3D illustration of a thrombus. Credit: Mecder, CC BY-SA 4.0, via Wikimedia Commons
There is an increased risk of developing deep vein thrombosis (DVT) for six months after a COVID, a study published in the BMJ suggests, as well as increased risk of pulmonary embolism and bleeding for shorter periods. The risk was particularly evelated for those with severe COVID as well as those infected during the first wave.
This highlights the importance of COVID vaccination, the researchers said. While there has been concern over the risk of blood clots after vaccination, the risk is far smaller, according to a large study last year.
It had previously been observed that people who had COVID had an increased risk of blood clots, and the researchers wanted to find out when that risk returns to normal levels.
The researchers tracked the health of just over one million people in Sweden who tested positive for COVID between February 2020 and May 2021 in Sweden, comparing them against four million people age- and sex-matched non-infected individuals.
Adjusting for confounding factors such as comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event, the researchers found an increased risk of:
first DVT, for up to three months
first pulmonary embolism, for up to six months
first bleeding event, such as a stroke, for up to two months
Comparing blood clot risk after COVID to the normal level of risk, the results showed that:
four in every 10 000 COVID patients developed DVT compared with one in every 10 000 non-infected individuals
about 17 in every 10,000 COVID patients had a blood clot in the lung compared with fewer than one in every 10,000 non-infected individuals
The authors wrote that the increased risk of blood clots was higher in the first wave than later waves, probably because treatments improved during the pandemic and older patients were starting to be vaccinated by the second wave.
Pulmonary embolism risk in people with severe COVID was 290 times greater than normal, and seven times higher than normal after mild COVID. However, there was no increase in bleeding risk in mild cases.
“For unvaccinated individuals, that’s a really good reason to get a vaccine – the risk is so much higher than the risk from vaccines,” said principal study investigator Anne-Marie Fors Connolly, from Umea University in Sweden. While COVID’s causing the blood clots cannot be proven in this study, the researchers have a number of theories on the mechanism. It could be the direct effect of the virus on the layer of cells which line blood vessels, an exaggerated inflammatory response to the virus, or the body making blood clots at inappropriate times.
Though vaccines are very effective against severe COVID, but less so against infection, especially with the Omicron variant. This means repeat symptomatic infections are commonplace.
Researchers looking for new anti-clotting drugs have discovered a unique class of medications that act as blood thinners by inhibiting an enzyme in the genes of tick saliva.
The study, published in Nature Communications, focused on novel direct thrombin inhibitors (DTI) from tick salivary transcriptomes, or messenger RNA molecules expressed by an organism. As a result of the research, there are now new anticoagulant medications that can be developed for the treatment of patients with a variety of coronary issues, including heart attacks.
“Interest in ticks as a model for developing drugs that prevent blood clotting – [often] the cause of heart attacks and strokes – is firmly rooted in evolutionary biology,” said Professor Richard Becker, a co-author of the study.
“Analysis of backbone structures suggest a novel evolutionary pathway by which different blood clot inhibiting properties evolved through a series of gene duplication events. Comparison of naturally occurring blood clot inhibitors of differing tick species suggests an evolutionary divergence approximately 100 million years ago.”
Prof Becker and his international colleagues discovered DTIs from tick salivary transcriptomes and optimised their use as a pharmaceutical. The most potent is a key regulating enzyme in blood clot formation with very high specificity and binding capacity that is almost 500 times that of bivalirudin, a drug used during a typical nonsurgical procedure used to treat narrowing of the coronary arteries. Those minimally invasive procedures are performed in roughly 1 million persons yearly in the United States.
“Despite their greater ability to reduce the incidence of the formation of blood clots, the drugs demonstrated less bleeding, achieving a wider therapeutic index in nonhuman models,” Becker says. “The higher potency of the drug means it’s not necessary to use a lot of it in treating patients, which holds the cost of goods and manufacturing down.”
According to Prof Becker, tick saliva, as in other blood-feeding such as mosquitoes, contains pharmacological and immunological active compounds, which modulate immune responses and induce antibody production. This research leveraged an understanding of tick-host interactions and antibody formation.
