Blood thickness is emerging as an important indicator of dangerous complications in Covid-19 patients, causing demand for blood viscometers.
August 3, 2020 — The battle against Covid-19 looks set to be a long one, and much remains to be understood about this virus. One significant recent development originated at Emory University in the USA and has dramatically increased demand for the instruments made by Benson Viscometers, a West Wales company that designs and manufactures a sophisticated clinical blood viscometer. Recognising that a second wave is likely, medical providers are now eager to equip themselves with testing equipment that is emerging as having a key role in directing the treatment of Covid-19 patients.
The link between blood viscosity and Covid-19 began to emerge in June when doctors at Emory University noticed that many Covid-19 patients had unusual blood clotting that did not respond to the usual anti-clotting medication.
“We were unsettled by the fact that some patients with severe Covid-19 had atypical blood clots, even when therapeutically anticoagulated,” says Cheryl Maier, Assistant Professor of Coagulation and Transfusion Medicine, Department of Pathology and Laboratory Medicine, Emory University School of Medicine and medical director of Emory’s Special Coagulation Laboratory.
“Despite prescribing medications to prevent blood clots to Covid-19 patients, clotting still occurred, which is quite unusual,” says Maier. “One thing that stood out was the extremely high levels of fibrinogen, a big sticky protein that increases with inflammation and is a key building block for making blood clots.”
This team went on to consider other causes of clot formation, like hyperviscosity, which can be detected by plasma viscosity (PV) testing. Hyperviscosity syndrome, where the high viscosity leads to dangerous sludging of the blood in the brain and other organs, produces viscosity levels similar to those seen in the sickest Covid-19 patients.
“We found that the sickest patients with Covid-19 had the highest PV levels, more than twice normal levels,” says Maier. “We also found that patients with the highest viscosity levels were more likely to have a blood clot. We think that the inflammation caused by SARS-CoV-2 infection causes the hyperviscosity, which may contribute to blood clots in some patients.”
The team is now exploring alternative treatment options based on this new finding. These include the use of therapeutic plasma exchange, which thins the blood and is a standard treatment for other conditions associated with hyperviscosity.
“During plasma exchange the plasma of Covid-19 patients is replaced with donated plasma,” explains Maier. “This reduces the viscosity by normalizing the fibrinogen and other factors contributing to the stickiness and, potentially, may reduce clotting. Still, correlation does not mean causality, and we need to study this in large trials to understand whether viscosity is simply a marker of disease or actually contributing to clotting.
“Covid-19 is a unique disease. There is more going on with these atypical blood clots than we first realised. Hyperviscosity may be an important piece of the puzzle in linking inflammation to clotting.
“We need larger studies to understand whether hyperviscosity is simply a marker of severe Covid-19 or actually contributing to blood clots in these patients,” she adds. “Nevertheless, we’re trying to determine any beneficial role of lowering the viscosity in these patients through a treatment called plasma exchange.”
News of the potential significance of hyperviscosity in Covid-19 patients has been spreading. A paper in The Lancet on May 25th details Emory University’s findings, while an article in Newsweek on May 28th further explored this study and the links between PV and Covid-19.
In the UK, Addenbrookes Hospital is using Benson Viscometers’ equipment to explore how best to understand and treat Covid-19. They have been carrying out the test on all 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.
“The tentative results so far, prior to sufficient statistical analysis, clearly show that there is an increase in the PV level associated with a positive Covid result. This is in line with what we would expect,” says Daniel Gleghorn, Senior Biomedical Scientist - Automation Lead, Clinical Haematology, Cambridge University Hospitals NHS Foundation Trust.
“I believe the PV has potential as a useful marker in the diagnostic assessment of patients with suspected Covid-19 and for monitoring disease progression.”
He adds that the PV test has some important advantages over other tests that are used to detect inflammation, including cost and availability.
“From a laboratory management perspective, it is well documented that the PV provides a more useful indicator of infection, inflammation and malignancy than the traditional ESR,” he says. “It is also a cost-effective test compared with other expensive biochemical methods, can be performed on the same EDTA tube used for a full blood count and is quick and easy to perform.
