Covid-19: an endothelial disease?
Bernard Ross, Founder and CEO of Sky Medical Technology, discusses the emerging data and clinical opinions that suggest Covid-19 is an endothelial disease. Endothelial cells line blood vessels, and release protective substances which influence everything from blood clotting to the immune response.
Endothelials are critical cells that line all organs and run throughout the miles of arteries throughout the human body. Eight months after the first reported case in China, UK ICU clinicians and leading epidemiologists share the view that endothelial dysfunction is a common clinical manifestation in seriously ill Covid-19 patients. This has given voice to the concept that it is an endothelial disease.
As early as January, studies from China confirmed what many ICU teams in the UK and worldwide were seeing. Hospitalised patients with Covid were presenting with a high risk of blood clotting and bleeds – an incidence rate of over 60 per cent1 in immobile critically ill Covid patients. Collectively, the studies have called for improved blood clot prevention strategies and stressed the importance of individual patient bleed risk assessment, prior to prescribing high-dose blood thinners (which can worsen bleed risk).
Much less reported but now also emerging, and at pace, is the high incidence of lower-limb deep vein thrombosis (DVT) and resultant pulmonary embolism (a blockage of a lung artery) in hospitalised patients with Covid-19. A compelling study by Zhang et al2 assessed 143 hospitalised Covid patients and found that 46.1 per cent had DVT in their lower limbs. Those with DVT had a worse prognosis, with fewer discharges and a high death rate. The study concludes that the clotting is due to multiple comorbidities, invasive Covid tests and treatments, and prolonged immobilisation. Again, the paper calls for improved lower-limb venous thromboembolism (VTE) prevention strategies to prevent lower-limb DVT.
With new data emerging by the day, there is growing widespread opinion that inflammation of the endothelium (endotheliitis) can explain the systemic impaired macro and microcirculatory function that is causing multiple organ failure. This hypothesis is driving the rationale to identify and test therapies that help to stabilise and protect the endothelium. These include anti-inflammatory and anti-cytokine drugs, which are currently being hailed as a breakthrough, as well as ACE inhibitors and statins – all used alongside blood thinners for clot prevention.
A study published in The Lancet has been among the first to report that Covid-19 infects the endothelial cells lining the blood vessels. The study reported damage to endothelial cells in the lungs, heart, kidneys, liver and intestines of critically ill patients. This study is adding weight to the concept that Covid-19 is not a respiratory illness alone, but rather a respiratory illness that can quickly become vascular.
Impaired blood circulation is also recognised as a mechanism that can trigger endothelial dysfunction3.
Normal blood flow exerts shear stress on the vascular endothelium, which releases protective substances such as nitric oxide and prostacyclin, both of which reduce the risk of thrombosis.
Endothelial dysfunction occurs predominantly at sites of low shear stress, where the blood flow might be reduced or turbulent. This can lead to damage to endothelial cells and in turn can initiate inflammation and blood clotting. In regions of the vasculature that are exposed to shear stresses, where the blood flow is laminar or steady, are protected4.
With blood clotting established as a major contributor to Covid-19 multiple organ failure, anticoagulation (drugs that prevent clotting) is critical and drug prophylaxis is the primary intervention, especially for immobile ICU patients on ventilators. It is important to note that similar increases in thrombotic risk were seen with H1N1m influenza (swine flu). The phenomenon is therefore not new, but has not been seen before on this scale5.
Covid patients at high risk of VTE can have bleeding issues related to the virus or have an unacceptable bleed risk history and, for these patients, drug prophylaxis can cause further bleeding. In these instances, clinicians rely on mechanical compression prophylaxis, using either Intermittent Pneumatic Compression (IPC) or more recently the geko™ device to prevent VTE and minimise the risk of bleeding with or without drug prophylaxis. The geko™ device is also clinically proven to produce physiologically normal shear stress on endothelial cells, increasing the production and the release of anti-thrombotic, pro-fibrinolytic, vasodilation agents to help prevent clots6.
The geko™ device represents a unique alternative to IPC prophylaxis. IPC devices enclose the leg in a plastic cuff filled with air from an electric pump. The cuff repeatedly inflates and deflates, moving blood through the veins towards the heart. The blood flow increase helps prevent the blood clot formation. While IPC devices do not cause the same bleed complications as drug therapy, IPC is not suitable for all patients, due to fragile skin, a recent wound, leg ulcer or allergy to cuff materials. The electronic pump is also moved between patients, requiring decontamination – a potential source of virus transmission if not sterilised fully.
