Factor can be consumed by the huge number of platelets. 
• Unfortunately there is therefore no specific guidance for acute, significant thrombocytosis as each patient need to be managed individually, but in almost all cases, the platelet count will settle over days with no intervention needed. If clinical concern, discuss with haematology.

Links:  BMJ (subscription required)    BSH Guideline 

Specific References;

• Griesshammer, M. Bangerter, T. Sauer, R. Wennauer, L. Bergmann, and H. Heimpel, Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. Journal of Internal Medicine, vol. 245, no. 3, pp. 295–300, 1999. 
• Saadi Z, Inaba K, Barmparas G, Salim A, Talving P, Plurad D, et al. Extreme thrombocytosis in trauma patients: are antiplatelet agents the answer? Am Surg. 2009;75:1020–1024
• https://cks.nice.org.uk/topics/lung-pleural-cancers-recognition-referral/diagnosis/symptoms-suggestive-of-lung-pleural-cancers/

Quick Tip; Bleeding from mucosal surfaces such as the gums or tongue in the context of thrombocytopenia are associated with an increased risk of serious bleeds such as intracranial bleeds therefore require urgent assessment & management

The common causes for thrombocytopenia can be broadly divided into more acute or chronic causes.

Acute thrombocytopenia

• Consumptive (Sepsis/trauma)
• Immune Thrombocytopenia Purpura (ITP)
• Acute viral infection
• Drugs (cytotoxic agents especially)*
• Disseminated intravascular coagulation (DIC)/Microangiopathic haemolytic anaemia (MAHA e.g aHUS/TTP)
• Acute leukaemia
• Heparin-induced thrombocytopenia
• Post-transfusion purpura
• Pregnancy- pre-eclampsia and HELLP syndrome

Acute investigations;

• Repeat FBC with blood film (checking for platelet clumping, signs of haemolysis or red cell fragmentation)
• Liver function tests
• Coagulation screen and urgent referral to haematology if DIC/TTP or ITP suspected or profound thrombocytopenia (platelets <50x10⁹/L), especially in content of bleeding from the oral mucosa. See the DIC module for more information.

Chronic/gradual thrombocytopenia 

• Hypersplenism (Decreased platelet lifespan, increased sequestration in spleen)
• Cirrhosis (Thrombopoietin is produced in the liver, associated portal hypertension))
• Alcohol abuse (Direct marrow toxicity of alcohol, cirrhosis, hypersplenism) 
• Drugs (cytotoxic agents especially)
• ITP or other autoimmune disease including antiphospholipid syndrome
• B12/folate deficiency
• Myelodysplastic syndrome/lymphoma or other marrow infiltration
• HIV/Hepatitis B/C
• Inherited causes such as May-Hegglin or Bernard-Soulier syndrome (very rare)

Workup

• Repeat with blood film (checking for platelet clumping)
• Coagulation screen
• Liver function tests
• B12 level
• TSH
• Autoimmune screen
• HIV/Hepatitis B and Hepatitis C testing
• Ultrasound of the abdomen if at risk of hypersplenism

* Some of the medications most frequently associated with thrombocytopenia include; Heparin, quinine, penicillins, cephalosporins, rifampicin, NSAIDS, anticonvulsants, disease-modifying anti-rheumatic drugs, tirofiban, amiodarone, furosemide (See refs)

ITP does not have any specific diagnostic tests therefore referral to haematology should be performed in the case of a prolonged or severe thrombocytopenia, and when non-haematological causes seem unlikely. 

