Since 1947, when John Harkness published his seminal work on clinical plasma viscosity analysis in the British Medical Journal, the test has been generally misunderstood and certainly underutilised. With the infection of humans by SARS Cov2 since late 2019, the pandemic has forced scientists to take a fresh and detailed look at infections and PV; not just PV per se, but its values, trends and the fact it can be used in the calculation of a possible predictor of severity. The world may well now see that Professor Harkness was a man before his time, and he will posthumously receive his due recognition. In May 2020, a paper published in the Lancet from a team at the Emory Medical Centre in Atlanta Georgia showing that Covid-19 patients who developed severe symptoms had markedly raised plasma viscosity levels. This raised the profile of the test among medical and scientific professionals trying to cope with the new pandemic. (COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Cheryl L Maier Alexander D Truong Sara C Auld Derek M Polly Christin-Lauren Tanksley Alexander Duncan The Lancet Volume 395, ISSUE 10239, P1758-1759, June 06, 2020)
During the 70+ years since Harknesss work, there have been many publications confirming the clinical value of using plasma viscosity for investigating patients with an acute phase response or with paraproteins. In early publications plasma viscosity was compared against the established erythrocyte sedimentation rate (ESR), and later against both the ESR and the C-reactive protein (CRP). The plasma viscosity test was reported on very favourably by many of the papers.
Acute Phase Response
In the acute phase response patients produce increased quantities of immunoglobulins (antibodies), the blood clotting protein fibrinogen, CRP and various inflammatory cytokines (signalling proteins).
Plasma viscosity is determined by 2 factors:
· The concentration of proteins
· The shape of the molecules
Antibodies and fibrinogen are found at high concentrations in human plasma. The shape of their molecules has a high length to width ratio, which is the shape that increases the viscosity the most. This means that viscosity measurements are extremely sensitive to increased levels of these proteins.
As long ago as 1988, the worlds leading haematologists recognised the value of the plasma viscosity test for monitoring the acute phase response. Published under the auspices of the International Committee for Standards in Haematology they published a guidance paper on methods for investigating acute phase response and stated “Measurement of plasma viscosity has several advantages over the ESR, including independence from the effects of anaemia; a single reference range that is independent of sex and less dependent on age; instruments that can be calibrated; convenience of quality control checks; and results that are available within 15 minutes.(Guidelines on selection of laboratory tests for monitoring the acute phase response INTERNATIONAL COMMITTEE FOR STANDARDIZATION IN HAEMATOLOGY(EXPERT PANEL ON BLOOD RHEOLOGY) J Clin Pathol 1988;41:1203-1212)
Some laboratories perform the PV test in preference to the ESR and often clinicians will be advised to use the PV test in preference (https://www.gloshospitals.nhs.uk/our-services/services-we-offer/pathology/tests-and-investigations/plasma-viscosity/).
PV is no longer just a non-diagnostic support test and an alternative to ESR. It is much more than that and is probably a better test to reflect plasma protein changes in such inflammatory conditions as polymyalgia rheumatica.
Feedback from laboratories suggest many benefits plasma viscosity testing, not just to patients, but also clinicians and from a laboratory management perspective.
It is a cost-effective test and efficient to perform
Automatable, and can be performed on existing EDTA samples as it uses a small sample volume
Safer for high-risk samples such as Covid-19 as it can be performed on sealed tubes
Easy to perform and tests are completed in minutes with results reported to any LIMS
Modern clinical viscometers have the capability for serum viscosity (SV) to be performed without any changes to equipment or additional reagents
Clinical viscosity is a known measure of inflammatory response with the potential to be a measure of recovery and/or antibody response especially if combined PV/SV is performed as this will exclude the increased acute phase response of fibrinogen
Clinical viscosity results become abnormal earlier in disease than ESR and is not affected by haematocrit
Has a much lower instance of false normal values
Performing a PV test has practical advantages for a laboratory as it can be carried out on a sample up to 7 days after blood being drawn compared to an ESR which has to processed within 4hrs. This makes PV ideal for rural areas or when the test is outsourced
Relatively small changes in PV from the norm are clinically significant for any individual
Clinical plasma viscosity testing is technically reproducible and standardised
PV is more informative and stable than ESR. It has a definitive numerical result that can be easily referenced against condition charts
It is expected that the PV value will be increased in any infection but if clinicians look beyond that they can follow trends through daily monitoring that will correlate with severity.
