Brain Hemorrhage in Boy with Hemophilia Treated with Transfusions

BY Margarida Azevedo 

Researchers in India recently reported the case of child with hemophilia and traumatic intracerebellar hemorrhage, who was successfully treated with transfusions of plasma. They recommend a conservative approach as a first line of treatment, before more invasive alternatives such as surgery.

The case report, “Intracerebellar haemorrage in a haemophilia child,” was published in the Asian Journal of Neurosurgery
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Hemophilia A is caused by deficiency of clotting factor VIII, and its treatment is usually managed with factor replacement products and medications. Access to these products, however, can be difficult for patients in developing nations.

A 12-year-old boy, with a history of transient loss of consciousness and vomiting, sustained a head injury in a fall, and was taken to SCB Medical College and Hospital, in Cuttack, Odisha. Through a computed tomography (CT) scan, physicians identified a well-defined lesion in the intracranial cavity of the boy’s brain. As acute intracerebellar bleeding was suspected, the child was advised to see a neurosurgeon. But his condition was stable, and his parents decided to differ.  Some six weeks after the incident, however, the boy returned to the hospital with symptoms of headache, intermittent vomiting, and an unsteady gait. Magnetic resonance imaging of brain revealed mid-posterior cerebellar, sub-acute, intracerebellar bleeding.

The boy’s coagulation profile was suggestive of moderately severe hemophilia. He was treated with six units of fresh frozen plasma and intravenous tranexamic acid, a medication used to control unwanted bleeding. This treatment led to clinical improvement  and, eventually, the hematoma spontaneously resolved. Such results indicate that early detection and correction of factor levels when intracranial bleeding occurs could prevent possible life-threatening complications.

“Choosing safe sports is vital for children with hemophilia. In case of traumatic intracranial bleed, prompt diagnosis and conservative approach through procoagulant transfusion and intravenous fibrinolysis inhibitors should be tried as first line of management. Before daring for surgery, sufficient amount of factor replacement should be kept available,” the researchers concluded.

 source: http://hemophilianewstoday.com/2016/08/30/brain-hemorrhage-in-hemophilia-boy-successfully-treated-with-transfusions/

New exciting aspect of the coagulation system

All the players in the coagulation system are known—or are they? Thrombin is a key enzyme in the system that controls clot formation; too much or too little can lead to either hemorrhage or thrombosis. At the medical plenary “Rethinking Events in the Hemostatic Process: Role of factor V and TFPI,” Rodney Camire, Philadelphia, Pennsylvania, USA, explained that extrinsic Xase, intrinsic Xase and prothrombinase are regulators of thrombin. “By dampening inhibitors you can control thrombin,” he said.

Camire shared his expertise with hundreds of attendees Monday morning. “FV is very similar to FVIII in some ways and needs to be processed at specific sites,” he said, pointing out however, that FV is a procofactor requiring proteolytic activation in the B domain. The role of the B domain is to keep the molecule active. By looking at sequences for the alignment of FV B domain, Camire and his research team experimented with how both the basic region (BR) and the acidic regions (AR) contribute to keeping the molecule active.

Camire stated that the FV BR fragment and FXa compete for FV-810 binding. There is a discrete segment of the B domain that serves an essential autoinhibitory function to maintain FV as a procofactor. “Disseminating this region is the driving force to unveil a high affinity binding site for FVa,” he explained.

He pointed out that an important step in thrombin generation is the activation of FV to FVa. Mr. Camire said that certain Australian snakes have a unique form of FV in their venom with these inhibitory sequences removed, thereby creating an active procoagulant cofactor.

Tissue factor pathway inhibitor (TFPI) naturally forms in the blood. TFPI binds FV in plasma, but shows no affinity to FVa. “There are two to three different forms of FVa that are generated during the initiation of coagulation that are sensitive to TFPI alpha (TFPIα),” said Camire.

Camire also said that there are new physiologic forms of FV. Citing research from east Texas (USA), individuals have been found that have a mutations in exon 13 of FV, which causes a spliced transcript. Thus, there are forms of FV that are B domainless, that lack the BR, but harbor in the acidic region. Known as FV short, this binds to TFPIα. These patients were shown to have 10 times the level of TFPIα. TFPIα via the BR can block FVa function. This is currently a therapeutic target for hemophilia treatment.

In summary he said blocking TFPI function will enhance coagulation. “Antibodies targeting TFPI are in clinical trials. Specific B domain sequences are key autoinhibitory elements responsible for keeping FV as a procofactor. Dismantling these sequences drives FV activation. These mutations change a weak splice site into a strong splice site.”




source: http://www.wfhcongressdaily.org/2016/07/new-exciting-aspect-of-the-coagulation-system/

Jeanne White-Ginder: mother of Ryan White

Hear the Ryan White Story as told by his mother, Jeanne White-Ginder. Ryan was a boy living with hemophilia and diagnosed with AIDS following a transfusion of tainted clotting factor in December 1984.

