Congenital Factor X-Riyadh (Stuart-Prower) Deficiency With Isolated ...
Study Links AstraZeneca COVID-19 Shot To Bleeding Disorder ITP
Researchers in Scotland have identified a possible link between the Oxford University/AstraZeneca COVID-19 and a mostly mild and generally treatable bleeding disorder.
The scientists examined real-world public health data from all individuals in Scotland who received either the AZ or Pfizer/BioNTech vaccines up until 14 April and found a possible association between the AZ shot and an autoimmune disorder called idiopathic thrombocytopenic purpura (ITP).
ITP leads to a reduction in blood platelets and is usually mild and self-limiting, with symptoms such as bruising and bleeding episodes, although in very rare cases it can be more serious.
The authors of the study published in Nature Medicine looked at data from 5.4 million people and concluded that ITP was marginally higher among those receiving a first dose of the AZ vaccine than in an unvaccinated control group, with an incidence of 1.13 cases per 100,000.
Patients with ITP tended to be older, with chronic health conditions and in hospital, and almost half of them were also taking medications that could raise the risk of ITP.
Meanwhile, the study found no association between the AZ vaccine and venous thromboembolic (clotting) events – including cerebral venous sinus thrombosis (CSVT) – although there was an increased risk of arterial clotting and bleeding events.
"Given these small increased risks for ChAdOx1, alternative vaccines for individuals at low COVID-19 risk might be warranted when supply allows," they conclude.
The scientists have been quick to point out the limitations of the trial, including a small proportion of people aged under 40 and some people who had already received two doses, as well as limited access to hospital records and the inherent difficult in diagnosing ITP accurately.
In addition, they note that ITP has also emerged as an important complication of COVID-19, with a rate estimated at around 0.34% in hospitalised patients, and it has also been associated with other vaccines including jabs for hepatitis B, measles, mumps and rubella (MMR) and influenza.
Statistician Prof Kevin McConway of the Open University said the trial was well-designed and statistically sound, but pointed out that it is not possible to distinguish between ITP and vaccine-induced thrombotic thrombocytopenia (VITT), a condition that also involves platelets and can lead to serious blood clotting disorders that has been linked to both the AZ and Janssen vaccines.
The risk of ITP of about 11 in every 11 million doses is "very small…even if it turns out that it is caused by the vaccine, and it's tiny compared to the risks arising if someone is not vaccinated and developed COVID-19," he added.
Haematology specialist Prof Adrian Newland of Queen Mary University of London also noted that the background rate in the normal population of ITP in adults is around 60 per million, which suggests there would have been around 535 new cases of ITP in the study population over the course of follow-up.
"It is difficult to be certain whether these are vaccine related or chance associations, although the close association of some to the vaccine suggests that it is likely to be related," said Newland.
Many countries around the world – including the UK – are already recommending that alternative vaccines be used in younger people given the risks of clotting-related side effects.
COVID-19 Severity Linked To Autoantibodies Against Blood Clotting Protein
In a recent article published in the journal Scientific Reports, researchers performed a prospective observational study in three healthcare centers in Germany to understand the impact of ADAMTS13 activity during coronavirus disease 2019 (COVID-19).
Study: Generation of potentially inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019. Image Credit: peterschreiber.Media / Shutterstock.Com
BackgroundADAMTS13, also known as von Willibrand factor (VWF)-cleaving protease, cleaves VWF to prevent the formation of ultra-large VWF multimers. ADAMTS13 deficiency can lead to a condition known as thrombocytic thrombocytopenic purpura (TTP), a rare and life-threatening blood disorder often treated with plasmapheresis.
Recent studies have demonstrated that COVID-19 markedly increases VWF antigen levels which, in turn, exceeds ADAMTS13 processing capacity. Eventually, this leads to the formation of large VWF multimers similar to what occurs in TTP. Thus, the ADAMTS13/VWF antigen (VWF:Ag) ratio can be used as an independent predictor of COVID-19 severity and mortality.
