Blood diseases’ toll on thousands of Filipino lives

Abnormal Uterine Bleeding May Be Caused By Clotting Factor Deficiencies

A new review article illuminates why physicians should keep coagulation disorders in mind when evaluating patients with heavy abnormal uterine bleeding.

Physicians treating patients with heavy menstrual bleeding (HMB) should consider the possibility that rare bleeding disorders and hemophilia carrier states are at play if other, more common causes of bleeding have been excluded, according to a new report.

The report, a literature review published in Life (Basel),1 outlines several coagulation disorders and offers physicians guidelines on how to spot and treat hemostatic disorders.

Authors explain that current literature suggests 10% to 35% of women experience HMB at some point during their reproductive years. There are several potential causes of such bleeding, and physicians can use the PALM-COEIN system to help identify the underlying cause.

This system of abnormal uterine bleeding classification, from the International Federation of Gynaecology and Obstetrics,2 includes structural causes like polyps, adenomyosis, leiomyoma, malignancy, and hyperplasia, and functional causes, including coagulopathy, ovulatory disorder, endometrial disorders, iatrogenic conditions, or not-yet-classified causes. The existing literature suggests that an underlying inherited bleeding disorder is at play for 10% to 62% of adolescents with HMB. The most common such disorder is von Willebrand disease, but the authors said several other, less-common conditions should also be considered. Those less-common conditions are the focus of the review article.

The authors first reviewed several rare coagulation factor disorders. For instance, they said factor I, or fibrinogen, is a soluble plasma glycoprotein that in some patients is absent (congenital afibrinogenemia) or reduced (hypofibrinogenemia). In the former, patients can have a wide range of clinical manifestations, from minimal bleeding to serious hemorrhages, the authors said. Such patients may also experience arterial or venous thrombosis. In coagulation tests, partial thromboplastin time (PTT), prothrombin time (PT), thrombin time (TT) are all "infinitely prolonged," the authors said, since all of the parameters require the formation of fibrin.

Patients with hypofibrinogenemia are often asymptomatic if their fibrinogen levels are above 1 g/L, but the authors said these patients sometimes experience bleeding or thrombotic complications.

"In affected individuals, PT, PTT, and TT are variably prolonged, with TT being the most sensitive assay," they said.

Factor VII deficiency is believed to make up about one-third of rare coagulation disorders. The factor is vitamin K dependent and, like factor I, is synthesized in the liver and secreted in the plasma, the authors said. Patients with a deficiency of factor VII can have a wide range of manifestations, the authors said, "from asymptomatic or mildly symptomatic cases—for example, easy bruising, gum bleeding, and epistaxis—to severe cerebral and gastrointestinal hemorrhage."

Unfortunately, there are no clear treatment guidelines for factor VII deficiency, the authors said, although the published literature suggests a number of potential treatments, including surgery and blood transfusions.

Factor XIII deficiency is one of the rarest coagulation disorders, with only 500 cases reported globally since 1960, the authors said.

"Factor XIII is a transglutaminase that cross-links fibrin fibers between amino acid residues, hence stabilizing a fibrin clot," they wrote.

Patients with the deficiency can present with abnormal uterine bleeding, umbilical bleeding, or severe ovulation bleeding, among other clinical manifestations. However, the authors said factor XIII deficiency can be difficult to diagnose because clotting factor tests and platelet counts are normal in patients with the deficiency.

"The diagnosis can be made by measuring FXIII antigen levels using enzyme-linked immunosorbent assays and/or by measuring its activity with functional methods," the authors said. "Genetic testing of the genes encoding FXIII A or FXIII B is also an option for more specific assessment."

The authors also described several other disorders, including deficiencies of factors V, VIII, X, and XI, and hemophilia.

The investigators said they hope their report serves as a "useful guide" for physicians investigating abnormal uterine bleeding.

"We hope that this review can serve as a roadmap for busy clinicians to familiarize themselves with coagulation factor disorders as a cause of heavy menstrual bleeding and guide them towards more targeted research," they said.

