Doctors Simultaneously Treat Patient’s Acquired Hemophilia A and Prostate Cancer

by Özge Özkaya, PhD

Researchers from San Joaquin General Hospital in California reported the case of a 66 year-old man who was simultaneously treated for acquired hemophilia A and prostate cancer.

“To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in a favorable patient outcome,” Dr. Chirag Sheth and colleagues wrote.

The report, “Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer,” was published in the Journal of Community Hospital Internal Medicine Perspectives.

The patient came to the hospital because of pain and swelling in his right thigh and an inability to walk for one month. He was diagnosed with hematoma (or abnormal collection of blood outside the blood vessels) in his right leg, which was removed by surgery.

However, following the operation, the patient started bleeding excessively and required an emergency blood transfusion.

On further analysis, researchers saw that the level of factor VIII inhibitors in his blood was very high and the factor VIII activity was less than 1 percent of normal. He was diagnosed with acquired factor VIII deficiency, also called acquired hemophilia A. It’s a very rare condition characterized by the acquisition of autoantibodies against factor VIII, an essential blood clotting protein, which leads to a predisposition to the formation of hematomas. The condition is associated with autoimmune diseases, pregnancy, giving birth, drugs, and cancer.

Once it was established that the patient had acquired hemophilia A, he was given drugs to block the production of factor VIII inhibitors.

Further investigations to determine the underlying cause of his condition revealed significantly high prostate-specific antigen in his blood, which led the scientists to diagnose him with locally advanced prostate cancer.
Based on his high risk of bleeding and his overall critical condition, the patient was given only hormonal therapy to treat the cancer.

After a 35-day period of hospitalization, and a two-day intervention against minor bleeding, the patient was discharged.

At the three months follow-up, no more bleeding episodes were recorded, there were no factor VIII inhibitors in his blood, and factor VIII activity was increased to 170 percent.

According to the researchers, “the patient continues to remain asymptomatic with regular follow-up in our outpatient hematology and oncology clinic.”

The authors concluded that this case demonstrates the importance of recording episodes such as sudden onset of bleeding in patients who had no prior personal or family history of similar bleeding episodes.
They said this patient’s case illustrates that simultaneous treatment of underlying cause (in this case prostate cancer) along with immunosuppressive therapy can result in a favorable outcome in acquired hemophilia A.

source: http://hemophilianewstoday.com/2016/09/14/simultaneous-treatment-acquired-hemophilia-prostate-cancer/

Knee Problems in Hemophilia Best Treated by Factor Replacement Therapy, Paper Says

by Alisa Woods, PhD

Joint problems caused by chronic bleeding often trouble people with hemophilia, especially in the knees, ankles, and elbows. A paper by scientists in Spain and the U.S. reviewed existing literature on knee treatments for people with this disease, focusing on best current practices — including a preventive, if inconveniently lifelong, therapy — and future treatment directions.

The article, “Orthopedic disorders of the knee in hemophilia: A current concept review,” was published in the World Journal of Orthopedics.

Hemophilia’s two forms are caused by deficiencies in clotting proteins,  factor VIII (FVIII) for hemophilia A and  factor IX (FIX) for hemophilia B. According to a recent study reported in Hemophilia News Today, these problems may be more severe in people with hemophilia A than those with hemophilia B.

The study’s lead authors, E. Carlos Rodriguez-Merchan of the Department of Orthopedic Surgery, La Paz University Hospital-IdiPaz, Madrid, and Leonard A. Valentino of Rush University Medical Center, Chicago, report that factor replacement therapy (FRT) is the optimal approach for preventing knee and other joint problems (known as hemophilic arthropathy), through infusions to replace the deficient protein. But use of FRT therapy is  lifelong, making adherence a challenge, and breakthrough bleeding is common. Surgery can correct damage to the knee, but is difficult in people with this bleeding disorder.

If FRT therapy is insufficient, hemophilic synovitis can develop, a condition affecting the synovial membrane that lines joints such as the knee. Rodriguez-Merchan and Valentino recommend radiosynovectomy as the best way to reduce bleeding in people with this condition. This involves injections of radioactive nucleotides into the knee. The method can replace surgical synovectomy (the removal of the synovial membrane).