Conversely, the daily disposable geko™ device – the size of a wristwatch and discarded after patient use – is a single-use therapy that takes just 60 seconds to fit to one or both legs, ensuring less nurse-to-patient contact time, less exposure to viral load and with no cross-contamination risk. Its small size also ensures greater compliance for patients with fragile skin or cardiovascular-related contraindications.
The device has been in use for over three years for blood clot prevention in immobile, high-risk acute stroke patients, with over 700,000 individual units sold to date. This is alongside 4,700 pairs of devices purchased by the NHS supply chain for use in the London Nightingale Hospital at the peak of the crisis.
The gekoTM device and its mechanism of action
The innovative geko™ device is clinically proven to prevent blood clots and improve endothelial function. Recommended by NICE7 and cleared by the FDA8 for blood clot prevention, the geko™ device is a small battery-powered, disposable, neuromuscular electro-stimulation device that is applied non-invasively to the skin over the common peroneal nerve at the side of the knee. It gently stimulates the nerve, once every second, activating the calf and foot muscle pumps resulting in increased laminar blood flow in the deep veins of the calf, at a rate equal to 60 per cent9 of walking. This exerts systemic protective shear stress on the endothelium in immobile, critically ill Covid-19 patients, without a patient having to move. All other mechanical IPC devices increase blood flow only once every minute.
Prior to the pandemic, the geko™ device has been in routine use to treat and prevent a range of vascular and orthopaedic-related conditions. Sky Medical Technology has proven10, through a real-world study of over 1,000 patients, conducted in partnership with the NHS, that the geko™ device can prevent VTE. Immobile hyper-acute stroke patients had their contraindication or intolerance to IPC reviewed and quantified. The study showed that 68.8 per cent of patients were in need of IPC but 29.5 per cent of these patients were either contraindicated or were unable to tolerate this intervention, revealing a significant unmet need for an alternative anti-stasis intervention. It is to this cohort the geko™ device was fitted for unmet need.
The study measured VTE events at 90 days post-stroke. The data shows that of the patients treated with IPC alone, as the standard of care, 2.4 per cent suffered a VTE event, compared to a 0 per cent incidence of VTE in patients prescribed the geko™ device alone. Patients prescribed the device also showed no adverse events and reported a greater tolerance of the geko™ device compared to IPC. Furthermore, the geko™ device provided an anti-stasis intervention, where previously patients would have had no other intervention available to them – as drugs following acute stroke are not recommended by NICE – ensuring that no immobile stroke patient, with a high risk of VTE, was without a mechanical VTE prophylactic intervention.
NICE guidance health economic analysis also shows that the geko™ device is cost saving compared with the cost consequence of no VTE prophylaxis.
Studies exploring the anti-stasis and endothelial function capabilities of the geko™ device in hospitalised Covid-19 patients are being progressed and Sky Medical Technology is actively seeking wider clinician engagement to collaboratively explore blood flow increase as part of Covid-19 treatment strategies.
The pandemic is without doubt the public health challenge of our time. The scale of the problem is unprecedented but is more than matched by the scale of the response and a spirit of partnership that is willing to embrace innovation – this brave new thinking is defining the new normal.
1. Xu, et al, Risk assessment of venous thromboembolism and bleeding in Covid-19 patients.
2. Zhang L, et al. Deep Vein Thrombosis in Hospitalized Patients with Coronavirus Disease 2019. (COVID-19) in Wuhan, China: Prevalence, Risk Factors, and Outcome. Published in Circulation, ahead of print. 18 May 2020.
3. Jeng-Jiann Chiu, et al. Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives. Physiol Rev. 2011 Jan: 91 (1): 10.1152/physrev.00047.2009.
4. Aamer S, et al. The Endothelium and Its Role in Regulating Vascular Tone. Open Cardiovasc Med J. 2010; 4: 302–312. Published online 23 December 2010doi: 2174/1874192401004010302.
5. Increased risk of VTE found in critically ill H1N1 patients with acute respiratory distress. Venous news. 31 May 2019.
6. Lavi S, et al. Peripheral muscle stimulation increases coronary blood flow. Springer 23 November 2015.
7. NICE medical technologies guidance [MTG19] Published date 20 June 2014.
8. FDA clearance. Data on file Firstkind Ltd.
9. Tucker A, et al. Augmentation of venous, arterial and microvascular blood supply in the leg by isometric neuromuscular stimulation via the peroneal nerve. The International Journal of Angiology: official publication of the International College of Angiology, Inc. 2010 Spring;19(1): e31-7.
10. Williams J, et al. The use of the geko™ device and the activation of the foot and calf pumps for prevention of venous thromboembolism in patients with acute stroke. Data on file Firstkind Ltd.