See "Transfusion Threshold" module for advice on safe platelet levels peri-operatively and pre-procedures

Specific references;

Visentin G, Liu C. Drug-Induced Thrombocytopenia. Hematology/Oncology Clinics of North America. Volume 21, Issue 4, Pages 685-696

Aster R, et al. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. Journal of Thrombosis and Haemostasis. Volume 7, Issue 6, June 2009, Pages 911–918

Links:   BMJ (requires subscription)   Guideline 

Quick Tip; Unless significantly raised the white cell count itself does not indicate likelihood of an underlying haematological disorder, as leukaemia and lymphoma may have a normal or low white cell count therefore a thorough assessment with blood film is critical

Broadly speaking a high white cell count will be either due to increased myeloid cells (neutrophils or less commonly eosinophils, basophils, blasts) or lymphocytes. The pathology also varies hugely according to the rate of change and the type of cell. See below for a simplified strategy to think about leukocytosis;

Commonest acute causes (days/weeks) of leukocytosis;

• Reactive to infection/inflammation/surgery - usually neutrophils +- lymphocytes
• Glucocorticoid administration
• Haematological disorder
  • Acute myeloid leukaemia
  • Acute lymphoblastic leukaemia
  • Note that if acute leukaemia is the cause for this raised total white blood cell count, the laboratory team will identify this and notify the haematology team immediately to review the blood film and they will contact the referring clinician.

Commonest chronic causes (months/years) of leukocytosis;

• Reactive
  • Smoking
  • Chronic infection
• Hyposplenism (mild)
• Haematological disorder
  • Chronic myeloid leukaemia - usually a mix of neutrophils, eosinophils, basophils and ('left-shifted' neutrophils which means more immature forms of neutrophil)
  • Chronic lymphocytic leukaemia - usually a slowly rising lymphocyte count with an otherwise normal full blood count over years in an older person
  • Certain lymphoma subtypes (but Note MOST lymphoma types do not have a raised white cell count)

Investigations are merited if;

• The elevation is persistent
• Other cell lines are also affected (anaemia/thrombocytopenia)
• Blood film comments on any significant haematological pathology
  • As commented above, if the blood results and film and in keeping with acute leukaemia, the lab team will speak to the haematologists who will review and contact the referring clinician

Workup

• Blood film with differential to help identify whether elevated cell counts are myeloid or lymphoid
• If blood film shows reactive picture then could repeat at reasonable interval after improvement in inflammatory/infective problem to check findings resolved
• If there is any concerning pathology (e.g blasts/immature cells on the film or other cell cytopenias, then a comment would be given on the blood film with advice for further management or, if not, contact the on call haematologist for advice)
• See our other modules on high neutrophils, high lymphocytes and other raised white cell counts to advise on further investigation in these specific circumstances

If the blood film reports that a malignancy such as leukaemia is likely, haematology will be involved by the lab team, but you can see the 'Workups' submenu for next steps in investigation. 

Quick Tip; Neutrophilia is only very rarely is caused by a malignant problem 

Almost all cases of neutrophilia are due to an acute insult, and reactive counts of over 50x109/L can sometimes be seen 

Common causes; 

• Acute causes; 
• Bacterial infection 
• Corticosteroid use 
• Chronic causes 
• Smoking 
• Corticosteroid use 
• Chronic myelomonocytic leukaemia (associated with monocytosis and dysplastic features on blood film) 
• Chronic myeloid leukaemia 
• Chronic neutrophilic leukaemia (very rare) 

Workup; 

• History and examination 
• Medication review 
• Full blood count and blood film 
• CRP 

Review of trend is the most important feature in assessing neutrophilia.  

These are some features to help identify probable aetiology 

• Bacterial infection- Acute rise, will drop quickly after insult resolves. Can sometimes rise even above 50x109/l- no specific action needed unless the neutrophilia fails to resolve within a few short weeks after the insult has 

• G-CSF use in patients on chemotherapy – can also give an acute rise with very high neutrophils, but will also resolve as the G-CSF is stopped.  

• Smoking can lead to a persistent neutrophilia (see reference below about blood donors- neutrophilia seen in 22% of smokers and 2% of non-smokers) 

• CMML is a slow-growing leukaemia which usually presents as an incidental finding of chronic, slowly rising neutrophilia and monocytosis in a middle aged/older person. This comes on over months/years. The blood film will usually show dysplastic features. It would require a non-urgent referral to haematology (although officially is a malignancy so see local protocols for referral guidance). If other counts (haemoglobin and platelets) had reduced, or there were systemic symptoms e.g splenomegaly/weight loss, urgent referral is recommended. 