They added, however, that theirs was not a systematic review, and therefore it should not be considered an exhaustive guide to diagnostic decisions.

References

1. Livanou ME, Matsas A, Valsami S, Papadimitriou DT, Kontogiannis A, Christopoulos P. Clotting factor deficiencies as an underlying cause of abnormal uterine bleeding in women of reproductive age: a literature review. Life (Basel). Published online June 5, 2023. Doi:10.3390/life13061321

2. Munro MG, Critchley HOD, Broder MS, Fraser IS; FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113(1):3-13. Doi:10.1016/j.Ijgo.2010.11.011

What We Know So Far About AstraZeneca Vaccine Blood Clot Link

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European regulators this week acknowledged a potential link between the Oxford/AstraZeneca COVID-19 vaccine and extremely rare blood clotting disorders.

What scientists and regulators don't yet know is how exactly the vaccine might be causing them.

As investigations continue, EU countries and the U.K. Have taken national decisions to either continue use or to restrict the vaccine to certain age groups.

Here's what we know so far based on public briefings from both the European Medicines Agency (EMA), the U.K.'s Medicines and Healthcare products Regulatory Agency (MHRA), and a subsequent press briefing involving scientists in the U.K. Directly involved in assessing the rare blood clot cases.

Does the Oxford/AstraZeneca vaccine cause blood clots?

There is now enough evidence to suggest that the Oxford/AstraZeneca vaccine is possibly the cause of rare blood clots and bleeding among a very small number of people who have received the vaccine. However, work is ongoing to definitively conclude this.

Sabine Straus, chair of the EMA's drug safety committee, concluded Wednesday that "these clotting disorders are very rare side effects of the vaccine," while June Raine, head of the U.K.'s MHRA, said the evidence suggests a "reasonably plausible link."

What's the evidence to date?

The EMA and MHRA have examined cases of unusual blood clots with low levels of blood platelets, small cell fragments that form clots and prevent bleeding.

As of April 4, the EU drug safety database had received a total of 169 cases of cerebral vein sinus thrombosis (CVST) — which occurs when a blood clot forms in one of the brain's veins, preventing blood from draining out of the brain — following vaccination. There had also been 53 cases of splanchnic vein thrombosis (SVT), an unusual manifestation of clots in one or more abdominal veins.

As of March 22, 18 of these cases were fatal. These cases were reported from among the 34 million people vaccinated so far with the Oxford/AstraZeneca jab in the European Economic Area, and the U.K.

What are the risk factors for these side effects?

So far, we don't know. "Based on the current available evidence, specific risk factors such as age, gender, or previous medical history of clotting disorders, have not been able to be confirmed, as these rare events are seen in all ages and in men and women," Emer Cooke, EMA chief, said on Wednesday.

Straus added that it was not possible to draw any conclusion on risk factors like age because of the different ways the vaccine is being used in different countries. The manufacturer, AstraZeneca, has been instructed by the EMA to carry out studies, and the regulator has also commissioned research to further investigate these side effects.

Why have countries stopped giving the vaccine to younger adults?

Several EU countries, including Germany, France and the Netherlands, have stopped giving the vaccine to younger adults. Without publishing the full reasoning from their vaccine committees, it's not clear exactly why. In Germany, by March 30, there were 31 suspected cases of blood clots in the brain, mostly in women aged between 20 and 63. Chancellor Angela Merkel announced the suspension of giving the Oxford/AstraZeneca jab to the under-60s, so it appears to be associated with the age range of the reported blood clot cases.

On April 7, the U.K.'s vaccine committee recommended offering the under-30s a different COVID-19 vaccine based on the benefit-risk profile for this age group. The committee said that when there is low prevalence of coronavirus, the potential benefit of averting serious illness from administering the vaccine in people aged under 30 does not outweigh the risk of harm from the jab. However, when coronavirus prevalence is high, the balance shifts, with the benefits outweighing the risks of harm in this group.

