Quick tip; The majority of cases of easy bruising are constitutional or medication-related
'Easy bruising' can be hugely variable in reporting by patients, therefore a through history is needed to identify nature of the bruising, and any associated significant bleeding history or family history of a bleeding disorder as these will increase the likelihood need for referral to haematology.
There are no absolutes for referral, but clinically concerning history or examination (especially features in bold), or abnormal FBC or coagulation screen would merit referral.
In cases where there are no concerning features from the history and there could be other aetiological factors such as medications consider the benefits vs risks of reducing those risks (e.g stopping medications) or simply observing the bruising.
Quick Tip; A positive DAT screen is sensitive but not always specific for haemolysis
Haemolysis should be considered in cases of anaemia when no source of bleeding is evident or there are clinical features to suspect a haemolytic process, either from patient history of laboratory findings. Almost all haemolysis is extravascular but around 15-20% will be intravascular (mechanical e.g metallic heart valves, or thrombotic microangiopathy e.g Thrombotic Thrombocytopenic Purpura (TTP))
Risk factors for haemolysis;
Quick tip; When identifying a paraprotein, 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)
A raised paraprotein may be found as part of a workup for anaemia of unclear cause or during investigation of pathological fracture, and occasionally 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. Also included is an explanation of light chains and their relevance. There is also a further subsection on 'MGUS' as this subject can seem complex and needs further explanation.
A paraprotein is a clonally produced non-functioning immunoglobulin.
It 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
*IgM is more commonly associated with lymphoplasmacytic lymphoma/ Waldenstroms macroglobulinaemia
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.
Myeloma is a condition of a clonal population of terminally differentiated B cells, plasma cells, commonly producing a paraprotein with or without end organ damage. The myeloma cells may will normally produce a paraprotein, but may only produce light chains (the small terminal projection of the immunoglobulin) or be completely non-secretory.
Tests for light chains will be reported as the amount of kappa and lambda, and a ratio of kappa:lambda. The kappa:lambda reference range varies between hospitals but will be in the region of 0.31 - 1.56. Light chains will rise in inflammation in proportion, similar to immunoglobulins. Pathology is more likely when a significant change in the kappa:lambda ratio is identified. This may be either as part of a paraprotein or as part of a light-chain only myeloma. If a significant difference in ratio is identified, then investigations should be performed as for a suspected myeloma and haematology should be involved
Quick tip; Overall progression of MGUS to myeloma at 20 years is around 20%
Monoclonal gammopathy of uncertain significance (MGUS) is an entity in the same family of conditions as myeloma. MGUS is an identified paraprotein in the absence of any end organ damage from myeloma. All cases of myeloma are thought to originate from an MGUS but not all cases of MGUS will progress to myeloma.
Priorities of management of an identified paraprotein to diagnose MGUS are to take a history for paraprotein-related clinical conditions, rule out myeloma end-organ damage and risk assess for transformation to myeloma to decide appropriate follow up. Note that MGUS can also progress to amyloid, plasmacytoma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome.
History and examination should look for;
Myelomatous end-organ damage can be;
Three main features seem to convey a higher risk of transformation to myeloma (Rajkumar);
With each of these features, the risk of progression to myeloma at 20 years increases by roughly 15%- if all 3 are present, the risk of progression to myeloma at 20 years is 58%. Although still relatively low, the aim of risk stratification is to refer patients who are at risk before end organ damage is present as this is often irreversible.
Referral to haematology is reasonable if any of the above 3 features are present, or critically if any evidence supporting a diagnosis of myeloma such as end organ damage is present. Local guidance should also be followed for referral policy for MGUS.
If no high risk features are present and there is no evidence of myeloma then patients can be monitored with 6-monthly and then annual community bloods tests (electrophoresis, serum light chain, urine Bence Jones protein, FBC, bone profile, and renal function) with referral to haematology if an increase in the paraprotein of over 25% or any indication of end organ damage (please check local referral policy for local practice).
Rajkumar SV, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005 Aug 1;106(3):812-7
Kyle R, et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 2018;378:241-9.