• Chronic myeloid leukaemia is also slow-growing and usually associated with basophilia (fairly unique to CML and other myeloproliferative neoplasms), thrombocytosis and splenomegaly. This would also merit a non-urgent referral to haematology so long as no blasts are seen on the blood film and there are no other cytopenias (although officially is a malignancy so see local protocols for referral guidance). 

• Chronic neutrophilic leukaemia is very rare and associated with an isolated, persistent and progressive neutrophilia. 

Specific references 

Smoking as a Cause for Mild Chronic Neutrophilia. Stemmelin G et al. Blood 2004 104:3796. 

Links:   Elsevier summary 

Quick Tip; A count of 1 x 10⁹/L or more is unlikely to be associated with a significant risk of infection

Most cases of incidental neutropenia will resolve on a repeat after a reasonable period as they will be due to transient infection. For those that do not resolve, around a third will be chronic idiopathic (see ref Lima et al.-note small study population), with other causes listed as below.

Neutropenia is defined as mild: 1-1.5 x10⁹/L, moderate: 0.5-1 x10⁹/L or severe: <0.5 x10⁹/L.

Common causes;

• Viral infection (will resolve within a few short weeks)
• Racial variant- Middle Eastern and black people have a lower baseline neutrophil count (if mild, there is no increased risk of infection so long as there is an adequate neutrophil response at times of infection) (see ref Haddy et al.)
• Drugs- antibiotics, anticonvulsants (not an exhaustive list)
• Autoimmune disease or autoimmune neutropenia
• Congenital or cyclical neutropenia
• B12/folate deficiency
• Felty's syndrome (or isolated splenomegaly)
• Thyroid disease
• Iron deficiency
• Bone marrow failure (e.g myelodysplasia, aplastic anaemia. However it is uncommon for neutropenia to be the only cytopenia in this situation)

Workup;

• History and examination
• Medication review
• Blood film
• B12 and folate
• TSH
• Autoimmune screen
• HIV, Hepatitis B/C screen
• Ferritin

If neutrophil count >1 x10⁹/L, chronic and the patient has no clinical features of neutropenia (frequent infections, mouth ulcers) and initial investigations for an underlying disorder are negative then it is likely that no further action is needed apart from a repeat count in a few months to measure the trend in neutrophil count. If any clinical concern, especially in the context of other low cell counts or evidence of infection/organomegaly/mouth ulcers/fever then discuss with haematology.

In the case of fever and neutropenia prompt treatment with antibiotics is critical, especially in those patients with a neutrophil count of less than 1 x10⁹/L.

Specific references

• Lima CS, Paula EV, Takahashi T, et al; Causes of incidental neutropenia in adulthood. Ann Hematol. 2006 Oct85(10):705-9. Epub 2006 Jun 29
• Haddy TB, Rana SR, Castro O; Benign ethnic neutropenia: what is a normal absolute neutrophil count?. J Lab Clin Med. 1999 Jan;133(1):15-22.

Links:   BMJ (needs subscription)  BMJ best practice (needs subscription)

Quick tip - A normal lymphocyte count does not rule out lymphoma 

Lymphocytosis will often be identified as an incidental finding on routine bloods. Many cases will be benign and some may indicate chronic haematological malignancy. Acute leukaemia will not be reported on a full blood count as a lymphocytosis, because the cells 'look' different to the analyser machines. In the case of a leukaemia, the analyser 'flags' the cells as abnormal and the laboratory performing the test will urgently review the blood film to see if it is leukaemia.

