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The Meaning of Life

How does a sixteen-year-old boy react when he is told he has less than a year to live? When Brent developed pneumocyistis pneumonia, a complication of AIDS as a result of HIV infection from contaminated AHF he had infused many times to treat hemophilia, his doctor soberly told him that at most, he had a year to live.

Brent became discouraged and told his mother that maybe his life was not meant to have any meaning. Hemophilia was not too bad, he could live with it, but AIDS was a death sentence.  His mother responded saying to him that what keeps people going when confronted with hopelessness is the recognition of the meaning of their lives. The meaning of his life was more than making him happy.  It was about making her and his family happy. She reminded him that his life had contributed a great amount of pleasure and happiness to others.

Brent responded by suddenly quitting school when a meeting was scheduled with the high school principal and teachers to inform them that one of their students, Brent, was infected with HIV.  Rather than surrendering and let them expel him from school, when they learned that he was HIV infected, he would choose his own destiny.  He could not choose the circumstances or conditions of his life but he could choose how he reacted to them. He discovered that his life had meaning and he would choose his own existence. During his short life he had enriched the lives of his family and others. He chose to be upbeat rather than downbeat. Recognition of the meaning of his life empowered him.

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Progress in Hemophilia Treatment

There is an adage saying that sometimes when good things are done, bad things happen. In the case of hemophilia, a counter reply could be that when bad things occur, sometimes good things happen.  Recalling the dark days of the early 1980s, the days when HIV and hepatitis-contaminated AHF concentrates leading to premature death, there is a remarkable contrast with the present treatment of hemophilia that has been emerged over the past thirty years. Life expectancy in hemophilia was cut short because of AIDS, the result of HIV contaminated concentrates.

In contrast, in 2011 life expectancy in hemophilia is more than sixty years and nearly approaching normal longevity. This remarkable advance came into being because of the great tragedy of AIDS. Research following the discovery of HIV has resulted in safe, deviralized plasma-derived AHF and recombinant AHF.  Since the beginning of their use as FVIII and FIX replacement treatment there have been no instances of virally transmitted diseases from AHF concentrates. The safety and dependability of these products has allowed children to progress without deformities or suffering from agonizing painful joint bleeds. The threat of intracranial hemorrhage, that claimed the lives of children in the past,  has been greatly reduced.

Although the development of recombinant AHF was complex, the experience has been valuable in preparation for the next generation of treatment modalities. Added to this experience has been the discovery of the nature of the retrovirus, HIV.  The acquired knowledge is now being applied to the development of gene transfer to hopefully cure, not just treat, hemophilia. When gene transfer becomes successful in the treatment of hemophilia, rather than AFH infusions every two or three days, a person would require an injection treatment only every four or five years or maybe even only once in their lifetime.  Hemophilia is regarded as a model system for developing the strategies for the treatment of genetic disorders.

Researchers have developed adeno-associated viral vectors that transfer the inserted FIX gene into the muscles of  mice and canines as well myotube cultures of human muscle cells resulting in the production of human Factor IX.  After discovering that some mutations in hemophilia are the result of transposons, segments of DNA that jump around or are transposed, attempts are under way to insert the FIX gene into a transposon to deliver the transposed gene to cells that could make FIX.  Hemophilia research has advance because there are model animals, mice and canines, for experimentation before applying the developed methods to humans.

Although there are hurdles to jump in the pathway to curing hemophilia by gene transfer, for FVIII and FIX, the progress made so far is exciting and appears to be as likely to make as great a change in hemophilia care within the next thirty years as was witnessed in the last thirty years.

Although infection with hepatitis and HIV were tragic events in the past treatment of hemophilia, they were the impetus that spurred progress in new treatment modalities. The memories of those who died will be brightened when gene transfer becomes a reality and hemophilia is cured.

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Hemophilia 101: What is it, and How is it Treated?

What is Hemophilia?

Persons affected by hemophilia have a disturbance in their blood coagulation. Blood circulates many many times in its endless course through a person’s blood vessels without leaking. Damage to a blood vessel may result from a noticeable injury such as a twisted ankle, or even an unnoticeable event such as bumping into the corner of a table.

Bleeding episodes in hemophilia are recurrent, as often as every three or four days, with many persons experiencing more than 1,000 hemorrhages during childhood and adulthood.

When a blood vessel is damaged, allowing blood to escape, a person’s body reacts in three different ways:

  1. First, adrenalin is released by the presence of injured tissue producing vasoconstriction (that restricts the flow of blood in the injured blood vessel).
  2. Secondly, platelets from the blood stream are attracted to the site of injury in the blood vessel wall. The platelets form a plug to stop the bleeding.
  3. Thirdly, fibrin is laid down in the platelet plug to give it strength and allow the plug to retract promoting healing to take place. In a person who has hemophilia, the third step–fibrin cementing of the platelet plug–is deficient. As a result, the platelet plug that forms does not solidify; it is mushy. Oozing of blood continues sometimes for days that may be visible as a bruise or a painful hemorrhage referred to as a bleed by persons who have hemophilia.