“The holy grail of anticoagulant therapy has always been specificity, selectivity, efficacy and safety,” said Prof Becker. “Clinician-scientists must have the training and an environment that embraces asking questions and finding solutions, including those potential found deep within nature. An ability to both measure and adjust the drug dose and rapidly reverse its effects is particularly important for safety purposes. The next step is to complete pharmacology, toxicology, drug stability and other important regulatory steps before conducting clinical trials in humans.”
COVID patients in intensive care units (ICU) receiving full-dose anticoagulants are significantly more likely to experience heavy bleeding than patients prescribed a smaller yet equally effective dose, according to a recent study.
The research, which compared the safety and effectiveness of blood clot treatment strategies for more than 150 critically ill COVID patients at two hospitals, found that almost all patients who experienced significant bleeding were on mechanically ventilation and receiving full-dose anticoagulants.
The results, published last month in Hospital Pharmacy, may inform treatment guidelines for blood clots in hospitalised COVID patients, who are at an increased risk for both blood clots and severe bleeding. Previous reports have found that 17% of hospitalised COVID patients experience blood clots, said first author Maya Chilbert, PharmD, clinical assistant professor in the UB School of Pharmacy and Pharmaceutical Sciences.
“A wide variety of practice exists when it comes to approaching blood clots in hospitalized patients with COVID, and there is little data to suggest improved outcomes using one strategy versus another,” said Chilbert. “Caution should be used in mechanically ventilated patients with COVID when selecting a regimen to treat blood clots, and the decision to use full-dose blood thinners should be based on a compelling indication rather than lab markers alone.”
The study analysed the outcome of blood clot treatments and the rate of bleeding events for more than 150 patients with COVID-19 who received either of two blood thinner regimens: a full-dose based on patient levels of D-dimer, and the other a smaller but higher-than-standard dosage.
Patients’ average age was 58, and all experienced elevated levels of D-dimer, fibrinogen, and prothrombin time.
Significant bleeding events were experienced by almost 14% of patients receiving full-dose anticoagulants, compared to only 3% of patients who received a higher-than-standard dosage. All patients who experienced bleeding events were on mechanical ventilation. No difference was reported in the regimens’ effectiveness at treating blood clots. Further investigation is needed to determine the optimal strategy for treating blood clots and bleeding in hospitalised COVID patients, said Asst Prof Chilbert.
A cloud of platelet factor 4 proteins interacting with the electrostatic surface of the Oxford vaccine, as seen through the computational microscope. Credit: Chun Kit Chan, Arizona State University
An international team of scientists believe they may have found a molecular mechanism behind the extremely rare blood clots linked to adenovirus vaccines.
Scientists led by a team from Arizona State University, Cardiff University and others worked with AstraZeneca to investigate vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS), a life-threatening condition seen in a very small number of people after receiving the Oxford-AstraZeneca or Johnson & Johnson vaccines.
“The mechanism which results in this condition, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), was unknown,” said Abhishek Singharoy, an Arizona State University scientist and corresponding author of the study who teamed up to lead an international effort to tease out the details.
Together, the team worked to solve the structural biology of the vaccine, and see the molecular details that may be at play, utilising state-of-the cryo-EM technology to analyse the AstraZeneca vaccine in minute detail. They sought to understand whether the ultra-rare side effect could be linked to the viral vector which is used in many vaccines, including those from Oxford/AstraZeneca and Johnson & Johnson.
Their findings suggest it is the viral vector – in this case, an adenovirus used to shuttle the coronavirus’ genetic material into cells – and the way it binds to platelet factor 4 (PF4) once injected that could be the potential mechanism.
In very rare cases, the scientists suggest, the viral vector may enter the bloodstream and bind to PF4, where the immune system then views this complex as foreign. They believe this misplaced immunity could result in the release of antibodies against PF4, which bind to and activate platelets, leading to clustering and blood clotting.
“It’s really critical to fully investigate the vector-host interactions of the vaccine at a mechanistic level,” said Singharoy. “This will assist in understanding both how the vaccine generates immunity, and how it may lead to any rare adverse events, such as VITT.”