The investigations of myeloma are often one of the biggest sources of confusion in the understanding of the disease. Below is a bare-bones process of how to investigate for myeloma if there is a clinical/biochemical suspicion. Complete all 3 steps for a thorough workup.
|1.Electrophoresis for Paraprotein (PP)||2. Serum free light chain ratio OR =>||2. Urine Bence Jones protein||3. End organ damage||Diagnosis|
|Normal ratio||No Bence-Jones protein detected||Absent||No plasma cell disorder (Caveat-see bottom row)|
|No PP||Abnormal ratio||Bence-Jones protein present||Absent||Light chain MGUS|
|No PP||Abnormal ratio|| |
Bence-Jones protein present
|Present||Light chain-only myeloma|
|PP present (usually under 10 g/L)||Abnormal ratio||Bence-Jones almost always present||Absent||PP MGUS|
|PP present (usually over 10 g/L)||Abnormal ratio||Bence-Jones almost always present||Present||Multiple myeloma|
|No PP||Normal ratio||No Bence-Jones protein detected||Lytic lesions +- hypercalcaemia +- anaemia||Non-secretory myeloma (see below)|
MGUS- Monoclonal gammopathy of uncertain significance- a PP or abnormal LC ratio but with no end organ damage
Therefore, if as on the top row, there is no paraprotein, the light chain ratio is normal/Bence Jones negative, and no end organ damage which cannot otherwise be explained, myeloma will be ruled out in almost all cases.
Non-secretory myeloma is a myeloma type which makes neither PP or abnormal LC. This is very rare however and only represents 3% of myeloma. Therefore, if clinical suspicion of myeloma is low or intermediate, and no PP or abnormal LC ratio detected, myeloma is incredibly unlikely. If clinical suspicion is high, because of lytic lesions on imaging for example, discuss with haematology as the way to diagnose could be a bone marrow biopsy or biopsy of affected area.
Pathway for monitoring and referral regarding paraprotein and serum free light chain results. Courtesy of Dr Kartik Ramasamy, Dr Ross Sadler and Faouzi Djebbari at Oxford University Hospitals-Many thanks. This is purely for information and education- local protocols may differ.
Quick tip; Night sweats are a common presentation of malignant haematological disease but can be present in other systemic illness
A typical description of pathological night sweats are that they are 'drenching' and they often need the sheets and bed clothes to be changed.
The history is critical to identifying a cause. It is important initially, especially with a short history of sweats, to rule out infection as the cause. This includes;
Other causes of night sweats include autoimmune or autoinflammatory conditions such as;
If these conditions are not considered to be likely or there are other concerning features causing suspicion of underlying malignancy, it is important to recognise clues as to the malignancy causing the fevers as both solid organ (lung and renal for example) and haematological malignancies can cause fevers. Features that may hint more at a haematological malignancy such as lymphoma include regular fevers, weight loss and lymphadenopathy associated with the night sweats, although these features are not exclusive to lymphoma.
If there is suspicion of a specific malignancy after history and examination (a chronic cough or haematuria for example) then a referral to the appropriate specialty would be advised. If however there is ambiguity about the possible cause or a haematological disease is suspected the next recommended investigations would include;
Particular indications for Haematology referral would include lymphadenopathy or splenomegaly, significant full blood count abnormalities (although this can be completely normal in lymphoma) or a paraprotein identified on serum immunoglobulin electrophoresis.
Quick tip; Pancytopenia can be due to one pathology, but consider whether it could be multifactorial
Pancytopenia is a reduction in all of the 3 main bone marrow cell lines (red cells, white cells and platelets). If only two are affected it can be called bicytopenia but this is rarely used. Pancytopenia has a few possible causes and this is one way to consider it;
Another approach is to use speed of cytopenia development to guide the differential diagnosis (not exhaustive);
Quick Tip; Mild splenomegaly (up to 14cm) often has no identifiable cause
Splenomegaly can be a presenting symptom with traditionally an ache in the left upper quadrant, or an incidental finding on abdominal imaging. The approach to splenomegaly can be by pathogenesis or by size (conditions causing massive splenomegaly are identified in bold)
Spleen size is also dependent on height and gender, therefore consider using a tool such as the Calculate App by QxMD as this has a spleen size calculator for these variables. This is taken from data of a cohort study of 1200 individuals (see ref). This could avoid referral for what is actually a 'normal' spleen for taller patients.
NICE guidance (see links) recommends that all patients with splenomegaly be considered for 2WW referral taking into account associated symptoms. In patients with only borderline splenomegaly (<14cm) with no symptoms to indicate a possible myeloproliferative/lymphoproliferative diagnosis (and there are no features to suggest other aetiologies), it may be appropriate to repeat the ultrasound at 3-4 months to check for any change in size. If it increases then refer to haematology as a 2WW, whereas if it remains static it could have serial ultrasound scans until confident there is no increase in size.
Links; NICE 2WW guidance
Chow KU et al. Spleen Size Is Significantly Influenced by Body Height and Sex: Establishment of Normal Values for Spleen Size at US with a Cohort of 1200 Healthy Individuals. Radiology 2016 Apr;279(1):306-13.