Clinical viscosity can be used to calculate the rigidity (flexibility) of red cells in a way no one has practiced previously. This has enormous potential for patient benefit. With the addition of SV it adds another dimension of possibility.
The ratio of the two could prove remarkably interesting clinically. There remains the question of why some BAME (Black, Asian, and minority ethnic) patients are more susceptible than their Caucasian (white European ancestry communities) equivalents. Can this be detected by PV, SV, or a combination of the two?
One condition where early diagnosis is vital is giant cell arteritis. A paper published by Gudmundsson in 1993 stated that PV was better than both the ESR and CRP for predicting flare ups in the condition (Plasma viscosity in giant cell arteritis as a predictor of disease activity. M Gudmundsson, E Nordborg, B A Bengtsson, and A Bjelle Ann Rheum Dis. 1993 Feb; 52(2): 104–109.)
In 2011 Finke went even further, stating in his study that it appeared that the plasma viscosity test measured a more specific inflammatory marker for giant cell arteritis than either the CRP or ESR and in patients outside the criteria suggested by the American College of Rheumatology “plasma viscosity may significantly contribute to a reliable diagnosis early in the course of the disease”. (Plasma Viscosity in Giant Cell Arteritis: Carsten Finke Jan Schroeter Ulrich Kalus Christoph J Ploner : September 2011 European Neurology 66(3):159-64)
Conditions that produce paraproteins include the myelomas and lymphomas. Paraproteins are immunoglobulins (antibodies) which are produced in abnormally large quantities by malignancies of the lymphoid B cell lineage. During the last 50 years in the United Kingdom (UK), plasma viscosity has been, and still can be, used to screen for and monitor the paraproteinaemias.
Early diagnosis of Myeloma is important as the malignancy is easier to treat the earlier it is diagnosed. However, early symptoms are not specific, and this rare condition is difficult to diagnose in primary practice. A paper published in the British Journal of General Practice in 2018 showed that in conjunction with a normal haemoglobin concentration, a normal plasma viscosity level could be used to rule out the disease. Researchers also said that GPs should use simple blood tests to support symptoms when diagnosing patients with multiple myeloma, in order to improve early detection rates and that plasma viscosity was one of the best inflammatory markers to supplement symptoms. (Early detection of multiple myeloma in primary care using blood tests: a case–control study in primary care: Br J Gen Pract. 2018 Sep; 68(674))
Going as far back as 1974, 4 cases of IgA multiple myeloma with raised serum or plasma viscosity and clinical features of hyperviscosity syndrome were reviewed. It was felt that serum viscosity measurement was essential for rational clinical management (https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2141.1974.tb06775.x)
A specific condition, Waldenstroms Macroglobulinaemia, causes an increase in a class of immunoglobulin called IgM. IgM protein is a large asymmetrical molecule which causes the blood viscosity to rapidly rise to levels which cause major organ damage. Monitoring the patient by plasma viscosity analysis can lead to earlier treatment, thus reducing the risk of hyperviscosity syndrome. For those patients who do develop hyperviscosity syndrome the treatment is frequently a plasma exchange and using the plasma viscosity test to monitor the treatment, clinicians can rapidly determine if sufficient rounds of treatment have been undertaken.
Benefits Realisation from Plasma Viscosity Analysis
As demonstrated above there is a lot of literature available demonstrating that plasma viscosity is a clinical test which can help in the diagnosis and treatment of several conditions. The test has been available for over 70 years and yet it is still not fully understood, why?
The main reason appears to be a misconception that performing a plasma viscosity test is difficult to do. This probably was the case until the 1980s. In the UK, Coulter Electronics developed a semi-automated plasma viscometer (Visco II) which allowed batch analysis. Plasma could be put in cups on a carousel and the machine automatically sampled and analysed. However, the parent company did not market the device in the USA and in the 1990s Coulter UK withdrew the product. Most of the world were therefore left to use adapted (or not) industrial viscometers to analyse clinical samples. These devices were time consuming to use and had little or no clinical calibration. This has led to a significant number of papers publishing results as relative viscosity. That is comparing the viscosity to the viscosity of water.
Another issue has been using the wrong type of viscometer. The Coulter Visco II was designed as a clinical instrument, calibrated within the range of plasma viscosities and most importantly was a capillary viscometer. It also reported in SI units, meaning all machines gave the same results for the same sample (within manufacturing tolerance).Capillary viscometers are suitable for use on Newtonian fluids like blood plasma and serum, they also have the advantage that a calibrant can be analysed with each batch or number of tests and they can be easily cleaned automatically by sampling and processing a cleaning reagent.