With coronavirus prevalence in the U.K. Now at about 1 case in 500 people — according to this week's latest REACT-1 study published by Imperial College London and Ipsos MORI — the committee has recommended a different vaccine for the under-30s.

What is happening in these rare cases?

Research to date suggests that an immune response is causing the rare blood clots. "Early evidence suggests that this constellation of symptoms is caused by an immune response against platelets, which allows the platelets to then lead to clotting in different parts of the body," said Munir Pirmohamed, chair of the U.K.'s Committee of Human Medicines.

This immune response leads to a condition similar to that seen in rare cases in patients treated with the anticoagulant heparin, called heparin-induced thrombocytopenia, according to Cooke at the EMA.

The cases that have been tested so far all have "a very odd antibody," said Beverly Hunt, professor of thrombosis and hemostasis at King's College London. It's an antibody to a molecule called platelet factor-4, which can also be a rare reaction to heparin.

When this happens, "you tend to activate platelets," she said, and by using up lots of platelets to form blood clots, the remaining circulating platelet count will fall. This is why you see clots and sometimes bleeding.

In addition, another marker called D-dimer, a small-protein breakdown product of clots, "is very high in these patients," she said, "showing that they've made clots." And some cases have also seen low levels of fibrinogen, the final protein involved in coagulation, also suggesting they are being used up in clotting.

Why is the vaccine linked to these rare blood clotting events?

Scientists have so far figured out what is happening in the blood, but not how the vaccine is causing these events.

This immune response could be caused by the vaccine or a prior COVID-19 infection, or something else, Pirmohamed said. "But what we don't have clearly is the link between the vaccine and how the immune response becomes activated against the platelets," he added.

Why is it important to find out why the vaccine causes this?

Scientists want to know what is causing these events so that they can identify if there are any risk factors. If we can understand the mechanisms "it might provide us with ways of being able to prevent this in the future," said Pirmohamed.

In addition, understanding how the vaccine may trigger this may allow scientists to modify the vaccine, so that it does not cause this particular adverse event in the future, he said.

The Oxford/AstraZeneca vaccine is an adenovirus viral vector jab. Is this side effect the same for all vaccines that use this technology?

So far, there's no evidence to suggest the Johnson & Johnson vaccine and the Sputnik V vaccine also have this side effect. However, data on these vaccines is limited, with Sputnik not approved for use in the EU and used only in a small number of people in EU countries that have bought it. And the J&J vaccine has not yet seen the mass rollout of the Oxford/AstraZeneca vaccine that has allowed the detection of very rare side effects.

"You could conceive that this is a [spike] protein related problem and that the mRNA vaccines are not doing it for some reason related to dose or expression," suggested Adam Finn, professor of pediatrics at the University of Bristol.

"I don't think we should be jumping to the conclusion that it's a viral vector problem specifically," he said. "I think that's one of several different possibilities."

Is prior COVID infection a risk factor?

It's something scientists are looking into. So far, about 25 percent of cases have shown a prior COVID-19 infection, but more data is coming on all of the cases. "Beyond that, we've not got analysis that tells us whether those cases are definitely different in any way or more severe," Finn said.

How can we prevent deaths from this side effect?

Doctors now know what to look out for if a patient presents with symptoms after vaccination, including severe headache, bruising, confusion, seizures, and chest or abdominal pain. And health care professionals have been updated.

"We feel fairly confident we're identifying the cases," said Hunt at King's College London. Treatment is similar to heparin-induced thrombosis and thrombocytopenia, which involves intravenous gamma globulin, "concentrated antibodies …. That block the effects of antibodies that are causing harm," she said.

She advised against anyone self-medicating with aspirin if they are worried about getting the jab.

Will under-30s be given the vaccine if there isn't an alternative in the U.K.?

