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Hemophilia is one of the most well-known rare diseases in the world. It is a genetic disease, where men have hemophilia and women are carriers. A person with hemophilia lacks the genetic information to produce one of the proteins needed for blood clotting. Most hemophiliacs have a shortage of Factor VIII, causing hemophilia A, whereas a smaller population lacks Factor IX, causing hemophilia B.

In the mid-1960s, treatment with blood plasma containing high levels of the missing clotting factors became available. These clotting products are injected in a vein, which places high demands on product purity. A substantial proportion of the plasma available was contaminated causing the spread of hepatitis and HIV among people with hemophilia. Today, the threat of viral transmissions via plasma has been minimized, but hemophiliacs remain ‘the canaries in the coalmine’, being the first victims of any changes made to treatment options.

This book serves as a strong plea for European selfsufficiency in ‘red’ blood and ‘yellow’ plasma from voluntary non-remunerated donors. It is disturbing that today’s policy makers pay so little attention to the world of blood transfusion and plasma products. In a neoliberal market economy, the trade in human substances is too easily accepted.

This book tells the story of Cees Smit, who was born with hemophilia A almost seventy years ago. No one ever expected him to survive long into adulthood, much less old age. He survived all stages of medical innovations, with both highlights and drawbacks. Today he is a lobbyist for patients’ rights and the improvement of patients’ position in the healthcare system.

One of his major concerns is the large-scale trade in human blood plasma—a topic he has discussed in various publications since 1979. Amidst the COVID-19 pandemic, this book has even more meaning, urging us to return to the traditional ideals of altruism, self-sufficiency, unity, and solidarity.

This story is a tribute to a large group of professionals who have supported him, including doctors, nurses, friends, and family. It is an homage to the wonderful people he met during the AIDS crisis—most of whom have since died. It is for them that this history of hemophilia, hepatitis, and HIV is written.

Marcel Levi, Chief Executive of the University College London Hospitals, writes in his foreword to the book: ‘Cees Smit’s story is extremely relevant […] the story warns us that caution should be exercised because unexpected side effects can have disastrous consequences. It is also a stark reminder that commercial value and the pursuit of profit are not always in sync with the interests of sick people.’

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CEES SMIT

Surviving hemophilia

A road trip through the world of healthcare

Edited by

Annemarie de Knecht-van Eekelen

With a foreword by

Marcel M. Levi

2020

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IN MEMORY OF THOSE

WHO DID NOT GET THE TIME

TO WRITE A BOOK LIKE THIS

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This book could be published thanks to the generous funding I received from the Stichting Haemophilia and the Landsteiner Stichting voor Bloedtransfusieresearch.

DISCLAIMER

To parents of young children, adolescents with hemophilia, and carriers of hemophilia: Your future will be totally different from my history described in this book. Nowadays, in countries like the Netherlands, with a proper health care insurance system, a choice of treatment options for people with hemophilia is available. I advise you to talk with an experienced hematologist in hemophilia care.

This book reflects my personal experiences and my views on difficult periods in the history of hemophilia care. Although this is a personal account of a life with hemophilia, we have given utmost attention to check the facts described in this book. See our references and illustration credits.

For correspondence: info@smitvisch.nl.

FOOTNOTES

No footnote numbers are used in the main text. Footnotes are to be found at the end of the book and are recognized by the first words of the sentence. This will contribute to the readability of the book.

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Acknowledgements

How to write a book about my own life? What shall I tell? I am almost seventy years old and a lot has happened in my life, too much for one book. Is it necessary to write this book? For whom am I writing? Who wants to read about me? These are some of the questions I asked myself. I discussed my ideas with Dr Annemarie de Knecht-van Eekelen. During the last two decades, I spent quite some time writing and publishing books together with her. Annemarie is a medical biologist by training, and she has a degree in medical history. In 1998, Annemarie published a history of the Van Creveld Clinic (VCK), a center for hemophilia treatment in the Netherlands. From that time on, she became more and more involved in topics on hemophilia and health care. My first publication with her and Dr Eveline Mauser-Bunschoten, hemophilia doctor at the VCK, was Rare Bleedings in Haemophilia (2002), followed by Ageing with hemophilia (2007). After that, more books on health care followed and our cooperation intensified.

To me, it was obvious that – if I would write a book – I would ask Annemarie to assist me. Our first idea was to write a history of hemophilia treatment in the Netherlands and combine this with my personal history. We produced several chapters along this line and asked some good friends to comment on these. One of the commentaries changed our view on what we were trying to achieve. It was Dr Paul Strengers who said: “Why don’t you stick to your personal story, that is interesting enough, you don’t need to cover the whole hemophilia history.”