Adenovirus expert Professor Alan Parker said: “VITT only happens in extremely rare cases because a chain of complex events needs to take place to trigger this ultra-rare side effect. Our data confirms PF4 can bind to adenoviruses, an important step in unravelling the mechanism underlying VITT. Establishing a mechanism could help to prevent and treat this disorder.”
“We hope our findings can be used to better understand the rare side effects of these new vaccines – and potentially to design new and improved vaccines to turn the tide on this global pandemic.”
The AstraZeneca and Johnson & Johnson vaccines both use an adenovirus to carry SARS-CoV-2 Spike proteins to trigger an immune response.
Since VITT was seen in both vaccines, scientists wondered whether the viral vector was involved. Additionally, neither the Moderna nor Pfizer vaccines, both mRNA vaccines, showed this effect.
Using cryo-EM technology to flash-freeze preparations of ChAdOx1, the adenovirus used in the AstraZeneca vaccine, they produce microscopic images of the vaccine components.
They were then able to view the viral capsid structure and other critical proteins that allow entry of the virus into the cell.
In particular, the team outlined the details for the structure and receptor of ChAdOx1, which is adapted from chimpanzee adenovirus Y25 – and how it interacts with PF4. They believe it is this specific interaction – and how it is then presented to the immune system – that could cuase the immune system to see it as foreign and release antibodies against this self-protein.
The research team also used computational models to show that one of the ways the two molecules tightly bind is via electrostatic interactions. The group showed that ChAdOx1 is mostly electronegative, attracting other positively charged molecules to its surface.
First author Dr Alexander Baker said: “We found that ChAdOx1 has a strong negative charge. This means the viral vector can act like a magnet and attract proteins with the opposite, positive charge, like PF4.” Baker is a member of ASU’s Biodesign Center for Applied Structural Discovery and an Honorary Research Fellow at Cardiff University School of Medicine.
“We then found that PF4 is just the right size and shape that when it gets close to ChAdOx1 it could bind in between the negatively charged parts of ChAdOx1’s surface, called hexons.”
The research team are hopeful that armed with a better understanding of what may be causing rare VITT they can provide further insights into how vaccines and other therapies, which rely on the same technology, might be altered in the development of the next generation vaccines and therapies.
“With a better understanding of the mechanism by which PF4 and adenoviruses interact there is an opportunity to engineer the shell of the vaccine, the capsid, to prevent this interaction with PF4. Modifying ChAdOx1 to reduce the negative charge may reduce the chance of causing thrombosis with thrombocytopenia syndrome,” said Baker.
The team likened it to the ‘two birds, one stone’ effect. The key contacts of individual amino acids that are essential to the capsid protein’s proteins interaction with PF4 can removed or substituted.
“The modification of the ChAdOx1 hexons to reduce their electronegativity may solve two problems simultaneously: reduce the propensity to cause VITT to even lower levels, and reduce the levels of pre-existing immunity, thus helping to maximize the opportunity to induce robust immune responses, said Singharoy.”
Researchers at Stellenbosch University had discovered that an overload of inflammatory molecules, literally ‘trapped’ inside insoluble microscopic blood clots, might be behind some Long COVID symptoms.
From almost the beginning of the pandemic, blood clots have been reported in COVID patients in various organs besides the lungs.
Prof Resia Pretorius, a researcher at Stellenbosch University (SU), made this finding when she began examining micro clots and their molecular content in blood samples from individuals with Long COVID. The findings were reported in Cardiovascular Diabetology.
“We found high levels of various inflammatory molecules trapped in micro clots present in the blood of individuals with Long COVID. Some of the trapped molecules contain clotting proteins such as fibrinogen, as well as alpha(2)-antiplasmin,” Prof Pretorius explains.
Alpha(2)-antiplasmin prevents blood clot breakdown, while fibrinogen is the main clotting protein. Normally, the body’s plasmin-antiplasmin system maintains a fine balance between blood clotting and fibrinolysis.
With high levels of alpha(2)-antiplasmin in the blood of COVID patients and individuals suffering from Long COVID, the body’s ability to break down blood clots is inhibited.
Dr Maré Vlok, a senior analyst in the Mass Spectrometry Unit, noticed that the blood plasma samples from individuals with acute COVID and Long COVID continued to deposit insoluble pellets at the bottom of the tubes after dilution (a process called trypsinisation).