That's unlikely to happen, according to Anthony Harnden, deputy chair of the U.K.'s Joint Committee on Vaccination and Immunisation, because the U.K. Isn't yet vaccinating that age bracket and more vaccines are coming. "We have good supplies of Pfizer, and Moderna's coming online, and there will be other vaccines which the government have ordered," he said.

How does the clotting risk compare with taking the contraceptive pill, and should we make this comparison?

According to Keir Shiels, a pediatrician at Great Ormond Street Hospital in London, the incidence of serious blood clots from the pill is far higher than the incidence of serious blood clots from the AstraZeneca vaccine.

"The combined oral contraceptive pill is probably the commonest cause of cerebral sinus thrombosis. So, it is a very good comparison," said Hunt.

"For the vast majority of people, if you want to reduce your risk of dying or getting hospitalized with a blood clot or any other illness if you're offered the AstraZeneca vaccine, you can reduce those risks by taking it," said Finn.

CORRECTION: This story was updated to clarify that several countries have stopped giving the Oxford/AstraZeneca vaccine to younger adults.

This article is part of POLITICO's premium policy service: Pro Health Care. From drug pricing, EMA, vaccines, pharma and more, our specialized journalists keep you on top of the topics driving the health care policy agenda. Email [email protected] for a complimentary trial.

Five Liters Sets Clinical Sights On Novel Bioelectric Treatment For Von Willebrand Disease

Wearable auricular neurostimulation device could offer a novel treatment option for the most common inherited bleeding disorder.

DALLAS, TX and MANHASSET, NY, July 06, 2023 (GLOBE NEWSWIRE) --  Five Liters, a Dallas-based wearable neuromodulation company, is embarking on a series of groundbreaking first-in-human studies to demonstrate the effectiveness of non-invasive, wearable neurostimulation in reducing blood loss. This significant milestone is made possible through Five Liters' collaboration with the Feinstein Institutes for Medical Research, marking the first translational step from their recently published Nature Communications study titled Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice.

Five Liters, a subsidiary of Spark Biomedical, is dedicated to exploring the hemostatic effects of vagus nerve stimulation (VNS), specifically transcutaneous auricular neurostimulation (tAN). The focus is on preventing life-threatening bleeding events commonly associated with various conditions, including:

Blood disorders

Surgical blood loss

Traumatic Bleeding

Should the initial human feasibility study yield positive results, Five Liters will prioritize Von Willebrand Disease, the most prevalent inherited blood-clotting disorder worldwide, affecting approximately 0.6 to 1.3% of the global population (equivalent to 1 in every 100 Globally)1. VWD manifests with varying degrees of bleeding tendency, such as excessive bleeding from injuries, surgical or dental procedures, persistent nosebleeds, heavy or prolonged menstrual bleeding, and bleeding during labor and delivery. Other symptoms include blood in urine or stool, easy bruising, and hematomas.

Dr. Navid Khodaparast, Chief Science Officer of Spark and Five Liters stated "Von Willebrand Disease is an inherited bleeding disorder in which blood does not clot properly, leading to bleeding events and joint problems. In females with VWD, nearly 80% experience heavy menstrual bleeding, also known as menorrhagia. These monthly occurring bleeding events not only can take a toll on their physical health but can also affect their mental health, leading to significant depression and anxiety. At Five Liters, our primary clinical initiative is to demonstrate that tAN therapy can safely alleviate menorrhagia in females with VWD. This clinical trial is scheduled to begin later this year."

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Currently, there is no cure for VWD. However, based on the promising pre-clinical work conducted by the Feinstein Institutes for Medical Research, the recently published Nature Communications article, and Five Liters' affiliation with Spark Biomedical's clinical research, the company remains optimistic about the potential for a non-invasive, non-pharmacological treatment option.

Spark Biomedical, a leader in wearable neurostimulation solutions and the parent company of Five Liters, launched a collaboration with The Feinstein Institutes for Medical Research at Northwell Health to commercialize a wearable neurostimulation solution focused on reducing excessive blood loss in June of 2022. The collaboration leveraged the Feinstein Institutes' years of research and patented solution concept in VNS for blood loss reduction and Spark Biomedical's Food and Drug Administration (FDA)-approved tAN therapy device underpinnings. Thanks to this partnership and the Nature article, Five Liters is thrilled to move forward with its mission.