We took his advice and Annemarie started to rearrange the text we had already produced, while discarding lots of it. I tried to write a personal account of the major events in hemophilia history that I witnessed. Annemarie edited my stories, encouraging me to describe my views and feelings, not only the matter-of-fact happenings. I sincerely thank Annemarie for all her time and efforts to complete this autobiography with me.

As the coordinator of the Dutch Society of Hemophilia Patients (NVHP), and later as a patient advocate, I have plenty of contacts, both national and international. To refresh my memory about international developments, I contacted Brian O’Mahony, the present Chief Executive of the Irish Haemophilia Society, and Terkel Andersen, since 2003 the President of Eurordis. I know them both since the 1990s. Brian previously served as Chair of the Irish Haemophilia Society from 1987 to 2003, as President of the World Federation of Hemophilia (WFH) from 1994 to 2004 and as President of the European Haemophilia Consortium (EHC) from 2011 to 2019. Terkel served as President of the Danish Haemophilia Society from 1985 to 2017. From 1992 to 2002, he was a member of the WFH executive board; and from 1993 to 1999, he was Chairman of the EHC. These international patient organizations play a significant role in this book. Together with Annemarie, I wanted to interview them. We went to meet Brian in Dublin, Ireland, but my participation in a trip to Copenhagen, Denmark, was hampered by a serious bleed. Annemarie went there alone. We thank Brian and Terkel for the time they took to share their thoughts with us.

I also wanted to cover several issues that are close to my heart, topics I have been fighting for during decades. With Piet J. Hagen, I researched the plasma market in the 1970s, at a time when no one could expect the enormous tragedy that would be caused by tainted blood. Piet started his career as a journalist, working for the Dutch newspaper Trouw. He continued at the School for Journalism in Utrecht, the Netherlands, first as a teacher, later as the School’s director. For twenty years, Piet and I published the magazine Faktor, the periodical of the NVHP. I value my friendship with Piet. His comments on the manuscript of this book are greatly appreciated.

Since the late 1970s, I closely followed developments on the plasma market, both in the Netherlands and abroad. When I got a job as the coordinator of the NVHP in 1988, my office was in the building of the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (CLB) in Amsterdam. This made contacts easy, and later, when the NVHP moved out, I continued to be a regular visitor. In 1998, CLB merged with the Dutch blood banks and was named Sanquin. One of Sanquin’s divisions is Sanquin Plasma Products (SPP) that produces medicines from plasma. I enjoy a good relationship with Sanquin that supported my previous publications. The directors and staff are always willing to give me up-to-date information. For this book, we contacted Theo Buunen, Sanquin CEO till 2013; Prof. René van Lier, Sanquin Vice President; Ruud Zoethout, Director Unit CMO SPP; and, of course, Paul Strengers, who started his career at CLB as Head Medical Department in 1986. Later, he became Director Medical Affairs and Product Development of SPP and Executive Director of the International Plasma and Fractionation Association (IPFA). We had many inspiring conversations about the world of blood and plasma donations from an international perspective since the end of the 1980s.

IPFA and its member organizations support the “gift model” of blood and plasma donation without remuneration (Voluntary Non-Remunerated Blood Donation). Another association that works along the same lines, is the European Blood Alliance (EBA), the umbrella organization of the not-for-profit Blood Establishments, with its members throughout the European Union, Iceland, Liechtenstein, Norway, and Switzerland. We met with EBA’s former Executive Director Dr Kari Aranko, and later with his successor Catherine Hartmann, along with Prof. Philippe Vandekerckhove, CEO of the Belgian Red Cross-Flanders and EBA President till 2019. We discussed issues on the blood and plasma supply in Europe, and the need of European self-sufficiency.

The counterpart of IPFA is the PPTA, the Plasma Protein Therapeutics Association, that represents the private sector manufacturers of plasma protein therapies and the collectors of source plasma used for fractionation. In January 2014, Annemarie and I published an article about the growing European dependence on foreign plasma products. In response, Jan M. Bult, at that time President & CEO of PPTA, invited us to visit a plasma donor center. In May 2018, we accepted his invitation and went to Vienna. In Vienna, the director of BioLife, Dr Matthias Gessner showed us around a BioLife commercial plasma collection center. BioLife Plasma Services operates such facilities in Austria and in the USA; it is now part of Takeda Pharmaceutical Company Ltd. At the Vienna plasma fractionation center, which at that time was part of Shire (now Takeda), we got an extensive overview of the activities from plant manager DI Karl-Heinz Hofbauer. To hear the story from the side of the Austrian Red Cross [Österreichisches Rotes Kreuz, ÖRK] we discussed blood and plasma donation with the previous ÖRK President, Prof. Wolfgang R. Mayr. We thank them all for their involvement.