He alerted Prof Pretorius to this, which she then investigated further, using fluorescence microscopy and proteomics analysis. This marks the first reported detection micro clots in blood samples from those with Long COVID. “Of particular interest is the simultaneous presence of persistent anomalous micro clots and a pathological fibrinolytic system,” they wrote. This implies that the plasmin and antiplasmin balance may be central to pathologies in Long COVID, and provides further evidence that COVID, and now Long COVID, have significant cardiovascular and clotting pathologies.
Further research is recommended into a regime of therapies to support clotting and fibrinolytic system function in individuals with lingering Long COVID symptoms.
Working with vascular internist and article co-author, Dr Jaco Laubscher from Mediclinic Stellenbosch, they now plan to perform the same analysis on a larger sample of patients.
A new study found the use of e-cigarettes containing nicotine has a number of immediate effects, which include increased blood clot formation, blood vessel dysfunction, as well as raised heart rate and blood pressure.
These effects are similar to smoking traditional cigarettes with heart attack or stroke risk with long-term use, according to researchers. The study was presented at the ERS International Congress by Gustaf Lyytinen, a clinician at Helsingborg Hospital and researcher at the Karolinska Institute in Stockholm, Sweden.
Each of the 22 occasional smoker volunteers was tested before and after taking 30 puffs from an e-cigarette with nicotine, and before and after 30 puffs from an e-cigarette without nicotine. These two sets of tests were conducted on separate occasions, at least one week apart.
On each occasion, the researchers measured volunteers’ heart rate and blood pressure and took a blood sample before they used the e-cigarettes, then 15 minutes after use and again 60 minutes after use. A laser was used to measure dilation of skin blood vessels before volunteers used e-cigarettes and 30 minutes afterwards. E-cigarettes with nicotine caused an immediate short-term change: a 23% average increase in blood clots after 15 minutes, that returned to normal levels after 60 minutes. Average heart rates also increased from 66bpm to 73bpm. as did blood pressure from 108mmHg to 117mmHg. Researchers observed temporary narrowing of blood vessels after nicotine-containing e-cigarettes use.
These effects were not observed after volunteers used e-cigarettes without nicotine. Nicotine is known to raise levels of hormones including adrenaline, which can increase blood clot formation.
Dr Lyytinen said: “Our results suggest that using e-cigarettes that contain nicotine have similar impacts on the body as smoking traditional cigarettes. This effect on blood clots is important because we know that in the long-term this can lead to clogged up and narrower blood vessels, and that of course puts people at risk of heart attacks and strokes.”
A UK study has furthered the understanding of the novel blood-clotting condition associated with the Oxford/AstraZeneca vaccine.
Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is characterised by a blockage of veins and a marked platelet reduction. The rare condition was first identified in the UK by Professor Marie Scully (University College of London Institute of Cardiovascular Science), also a Consultant Haematologist at UCLH, and Dr Will Lester from University Hospitals Birmingham NHS Foundation Trust.
In a paper published in the New England Journal of Medicine (NEJM), the first 220 cases of definite and probable VITT in the UK are detailed.
The cases were presented by 182 consultant haematologists, and builds on understanding about the condition outlined in an April 2021 NEJMpaper led by Professor Scully.
Meanwhile, a study led by Dr Richard Perry (UCL Queen Square Institute of Neurology and UCLH) published in the Lancetearlier this month provided the most detailed observations so far of cases of cerebral venous thrombosis (CVT). one of the commonest and severest manifestations of VITT.
The overall mortality rate of those presenting to hospitals with definite or probable VITT was 23%, the paper reported. The condition almost entirely manifested between five and 30 days after their first vaccination, with no sex differences seen, and no predisposing prior medical conditions.
The chances of death increased significantly the lower the platelet count and the greater the activation of the blood clotting system, increasing to 73% in patients with a very low platelet count and intracranial haemorrhage following blood clots in the brain.
Overall, 41% of patients had no previous medical diagnoses and 85% were less than 60 years old. Overall incidence in individuals under 50 was estimated to be 1 in 50 000 – in line with reports from other countries.