“There is also the benefit of a less complicated and reliant supply chain for consumables and reagents. This has been significantly affected for other tests (CRP, procalcitonin and Interleukin-6) where this is not the case due to a worldwide increase in demand and the effects of lockdowns on distribution networks.”
Meanwhile, Health Services Laboratories in London is also on the case. HSL is a partnership between the Australian company TDL (The Doctors Laboratory), UCLH (University College London Hospitals NHS Foundation Trust), The Royal Free London NHS Foundation Trust and North Middlesex University Hospital. HSL’s flagship laboratory, The Halo in London (one of the largest pathology laboratories in Europe) is using the PV test to monitor inflammatory status in certain groups of Covid-19 patients, and is exploring the possibility that high inflammatory markers might indicate the need for alternative strategies for stroke prevention in these patients.
“We are running PV now to monitor inflammatory status in the following patient groups: those with high risk TIA (transient ischaemic attack) commenced on DAPT (dual anti-platelet therapy), those with treatment failure on anti-platelet therapy, and those with high risk carotid/vertebral or intracranial stenosis,” says Deepak Singh, Head of Department, Haematosis, at Health Service Laboratories. “This is to ensure anti-platelet drug therapy efficacy.
“The aim is to get an overall insight on the reoccurrence of strokes despite patients being on anti-platelet medication and to identify the battery of tests available that can help in these cases.”
They are not alone: laboratories all around the world are now exploring the role that measuring PV can play in monitoring the progression of Covid-19, helping to develop a more scientifically targeted treatment for patients and producing improved recovery outcomes. A growing number of long-standing experts in the field are backing this development.
Paul Woods, a former pathology laboratory manager at Nobles Hospital in the Isle of Man, reports that PV testing is being used there: "Some laboratory tests are being utilised by the emergency department in relation to Covid-19 particularly d-dimer and ferritin,” he says. “These tests are also being used to monitor patients who appear to be deteriorating and may be in need of more intensive care. The laboratory recently also facilitated PV availability 24/7 in relevant Covid-19 cases, which is notable, given it is not normally an out of hours test."
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.”
Experts are also highlighting the reliability of the PV test. David Norcliffe, a recently retired biomedical scientist specialising in haematology and a much respected ambassador in this field, has been aware of the importance of PV measurement in many clinical conditions including inflammation, different types of infection, malignancies and many blood disorders for most of his 43 working years in the NHS.
“While there are alternative tests for inflammation and infection none of them surpass the accuracy, precision and suitability of PV for diagnosis and monitoring,” David says. “There are constantly new applications found for PV, serum viscosity and red cell deformability on an almost daily basis and none more so than in the current climate of battling Covid-19. 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 treatment.
“Overall I believe the study of blood flow (Haemorheology) is of paramount importance in the diagnosis and monitoring of many disease processes and could potentially improve the lives of hundreds of thousands of patients in the future. It also allows for a fresh look at long established diseases in times to come.”
Explaining the significance of the PV test further, he highlights the fact that all tissues and organs are dependent on a good blood supply for their function and integrity. Blood flow is dependent on three things: PV, haematocrit (the percentage of red cells in blood) and the degree of red cell flexibility.
“A small numerical change in any of these represents a significant clinical change,” he says. “Hence the method of measurement must demonstrate a high degree of accuracy (the degree of closeness to a fixed, known value) and precision (the degree of reproducibility or repeatability). Only Benson Viscometers can do this to the level required and also has the advantage of using only a small amount of blood.”
For Benson Viscometers, these developments have led to heightened interest in the clinical analysers the company has been making for over 20 years. Demand for viscosity testing has now risen so much in the light of Covid-19 that the company is about to take on additional premises in Haverfordwest in order to increase its production capabilities.
The family-run company started life in 1999 and has established itself as the leader in the provision of clinical blood viscometers throughout the UK. The majority of the analysers have been installed in National Health Service (NHS) Pathology laboratories, but private laboratories located in Europe and the USA also use its equipment. Its blood viscometer analysers have the ability to provide fast, effective and accurate results and support compliance with ISO 15189.
Benson Viscometers’ clinical analysers facilitate the safe processing of high risk samples as they incorporate ‘closed vial’ sampling in their operation. This capability within their viscometers ensures direct exposure to the biological fluid is minimised as the sample tube cap does not need to be removed for the sample to be tested.
