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Photo by Daniel Kahana

Roland is one of dozens of hemophilic dogs Dr. Monica Revel hopes to help by raising awareness and funds for a second-ever gene therapy study focusing on pet dogs with the genetic bleeding disorder.

Dr. Monica Revel has neutered countless dogs, with few hitches, in her more than two decades as a small animal veterinarian. So she was flummoxed in 2023 when the incision she made in a cockapoo puppy named Roland started oozing and bleeding during recovery.

The surgical site looked terrible, she said during a recent call from her Southern California practice. She reopened the incision to double-check her work and could find nothing amiss. "I didn't know what I had done wrong," she said.

The oozing stopped before Revel discharged Roland with strict instructions for the owner to head to an emergency hospital if it resumed. Then, she anxiously awaited word on the blood sample she'd sent to her regular diagnostic laboratory.

"I was up all night refreshing the website, waiting for those results to come in," Revel said. Sometime in the wee hours, she learned that the time it took Roland's blood to clot, measured by a test known as partial thromboplastin time, or PTT, was longer than normal. The result triggered the memory of a study mnemonic she devised during her first year of veterinary school: "Slightly elevated PTT, that's hemophilia A or B."

Hemophilia is a relatively rare genetic coagulation disorder that causes excessive bleeding. In severe, untreated cases, it can kill.

On learning the bad news, Roland's owner took the 8-month-old puppy directly to a specialty hospital, which confirmed the diagnosis through the Comparative Coagulation Laboratory at Cornell University, the only lab in the United States that routinely performs hemophilia tests for veterinary patients. The hospital staff brought Roland's bleeding under control with a blood product transfusion, a standard treatment for hemophilia.

In the two years since, Roland has needed three more transfusions. Dogs with severe hemophilia may need a half-dozen or more transfusions a year.

The experience motivated Revel to dive deeply into the disease, which she had never seen in a patient before. That's true for most veterinarians.

She soon discovered that a gene therapy technique to correct a genetic mutation in the liver cells — where most of the essential blood-clotting factors are produced — had been shown in research to reduce bleeding episodes. She also learned that a dozen pet dogs had received the gene treatment in the past decade as part of a proof-of-concept study published last year on the use of gene therapy for humans with hemophilia.

The therapy is now available for human patients. But although its development was based on research in laboratory dogs, no company has sought approval from the U.S. Food and Drug Administration's Center for Veterinary Medicine to provide the treatment to veterinary patients. For now, the therapy can be administered to dogs only in a research setting.

Revel is determined that more pet dogs, including Roland, should have access to gene therapy. She tapped into a small but mighty coterie of physicians, veterinarians and researchers, many with several decades of experience in hemophilia. She's found willing partners in her effort to open another study. Now, under the umbrella of an organization called Hemophilia Hounds, she's trying to raise $50,000 to $100,000 to pay for the vector and to bring together owners of hemophilic dogs wanting to participate in a study. 

Identifying and caring for a 'glass animal'

An inherited disorder that is carried and passed on by the mother, hemophilia is caused by a deficiency in one of the blood proteins, called factors, that control coagulation. It most often occurs in males. 

Hemophilia A, sometimes known as classic hemophilia, is caused by a factor VIII deficiency. Hemophilia B is caused by a factor IX deficiency. Of the two types of hemophilia, A is much more common. About 103 new hemophilia A cases are diagnosed in male dogs in the U.S. each year, compared with approximately 10 hemophilia B cases, according to numbers provided by the coagulation lab at Cornell.

Revel, who has been actively seeking dogs with hemophilia A for the Hemophilia Hounds project, said she is aware of about four dozen dogs with hemophilia A in Australia, Canada, the Cayman Islands, England, Ireland, Germany, Poland, Scotland and the United States.

It is believed that hemophilia can occur in all mammals. Hemophilia A affects around 12 in 100,000 men in the U.S., according to the National Bleeding Disorders Foundation.

The disease is often diagnosed in dogs before they are 1 year old. Clinical signs include subcutaneous hematoma, a swelling caused by blood pooling under the skin; intermittent bleeding at an injection site, such as for a vaccination; prolonged bleeding of the gums as baby teeth emerge; abnormal bleeding from minor wounds or due to surgery, as in Roland's case; lameness due to bleeding into joints; bleeding into the chest or abdomen; and even bleeding into the brain or spinal cord, causing neurologic abnormalities.

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Photo courtesy of Regina Butler

Bleeding in the joints is a common condition for dogs with hemophilia. Bandido, one of a dozen pet dogs to receive gene therapy for hemophilia, is shown being treated with ice packs to stem a joint bleed.