Though optimal treatment was still uncertain, it was being continually refined in real time, the researchers wrote. For instance, the introduction of the use of plasma exchange in the most severe cases has led to survival rates that were significantly better than would be predicted based on baseline characteristics.
The research adds to evidence for use of non-heparin-based blood thinners to tackle blood clotting in cases of VITT, and that use of intravenous immunoglobin was associated with better outcomes.
Professor Scully said: “As a new condition we are still learning about how best to diagnose and manage VITT, but as time goes on, we have been able to refine our treatment approaches and improve rates of survival and chance of recovery. This continuous learning in real time has been made possible thanks to collaboration between colleagues across the UK.”
Lead author Dr Sue Pavord, at Oxford University Hospitals NHS Foundation Trust, said: “We have worked relentlessly to understand and manage this new condition, so that the hugely successful vaccine roll out can continue, which is the most viable solution to the global pandemic.”
Monroe Carell Jr Children’s Hospital at Vanderbilt has launched a study to test out a predictive model for identifying paediatric patients at risk for developing blood clots or venous thromboembolisms.
The study examined the use of advanced predictive analytics to predict the development of blood clots in paediatric patients at risk for them.
“Hospital-associated blood clots are an increasing cause of morbidity in paediatrics,” said the study’s principal investigator, Shannon Walker, MD, clinical fellow of Paediatric Haematology-Oncology at Children’s Hospital.
Though they are rarer events in children than in adults, morbidity and mortality is higher and Dr Walker nevertheless noticed that blood clot development in children was on the rise.
“The reason children get blood clots is very different from adults,” said Dr Walker. “There was no standardised protocol for preventing clots in paediatric patients. As we noticed that the rate of blood clots was going up and recognised that the adult strategy wasn’t going to work for our patients, we wanted to look at each patient’s individual risk factors and see how we could focus our attention on targeted blood clot prevention.”
The study, which will be published in Pediatrics, describes how the team built and validated a predictive model that can be automated to run within the electronic health record of each patient admitted to the hospital.
The model includes 11 risk factors and was based on an analysis of more than 110 000 admissions to Children’s Hospital and has been validated on more than 44 000 separate admissions.
Currently the team is studying using this model along with targeted intervention in the clinical setting in a trial called “Children’s Likelihood of Thrombosis,” or CLOT.
The prediction model follows this procedure: every child admitted to the hospital has a risk score calculated. The patients are randomised, so in half of the patients, elevated scores are reviewed by a hematologist, and then discussed with each patient’s medical team and family to determine a personalised prevention plan. All patients, regardless of their assigned group, continue to receive the current standard of care.
“We are not utilising a one-size-fits-all plan,” said Walker. “This is an extra level of review allowing for a very personalized recommendation for each patient with an elevated score. Each day the score is updated, so as risk factors change, the scores change accordingly.
“We are, in real-time, assessing the use of this model as a clinical support tool. We saw a clinical opportunity of something we could improve and have moved forward with building the model—to identify high-risk patients and are currently performing the CLOT trial, which will run through the end of the year.”
The Advanced Vanderbilt Artificial Intelligence Laboratory (AVAIL) was instrumental in Walker’s study. Only in its second year, the programme is leading the way in supporting artificial intelligence tools at Vanderbilt University through project incubation and curation, including facilitating clinical trials to assess their effectiveness.
“AVAIL served as a catalyst, in this instance by bringing experts in a complex trial development into proximity so that a great synthesis could happen,” said Warren Sandberg, MD, PhD, who is executive sponsor of AVAIL, along with Kevin Johnson, MD.
“What is unique about this particular project is that we were not only able to predict complications but also able to test the model in a rigorous, pragmatic, randomized, controlled trial to see if it benefits patients,” said Dan Byrne, senior biostatistician for the project and director of artificial intelligence research for AVAIL.
“The future of this kind of work is unlimited,” he said. “We can hopefully use this approach to predict and prevent pressure injuries, sepsis, falls, readmissions or most any complication before they happen. At Vanderbilt, we are raising the bar when it comes to the science of personalised medicine and application of artificial intelligence in medicine in a way that is both ethical and safe.”
A new study into rare cases of blood clots in the brain with low platelets seen in some patients after vaccination has been published in the New England Journal of Medicine.