New developments in hemophilia treatment have my undivided attention. One of the promises for the near future is gene therapy. One of the pioneers in this field is Prof. Sander van Deventer, founder and managing partner of Forbion Capital Partners. Van Deventer is a certified internist and gastroenterologist, who supervised the development of Glybera, the first gene therapy product to be approved in Europe. We spoke with him about the research at uniQure B.V., where he is Executive Vice President, Research and Product Development. uniQure is working on gene therapy for hemophilia.

Just now that I correct the proofs, I read that uniQure and CSL Behring “have entered into a licensing agreement providing CSL Behring with exclusive global rights to uniQure’s […] investigational gene therapy for patients with hemophilia B” for which uniQure is “eligible to receive more than $2 billion.”

One of my friends to whom I can turn for answers on new developments is Prof. Frits R. Rosendaal. Frits is professor of Clinical Epidemiology at the Leiden University Medical Center (LUMC), but when I first met him in 1985, he applied for a job, just like me. We both participated in the third “Hemophilia in the Netherlands” survey, and since then we never lost sight of each other. Annemarie and I visited him last year, and I regularly ask his opinion. Even during the present days, occupied as he is with the COVID-19 pandemic, he finds the time to answer me.

The same can be said about Prof. Marcel M. Levi, who is at present the Chief Executive of the University College London Hospitals (UCLH). It is unbelievable how Marcel continues to answer all requests; he receives 1500-2000 emails a day, all of which he tries to answer. I know Marcel for about thirty years; from the time he was a doctor for internal medicine at the hemophilia department of the Amsterdam Medical Center (AMC). At the beginning of his career, Marcel saved the life of one of my friends with hemophilia, who got a bleed in his brain. Marcel’s decisiveness in an emergency impressed me. He prepared a team at the AMC to act immediately on the patient’s arrival. I am very grateful that Marcel was willing to write a foreword to my book, I greatly appreciate his contribution.

Something that I really want to show, are my paintings. I started painting in 2000, when my physical condition was very unstable, and I had to stop working. It was a relief not needing to work from 9 to 5, but it also caused a kind of empty feeling. I really enjoyed learning to paint. For this book, I produced a series of gas stations. One might wonder, why gas stations?

That is related to a short story by Sarah Smarsh about the experiences of a “Blood brother”, a plasma donor. The first lines read: “Your brother has a hole on the inside of each arm that never quite closes. A blood tap, really like an oil well for drilling. He is a tall, strong man in his early thirties – an ideal source for plasma.” Moreover, the separation of blood in its components can be compared to the refining of crude oil. I painted the gas stations during the writing of this book, from the end of 2018 till the beginning of 2020. I thank Pauline Bakker who instructed me how to paint my gas stations.

Piet Hagen, Paul Strengers, Ernest Briët and Aad van Yperen have commented on previous versions of this book. I know Prof. Ernest Briët since the 1980s, when he worked as hematologist in the LUMC. Ernest supervised the “Hemophilia in the Netherlands” surveys that provide us with 50 years of data on people with hemophilia in the Netherlands. He was my promotor, when I received my honorary doctorate in 2003. With Aad, who was member of the NVHP Board, and others, I prepared the NVHP complaint against the Dutch Government in 1994. We were successful in receiving a financial compensation for hemophilia patients who were infected with HIV through plasma products.

Writing a book is one thing, publishing is something different. Writing in English, which is not our native language, is a challenge. Annemarie’s niece, Sumedha Mahajan, took the time to improve our writings; we are very grateful that she went through the manuscript. The books I wrote together with Annemarie, were always produced in cooperation with Suzan Beijer and the printer she chose. Annemarie and I work for free, but editing and printing cost money. We are very pleased that our work is sponsored by the Haemophilia Foundation and the Landsteiner Foundation for Blood Transfusion Research. We thank them for their valuable financial support. Suzan Beijer was once again willing to work with us, and we thank her for her creative and indispensable participation. To reach a larger audience, we contacted Maarten Fraanje, Eburon Academic Publishers. We are grateful that he found our book worthwhile to include in his publishing house.

I could not write this book without the lifelong care and assistance of all the medical personnel, nurses, doctors, physiotherapists, who accompanied my road trip through the world of healthcare. Many thanks and a tribute to their work. I am grateful to the many Dutch voluntary non-remunerated blood plasma donors enabling me to use a Factor VIII product. Finally, the support of my parents, my sister Wil and her husband Rinze Dragstra, my partner Herra and her children and five grandchildren – what a joy – was invaluable.

Hoofddorp, April 2020

Cees Smit

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Foreword

Cees Smit was born with hemophilia, an inherited disorder which means his blood does not clot properly. Hemophilia is a serious and potentially life-threatening disease which causes recurrent and spontaneous bleeding that is painful and debilitating. During Smit’s childhood in the 1950s, it was untreatable.