Fibrin does not circulate normally in blood. If it was always present, an undesirable blood clot might form resulting in a stroke or heart attack.   Fibrin requires activation from its precursor, fibrinogen, by another blood protein, thrombin. And thrombin must be activated from its precursor, prothrombin. Two of the proteins that activate prothrombin are Factor VIII and Factor IX.  In the most common type of hemophilia, Hemophilia A, Factor VIII is deficient. In persons who have Hemophilia B, Factor IX is deficient.  The antihemophilia factors , AHF, activate prothrombin to form thrombin that activates fibrinogen to fibrin during blood coagulation to form a firm platelet plug while healing takes place in the injured blood vessel wall.

Persons who have Hemophilia A and Hemophilia B have a mutation in their Factor VIII or Factor IX gene. Both genes are on the X chromosome. Several different mutations in both genes have been described.  Although multiple molecular defects have been discovered, they all have nearly the same medical effect.  The most common hemophilia mutation, intron 22 inversion, accounts for one-half of Factor VIII deficiency.

Hemophilia Facts:

  • In the USA, approximately 400 babies are born each year that have hemophilia with a frequency at birth of 1 in 7,500 newborn males.
  • One-third of newborn babies with hemophilia are the first instances in their family. However, the mothers of such infants may be carriers of hemophilia by receiving mutant sperms from their non-hemophilic fathers when they were conceived.
  • Hemophilia nearly always occurs in males and is present in all countries and ethnic groups.  Males who marry and have children will transmit their mutant hemophilia gene to all of their daughters and none of their sons.

Hemophilia Treatment

Prior to 1960, life expectancy for a person born with hemophilia in the USA was eleven years.

The most common life threatening hemorrhage was an intracerebral bleed. Those who survived severe hemophilia suffered and were disabled from recurrent joint bleeds. During childhood, recurrent bleeding episodes were sometimes as frequent as several times each week. With advances in Factor VIII  and Factor IX AHF replacement treatment, painful suffering and life threatening hemorrhages in hemophilia have been greatly diminished.

Following the turmoil in hemophilia treatment caused by HIV infection and death from AIDS,  improved AHF from plasma-derived Factor VIII and recombinant Factor VIII and Factor IX is restoring life expectancy toward normal and minimizing agony and suffering from recurrent hemorrhages in countries of high income where a method of payment for AHF exists.  With replacement AHF, persons with hemophilia are able to attend school without bleeds interfering with their attendance, attain dental care, and even withstand surgery.  They can become productive adults with the security of employment. Marriage and having a family are attainable.

Hemophilia will never disappear.  There will always be new mutations as part of human nature. But there may be a cure someday, more than just treatment, with the further refinement of gene transfer.  Hemophilia will probably be one of the first genetic disorders to be cured with gene transfer.

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Cost of Treatment: An Obstacle to Hemophilia Care

A second hurdle has appeared in the path to treatment of hemophilia.  After the introduction of commercially available Antihemophilia Factor for treating hemophilia with Factor VIII and Factor IX in the early 1970s, life completely changed for those boys and men who suffered pain and agony, becoming disabled ending with a short life expectancy prior to the new AHF concentrates. For 10 years life for persons with hemophilia was sailing along almost equal in quality to a person without hemophilia.

The first hurdle that interrupted the treatment was the contamination of the new medicine with HIV and hepatitis viruses.  Many persons died of AIDS or liver failure as the result of the viruses in the medicine. By 2008, in person with hemophilia, 13,083 developed AIDS.   Those days are past as the result of the entrepreneurship of the pharmaceutical manufacturers who have  produced safe medicines utilizing advanced methods  including genetic engineering resulting in a recombinant AHF.  Plasma derived AHF has been deviralized and made safe.

The second hurdle in the path of treatment for hemophilia is cost.  The comprehensive study of Factor VIII use around the world by Stonebraker and colleagues ( 2010) revealed that medicine to treat hemophilia is used primarily in countries with high incomes. One-half or more of the hemophilia persons in the world receive inadequate or no treatment. Most low income countries have other conditions that receive a higher priority such as infectious disease, malaria, violence, natural disasters and inadequate economic development.

The population of the United States, 310 million compared to the world population,  7 billion, is only 4.7%. The annual world production of Factor VIII totals 6.9 billion units (2008). However 12,000 persons in the USA use 2.06 billion units amounting to 30% of the world production. The infusion of Factor VIII per person in the USA averages 171,670 units annually. When recombinant Factor VIII is used at $.90 -$.95 per unit the cost per person annually equals or exceeds $150,000.

