Tag: 15/9/22

Categories : COVIDTags : Leave a comment

More Evidence Linking Blood Clotting and COVID Severity

On By ModernMedia
Source: CC0

New research shows that the Omicron variants cause significantly lower levels of blood clotting, thereby providing further evidence for the link between the severity of the disease and the prevalence of persistent micro blood clots in individuals with acute and Long COVID.

Prof Resia Pretorius, a researcher in the Department of Physiological Sciences at Stellenbosch University (SU), South Africa, first made this connection late in 2020 when she detected small amyloid-like blood clots in the plasma of individuals suffering from COVID. Amyloids are a type of protein associated with various inflammatory diseases. As part of a long-term collaboration with Prof Douglas Kell from the University of Liverpool, they showed that these micro clots contained pro-inflammatory molecules. The results of both studies were published in the journal Cardiovascular Diabetology, in 2020 and 2021.  

These insoluble micro clots inhibit or may temporarily block blood flow to capillaries and hence impair oxygen transfer to tissues. At present, they believe that this oxygen impairment in various parts of the body can account for most of the symptoms of Long COVID, such as constant fatigue, shortness of breath, brain fog, joint and muscle pain.

Prof Resia Pretorius

Prof Pretorius said the persistent prevalence of micro clots may have significant clinical value: “Our findings suggest that hypercoagulation and vascular damage are key role players causing the wide range of symptoms we see in patients with Long COVID. There is a golden thread running through pathologies noted in post-viral syndromes such as Long COVID.”

More recently, Prof Pretorius and Prof Kell worked with a team of clinicians in South Africa and the United States, to ascertain whether the difference in the degree of clotting between different viral strains of the SARS-CoV-2 virus provides a plausible explanation for the relatively low severity of the Omicron variants during acute COVID infection.

While the earlier variants caused severe disease and critically ill patients, the heavily mutated Omicron variants have been shown to have milder symptoms, most commonly a runny nose, rhinitis headaches, fatigue (from mild to severe), sneezing and a sore throat.

For the purposes of the study, they revisited data and blood samples from stored blood samples from ten patients with COVID due to the Beta and Delta variants between October 2020 and September 2021 before the patients received treatment.

The team also collected blood from patients infected with the Omicron variants. In all ten samples it was found that the Omicron samples presented with a significantly lower total amount of microclots compared to earlier Beta and Delta variants.  

In a recent webinar on the topic, Dr Mark Walsh, an emergency medicine physician at the Saint Joseph Regional Medical Center in the United States of America, said the foundational work of Profs Pretorius and Kell has helped them to explain the clotting complications of COVID-induced coagulopathies (CAC) of patients with acute COVID. He is also one of the co-authors on the article.

“We could not understand why patients with CAC would clot and bleed at the same time. We now have the pathophysiological foundation for a point-of-care bedside medicine approach, based on the foundations of excellent research,” he said.

Early in the pandemic, Dr Walsh and his team of emergency physicians in the USA, developed a protocol to provide safe anticoagulation treatment to severely ill COVID patients. The team was guided by thromboelastography, a point-of-care protocol to monitor bleeding and clotting.

According to Prof Kell, more importantly, the findings are consistent with the view that these insoluble micro clots are not a side-effect of COVID-19, but a part of how the disease develops. However, he warned, we do not yet know how this will impact or relate to other post-viral syndromes such as Long-COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-Zika or post-Dengue diseases.

The paper, titled “Relative hypercoagulopathy of the SARS-CoV-2, Beta and Delta variants when compared with the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness” is in press in the journal Seminars in Thrombosis and Hemostasis, and a preprint is available at https://www.researchsquare.com/article/rs-1970823/v1

The webinar, “COVID-induced Coagulopathy (CAC): The clot thickens…or not?” is presented by Dr Mark Walsh, Prof Resia Pretorius and Prof Douglas Kell, and moderated by Dr Asad Khan. It is available at https://youtu.be/yyf7xunWydM

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A Practice-changing Treatment for Refractory Metastatic Colon Cancer

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Colon cancer cells
Colon cancer cells. Source: National Cancer Institute on Unsplash

In a phase III clinical trial, fruquintinib achieved improved overall survival (OS) in refractory metastatic colon cancer (mCRC) compared to best supportive care (BSC) alone, according to a randomised trial reported at the European Society for Medical Oncology (ESMO) annual congress.

BSC plus fruquintinib improved median OS to 7.4 months compared to 4.8 months with BSC plus placebo.

Patients with mCRC have few treatment options and a poor prognosis. Regorafenib is currently the only tyrosine kinase inhibitor (TKI) with an indication for mCRC.

The heavily treated patient population had received a median of five prior therapies, including regorafenib in about half of cases, N. Arvind Dasari, MD, of the University of Texas MD Anderson Cancer Center in Houston, presenting the results.

“These results are both clinically and statistically significant and consistent across all prespecified subgroups,” said Dr Dasari. “Fruquintinib was also well tolerated and consistent with a prior established safety profile. Overall, these results are consistent with [a prior trial conducted in China] and support a new practice-changing global oral treatment option for patients with metastatic colorectal cancer, enriching the treatment continuum for these patients.”