The WFH is very proud to be able to welcome Jeanne White-Ginder to the WFH 2016 World Congress. Jeanne will be telling the story of her son Ryan White, who was born with hemophilia and was diagnosed with AIDS following a transfusion of tainted clotting factor in December 1984. At the time, Ryan was 13 years old and was attending school and living in Komono, Indiana. He was given six months to live.

When Ryan tried to return to school after receiving his AIDS diagnosis, he fought AIDS-related discrimination in his Indiana community and was barred from attending public school. Ryan and his mother rallied for his right to attend school through a legal battle that gained national attention. The White family became the face of public education about AIDS.  His story captured the hearts of people worldwide including—most famously—Elton John and Michael Jackson, who both befriended the White family.

Ryan ultimately earned the right to return to school and continued to be a spokesperson for AIDS.  He spoke before the President’s Commission on AIDS, held regular media and talk show appearances, and spoke to over 10,000 teachers and educators at the Louisiana Superdome. Surprising his doctors, Ryan lived five years longer than expected. He died in April 1990, one month before his high school graduation and only months before the United States Congress passed the legislation bearing his name in August 1990: the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, which provides care and treatment to over 500,000 people each year.

Since Ryan died in 1990, Jeanne has continued to tell their story, educating people about the disease in the hope of making the world a more educated, compassionate and caring place for people living with HIV/AIDS.

source: http://www.wfhcongressdaily.org/2016/07/jeanne-white-ginder-mother-of-ryan-white/

Options in delivery of gene therapy explored

Scientists involved in cell-based therapy for bleeding disorders provided updates on this exciting discipline of gene therapy Tuesday morning. David Lillicrap, Canada, the chair of the session, “Gene Therapy”, said the momentum of clinical gene therapy is remarkable.

Chritopher B. Doering, Atlanta, Georgia, USA, took the audience through the process of using stem cells in gene therapy of hemophilia A. Stem cells were first applied to T cells in the 1990s, but safety concerns led the research back into academic laboratories, said Doering.

“Stem cells are rare populations of unspecialized cells that are self-renewing and can become other cells,” began Doering. “Donor cells from a non-affected individual (from the blood) are transplanted into the patient. In order to apply to hemophilia, this may require gene transfer.”

In order to implant stem cells, some of the patient’s cells must be negated to make room for the new cells. Doering said that it is possible to use the patient’s own cells harvested peripherally or from bone marrow.

Challenges to using stem cells include the optimization of transgene expression and producing biosynthesis, and also safe and effective pre-transplantation conditioning and clinical vector manufacturing, said Doering. “Stem cells can last for the life time of an individual so we have a potential cure.  We need only to target a few cells as each stem cell will produce hundreds of daughter cells.”

A pilot clinical trial design has been approved the US Food and Drug Administration with a single site trial at Emory University, USA, to start.

Matthew Porteus, Stanford, California, USA, said that genome editing is a method to correct disease causing variants. “This is a precise, controlled mutagenesis of the genome. Creating a break in the DNA will cause the cells look for this and make a repair. So we can stimulate mutations at the site of the break.”

The repair could change the DNA sequence to one that already exists in the genome or to something novel using synthetic biology. This second option “Creates a new therapeutic phenotype in the cell. In hemophilia it might be used to overly express a clotting factor,” said Porteus.

Using homologous recombination to change single nucleotide variants can be delivered on an adeno-associated virus (AAV) nanoparticle. “In research with sickle cell disease there is about a 20 percent success rate. We can also insert a gene cassette into a safe harbor or single location in the genome,” said Porteus.

“Targeting transgene addition without knocking out the target gene or knocking it into a highly expressed gene has some exciting applications,” noted Porteus. “There are opportunities and challenges for in vivo gene editing for hemophilia. There would be no need to give patients conditioning agents and it is a potential method to edit cells that naturally make clotting factors.” One drawback however, is a lesser ability to monitor efficacy and off-target effects, he added.

Porteus noted that an ethical concern of genome editing is equity and distribution and how to take it to the parts of the world where most people with hemophilia live.

Brigit E Riley, Sangamo BioSciences, USA, delivered new data on FVIII using AAV delivery. “Using AAV in clinical and preclinical trials for FIX has been successful, however there is a lag in the clinic for FVIII.”

She said liver-directed AAV FVIII CDNA gene therapy is being explored as liver cell DNA is separate from transgene DNA. Recombinant AAV is efficient and stable long-term in tissues that do not divide such as the liver, brain and muscle.

FVIII is not an ideal gene for AAV as it is constrained by gene size and low efficiency of transcription/translation. Thus, it requires multi-factorial modifications. “With the modifications, virus yield was improved 8 to 10 fold,” said Riley.