The portrayal of Cees Smit’s early years is typical of a boy and young man with a severe, chronic condition who, despite all the setbacks, and sometimes stubborn, patronizing, and at times inadequate doctors, bravely lives his life and overcomes various difficulties. He describes the hope he, and other hemophilia patients and their parents felt, when various new treatments became available, such as administering female sex hormones to prevent recurrent bleeding. Hopes were dashed time and time again when these treatments not only proved ineffective, but also caused significant and lasting side effects as well.

And then imagine the joy when one day an apparently effective treatment, derived from donated blood, becomes available. This modern treatment is introduced by a new generation of progressive and enthusiastic doctors who set themselves the goal of allowing hemophilia patients to lead completely normal lives. For many of these patients, it’s a journey from hell to heaven.

However, after a few years, this life-saving treatment suddenly turns out to be life-threatening as well. Disastrously, many hemophilia patients get infected with HIV and hepatitis because of their treatment. And many of them die from it. For them and their families, it feels like a return trip from heaven back to hell.

Cees Smit is not spared from these terrible complications, but luckily, he survives them. This gives him the opportunity to describe the medical roller-coaster of a chronic illness in the most intimate and incisive way. And not only that, Smit meticulously describes how the blood products used to treat hemophilia are nothing but merchandise for some unscrupulous manufacturers who, time after time, prioritize profit-making over the safety and well-being of patients.

This book tells the story of a ruthless and profit-seeking pharma industry that manages to entice national and international key opinion leaders using smoke and mirrors so that they turn a blind eye to patient safety in the interests of finance and commerce. It’s a story about how much damage commercial greed and exploitation of sick people can cause. Smit shines a light on a silent, and at times shameless conspiracy between manufacturers, international doctors, scientists and healthcare authorities which created unnecessary risk and caused disastrous damage to patients.

This story is extremely relevant in an era when new treatments for diseases that have been untreatable until recently, are being rapidly made available on the market. Despite all the promise, this story warns us that caution should be exercised because unexpected side effects can have disastrous consequences. It is also a stark reminder that commercial value and the pursuit of profit are not always in sync with the interests of sick people.

When reading this book, you will likely experience feelings of admiration for the courage of a young man with a chronic illness, and joy when new treatment offers him hope. You will also experience feelings of grief when this treatment causes unexpected serious complications, and then anger about the commercial misconduct of international producers of plasma products.

And finally, you will end the book feeling optimistic that people like Cees Smit and Annemarie de Knecht-van Eekelen, with so much life experience and expertise in this area, continue to fight for better and safer treatment for people with a chronic illness. For example, Cees Smit is a big advocate of the use of biotechnology in the development of treatments for rare diseases. He sometimes has to pursue his cause in the face of opposition from those who are well-intentioned but ill-informed.

The life course of Cees Smit reads like an exciting boy’s book, in which the hero manages to overcome setback after setback, and cheerfully and fearlessly makes the world a little better place.

London, March 2020

Marcel M. Levi

Chief Executive of the University

College London Hospitals (UCLH)

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Introduction

On a sunny evening in July 1979, a reception was held in honor of Frank Schnabel, the founder and first president of the World Federation of Hemophilia (WFH), in the King David Hotel in Jerusalem. The reception was one of the social events at the WFH Congress and was offered by Tom Hecht, President of a Canadian pharmaceutical company by the name of Continental Pharma Canada. His father had started it as a pharmaceutical distribution company, but under Tom’s leadership, the company became the world’s largest independent supplier of human blood plasma derivatives including clotting products. Hecht had a controlling position in North American Biologicals Inc. (NABI), with its huge plasma collection network and gamma globulin manufacturing facilities. He labelled the plasma industry as “the OPEC of the health care industry”.

Although impressed by the luxurious and wealthy environment of the King David Hotel, my West-Frisian character – plain and moderate – called all this luxury into question. How could it be that a hemophiliac like me ended up in such an expensive environment during this WFH Congress in Israel? The Congress itself was held in the very comfortable Hilton Hotel in Tel Aviv. Almost every evening, there were large parties and social events sponsored by the pharmaceutical companies that were involved in hemophilia treatment. Compared to the sober environments where my Dutch hemophilia patient organization held its meetings in the Netherlands, the contrast could not be bigger. It made me realize that there must be something different or even wrong.