Dr Dasari noted that the VEGF pathway is a key mediator of angiogenesis, and fruquintinib is a selective and potent inhibitor of VEGF receptors 1, 2, and 3. In the phase III FRESCO trial conducted in China, fruquintinib resulted in statistically significant improvement in OS and progression-free survival (PFS), and received an approved indication for mCRC in fourth line and beyond.

Dr Dasari reported findings from the FRESCO-2 trial, which was designed to evaluate fruquintinib in a more diverse, multiregional patient population. Investigators enrolled patients with mCRC and a treatment history that included chemotherapy, anti-VEGF therapy, and anti-EGFR therapy. Patients with progression or intolerance to TAS-102, and regorafenib were eligible, as well as patients previously treated with an immune checkpoint inhibitor or a BRAF inhibitor.

Patients randomised 2:1 to BSC plus either fruquintinib or placebo. Treatment continued until disease progression or development of unacceptable toxicity.

The primary endpoint was OS, and the principal statistical assumption was that the control arm would have a median OS of 5.0 months, which would be improved to 6.8 months with fruquintinib.

The trial had 691 patients with a median follow-up of 11.2 months. Almost all of the patients had prior exposure to a VEGF inhibitor, about 40% had received an EGFR inhibitor, about 60% had received TAS-102 or regorafenib, and about 40% had received both. Dr Dasari said the patient population resembled the patients that clinicians see in clinical practice.

The primary analysis showed a 2.6-month improvement in median OS with fruquintinib, which translated into a survival hazard of 0.662.

Treatment with fruquintinib more than doubled the median PFS, from 1.8 months with placebo to 3.7 months, a 68% reduction in the hazard ratio. Seven patients in the fruquintinib arm had objective responses versus none in the placebo arm. The clinical benefit rate (response plus stable disease) was 55.5% with fruquintinib and 16.1% with placebo.

Grade ≥3 treatment-related adverse events occurred in 36.0% of the treatment arm and 11.3% of the placebo arm.

FRESCO-2 was not designed as a head-to-head comparison with regorafenib and was instead designed to validate fruquintinib for mCRC, said ESMO invited discussant Filippo Pietrantonio, MD, of the National Cancer Institute in Milan, Italy. The primary endpoint would have been noninferiority or equivalence. Even so, the trial set a high bar, as almost half the patients were 65 or older, had received multiple prior lines of therapy, and there were limitations on the proportion of patients with prior regorafenib treatment.

“Despite the challenges, FRESCO-2 is a positive trial, so fruquintinib may be a new standard-of-care option in patients with refractory metastatic colorectal cancer,” said Dr Pietrantonio. “This agent significantly prolonged overall survival and progression-free survival independently from prior treatment.”

“Sustained inhibition of angiogenesis is still important in later treatment lines, and fruquintinib provided an additional incremental gain of survival,” he added. “Real world and phase IV data are necessary to further assess the safety of fruquintinib, especially in underrepresented populations, and quality-of-life data are necessary as well.”

Source: MedPage Today

Categories : Injury & Trauma PaediatricsTags : Leave a comment

Behavioural Problems in Kids after Traumatic Brain Injuries

On By ModernMedia
Boy hanging from tree
Photo by Annie Spratt on Pexels

Kids who experience a traumatic brain injury (TBI), even a mild one, have more emotional and behavioural problems than kids who do not, according to a study published in NeuroImage.

“These hits to the head are hard to study because much of it depends on recall of an injury since the impacts do not all require a visit to a doctor,” said study first author Daniel Lopez, a PhD candidate at Del Monte Institute for Neuroscience. “But being able to analyse longitudinal data from a large cohort and ask important questions like this gives us valuable information into how a TBI, even a mild one, impacts a developing brain.”

Researchers used MRI and behavioural data collected from thousands of children who participated in the Adolescence Brain Cognitive Development (ABCD) Study. They revealed children with a mild TBI experienced a 15-percent increased risk of an emotional or behavioural problem. The risk was the highest in children around ten years old. Researchers found that children who had a significant hit to the head but did not meet diagnostic criteria for a mild TBI also had an increased risk of these behavioural and emotional problems.

The University of Rochester Medical Center is one of 21 research sites collecting data for the National Institutes of Health ABCD Study. Since 2017, 340 children have been part of the 10-year study that is following 11 750 children through early adulthood. It looks at how biological development, behaviours, and experiences impact brain maturation and other aspects of their lives, including academic achievement, social development, and overall health.

Researchers hope future ABCD Study data will better reveal the impact these head hits have on mental health and psychiatric problems. “We know some of the brain regions associated with increased risk of mental health problems are impacted during a TBI,” said Ed Freedman, PhD, associate professor of Neuroscience and co-principal investigator of the ABCD Study at the University of Rochester. Freedman also led this study. “With more time and data, we hope to gain a better understanding of the long-term impact of even a mild TBI.”

Source: University of Rochester Medical Center