She noted that data from in vitro design saw good correlation between FVIII activity and levels along a range of doses. In vivo wild type mouse data showed FVIII level 2 times normal. In vivo hemophilia A mouse model FVIII activity was 3 times normal and levels were stable over time. A reduced bleeding time was also observed.  In vivo non-human primate data FVIII levels were 4 to 6 times normal levels. “Follow-up dose finding studies are aimed at determining minimal dose,” said Riley.

The challenge of financial incentives is one area to still be addressed. Porteus pondered, “With no established reimbursement model for a one time gene therapy, it begs the question, ‘Are stakeholders willing to take a chance on experimental curative therapies that have a different conceptual basis when the current paradigm has transformed the lives of hemophilia patients?’”

source:http://www.wfhcongressdaily.org/2016/07/options-in-delivery-of-gene-therapy-explored/

Inhibitors – What Have We Learned?

A medical session this afternoon chaired by Brigitte Keller-Stanislawski, of the Paul-Ehrlich-Institute and Mike Soucie, of the Centers for Disease Control and Prevention will ask the question, “Inhibitors, what have we learned?” Inhibitors to FVIII are today the most serious complication of treatment for hemophilia but there is contradictory information about how best to avoid inhibitors, especially in previously untreated patients (PUPs), the most vulnerable group.

Most inhibitors develop within the first 50 exposure days but questions remain about whether the choice of treatment product during that period has an effect on the risk of developing inhibitors. The recently published SIPPET paper suggests that, in PUPs, the risk of developing an inhibitor when using certain recombinant FVIII products is higher than when using plasma-derived FVIII concentrates that contain von Willebrand factor. The study was the first prospective, randomized, multicenter open-label trial in this area. It compared PUPs treated with recombinant factor VIII (rFVIII) to those treated with plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF). The results showed a higher rate of inhibitor (neutralizing antibody) development in the rFVIII-treated subjects compared to pdFVIII/VWF-treated subjects.

However, other datasets do not support the conclusion that the class of recombinant products carries a higher risk. This session will survey these contradictory studies and continue the debate. Dr. Keller-Stanislawski will describe an individual patient meta-analysis of the France coag, UKCHDO and PedNet/ RODIN studies on recombinant products. This analysis involves a very large cohort of PUPS all followed out to 50 exposure days or more. Other speakers will discuss the clinical and laboratory aspects of the immunologic basis of inhibitor development and further data related to the roles of product class and von Willebrand factor. Come to hear the latest thinking on this controversial and important topic.

Source: http://www.wfhcongressdaily.org/2016/07/inhibitors-what-have-we-learned/

The future of hemophilia treatment is very promising

source: http://www.wfhcongressdaily.org/2016/07/wfh-vice-president-medical-the-future-of-hemophilia-treatment-is-very-promising/

Hemophilia treatment has entered an exciting era, with new products making diagnosis and treatment available for a far larger population than ever before, said WHF Vice-President Medical Marijke van den Berg during her Tuesday morning VP Medical Plenary address.

The session covered a variety of studies in people with severe hemophilia A that demonstrate how early prophylaxis can prevent bleeding and is key for joint outcome. This replaces episodic therapy, which has been a frequently used hemophilia treatment regimen since the 1970s.

“Modern hemophilia treatment has completely changed the phenotype—but not in countries where early treatment is not available,” she said.

Ms. van den Berg cited a very large U.S. study of patients with severe hemophilia A, divided into four birth-date cohorts. Even in the age group born in the 1980s, disability was too high, she said, with more than five joint bleeds over six months, despite very high clotting factor consumption.

The large, international Musculoskeletal Function in Hemophilia (MUSFIH) study of children with severe hemophilia A showed that even very high factor dosing resulted in substantial bleeding, van den Berg said. The study also showed that the number of bleeds—but not the dose of episodic treatment—is responsible for joint outcome. This is a key understanding because joint function deteriorates after age 12.

Ms. van den Berg cited a small, randomized study showing that low-dose prophylaxis, rather than episodic treatment, reduces bleeding by 80 percent. Research also shows that early diagnosis is crucial. “Remember, more than 50 percent of those with severe hemophilia A have a negative family history,” van den Berg said.

But when and how do you start prophylaxis? van den Berg said research suggests that the key is to start earlier than age 3 because physical examination scores increase with treatment delay. Other research shows that low-dose prophylaxis should be done a minimum of once a week.

There is a correlation between joint scores and dosage of factor replacement. “With a 1,000-1,500 dose, there’s a lot to gain,” van den Berg said. The good news for people in developing countries, where factor supply is limited, is that data show that lifetime prophylaxis with 1,000 IU per kilo is much more effective than episodic treatment. “You can significantly improve outcome with limited factor consumption,” she said.