Common causes

• Viral infection (including Epstein-Barr Virus)
• Physiological stress, smoking and hyposplenism
• Malignancy; chronic lymphocytic leukaemia (CLL) or Non-Hodgkin lymphoma much less commonly (note a normal lymphocyte count does not rule out lymphoma if other clinical features suspicious of lymphoma)

Workup

• History and examination;
  • Looking for lymphadenopathy, organomegaly or 'B' symptoms (weight loss, fevers, night sweats)
  • Any recent infections including glandular fever
• Repeat full blood count and blood film
  • Most causes of a lymphocytosis are transient therefore it is important to repeat the test at a reasonable time interval unless there is clinical concern about the patient or the count is significantly raised, making it less likely to be reactive, in which case referral to haematology may be merited
  • Blood film may identify any morphology to support a diagnosis of a haematological disorder
  • CLL can also be associated with haemolytic anaemia or immune thrombocytopenic purpura
  • Full blood count features of concern would be a cytopenias in the other cells such as anaemia, thrombocytopenia or neutropenia. This may be more suggestive of a significant cause, or more advanced CLL for example.
  • If discussed with haematology, immunophenotyping may be recommended to identify CLL as this condition often requires simple monitoring if the patient is asymptomatic
  • A higher lymphocyte count does increase the likelihood of a haematological diagnosis such as CLL (persistently over 10 more suggestive) BUT does not correlate with disease severity or need for treatment. Some patients can have a lymphocyte count of 250x10⁹/L and not need treatment. Others will have one of 12x10⁹/L and have drenching night sweats and significant lymphadenopathy and need prompt treatment.

Referral to haematology is recommended in the case of persistent lymphocytosis, especially when associated with B symptoms, lymphadenopathy or hepatosplenomegaly.

A persistent lymphocytosis under 10x10⁹/L in an otherwise well patient may be reported as 'Monoclonal B cell lymphocytosis' on the blood film. This condition is a CLL precursor which needs monitoring alone, as without any clinical features it needs no treatment. Once the lymphocyte count is over 10x10⁹/L it is more likely to have a blood film comment of 'suspected CLL' possibly with advice for referral. 

Caring for known CLL in the community

The CLL disease course is most often slowly progressive and a slow increase in the lymphocyte count is expected. Features that would require a more urgent referral to haematology or more prompt follow up than planned would be a rapidly rising white cell count (doubling time less than 6 months), any new cytopenias, progressive lymphadenopathy, and progressive constitutional symptoms such as fevers or sweats.

Links:   BMJ (needs subscription)  

Quick Tip; Eosinophilia has a huge variety of causes, and a thorough systems review is required to plan investigations 

Eosinophilia is a relatively uncommon finding but elevated counts should be investigated if persistent or there is associated clinical concern. Eosinophils are involved in fighting parasites and in atopy and allergy.  

Common causes 

• Allergic reaction or atopy 
• Parasitic infection (consider possibly promoted/exacerbated by HIV) 
• Autoimmune disease (SLE, eosinophilic granulomatosis with polyangiitis, polyarteritis nodosa) 
• Medications (anticonvulsants, ACE inhibitors, proton pump inhibitors) 
• GI disease (Coeliac disease, inflammatory bowel disease) 
• Respiratory disease (Sarcoidosis, allergic bronchopulmonary aspergillosis) 
• Malignant disease (any solid organ malignancy) 
• Haematological neoplasm; Acute or chronic myeloid malignancies and lymphoid malignancies (incl. PDGFRA and PDGFRB mutations), myeloproliferative disorders, eosinophilic leukaemia, systemic mastocytosis 

Workup 

A history should concentrate on; 

• Symptoms of; 
  • Allergy 
  • Skin rashes, hair loss, arthralgia 
  • Cardiorespiratory/ GI symptoms 
  • Constitutional symptoms 
• And include; 
  • Travel history 
  • Drug history 
• Possible end organ involvement (see refs); 
  • Respiratory; Eosinophilic infiltration 
  • Cardiac; Endocardial fibrosis and thrombus formation 
  • Nervous system; Peripheral and central neuropathy 
  • Skin; Urticaria, angioedema 
  • Renal; Thrombotic microangiopathy 
• Investigations 
  • Full blood count and film 
  • Renal and liver function, Bone profile, ESR/CRP, B12, IgE 
  • Autoimmune and vasculitis screen  
  • Stool ova, cysts and parasites 
  • Chest Xray if respiratory disease suspected 
  • Investigations for non-haematological malignancy if suspected