Selling Factor VIII in the USA is possible despite the high costs because there is a way to pay for it.  In countries of low income, no method of payment exists.  Should there be a needed medicine that is available but not affordable?  The United States is a country of high consumerism. But it is also a country of high pollution. As a result of the contribution to global warming and pollution of the ocean with plastic debris by the USA, an economic effect has been felt in poor countries as their fishing has declined.  Citizens have been deprived of an income and cannot pay taxes.  There is no way to buy expensive medicines.

A solution might include transferring the modern technological methods of Factor VIII production to countries of low incomes while retaining domestic production of the medicine for use in the U.S.A.  The U.S.A. has an obligation to assist in the world economics. There are cars in the world and they cannot all be made in America. Similarly, the world’s production of Factor VIII cannot all be made in America. The production of Factor VIII by U.S. pharmaceutical manufacturers of medicine to treat hemophilia would not be threatened by assisting low income countries to produce their own medicine, for presently there are almost no sales of medicine to the countries of low income. The establishment of facilities to produce the medicine in other counties must be completed by the pharmaceutical industry, not the federal government.

Just as Nike makes shoes in Malaysia, Wyeth, Pfizer etc could make Factor VIII in Pakistan or Somalia. The drug companies would monitor and supervise and assist in production. Rather than selling poor countries AHF medicine, let’s show them how to make their own.  Such an action would create employment, relieve suffering and contribute to a better world.

-Everett Winslow Lovrien, M.D.

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St. Patrick’s Day: 3 Things We are Lucky to Have as Americans

  1. Let's hope for some luck of the Irish!

    HTC: We are Lucky because the federal  government in the USA successfully demanded that all persons in the USA who have hemophilia should be identified followed by a heath care plan for each individual. The first step in establishing good medical care is the identification of those who need it. In 1976 The Children’s Bureau of Health and Human Services  established and funded the Hemophilia Treatment Centers (HTC) in each of the ten Health Region of the country. Before then, many patients in the USA were not identified and did not receive adequate care.

  1. AHF:  We are lucky in the U.S. because we have a pharmaceutical industry where innovation in the development of medicines flourishes.  Research and development of AHF clotting Factors has resulted in the production of safe plasma-derived AHF and recombinant AHF for both Factor VIII and Factor IX types of hemophilia. The availability of replacement AHF therapy has increased life expectancy. Improvement in the quality of life for persons who have hemophilia includes dental and surgical procedures, regular attendance at school, ability to maintain employment, marriage, raising and supporting a family.
  1. Source of AHF: We are lucky to have a system of distribution and availability of AHF.  A medicine that is not available or that is unaffordable is useless.  A responsibility of the HTC is to recognize the need of AHF for hemophilia patients and to identify a method of payment for the cost of the medicine.  For each patient a reliable source of AHF is identified. No person who has hemophilia should lack medicine because of the cost of the medicine.   The availability of replacement AHF for infusions at home allows a patient to assume independence and responsibility accompanied by freedom and control of their lives.

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‘Doctor Guilt?’ Excerpt: Home Infusion Therapy

This excerpt is from Doctor Guilt?, pg. 250. These remarks are from Dick Wagner:

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Hemophilia Heroes: Inspirational Patients

David and Peter Witbeck faced life-threatening illness, painful procedures and discrimination, but left a lasting legacy in their community

The shocking discovery of hemophilia in David Witbeck followed circumcision in 1975. His mother, Carmelita, practiced inserting a needle into a ripe orange to acquire the necessary skill to infuse him intravenously with medicine to treat his recurrent bleeding episodes. A brother, Peter, was born three years later in 1978 who also had hemophilia.

Carmelita brought her two  young sons and their infant sister 200 miles to our clinic on a greyhound bus, to learn how to care for them in the small logging town in the mountains where they lived in a little house with a dirt driveway. The painful repeated bleeding episodes were relieved by their mother’s infusions of medicine. The mother sold her piano to help pay for medical expenses.

In 1985, when the brothers were ages ten and seven, tests revealed that they had become infected with HIV from the medicine they had received. To be closer to a hospital where they could receive medical care, the family moved from the mountains into a larger town. However, their admission to the public school was opposed by the parents of other school children because of the fear of AIDS. To avoid stressful confrontation, the brothers and their family returned to their mountain community where they previously lived.

The two brothers died of AIDS, one day apart, the day after Christmas in 1992. David was seventeen; Peter was fourteen.

Their lives had a profound effect on their community.  Despite their many days of pain and illness, they never complained–although they suffered from two life-threatening medical burdens, hemophilia and AIDS. Their lives were a message of the importance of love.  The local newspaper and the little town where they lived in the mountains proclaimed them as heroes.

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