Almost two millennia ago, the Jewish people apparently knew more about the hereditary bleeding disorder of hemophilia than anyone else did at that time.
Rabbi Judah Hanasi (Judah the Prince), who compiled the Mishna, decreed that if two brothers died of hemorrhaging after being circumcised, other brothers should not undergo a brit mila. This ruling, described in the Talmud, was officially codified by later sages, including Maimonides.
The first medical description of the disease had to wait until 1893.
As medicine advanced, rabbis ruled that if coagulation tests show that a firstborn male baby’s blood does not clot, he, too, should not face the danger of uncontrolled bleeding to which he would be exposed by the Jewish ritual.
The disease is in fact a group of several types that reduce the body’s ability to control the coagulation of the blood. Hemophilia A, the most common, means the individual lacks clotting factor VIII (8); this occurs in one out of 5,000 to 10,000 male births. Hemophilia B is caused by a deficiency of factor IX (9), which affects one in 20,000 to 35,000 baby boys.
April 17 was marked in Israel and abroad as World Hemophilia Day to raise awareness of the condition, for which there is no cure, but for which effective treatment exists.
The defective gene that causes the disease is located on the X chromosome. Since females have two and males XY pairs, males are much more likely to get hemophilia than females because the chance of a girl inheriting two defective copies of the gene is rare; she would have to be the daughter of a hemophiliac father and a carrier mother.
Females, however, can be unaffected carriers.
The disease shows up, however, in boys with only one defective X chromosome.
There is also hemophilia C, caused by the lack of factor XI (11), and this occurs most often in Jews of Ashkenazi origin and can cause the disease in both males and females.
But among these three types, there is an even more serious complication – inhibitors.
Due to genetic, ethnic and other causes, about a fifth of hemophiliacs will develop an antibody after too-frequently having to receive injected factor clotting concentrates to prevent or control episodes of bleeding. The body’s immune system starts to regard the factors as foreign substances and to reject them, thus producing inhibitors that make the drugs useless.
FORTUNATELY FOR the estimated 3,500 people who have developed such inhibitors and thus face life-threatening bleeding, a Swedish physician and scientist spent decades finding a solution to the inhibitor problem. Now retired at 79 from the Denmark- based pharmaceutical company Novo Nordisk, Prof. Ulla Hedner travels the world explaining how she did it.
Hedner, who first visited Israel in 1987 and has many scientist friends here, recently visited here for two days and lectured before physicians, scientists and pharmacology experts.
“My daughter worked in a kibbutz,” she told The Jerusalem Post in an interview, “and I have been here many times.” That daughter completed a thesis on a Judaic subject and today teaches Judaism in Sweden, even though the family is not Jewish.
Born in 1939 in Sweden, she was raised by a pharmacist father who first introduced her to the local hemophilia clinic, and her mother, who was a teacher. Ulla’s husband was a physician, and her two brothers are as well, both working in diagnostic radiation.
But although she graduated from the University of Lund’s medical school and worked for a while on psychiatry wards, she was more interested in biology and biochemistry.
“The human body is so interesting.
During my first summer break from medical school in Malmö, I worked in a blood clotting center, and it was there that I learned about hemophilia,” she recalled.
People born with hemophilia used to die at an average age of 16. They could play but had to be protected all the time with padding on their knees, helmets on their heads and carpeting on the floors. Many homes included padded rooms where affected children would play safely.
In the late 1950s and much of the following decade, fresh frozen plasma (FFP) was the main treatment for both hemophilia A and B. Each bag of FFP contained tiny amounts of factor VIII and factor IX extracted from human plasma, thus tens of thousands of units had to be processed to produce enough to save a hemophiliac from uncontrolled bleeding. Children losing their baby teeth could suffer from deadly hemorrhages, as could those who stumbled and skinned a knee or elbow. Untreated bleeding into joints often caused disease with disabling deformities.
The next major advance, in the mid- ’60s, occurred when scientists found a way to make factor VIII from FFP by thawing it as cryoprecipitated plasma and then storing it as a frozen concentrate that didn’t take up so much space. Later, the factors were freeze-dried.
But then, forms of dangerous hepatitis appeared, followed by the AIDS, ebola virus and “mad cow” disease that can make infusions of factors from plasma a serious risk to health. Many hemophiliacs were infected from such patients’ plasma – until it was realized that they could be heated to kill the viruses. Blood donors were screened for hepatitis, and HIV screening took a while longer.