The research team behind the study were the first clinicians in the UK to spot the link between the Oxford/AstraZeneca vaccine and rare cases of blood clotting along with a low platelet count, before identifying the correct diagnostic test for the syndrome. They recommended the treatment approach which avoids the use of heparin, an anticoagulant typically used to treat normal blood clots.
The researchers detailed the cases of 23 patients, who all presented with thrombosis and thrombocytopenia after receiving the AstraZeneca vaccine, and none of whom had underlying conditions which would predispose them to blood clots.
The presence of the PF4 antibody (platelet factor 4) was detected in almost all cases (21 out of 23). In rare instances, these antibodies are triggered by the blood-thinning drug heparin, a syndrome known as heparin-induced thrombocytopenia (HIT). However, HIT was ruled out because none of the patients in this study received heparin.
The investigators therefore concluded that they were seeing a heparin-independent PF4-dependent syndrome in the setting of the AstraZeneca vaccine. They cautioned that this syndrome needs to be identified quickly if present, because its treatment is very different to that of blood clots with low platelet counts.
Co-author Professor Tom Solomon commented: “Although it is a very rare side effect, this issue of clots in the brain and elsewhere combined with blood abnormalities following COVID-19 immunization is extremely important. It is critical we understand the disease mechanisms so we can provide the best treatment for patients. Here at the University we are part of a national program collecting information on such patients.”
The researchers stressed that vaccination is still the key means to end the pandemic, and everyone should continue to receive a vaccine when offered one.
Journal information: Marie Scully et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2105385
A large meta-analysis upheld the safety of tranexamic acid (TXA), even at higher doses.
TXA is an antifibrinolytic agent with a short half-life that is used for bleeding prevention and treatment, as in causes of trauma with open wounds. Current TXA is applied with caution due to perceived increased risk of seizures, MI, and other thrombotic complications.
The meta-analysis looked at 216 randomised trials involving 125 550 participants. The investigators found that the incidence of thromboembolic events, which included venous thrombosis, pulmonary embolism, venous thromboembolism, myocardial infarction (MI) or ischaemia, and cerebral infarction or ischaemia, was 2.1% of people receiving IV TXA and a similar 2.0% of peers getting placebo or another control, which was a non-significant difference.
TXA’s safety was inconclusive in those with neurological conditions, who showed increased heterogeneity and asymmetry in funnel plots, according to Patrick Meybohm, MD, of University Hospital Wuerzburg in Germany, and colleagues.
The review confirmed that TXA was linked to a significant reduction in overall mortality and bleeding mortality, but not nonbleeding mortality.
“The results of this study suggest that use of intravenous TXA may have utility in all medical fields, with some uncertainty for patients with neurological conditions,” the investigators concluded.
“Notably, we did not detect any dose-dependent association of TEs [thromboembolic events],” they stated. The included studies had participants with IV TXA administration at doses ranging 0.5-5g or 10-100mg/kg.
“There is little doubt that when used appropriately in the various patient populations evaluated with randomized clinical trials, TXA is effective. However, reasonable questions about thrombotic complications remain,” wrote John Holcomb, MD, of University of Alabama at Birmingham, and colleagues, in an invited commentary.
“Further research must focus on how to identify, as early as possible, the patients most likely to benefit from administration of TXA,” they urged.
One limitation mentioned by the investigators was the inclusion trials that evaluated thromboembolic events without ultrasound, so asymptomatic cases may have been excluded. Furthermore, many studies did not provide much information on thrombosis prophylaxis.
For Holcomb’s group, study’s main caveat was that it included “a notably heterogeneous population”, including a range of demographics and clinical conditions. Since the pooled studies were not “clinically homogeneous”, they violated “one of the cardinal tenets of systematic reviews and meta-analyses.”
Journal information (primary article): Taeuber I, et al “Association of intravenous tranexamic acid with thromboembolic events and mortality: a systematic review, meta-analysis, and meta-regression” JAMA Surg 2021; DOI: 10.1001/jamasurg.2021.0884.
Journal information (commentary): Holcomb JB, et al “Tranexamic acid and safety in the right patient” JAMA Surg 2021; DOI: 10.1001/jamasurg.2021.0929.