Back home, I discussed my experiences with my friend, the journalist Piet Hagen. In the Netherlands, the non-profit local Red Cross blood banks that produced Factor VIII concentrate, the missing clotting factor in hemophilia A, could not meet the demand. At the same time, US pharmaceutical companies tried to get Dutch import licenses for commercial Factor VIII products. Piet and I concluded that the plasma trade needed further investigation. We wanted to focus on the relation between poverty and the exploitation of paid donors. Later that summer, we visited the Leiden hematologist Dr Jan Veltkamp. He shared our concerns and recommended writing a book about the commercial business in plasma products. He mentioned the book Airport by Arthur Hailey as an example how to structure our knowledge. A thriller-like novel would get more attention than a dull textbook. We did not publish a thriller, but after this discussion with Veltkamp, we started with a research project for the Dutch newspaper Trouw. Based on our findings, Hagen wrote a book, titled Blood: Gift or merchandise. Towards an international blood policy. It was published in the summer of 1982. By that time, we discovered that Tom Hecht was a big broker in human blood plasma.

In that same summer of 1982, the first messages about a new, unknown disease reached the hemophilia community. This unknown disease, later known as AIDS, would create one of the biggest tragedies in hemophilia history. Since the early 1980s, more than 10,000 hemophiliacs died from tainted blood. Those who survived, still struggle with the consequences of the HIV infection.

The initial denial of the AIDS problem within the hemophilia community in the USA, by the National Hemophilia Foundation (NHF) and by the WFH, has certainly caused unnecessary HIV infections in the 1980s. This is even more distressing as there had already been warnings in the 1970s for contamination of plasma products with the hepatitis virus. Looking back at the history of paid plasma donors, we can state that there existed a tight interrelationship between some hematologists, the NHF, the WFH and pharmaceutical companies producing plasma products, which did not contribute to timely warnings. Schnabel, for whom the Jerusalem reception was hosted, died of AIDS in 1987. His “friend” Tom Hecht would later declare that all his plasma transactions had been in accordance with FDA regulations. In Hecht’s biography Frank Schnabel is not mentioned.

For some, these decades might feel far away, but for me it is different. I perceive that era as a time during which I experienced all the highs and lows in hemophilia treatment. When I was born in 1951, my life expectancy was perhaps 25 years or less. However, I survived, and I have devoted my life to the improvement of hemophilia care. This book tells the story of my life. It is dedicated to the many friends in the hemophilia community that I lost because of hemophilia, HIV or HCV. For them there was no time to write a book like this.

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Chapter 1 • A carefree childhood!

Being born with hemophilia

During a stormy night, while the neighbors rescued the thatched roof of our farmhouse, I was being born under that same roof on New Year’s Night 1951 in Nieuwe Niedorp. This is a small village in West-Friesland, in the north-west of the Netherlands, some sixty kilometers north of Amsterdam. My parents – Jan Smit and Marie Kroon – were married in 1943 during the Second World War and started a bakery for bread and pastries in this village. My sister Wil was born shortly afterwards in 1944. The house is situated on the Laagzijde, the lower part of the Dorpsstraat. The front part of the house where we lived, still exists (Figure 1a). It is a picturesque place with a lovely painting to show for it (Figure 1c). Figure 1b shows the houses opposite ours.

It sounds rather ridiculous to say that I had a carefree childhood, while I stayed a larger part of the first sixteen years of my life in hospital. And the more ridiculous it is, when one realizes in hindsight that my medical problems caused my parents and my sister a lot of stress. It was not that my parents kept the troubles of hemophilia away from me. For sure, I was just too young to realize the severity. Figure 2 shows images of my childhood.

Figure 1. My birthplace: a. The house where I was born still exists (2019); b. The houses opposite ours on a sunny morning in spring (1940s); c. The painting of my birthplace by Jannie Kuiper, a Dutch painter from Nieuwe Niedorp

Figure 2. Images of my childhood: a. In the arms of my mother; b. My birth announcement card; c. On the arm of my father; d. With my sister Wil; e. Outside the hospital with my parents, recovering from a bleeding

A timely diagnosis

It was not long after my birth that my mother saw some bruises on my back. She went to our general practitioner and showed him the discolorations. His answer was sympathetic, but also quite patronizing: she should handle me with more care. My mother was rather upset with him for saying so, as she knew how careful she lifted me in and out of my crib. As the bruises continued appearing and I also displayed pain while crawling, a referral to a pediatrician followed. She, it was a female doctor, had her practice in Alkmaar, a city about 25 kilometers away from our bakery.

Luckily enough, this pediatrician – Dr Anna G. Schoo – had been trained in Amsterdam by Prof. Cornelia C. de Lange, Professor in Pediatrics and the first female professor in a medical faculty in the Netherlands. Hemophilia was one of the topics studied in Amsterdam and Anna Schoo had a basic knowledge of hemophilia. I understood much later how lucky my parents had been in finding this pediatrician. Dr Schoo immediately diagnosed me with a severe form of hemophilia.