The researchers recommend that these knee surgeries be performed in specialized hospitals, with experienced teams of healthcare providers, to minimize the heightened risk of bleeding and infection.

“Until we are able to prevent orthopedic problems of the knee” in people with hemophilia, we “will have to continue performing orthopedic procedures (arthrocentesis, RS [radiosynovectomy], arthroscopic synovectomy, hamstring release, arthroscopic debridement, alignment osteotomy, and total knee arthroplasty)” to improve patients’ quality of life, the authors wrote.

But, they conclude: “The best treatment …  is primary prophylaxis [FRT therapy] replacing the deficient clotting factor with early institution of regular injections of concentrates of factor VIII or IX. In this way, not only is bleeding into the joints prevented but also the development of synovitis and articular degeneration.”

Alisa G. Woods, Ph.D., MS is an Assistant Professor of the Biochemistry & Proteomics Group in the Department of Chemistry & Biomolecular Science at Clarkson University in Potsdam, NY.

 source: http://hemophilianewstoday.com/2016/06/27/article-examines-knee-problems-in-hemophilia/

Boy with Hemophilia A Undergoes Successful Stem Cell Transplant, Researchers Report

by Margarida Azevedo

A number of clinical studies have reported that bone marrow-derived cells contribute to the production of clotting factor VIII (FVIII), the molecule linked to hemophilia A. Because the current treatment for this bleeding disorder is associated with some disadvantages and risk, hematopoietic stem cell transplant (HSCT) has become an emerging therapy approach for these patients.

In this study, researchers describe the case of a 4-year-old boy with mild congenital hemophilia A who underwent a successful HSCT.

The research paper, “Successful Allogenic Haematopoietic Stem Cell Transplantation in a Boy with Hemophilia A and MDS-RAEB,” was published in Klinische Padiatrie.

Treatments to manage hemophilia A, a disease caused by a deficiency of FVIII, has led to an increase in patients’ life expectancy. But risks exist, including developing leukemia or other neoplasia later in life, along with elevated incidences of diseases like HIV and hepatitis C.

This may indicate that more patients with hemophilia A and other bleeding disorders may need HSCT. While the liver is the main production site of FVIII, some studies have also reported a contribution of bone-marrow derived cells to FVIII-production, but little is known about the clinical relevance of this fact.

In this study, researchers said the boy who underwent allogeneic (from a donor) HSCT was first assessed at age 2, when he presented with easy bruising, prolonged partial thromboplastin time (PTT) — a test used to assess how long the blood takes to clot — and marked thrombocytopenia, the clinical term for platelet deficiency.

However, due to an unremarkable bone marrow analysis and a recent upper airway infection, the symptoms were attributed to another condition and ultimately resolved.

At age 4, the boy presented again with increasing bleeding symptoms and prolonged PTT and he was eventually diagnosed with mild hemophilia A with a residual FVIII-activity of 18 percent in absence of FVIII-inhibitors. Additional examinations revealed MDS-RAEB (myelodysplastic syndrome-refractory anemia with excess blasts). MDS is considered a type of cancer and occurs when the blood-forming cells in the bone marrow are damaged, which leads to low levels of any type of blood cell.

After HSCT, the FVIII activity spontaneously increased to a maximal level of 45 percent, remained elevated for four weeks, but ultimately declined to pre-HSCT levels two months later. The child’s recovery to the procedure went well, with no associated toxicity or immune system rejection.

“At the last follow-up the patient was well and in stable hematological remission. F-VIII-activity was 19.6 percent and he did not present any bleeding symptoms,” the researchers wrote.

Despite limited resource studies evaluating HSCT for hemophilia A, the researchers concluded that the procedure is not clinically relevant in terms of FVIII production.

“Although the experience is very limited, current clinical studies do not provide evidence for a relevant contribution of donor bone marrow-derived progenitors to FVIII-synthesis,” they wrote.

source: http://hemophilianewstoday.com/2016/09/01/successful-allogenic-stem-cell-transplant-boy-hemophilia-a/ 

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
 .
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/