Five Liters' commitment to advancing medical innovation and improving patient outcomes drives their pursuit of groundbreaking solutions. By harnessing the power of wearable neuromodulation, they aim to revolutionize the management of blood loss and provide hope for individuals affected by VWD and other related conditions.

###About Five LitersFive Liters, a subsidiary of Spark Biomedical, is a U.S.-based wearable neurostimulation solution developer leading the way in exploring and providing novel, non-invasive, non-pharmacological treatment options for those suffering from excessive blood loss. For more information, visit FiveLiters.Com or follow us @FiveLiters on LinkedIn and Facebook.

About Spark BiomedicalSpark Biomedical, Inc. Is a leading U.S.-based wearable neurostimulation solutions developer devoted to the life-saving work of helping 36.3 million people worldwide overcome withdrawal, heal from addiction, and achieve the better quality of life they deserve. With opioid-related misuse and overdose deaths on the rise, the company's mission is to eliminate opioid addiction by working to address the full opioid addiction lifecycle, including withdrawal management, opioid-sparing, relapse prevention, and PTSD/trauma abatement.Spark Biomedical is helping patients take the first step of overcoming acute opioid withdrawal with its FDA-cleared wearable technology, the Sparrow Ascent Therapy System — Transcutaneous Auricular Neurostimulation (tAN®) for Opioid Withdrawal Relief. Sparrow® Ascent Therapy provides an easy, safe, and effective drug-free treatment option supported by clinical evidence. Next steps are underway with the launch of two NIDA-funded clinical trials to improve adult relapse rates and help infants suffering from Neonatal Opioid Withdrawal Syndrome (NOWS).Learn more at sparkbiomedical.Com or on LinkedIn, Twitter, Instagram and Facebook.

About the Feinstein Institutes The Feinstein Institutes for Medical Research is the home of the research institutes of Northwell Health, the largest health care provider and private employer in New York State. Encompassing 50 research labs, 3,000 clinical research studies, and 5,000 researchers and staff, the Feinstein Institutes raises the standard of medical innovation through its five institutes of behavioral science, bioelectronic medicine, cancer, health system science, and molecular medicine. We make breakthroughs in genetics, oncology, brain research, mental health, autoimmunity and are the global scientific leader in bioelectronic medicine – a new field of science that has the potential to revolutionize medicine. For more information about how we produce knowledge to cure disease, visit http://feinstein.Northwell.Edu and follow us on LinkedIn.

About Northwell HealthNorthwell Health is New York State's largest health care provider and private employer, with 21 hospitals, 850 outpatient facilities and more than 12,000 affiliated physicians. We care for over two million people annually in the New York metro area and beyond, thanks to philanthropic support from our communities. Our 79,000 employees – 18,900 nurses and 4,900 employed doctors, including members of Northwell Health Physician Partners – are working to change health care for the better. We're making breakthroughs in medicine at the Feinstein Institutes for Medical Research. We're training the next generation of medical professionals at the visionary Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and the Hofstra Northwell School of Nursing and Physician Assistant Studies. For information on our more than 100 medical specialties, visit Northwell.Edu and follow us @NorthwellHealth on Facebook, Twitter, Instagram, and LinkedIn.

References

1 Du P, Bergamasco A, Moride Y, Truong Berthoz F, Özen G, Tzivelekis S. Von Willebrand Disease Epidemiology, Burden of Illness and Management: A Systematic Review. J Blood Med. 2023 Mar 2;14:189-208. Doi: 10.2147/JBM.S389241. PMID: 36891166; PMCID: PMC9987238.

CONTACT: Candace Rempe Spark Biomedical, Inc. 214.404.4162 candace.Rempe@sparkbiomedical.Com

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