It was known that hemophilia is a genetic disease occurring in males. A person with hemophilia misses the genetic information to produce one of the proteins that is needed for the blood clotting. The protein I am missing, is called Factor VIII. However, no one in our family seems to have had hemophilia before me. This happens regularly and is caused by a mutation. More than 30 percent of the boys with hemophilia are born in a family without a history of hemophilia. Later, my mother, my sister and one of my nieces were diagnosed as carriers. For those who want to know more about the genetics of hemophilia, I have made an overview in the following text box.

How I inherited the hemophilia gene

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Hemophilia is a recessive sex-linked genetic disease. Sex-linked means that the gene is located on one of the X-chromosomes. Humans have 23 pairs of chromosomes, one of those pairs consists either of two X-chromosomes or one X- and one Y-chromosome. If you have two X-chromosomes you are a female, with one X- and one Y-chromosome you are a male.

A recessive gene is a gene whose effects are masked in the presence of a dominant gene. When a woman has a genetic defect on one of her X-chromosomes, we call her carrier. A carrier does not have the disorder herself when the gene is recessive. There is a 50% chance that a carrier passes the X-chromosome with the defect to her son. Her daughter has a 50% chance of being a carrier. This is shown in Figure 3a. My father had no hemophilia. Men with hemophilia generally get no sons with hemophilia. However, their daughters will be carriers. The father with hemophilia transfers his defected X-chromosome to his daughters. This situation is shown in Figure 3b. I use the figures from a booklet that I published in 1996, explaining hemophilia for laypeople.1)

Unfortunately, I got hemophilia and my sister became a carrier, chance was not on our side. Carriers can experience bleeding problems during menstruation and after medical interventions.2) Mothers who carry the hemophilia gene, are at risk for serious bleeding after delivery.3)

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1) Smit C, Rosendaal FR. Hemofilie. AO reeks nr 2587. April 19, 1996.

2) Plug I, Mauser-Bunschoten EP, Bröcker-Vriends AHJT, et al. Bleeding in carriers of hemophilia. Blood. 2006;108(1):52-6.

3) Information on hemophilia for women. Retrieved 02/17/2020 from https://www.cdc.gov/ncbddd/hemophilia/women.html.

Figure 3. Genetics of hemophilia: a. Mother is carrier; b. Father with hemophilia

When I was born, there was only one type of hemophilia identified, now called hemophilia A. The missing plasma factor, which was named the “anti-hemophilic factor” (AHF), had only been discovered in 1950. AHF was later named Factor VIII. Subsequent research showed that one can have mild, moderate, or severe hemophilia depending on the level of clotting factor in the blood. The clotting factor level is shown as a percentage: mild = 6% to 50% factor level; moderate = 1% to 5% factor level; severe = less than 1% factor level. I have severe hemophilia A.

Without Factor VIII, a bleeding hardly stops. The greatest risk is not an external cut that continues to bleed – although it can be dangerous –, but an internal bleeding. This often occurs in a joint – knees, ankles, elbows –, or in a muscle when you bump into something. The most dangerous is a bleeding in the skull when you hurt your head. Bleedings can take place after an injury but also spontaneously. You can imagine how anxious my parents were to prevent me from getting a bleed.

Living the innocent life of a kid

As far as I can remember, I had a nice youth together with the neighborhood kids in the countryside. One of the neighbors had a farm with cows. My father had some pigs in our back yard that were fed with the leftovers of our bakery, especially old bread. My father worked in the baker’s tradition as is shown in Figure 4. To his nearby customers, he delivered the bread door-to-door using a special basket, named the “Kriel”. It had become a particularity that was described in an historical journal, together with my father’s picture.

The farm, the garden, and the grounds surrounding the house were our playgrounds, where we gradually discovered the world around. It resembles the life of the twin brothers Sietse and Hielke Klinkhamer in a famous Dutch children’s book series titled De Kameleon [= The Chameleon]. In about seventy books, you can read about the adventures of the twins with a boat. We only lacked the boat. Sometimes, I could not play because I had a bleed. When not, I played just like the other kids. One day, I fell off a hay wagon but without consequences. Brushing teeth was forbidden in those days as it could cause gums bleeds.

I was not allowed to swim and to cycle, so I had no bicycle. In Holland, everyone owns a bicycle, and it is the major means of transport. Having no bicycle is like having no shoes. To solve this problem, I just took the bicycle from one of the other kids. This made my parents buy me a bike too, even though it was against the formal advice. With our bikes, we cycled down our street, around the corner into another street and then to a high bridge over a canal with a typical Dutch windmill by its side.