According to BSH guidance if there is a count of 0.5-1.5 x 10⁹ and no end organ damage and a probable cause from the history then no further investigations may be required. If however, there is a probable cause that merits investigation, end organ damage or eosinophilia persistently over 1.5 x 10⁹ then further investigation is merited. This would traditionally be with haematology unless there is a recent history of foreign travel and suspicion of helminthic infection in which case an infectious disease referral may be more appropriate. 

Links:  BSH Guideline  BMJ (requires subscription) 

Specific references 

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515759/  (Eosinophilia end-organ damage) 

Quick Tip; Chronic monocytosis is most commonly caused by chronic myelomonocytic leukaemia in older patients

Monocytes are a phagocytic cell from the myeloid lineage (which includes neutrophils, platelets, eosinophils etc). Monocytosis is most often an acute finding, and when chronic has a relatively limited differential diagnosis.

Acute monocytosis common causes;

• Bacterial infection (can be seen with any but common associated pathogens are varicella-zoster, tuberculosis, brucellosis, bacterial endocarditis-not an exhaustive list) (ref. Lynch 2018)
• Autoimmune disease e.g vasculitis or systemic lupus erythematosus
• Corticosteroid use

Chronic monocytosis common causes;

• Chronic myelomonocytic leukaemia (CMML)
• Hyposplenism
• Hodgkin lymphoma (significantly less common-consider if lymphadenopathy or ‘B’ symptoms-unlikely to be the cause if monocytosis has been present for months/years and patient is otherwise well)

Workup;

• History and examination
• Medication review
• Full blood count and blood film
  • If film comments on hyposplenic features, and patient not known hyposplenic, consider coeliac screening
• Blood cultures/other relevant culture to possible pathogen

Chronic myelomonocytic leukaemia

CMML is a slowly progressive leukaemia which usually presents as an incidental finding of chronic, slowly rising monocytosis +- neutrophilia in an older person. The blood film will probably show dysplastic features. It would require a non-urgent referral to haematology. A caveat to this is that if other counts (haemoglobin, neutrophils or platelets) had reduced, or there were systemic symptoms e.g splenomegaly/weight loss, then urgent referral would be recommended.

If there are results dating back over a long period of a stable or very slowly growing monocyte count (usually remains under 10), with normal haemoglobin and platelets and no systemic symptoms (e.g hepatosplenomegaly), this could pragmatically continue to be observed with a full blood count at reasonable intervals. Many older patients will die from other causes before the CMML ever becomes a problem.

If there is a patient who is known to have CMML and they present with acute anaemia, thrombocytopenia or neutropenia and they appear unwell, this may be acute leukaemia as CMML can transform to AML-seek urgent haematology opinion if this is suspected.

Specific references

Lynch, DT, Hall, J, Foucar, K. How I investigate monocytosis. Int J Lab Hem. 2018; 40: 107– 114. https://doi.org/10.1111/ijlh.12776

Quick tip - 90% of patients with a ferritin level 300-1000 µg/L in routine medical practice will not have an iron overload disorder 

Raised ferritin is incredibly common in clinical practice, but the important feature to consider is whether there is any iron loading into organs such as the liver. 90% of patients with a raised ferritin in routine medical practice will not have an iron loading disorder [Olynyk], and instead their raised ferritin will be secondary to inflammation or another organ disease-liver disease for example. 

Even at levels of over 1500µg/L, cancer, inflammation, liver disease and alcohol abuse were all still more common than an iron loading disorder [Hearnshaw]. 