Clinical viscosity diagnostic tests are highly efficient as they can be carried out using the residue from the full blood count analysis, which would normally be carried out on a daily basis. PV results are rapid, precise, and are not affected by variations such as gender, age, early pregnancy, or the presence of other conditions, such as anaemia.
An advantage of the PV test is that it will continue to give clinically significant results up to seven days after the sample has been taken. More importantly, the results are not altered or interfered with by the patient having taken medication such as high dose steroids, cytotoxic drugs or aspirin.
Besides the new discoveries around Covid-19, other serious conditions are associated with a high PV result. High PV is a known risk-factor for thrombosis and can be caused by increased levels of plasma proteins, such as fibrinogen or immunoglobulins. PV results divide into a range of bands that can be of assistance to clinicians in interpreting the results.
Serum viscosity measures the fluid which is released during blood clotting and therefore does not contain the factors required for coagulation, of which fibrinogen is one. Therefore the main factor to affect serum viscosity is antibody concentration.
In current practice whole blood viscosity measurements are time consuming and difficult to perform. Many analysers require measurements at varying shear rates on the same sample. Fortunately in Covid-19 patients, the most valuable information is obtained from plasma and serum viscosity analysis.
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.
In an paper, 'The role of chronic hyperviscosity in vascular disease' written by Gregory Sloop, Ralph E. Holsworth, Jr, Joseph J Weidman and others, it has been recommended that blood viscosity should be measured routinely in medical practice.
The paper stated "cardiovascular disease is still the leading cause of deaths for both men and women worldwide. Many risk factors have been identified and current therapeutic efforts have been centered on addressing these risk factors. However, as of today, the role that blood viscosity plays in this disease has not yet received its due attention. Viscosity is a fundamental property of any fluid. It's important role in both normal individuals and patients afflicted with cardiovascular disease has been underestimated. Past and current research has reported the benefits in addressing this important factor; however, mainstream medicine has not appreciated or fully accepted this important measurement. With continued research and published, peer-reviewed studies pertaining to the importance of blood viscosity in cardiovascular diseases, this relationship will be recognized, appreciated and will no doubt reveal the positive aspects of hemorheology, which will save lives."
While demand for its blood viscometers continues to rise, Benson Viscometers is also proud of its ability to design and develop new systems and is currently testing a device which is not associated with viscosity to increase its market base. The aim of the new coagulation profiling device is to reduce the time delay to commence correct blood component therapy.
Benson Viscometers is developing a mobile coagulation profiler which profiles and plots the progression of the clotting of fresh whole blood in real time. The instrument is being designed to enable it to be used at the scene of an accident in areas such as the roadside, at a major trauma incident and for military front-line use, next to the injured patient. The instrument will operate beside the patient in mobile scenarios such as ambulances, in air ambulances, and in static areas such as accident and emergency units, operating theatres, and obstetric units.
Bernie Benson, who created Benson Viscometers, is pleased to see his equipment helping to shape the understanding of Covid-19 and the development of effective treatments.
“Amidst the huge strain and challenges caused by this global pandemic, we are grateful that we are able to make a positive contribution to improving patient outcomes,” he says. “The PV test is highly valued and routinely used by many eminent UK and USA hospitals for a range of conditions. We believe that routine clinical viscosity testing will lead to a significant breakthrough in outcomes for critically ill patients, and not just those with Covid-19.
"Looking to the future, there is clear potential for the viscosity test, and clinical viscometers to become mainstream tools in the treatment of Covid-19 patients."
“Covid-19 is not going away, well at least not for the next few years,” says Gleghorn. “There is, however, a need for a diagnostic and prognostic testing strategy not just for the short term, but for many years ahead. If it can be proven that a PV can be used as part of a diagnostic algorithm, possibly as a positive predictive indicator for Covid-19 it may then form part of a recognised battery of tests for this purpose.
“In addition, determining the prognostic value of PV will hopefully provide an aid to clinicians showing a potential improvement or deterioration in the patient’s condition. The clinicians can then act appropriately in a timely manner. PV at point of care for these patients may also be a possibility.”