However, to implement low-dose prophylaxis, comprehensive care centres are crucial, van den Berg said. She recently toured two international hemophilia training centers that are excellent examples of this: the centre in Campinas, Brazil, led by Margareth Castro Ozelo, and the centre in Johannesburg, South Africa, led by Johnny Mahlangu. The Johannesburg centre serves 1,200 patients, with an impressive 35 percent on prophylaxis and home therapy.

Unfortunately, these centres are the exception. Recent data from Africa show that not even 5 percent of hemophilia patients are diagnosed. “The main reason is because limited or no treatment is available,” van den Berg said.

The WFH Humanitarian Aid Program will substantially address that deficit. From 2016 to 2020, the program plans to provide a predictable supply of 500 million IUs of factor, van den Berg said. Availability of products will lead to more diagnosis, and that will lead to more training and, in some cases, corrective surgery.

In conclusion, van den Berg said that the evidence shows that only primary prophylaxis can prevent joint disease, and episodic treatment is not an appropriate regimen for severe hemophilia A. After joint bleeds, signs of arthropathy appear even with very high-dose prophylaxis. And signs of loss of joint function are often visible at puberty due to growth spurts.

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Think of self-care in a new way

Patrick Lynch formed a company, Believe Unlimited, and created an online comedy series styled after the TV show “The Office.” Dubbed “Stop the Bleeding,” the series—available at stbhemo.com—is a mockumentary about a dysfunctional bleeding-disorders nonprofit organization. It uses humor to tackle serious topics like self-care and self-infusion, women with bleeding disorders and the history of hemophilia.

In 2007, Patrick Lynch’s younger brother, Adam, died of an intracranial bleed at age 18. Both Patrick and Adam were born with severe hemophilia A.

Patrick was only 22 at the time. “As you can imagine, the months and, quite frankly, the years that followed were challenging. I remember saying, ‘[Hemophilia] got him. It’s not supposed to happen to us anymore, but it got him,’” Patrick said during the Wednesday morning “Empowerment Through Self-Care” plenary.
Desperate to discover why Adam died, Patrick searched for a clue. He found it in the bottom of a duffel bag buried in a corner in Adam’s college dorm room. The bag was full of factor. Patrick suspects his brother had stopped his prophylaxis.

“I spent a considerable amount of time thinking about why he fell off his regimen,” Patrick said. “I finally determined that it was because my brother never identified as having a bleeding disorder. That took him off his regimen.”

Patrick has never felt the same way. He developed an inhibitor as a child, but immune tolerance induction eradicated it when he was 13. He was able to go on prophylaxis and live, as he refers to it, “A much more empowered life.” He got involved in high school theater and majored in acting at Boston University.
Patrick has always valued self-care for his hemophilia, but Adam’s death made him realize that others—particularly children—may not.

“It made me think about how we as a community are engaging young people,” he said. “And I saw an opportunity to use my acting background to create something that didn’t exist.” His brother didn’t connect to the bleeding disorders community in traditional ways, but like many young people, he loved comedy and the internet.

So Patrick formed a company, Believe Unlimited, and created an online comedy series styled after the TV show “The Office.” Dubbed “Stop the Bleeding,” the series—available at stbhemo.com—is a mockumentary about a dysfunctional bleeding-disorders nonprofit organization. It uses humor to tackle serious topics like self-care and self-infusion, women with bleeding disorders and the history of hemophilia.

“We want to teach young people with a bleeding disorder, but we really want to inspire them,” Patrick said. The goal is to replace the stigma and fear of hemophilia with the idea that the disease can be “Funny or cool or even uplifting,” he said.

Since launching “Stop the Bleeding”, Patrick’s company has also created a live speaker series called “Powering Through”; the Impact Awards to recognize teens with bleeding disorders; a monthly podcast called “Bloodstream” and a claymation series called “Helping Hany” that examines the psychosocial implications of being a girl with a bleeding disorder. He’s also produced videos for the WFH Treatment for All initiative.

All of this fits within Patrick’s definition of self-care. “My journey and understanding of self-care has evolved,” he said. “It’s not just self-infusing, stretching, and maintaining a good diet. For me, self-care is giving back to and empowering the community.”

He also acknowledges that he has a “Privileged definition of self-care—a privilege not shared by 75 percent of our community in developing nations.” That’s why he believes people from the developed world have an obligation to help others who aren’t able to self-infuse or do other aspects of self-care because they lack treatment options. This can include asking product manufacturers how they help people in developing countries and contributing to the WFH Humanitarian Aid Program.

“I miss my brother. For years, I thought about him every day,” Patrick said, his voice breaking. “Let’s continue to ramp up our efforts for our brothers and sisters in developing countries so one day they too may enjoy a privileged definition of self-care.”

source: http://www.wfhcongressdaily.org/2016/07/multidisciplinary-plenary-empowerment-through-self-care-patrick-james-lynch-wednesday-july-27th-930-1000/