Nevertheless, there remains a lack of research on ADAMTS13 autoantibodies and their role in COVID-19. Recently, two small case series have examined severe COVID-19 patients, in which only one out of the 13 patients exhibited detectable ADAMTS13 antibodies.
About the studyCOVID-19 is associated with an increased risk of autoreactivity. In the present study, researchers investigated whether the generation of autoantibodies to ADAMTS13 contributes to the reduced ADAMTS13/VWF:Ag ratio observed in COVID-19.
A total of 156 patients at Ruhr-University Bochum, University of Duisburg-Essen, and Asklepios Klinikum Hamburg Harburg hospitals were included in the current study, 90 of whom were hospitalized due to COVID-19.
Each study participant's blood samples were obtained to measure ADAMTS13 activity, as well as ADAMTS13 autoantibodies exceeding 16 U/mL. A sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure the VWF:Ag ratio, which was calculated as ADAMTS13 (IU/ml)/VWF:Ag (IU/ml) × 100. Sodium dodecyl sulfate (SDS) agarose gel electrophoresis was used for the VWF multimer analysis.
ADAMTS13 autoantibodies during severe COVID-19ADAMTS13 autoantibodies were observed in nearly one-third of hospitalized COVID-19 patients. ADAMTS13 autoantibody activity was low, thus indicating an inhibitory effect on the protease. Notably, this phenomenon was not observed in intensive care unit (ICU) patients not diagnosed with COVID-19. These findings indicate the potential utility of using ADAMTS13 autoantibody levels to predict COVID-19 severity.
Along with increased VWF release, increased ADAMTS13 autoantibody levels contributed to a decreased ADAMTS13/VWF:Ag ratio. Notably, in the diagnosis of TTP, reduced ADAMTS13 activity and ADAMTS13 autoantibodies in serum are well-established criteria.
None of the patients in the study developed severe thrombopenia, defined as a platelet count of 50,000/µl or less. This indicates that the potential inhibitory effect of apathogenic ADAMTS13 autoantibodies was weaker in COVID-19 than in TTP.
Large VWF multimers accumulate in microthrombi; thus, their reduced concentrations in the blood likely contributed to COVID-19-induced immunothrombosis. SDS agarose gel analyses on samples from patients with COVID-19 confirmed these results.
Other studies have shown that COVID-19 patients exhibit lupus- and rheumatoid arthritis-like antibody patterns. Accordingly, critically ill COVID-19 patients also exhibit hallmarks of B-cell activation and B-cell repertoire (BCR) observed in autoimmune settings.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of thrombotic microangiopathy by two synergistic mechanisms. Due to the excessive release of VWF, the protease activity of ADAMTS13 exceeded the normal limit.
The COVID-19-induced autoreactive inflammatory environment leads to the formation of autoantibodies to ADAMTS13. The circulation of these autoantibodies subsequently reduced ADAMTS13 activity and contributed to the development of immunothrombosis. Both of these mechanisms may increase the risk of ultra-large VWF multimers formation in COVID-19, resembling those formed in TTP.
ConclusionsIn the current study, plasma exchange therapy in 25 severe COVID-19 patients with acute respiratory distress syndrome markedly decreased their VWF:Ag ratio and increased ADAMTS13 activity, thereby re-establishing the physiological balance between VWF and its protease.
Thus, the study findings provide evidence of an additional benefit of plasma exchange therapy beyond the attenuation or elimination of circulating cytokines and inflammation for the treatment of COVID-19. Furthermore, considering VWF, ADAMTS13 activity, and ADAMTS13 autoantibodies levels during the diagnostic workup of COVID-19 may also provide important insights into disease severity.
Journal reference:
Blood Condition Linked To Protection Against Alzheimer's
Stanford Medicine researchers have found that a common blood condition associated with several diseases may have a protective effect against Alzheimer's disease.
In the condition, clonal hematopoiesis of indeterminate potential, or CHIP, certain blood stem cells acquire mutations that strengthen their ability to survive and multiply. As a result, the mutant cells dominate, and just a few cells can give rise to much or even all of the body's blood and immune cells. In most cases of CHIP, a dominant blood stem cell gives rise to between 4% and 30% of blood and immune cells.