To compensate for not participating in sports, I joined a choir, but that was not a success. I took part in all kind of activities: there was the yearly flower show, the Floralia, in our village. It still is a big event in Nieuwe Niedorp where beautiful flower mosaics are shown. Figure 5 shows me at the Floralia as the injured cyclist. Together with the neighbor kids we performed a “First aid” act. In my younger years, I enjoyed living a full life, at least that is how I felt.

The only thing I remember from my visits to Dr Schoo was the house at the Emmastraat 3 in Alkmaar opposite the hospital, where she had her doctor’s practice. After every visit, my mother gave me an ice-cream. We had to take the bus from our village to Alkmaar, which was for us the “big city”. In fact, a bus ride was an attraction too in the mid-fifties. After some years, another pediatrician, Johan Hofstra, joined Dr Schoo. He knew a few other children with hemophilia. He took care of me until I was old enough to see an internist. I often had bleeds in my knees and joints for which I was hospitalized in the Centraal Ziekenhuis [= Central Hospital] in Alkmaar. My mother kept a record of my hospital admittances (Figure 6). In my memory, I was many more times in hospital; it shows what impact the hospital had on my childhood.

Figure 4. My father delivering bread to our neighbor Atie Vonk (1951)

Figure 5. I am the “injured cyclist” at the Floralia

Figure 6. My stays in hospital recorded by my mother

Side effects of treatment, the DES hormone

There was no effective treatment for hemophilia during the first sixteen years of my life. Because of that, I hardly survived some critical incidents in my youth. After a couple of these events, my pediatrician Hofstra told my parents that he used diethylstilbestrol (DES hormone) to treat his other two patients with hemophilia. DES was used as a medication for a variety of female reproductive problems and to stop growth in adolescent girls who were growing very tall.

The use of DES in hemophilia had been presented by a French pediatrician, Raymond A. Turpin, at a conference in Paris in the late 1940s. The idea that ovarian extract would have positive effects on hemophilia, had already been suggested in 1904. This was because hemophilia was not seen in women, which was interpreted as being due to a protective influence of the ovaries. In the 1930s, the newly found female sex hormones were thought to stimulate blood clotting. Turpin was not specialized in hemophilia, most of his work is devoted to Down syndrome.

Be that as it may, a Dutch pediatrician, who heard Turpin’s lecture, started using DES for three of his patients. From mid-1949 on, these boys, aged 7, 9 and 13, were treated with DES during one-and-a-half years. Their condition improved, they had less pain; however, their clotting time did not change. The physicians considered the positive effects of DES treatment prevailing over what they mentioned as “a little handicap”. This was the swelling of the breasts of the boys that asked for “measures when swimming”. I think that they had to wear a bathing suit covering the breasts. It is astonishing how these adverse effects were downplayed at the time. For me, the effects were even worse. The use of DES had a devastating impact on my growth. I gradually stopped growing. Its effect is still visible as my length is only 1.45 meters.

Unfortunately, some ideas are hard to kill. Around 1970, there were again doctors who promoted the use of female hormones, this time Lyndiol (The Pill), to treat hemophilia. It was based on the observed increased chance of clotting in women using Lyndiol. I know people who have been treated with hormones in these days, of course without any effect. In a few years’ time, this treatment was refuted.

Later in my life, I became involved in a DES lawsuit, when it became clear how catastrophic its use had been. DES caused a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. Also, prenatally DES-exposed males had an increased risk of testicular cancer, infertility and urogenital abnormalities; it is considered an established human carcinogen. DES and thalidomide brought about a reinforcement of the regulations for medical research. Thalidomide is the drug that was marketed between 1957 and 1961 as a sedative, and for morning sickness in pregnancy. Thalidomide caused major impairment of the development of the limbs of the fetus. In 1964, the World Medical Association (WMA) developed the Declaration of Helsinki as “a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data”. It has since undergone seven revisions, the last one in 2013 when the need to disseminate research results, including negative and inconclusive studies, was highlighted. For me, the lawsuit did not result in a settlement, because hemophilia treatment was not mentioned as an indication for DES on the package leaflet of the medicine.

The impact of my severe hemophilia on my family

As I was hospitalized frequently and for longer periods of time, my parents had to bring me to the hospital and visit me there. That was quite a burden for my mother, as she also took care of the household and the bakery shop. When I was just about ten, my parents decided to close the bakery and move to another village, Oudorp, a few kilometers from the hospital in Alkmaar. My father found a new job as a traveling salesman of rye bread, rusks and all kind of cookies. So, he often visited his former colleagues in West-Friesland.

Only later, I realized that this must have been a life changing event for them. Unfortunately, more in-depth questioning for this book is impossible, as my mother and father died respectively in 1987 and 1993. I always felt grateful that they both died before my other hemophilia-related issues became a big problem. Thankfully, they lived to see me grow up.