Caring for a hemophilic dog is stressful. One veterinarian told Roland's owner that he should treat the puppy like a "glass animal," according to an account on the Hemophilia Hounds website, which gives the stories of several affected families as well as information for veterinarians and pet owners on managing dogs with hemophilia.

Caring for a hemophilic pet is also expensive. The conventional treatment for bleeding due to a severe factor VIII deficiency in a dog includes transfusions of fresh or fresh frozen plasma, or ideally cryoprecipitate, depending on what is available. Cryoprecipitate is a precipitate of fresh frozen plasma made from thawing, and it contains high concentrations of factor VIII. A transfusion can provide enough factor VIII to stop active bleeding, although it sometimes takes more than one transfusion.

Treatments for a severe factor IX deficiency (hemophilia B) include transfusions of fresh frozen plasma or cryosupernatant (also called cryo-poor plasma). The latter is a byproduct of the production of cryoprecipitate and does not have high concentrations of factor IX.

A single transfusion can cost as much as $1,000; a full ER visit with multiple transfusions can run up to $10,000.

"Some dogs will be put down at some point because their owners can't afford to keep transfusing them," said Dr. Mary Beth Callan, an internist focused on hematology and transfusion medicine at the University of Pennsylvania School of Veterinary Medicine, or Penn Vet.

Lessons from research dogs

Most of the information and tools for managing hemophilia in dogs have come from laboratory dogs at universities, where researchers have studied therapies for the treatment of hemophilia in humans for seven decades.

One of those facilities is the Francis Owen Blood Research Laboratory at the University of North Carolina, Chapel Hill. It was started in 1947 with the purchase of two female dogs that were carriers of hemophilia A. The descendants have been continuously maintained and augmented by dogs with hemophilia B and von Willebrand disease, another bleeding disorder.

"During the 78 years that the dogs have been here in Chapel Hill, they've been on every major advance that has occurred in treating hemophilia," said Dr. Timothy Nichols, a physician and professor who directs the lab. Those advances at UNC began with the development of the first diagnostic assay for hemophilia (the aPTT, a version of the test Revel used for Roland). That was followed by simple blood products; factor concentrates; biochemically complex blood products that, for example, help the factor last longer in the bloodstream; and tools for gene therapy.

The nadir for everyone involved in hemophilia research and treatment came during the AIDS epidemic in the late 1970s and early '80s. Hemophiliacs were unknowingly transfused with plasma products contaminated with the human immunodeficiency virus (HIV) and hepatitis C. Many were infected and died. The crisis spurred the development of safe products, such as purified factor VIII, as described in a 2010 paper by the hematologist Dr. Gilbert White.

Nichols said dogs are excellent models for hemophilia research for two reasons.

First, he said, "If it works in dogs and it's safe in the dogs, it tends to work in humans in a parallel way."

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The second reason has to do with the randomness of bleeds in hemophilia.

"You can be looking at a dog or a human being, and they look fine, and an hour later, you look back and they have an incredible hematoma," often with no discernible cause, Nichols said.

The dogs at the lab have between six and 10 bleeds a year that require blood products and significant medical therapy, including infusions of concentrated factor.

"If you're trying to find a model of a random event … the dog is your model," Nichols said. "That's something you can't do with artificial intelligence, an organ on a chip, or an organoid. You have to have flowing blood in a living animal that's doing what living animals do."

Robin Raymer, research operations manager for UNC's blood research laboratory, has been caring for its dogs for more than 40 years, working closely with attending veterinarians from the university's Division of Comparative Medicine, who provide all the veterinary care. In her decades in the lab, she has learned a lot about managing their unique health challenges — lessons she willingly shares with outside veterinarians and private owners who find the lab while seeking information and help for "bleeder" dogs.

"It's really been eye-opening for me to find out just how little information is out there for veterinarians," Raymer said. From her experience, "learning it and living it and dealing with it every day," hemophilia is more manageable than most people think.

For example, transfusions aren't always necessary, she said. For a laceration that is bleeding, suturing even tiny cuts, steady use of bandages, elevating limbs, applying pressure, and keeping a dog calm are all helpful. For joint bleeds, the team deploys ice packs, analgesic drugs and strict rest. She said they also regularly draw from human medicine, giving the dogs tranexamic acid and aminocaproic acid, medications that prevent the breakdown of blood clots.

In the case of transfusions, Raymer reminds veterinarians that supplemented factors retain their full potency for only a limited time in the body, as few as eight hours in the case of factor VIII. "Many vets want to wait and watch after one transfusion, but in the event of a life-threatening bleed, they should plan for at least a second transfusion about six to 10 hours from the first one," she advised.