Studies by Stanford Medicine assistant professor of pathology Siddhartha Jaiswal, MD, PhD, and others have shown that people with CHIP are at much higher risk of developing various diseases. By analyzing medical databases and stored blood samples, Siddhartha and his colleagues have shown that people with CHIP are about twice as likely to develop coronary heart disease, twice as likely to develop chronic liver disease and 10 times as likely to develop blood cancers such as myeloid leukemias.
Researchers don't yet fully understand why CHIP is linked to diseases other than blood cancer, though some studies have suggested that CHIP mutations cause increased activation of the immune system.
Jaiswal and his colleagues investigated an association between CHIP and Alzheimer's disease, expecting to see either no association or a positive association with Alzheimer's disease.
He and colleagues analyzed a cohort of participants who had been followed over a period of 10 to 15 years, comparing medical records and blood samples. "We were surprised to find that CHIP was actually associated with a substantially lower risk of Alzheimer's disease," Jaiswal said. People with CHIP were found to have a 30% to 50% lower risk of developing the neurodegenerative disorder, compared with those who did not have the CHIP mutation, he said.
"The degree of protection from Alzheimer's dementia seen in CHIP carriers is similar to carrying an APOE ε2 allele," said Jaiswal, referring to a genetic variant that's known to decrease the risk of Alzheimer's.
The team saw the negative association with Alzheimer's and CHIP even when they accounted for other risk factors. "We thought there might be some kind of survivor bias -- that people with CHIP were more likely to die before developing Alzheimer's disease -- but the decrease in risk still held after adjusting for that," Jaiswal said. They also analyzed the association in another way, to see if people who had Alzheimer's disease were less likely to have CHIP. The researchers confirmed that they were.
Digging deeper
Of course, an association doesn't mean that there is a cause-and-effect relationship. So, Jaiswal and his colleagues conducted different forms of genetic analyses, finding evidence that CHIP could causally inhibit the development of Alzheimer's.
The connection between CHIP and Alzheimer's implied a somewhat unexpected link between brain cells and the cells that give rise to blood and the immune system, Jaiswal said.
The brain has its own immune cells, called microglia, and there is some evidence that microglia combat the inflammation and buildup of toxins that are associated with Alzheimer's disease. But over the last 10 years, scientists have come to believe that all microglia become established in the brain very early in human development, during the embryo stage. Since the blood-brain barrier normally prevents blood cells from crossing into the brain, there has been no known way for blood stem cells to become brain cells like microglia.
Yet, when Jaiswal and his colleagues looked at brain samples of people with CHIP for the CHIP-associated blood cell mutations, they saw them. And these mutations seem to exist in microglia cells. The investigators found that between 30% and 90% of the microglia in brain samples of those with CHIP harbored the CHIP mutations. The proportion of mutant microglia in any individual brain tended to match the proportion of mutant blood cells in the rest of the body.
"This suggests that cells are migrating from the blood into the brain," said Jaiswal, adding that the finding is in contradiction to the accepted dogma. "It's a remarkable finding."
How this affects the development of Alzheimer's disease is not yet clear, but researchers know that microglia help fight microbial invaders and clean up waste products in the brain. "One hypothesis is that the mutations that promote a growth advantage in blood stem cells also promote microglial expansion and activity, boosting microglia's ability to fight the conditions that lead to brain disease," Jaiswal said.
The scientists also saw that, in the brain samples of people with CHIP, levels of neurofibrillary tangles and amyloid plaques, both associated with Alzheimer's disease and thought to be causative, were lower.
Jaiswal and his colleagues are planning follow-up studies to learn more about how the mutated microglia might be protecting against Alzheimer's disease. Jaiswal plans to work with professor of pathology Marius Wernig, MD, PhD, to transform CHIP blood stem cells into microglia so they can understand how these cells behave differently than normal microglia.
Although there's much work to be done, the researchers hope that if they are able to understand these mechanisms, it could help guide the development of new therapeutics that could one day protect against Alzheimer's disease, they said.
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