Finally, the factors were produced through recombinant DNA methods in which molecules are created in the lab by amassing genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms.
These forms did not carry the risk of infection. Factor VIII was successfully cloned 30 years ago, and when approved by the licensing authorities in 1992, it was a boon to patients.
There are 586 hemophiliacs in Israel, one per 16,000 residents. “They are of all races and ethnic groups,” said Hedner, who was an expert in clinical chemistry at the University Hospital in Malmö and was professor in clinical coagulation research at the University of Gothenberg and the University of Lund. Hedner was also a visiting scientist at the University of Washington for two years. She has published over 250 medical articles in her field of hemostasis – the process of getting bleeding to stop. In 1983, she joined Novo Nordisk – which in the past 90 years specialized mostly in insulin and diabetes treatment – specifically to work on a method for producing the first treatment for hemophiliacs with inhibitors.
“There were then six patients with inhibitors in all of Sweden,” said Hedner. Her first died of AIDS. But her second was a 12-year-old Swedish boy named Johann who suffered life-threatening bleeding when his baby teeth began to fall out.
“Even biting one’s tongue and bleeding is enough to send patients to hospital,” she related. “We are so easily damaged if we don’t have the right proteins; one can bleed to death.”
The boy’s parents were forced to take him for weeks of treatment with each episode involving inhibitors. Hedner knew little about pharmaceutical industry and the huge investment it takes to produce new drugs, test them and get them approved.
The process of developing a recombinant drug is very complex, and she worked with hamsters, rabbits, dogs and monkeys.
The fact that treatment for hemophilia with inhibitors would be an “orphan drug,” to treat relatively few patients and thus generate little profit, complicated things even more. But Novo Nordisk, which puts much stress on community service in addition to profits, took up the challenge. “The company’s entry into the world of hemophilia was one that nobody could have predicted. It was born out of the principles that make Novo Nordisk a global leader within its field – the commitment to change. I’m really happy to say, with the new innovations, as well as the pipeline projects, that Novo Nordisk is living up to all my expectations.”
Hedner was determined to save Johann’s life and those of others like him and decided that factor VIIa – which is located in the blood vessel walls and had previously been ignored – could be the answer to his type of hemophilia. She purified a minuscule amount from human plasma, and hearing from his mother that another tooth was about to fall out, took the train to his hometown hospital to give him the first dose. It worked! “Johann was the proof of concept. I gave it to him twice, and he formed a clot. The infusion takes only a couple of minutes.”
Johann is alive today, and works as an economist in Stockholm, living a near-normal life. Hedner’s initial work on human plasma to make factor 7a eventually led to a synthetic form. Thousands of patients owe their lives to her Recombinant Factor 7a drug, which she developed under Novo Nordisk’s auspices.
Her drug lost its patent protected last year. “There is a company in Iran, of all places, and another in Russia that make unauthorized generic recombinant factor7a,” she says. Novo Nordisk has even established a $7,000 scholarship in her name for high school seniors and college or vocational students who suffer from a bleeding disorder, including factor VII deficiency.
Unlike in Israel, where creators of new drugs such as Copaxone or Exelon earn handsome royalties, in Sweden, drug developers are salaried employees of pharmaceutical companies or research institutions.
However, the company arranges trips for her around the world to discuss her work, and she has been to dozens of countries, including Lebanon, Jordan, Iran and Saudi Arabia – but Israel is one of her favorite places.
“I have always been impressed by the quality of Israeli scientists,” she says.
Retired from Novo Nordisk for five years, she also spends a lot of time with her two grandchildren.
THE DRUG is not free of complications. It can occasionally cause unwanted thrombotic events in the cardiovascular system.
“One has to watch patients very carefully, but it has been very successful.”
“China is catching up in medical treatment and drug development, as are India and Vietnam. But people still die of hemophilia in the developing world because they don’t have access to the drugs that would save them. Africa is still a black hole for us.”
Genetic counseling is given in Western countries to prevent the conception of hemophiliacs in carrier families. Amniocentesis is performed on women carriers to see if their fetuses are affected. “Some women who know there are good drugs in the event of hemorrhaging say such testing is unnecessary because there is treatment,” said Hedner. “However, I don’t think the numbers of people with hemophilia will decrease, but at least they will have longer lives and are able to contribute to society.”