Bringing pet dogs into the mix

Pet dogs had their first chance at gene therapy thanks to a persistent pet owner, according to Callan, the Penn Vet hematologist who was one of the researchers on the companion animal studies. She recalled that in 2013, the owner of a Staffordshire bull terrier with hemophilia living in Greece contacted Dr. Kathy High, a researcher at Children's Hospital of Philadelphia (CHOP).

"It was a little bold of her," Callan said, thinking back. At the time, High was a pioneer in a gene therapy used to treat hemophilia. The therapy uses a viral vector to carry a working copy of a gene to cells in a patient's body to counter the genetic defect that causes the disease.

The terrier owner's effort paid off. High recruited Callan, and Penn Vet provided the care for the study pets. The Clinical Vector Core, a nonprofit manufacturer of viral vectors at CHOP, produced the vector for the dogs, and UNC determined the gene mutations that caused the hemophilia in the participating dogs.

Initially, they treated two dogs, introducing the vector intravenously. The promising results were published in 2016. That study was expanded to include 10 more dogs. All 12 experienced improvements in their factor VIII or IX levels.

"We were able to convert the dogs with severe hemophilia to moderate or mild," explained Dr. Benjamin Samelson-Jones, a pediatric hematologist and researcher at CHOP and a co-author on the paper.

He noted that the study dogs' factor levels remained abnormal, the gene therapy didn't completely stop bleeding episodes, and that given surgery, they probably would still need a transfusion treatment. "But what they don't have or what would decrease in frequency is spontaneous bleeding, which is really the hallmark of severe disease," he said. "So instead of having bleeds 12 to 24 times a year, it might be one or two."

The experience of one of the dogs in the companion animal study — a flop-eared German shepherd mix named Bandido — illustrates Samelson-Jones' summary of the findings.

The dog had been given up to a veterinary clinic in Texas after his family could no longer afford his hemophilia treatments. Through the network that set up the study, he came to Philadelphia, where he received gene therapy and was adopted by the son of Regina Butler, the chief hemophilia nurse at CHOP.

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Photo courtesy of Regina Butler

After receiving gene therapy along with 11 other hemophilic pet dogs, Bandido had only one to two serious bleeds a year despite regular long hikes and playing with young children.

Butler, who has treated hemophilia patients for 51 years, helped her adult son care for Bandido. Unlike most dogs with hemophilia, Bandido lived a full life, going on long hikes and roughhousing with Butler's two young grandchildren. "We didn't treat him any differently than another dog; he wasn't protected," Butler said.

Although Bandido did have occasional breakthrough bleeds once or twice a year, they were less severe. By watching a YouTube video, Butler and her son learned to infuse the dog with a canine factor VIII created at CHOP. 

Ultimately, Bandido lived almost 11 years, a typical lifespan for a large dog.

Callan and Samelson-Jones said they believe a new study could have value beyond bringing the gene treatment to a handful of pets.

They point out that the project would allow researchers to expand the number of dogs studied and gather prospective quality-of-life data. In the previous study, some owners were asked to recall aspects of their dogs' health and behavior going back several years. New research would also provide a chance to test the latest generation of vectors, which are constantly evolving.

Hoping to change lives

Mercedes Segura, a chemical engineer in Boston, dreams of a life like Bandido's for her dog, Teddy. The red miniature poodle was diagnosed with hemophilia A after developing a large hematoma during a stay at a pet hotel in January 2024. He had just turned 1 year old.

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Photo courtesy of Mercedes Segura

From right: Mercedes Segura with daughter Nina (holding Teddy), son Logan and husband Gavin hope a new gene therapy can improve the life of their hemophilic dog.

His most frequent signs are limping episodes caused by bleeding in his joints. "It's extremely hard because you gotta be very careful with the dog," Segura said. "All the dog wants is to play, and we have to limit his exercise."

In her refrigerator, she keeps three different analgesic drugs, plus tranexamic acid, a medication that is supposed to boost what little coagulation activity he has.

"In the worst times, he literally is like a different dog," she said. "He's laying down, he doesn't want to move. I bring him the food. I bring him outside. He's limping and falling." More than once, Segura has discussed euthanasia with her veterinarian, but Teddy always bounces back after a day or two, and they carry on.

Now she is pinning her hopes on the Hemophilia Hounds effort, albeit tempered by knowledge of the challenges ahead. Segura has worked at several biotech companies, leading the teams that develop processes for manufacturing new cell and gene therapies, including vectors, for use in humans. She knows how hard it will be to get a study off the ground. She has offered to help Revel, the veterinarian leading the effort, in any way she can.

"Just the thought of enrolling Teddy in this and doing the fundraising and going through the motions is very rewarding," Segura said, "because it could potentially change his life."