Causes of raised ferritin (e.g. >300 µg/L in men and postmenopausal women; >200 µg/L in premenopausal women-check local reference ranges) 

• Acute or chronic inflammation, infection 
• Alcohol abuse, liver disease (ferritin released from damaged liver cells), renal failure, metabolic syndrome, malignancy 
• Genetic Haemochromatosis 
• Myelodysplasia (due to transfusion predominantly) 
• Thalassaemia 
• Rarer causes include Gaucher's disease, porphyria cutanea tarda, sideroblastic anaemia, haemophagocytic lymphohistiocytosis, Friedrich's ataxia 

Workup 

• Has the patient got any inflammatory/infective conditions? 
• Any clinical evidence of iron overload disorder such as genetic haemochromatosis (family history, joint pains, liver disease, arthropathy, bronzed skin, diabetes, endocrinopathy)? 
• FBC, biochemistry including Liver function tests, CRP +/or ESR, glucose & HbA1c, lipids 
• Ferritin level 
  • Under 1000 µg/L rarely associated with liver damage 
  • Persistently over 1000 µg/L presents a risk of cirrhosis in those with an iron loading disorder 
  • A fluctuating ferritin level is more suggestive of liver disease such as NAFLD, than an iron loading disorder 
• Transferrin saturation must be tested to interpret ferritin correctly 
  • If raised (>50% male, >40% female) , suggestive of iron overload disorder (FBC should be normal, if not, may suggest rare aetiologies).  
    • Check HFE mutation if the above criteria are met (and patient North European ancestry) - see below 
  • If TSat normal, iron overload disorder unlikely - review causes for non-overload hyperferritinaemia; 
    • Alcohol excess, inflammation, metabolic syndrome, malignancy. 
• If level under 1000 µg/L, TSat normal and no evidence of end organ damage and suspicion of an alternative cause, consider repeat at 3-6 months. 
• If level over 1000 µg/L but TSat normal, consider assessment of liver iron stores- refer to hepatology/gastroenterology 
• Consider ultrasound abdomen if suspicion of underlying liver disease 

HFE genotyping aims to identify the two commonest mutations seen in the HFE gene, and thus in hereditary haemochromatosis; C282Y and H63D. Homozygotes for C282Y represent the majority of those with genetic haemochromatosis in the UK. Heterozygous C282Y is the carrier state, and not associated with iron loading when the sole mutation. The H63D mutation appears to carry a much lower risk of iron loading. A compound heterozygote of C282Y and H63D mutations (1 of each allele) can also lead to an iron loading phenotype but usually only if there are other iron-loading pathologies.  

References;  

Olynyk JK, Cullen DJ, Aquila S, et al. Population based study of the clinical expression of the haemochromatosis gene. N Engl J Med1999;341:718-24. 

Hearnshaw, S., Thompson, N.P. & McGill, A. (2006) The epidemiology of hyperferritinaemia. World Journal of Gastroenterology, 12, 5866–5869. 

Links: BMJ (subscription required)    GP journal summary article   BSH Hyperferritinaemia guideline 

Quick tip; When a paraprotein has been identified, the most important step is to identify whether end organ damage from any possible underlying disease is present (bone pain, anaemia, new/progressive renal impairment or signs of lymphoma)

A paraprotein may be found as part of a workup for anaemia of unclear cause or during investigation of pathological fracture, and occasionally as an incidental finding. Below are the common causes and recommended further management of these patients. There is a supplemental 'notes' section below giving further information on paraproteins and their significance.

Common causes

• Monoclonal Gammopathy of Uncertain Significance (MGUS)
• Myeloma
• Lymphoma (most commonly lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinaemia)
• Amyloidosis
• Inflammatory conditions (very rare)

Workup;