Historically, the USA continued to mainly use industrial cone and plate technology which lose the benefits of capillary analysers. The cumbersome cleaning requirements, lack of standardisation and SI reporting units made clinicians sceptical of the results and hence the test.
In recent years there has also been a drive to reduce costs within the NHS across the UK. Pathology tests were highlighted as an area which were associated with substantial spending. GPs were directed to be more selective in their requests for a diagnostic test and to reduce the number of tests they requested as it was identified that often GPs would request multiple tests which, in some cases, were seen to overlap or duplicate (https://bjgp.org/content/66/644/e200).
However, this activity has led to several outcomes. The ability to readily request certain tests have been made more difficult, this in turn has led to a decline in some tests being requested which has ultimately led to inefficiencies in delivering the ability to conduct the test and a perception that these tests are expensive as there is no longer the economies of scale. There has been an increase acceptance of less appropriate tests as meeting the clinical need and a mindset of “it will do”. The strive for clinical excellence has been overtaken by thoughts of money and the strategic activities to save it. Whilst value for money is a worthwhile goal, there should be no compromise to patient care.
There is immense scope for the education on clinical viscosity testing to be enhanced and improved to incorporate its full potential and to raise the vision in the possibilities it has to improve patient outcomes and to provide invaluable information to clinicians. Incorporating clinical viscosity testing globally into associated condition pathways, will encourage and ensure clinical excellence, consistency and equity for patients.
So What Has Changed?
Two things have changed, the first is that clinical capillary viscometers have continued to develop, and now clinical viscosity analysers are available with advanced health and safety features, increased throughput, improved reliability, and most importantly improved precision. There is now true load up and walk away analysers that sample from a sealed, cap on primary (draw) tube to avoid potential biohazards, which incorporate software to perform auto calibration and quality control checks between every few samples to monitor for drift. Viscometers which have been specifically designed and manufactured for clinical use should be the only standard any healthcare provider accepts.
The second change is Covid-19. Clinicians around the world are trying to establish a strategy to determine which patients infected with SARS Cov2 develop severe non respiratory complications. So far, the key screening test appears to be the plasma viscosity test. As stated in the introduction patients suffering with severe Covid-19 symptoms have a greatly raised plasma viscosity level. This is expected because they will develop an acute phase response and indeed, they produce a mega response with fibrinogen levels up to 10 times the norm, with a subsequent rise in the plasma viscosity to levels only previously seen in patients with hyperviscosity syndrome.
Recent research illustrates a significant change in some of these parameters in the immediate time leading up to symptoms developing which is potentially an exciting finding and might save the lives of many patients by early diagnosis and specific targeted treatment. Leading hospitals are exploring how best to understand and treat Covid-19. They have been carrying out the plasma viscosity test on suspected Covid-19 patients to establish a link between PV and Covid-19 and to explore how PV relates to the severity of and/or recovery from the disease. This has extended to ensuring anti-platelet drug therapy efficacy by monitoring the inflammatory status in those with high risk TIA (transient ischaemic attack) commenced on dual anti-platelet therapy, those not responding as expected on anti-platelet therapy, and those with high risk carotid/vertebral or intracranial stenosis. Increased blood viscosity is an indicator for potential stroke and heart attack induced by a low flow of blood in the capillaries leading to an inadequate delivery of vital oxygen and nutrients to body tissues.
Haematology experts have stated that while there are alternative tests for inflammation and infection none of them surpass the accuracy, precision, and suitability of PV for diagnosis and monitoring. There are constantly new applications found for PV, SV and red cell deformability on an almost daily basis and none more so than in the current climate of battling Covid-19.
The significance of these developments should not be underestimated. Gregory Sloop, Associate Professor of Pathology, Idaho, wrote in a recent article on Medium.com: “Regarding the unusual presentations of Covid-19, Yale School of Medicine cardiologist Harlan Krumholz, M.D. said Our ignorance is profound. Much of this mystery stems from ignoring blood viscosity. Because blood viscosity is inversely related to blood flow, elevated blood viscosity increases the risk of clotting and causes hypoxemia.”
With the USA seeing many Covid-19 patients, clinical establishments are undertaking research into the condition and are publishing papers with plasma viscosity data; Some using outdated cumbersome equipment inherited from the petrochemical industry. USA medical centres are starting to look to the UK for state-of-the-art clinical equipment that will allow them to rapidly and safely analyse high risk clinical samples. And when the USA leads, the rest of the world follows.
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