• History;
  • Any history of inflammatory or autoimmune disorder (secondary causes of paraprotein)
  • Any symptoms of myelomatous end organ damage; bony pain, lethargy or shortness of breath from anaemia
    • If bony pain consider Xray but if this will take time and clinical suspicion of myeloma is high, do not let this delay an urgent referral
  • Any lymphadenopathy or hepatosplenomegaly
  • Any B symptoms; weight loss, night sweats, fevers
  • Any features of amyloidosis (postural hypotension, diarrhoea, bleeding, neuropathy, macroglossia, nephrotic syndrome)
  • Any features of hyperviscosity (seen with higher paraprotein levels) such as visual blurring and headaches
• Full blood count- ?normo/macrocytic anaemia
• Renal function
• Bone profile including calcium
• Liver function tests including alkaline phosphatase
• Serum free light chains (see notes below and 'Elevated light chains' module)
• Urinary Bence Jones protein (this is free light chains seen in the urine therefore only perform if cannot perform serum free light chains)
• Blood beta-2 microglobulin - a useful prognostic marker in myeloma but not a diagnostic test
• Urgent referral to haematology with these results if myeloma felt to be the cause of the paraprotein

Notes

• Serum immunofixation is also performed to identify and quantify the paraprotein-this might or might not be commented on.
• Frustratingly, reporting of serum electrophoresis is not standardised and it can be hard to tell whether there is a paraprotein present. If it is not clear from the report from the electrophoresis, contact your immunology lab to ask if a paraprotein is present.

If identified, a paraprotein will be reported as the paraprotein heavy chain (in black in the image below); IgG, IgA, IgM, IgD, IgE (listed in decreasing frequency) and the associated light chain (in purple in the image below); kappa or lambda, e.g IgG kappa of 7g/L

Another description of the paraprotein may be as a 'band' in the 'gamma/beta zone' - this is the area on the immunofixation that corresponds to paraproteins. Other zones such as alpha and sometimes beta correspond to inflammation or other autoimmune/inflammatory disorders rather than myeloma/MGUS. Polyclonal rises are seen in inflammation and are not indicative of myeloma/MGUS. Again, a significant result such as a paraprotein should be specifically reported-if unclear, call the immunology lab for clarification of the result. 

If there is no paraprotein detected, and the serum free light chain results are normal, the probability if myeloma is incredibly small, as only 3-5% of patients have a myeloma which produces no clonal protein ('non-secretory' myeloma).

Links:   BMJ (requires subscription)    BMJ Best Practice (requires subscription)

Quick tip; The most relevant part of a serum free light chain test is an abnormal ratio of kappa to lambda rather than increases in the kappa or lambda individually 

Light chains are a distal fragment of the immunoglobulin protein (purple lines on the below image) 

In myeloma and other plasma cell disorders, the malignant plasma cell makes the same protein over and over again.  

75% of myeloma cases secrete a protein with both a heavy (e.g IgG, IgA) and light chain (kappa or lambda). 20% secrete light chains only. 3-5% produce no protein at all ('non-secretory' myeloma).  

The light chain can only be kappa or lambda, and therefore if one is produced clonally (again and again by malignant cell), it will increase significantly in proportion to the other. 

A standard serum free light chain screen will report Kappa and Lambda light chain levels and a ratio of Kappa:Lamba. The reference range varies between hospitals- please see your local reference range. 

A proportional rise in light chain subtypes is seen in inflammation and renal impairment. For example a patient has both kappa and lambda levels raised to around 150mg/L, but the ratio of one to the other is maintained. Alternatively there may be one that is only just outside the reference range. 

A significant imbalance in this ratio however may be in keeping with myeloma; either as part of a paraprotein or as part of a light-chain only myeloma. 

Some examples; 

The above results are reference ranges are purely for educational purposes and each set of results must be interpreted in the clinical context of the presentation. 

Note that the inflammation example has a ratio outside of the reference range, but levels of the kappa light chain are only mildly increased. In this example, it would usually be advised to repeat the test when the inflammatory episode has resolved. 

Note in renal impairment, a wider ‘normal’ range for the light chain ratio is used (impaired kidneys cannot clear light chains as effectively). Rather than 0.26-1.65, a range more like 0.4-3.1 (for example-check local range) is used. Therefore even if the light chain amounts are increased, even up to almost 200 for example, it is still most likely due to the renal impairment so long as the ratio is in range. 

If a significant discrepancy is identified between the light chains, as in the bottom example, investigate as per the Myeloma workup section.