My sister was around seventeen when we moved. It had a great impact on her life. She lost most of her friends and it took her quite some time to get used to the new situation. In those days, she got to know her future husband Rinze Dragstra. He often mentioned to her and to his family that I would not grow very old. That is what the physicians had told my parents. Before 1940, the average life expectancy of a Dutch hemophilia patient was 16 years of age and in the early 1960s it was still only 23 years.

Although I was often absent at primary school, I did well and was advised to go the Rijks HBS in Alkmaar. The HBS was a type of secondary education with a five years course that focused on modern languages, mathematics and sciences. The HBS had been established in 1863 as an alternative for the gymnasium where the classical languages Latin and Greek were taught. Since 1917, an HBS diploma gave access to most university studies. My parents thought that – if I would grow older, which was not that sure by then – I would have to earn my living using my intellectual abilities, and not with hand labor. My family encouraged my education. From my grandparents, I got a special present: a large round globe, as I was so much interested in geography. It was only one of my many interests at that time. The globe is still present in my study. My grandparents were proud that their grandson was attending a school at such a high level. They themselves had only basic education. They owned a grocery store in Oudkarspel, not far from Nieuwe Niedorp.

Hemophilia research till the early 1960s

To understand why there was no proper treatment for my hemophilia, I have added a little history about the discovery of the clotting factors. Just remember that blood clotting or coagulation is a biological process that stops bleeding. The question was of course: “What happens in this process”? The Dutch pioneer in hemophilia research, the physician Simon van Creveld, wrote as early as 1925: “There is still a variety of opinions about the cause of the delayed clotting in hemophilia. Most researchers agree that platelets, fibrinogen and thrombin values are normal. Some suppose that there is an inhibiting substance in the plasma that prevents clotting.” Together with the chemical engineer Willem M. Bendien, Sc.D., Van Creveld showed that there was no inhibiting substance. They discovered that human blood plasma contains a substance that accelerates coagulation. However, Van Creveld’s publications between 1935 and 1941 were disregarded abroad.

Cohn fraction I

Van Creveld was nominated as Professor of Pediatrics at the University of Amsterdam in 1938 as the successor of Cornelia de Lange. In World War II, Van Creveld had to step down, because he was a Jew. After the war, he was reinstated and continued with his investigations on blood plasma. He had read about the breakthrough that was achieved by the Harvard biochemist Edwin J. Cohn, head of the Department of Physical Chemistry. Cohn succeeded in fractionating plasma, which is a biochemical processing technique separating plasma into its functional components. He got five main fractions, which were named Cohn fraction I-V. Cohn fraction I is rich in fibrinogen and other serum proteins that facilitate clotting. The significance of plasma fractionation for hemophilia research was clear.

In the 1950s, several research groups developed production methods to concentrate the anti-hemophilic factor AHF. Van Creveld mentioned that these products were not used regularly. He himself used transfusions with whole blood or with plasma to treat his patients. By the end of the 1950s, the required quantity for transfusion and the transfusion time could be monitored by the determination of AHF in the patient’s blood. Van Creveld stated that in serious bleedings a continuous infusion for 4-6 days was required, and in cases of an operation or very serious bleeding up to ten days.

Fractionation: separation in components

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After a donor has donated blood, the unit of blood is spun in a centrifuge to separate it in three components: red blood cells, platelets and plasma. The separation of plasma in its proteins can be compared with the refining of crude oil. The oil is transformed and refined into several useful products. That is like what happens with a donation of blood. Blood plasma is the source of products that are further separated, freeze-dried and have a long-shelf life. These are different proteins like albumin, immunoglobulins, clotting factor concentrates (FVIII and FIX) and others (Figure 7).

Figure 7. The plasma fractionation process

What Factor is missing?

Using Cohn fraction I, researchers expected to find what plasma factors were involved in hemophilia bleeding. First, AHF (= Factor VIII) and subsequently, at the end of 1952, the Christmas Factor (= Factor IX) was discovered. A lack of Factor VIII causes hemophilia A, while a deficiency of Factor IX causes another type of hemophilia that was named hemophilia B.

The number of bleeding disorders and clotting factors seemed to increase exponentially. The existence of female bleeders contributed to further confusion. In 1926, Erik A. von Willebrand, a physician from Finland, had described a hereditary bleeding disorder affecting both sexes. This disease was thought to be quite distinct from hemophilia, because both sexes are affected, and the pattern of inheritance is different. Von Willebrand Disease (vWD) showed autosomal, dominant inheritance, in contrast with the sex-linked, recessive inheritance of classic hemophilia.

There were other findings that obscured the understanding of the anti-hemophilia factors. From 1949 on, Van Creveld published his results of plasma infusions for his hemophilic patients. One of his first observations was the return of a prolonged clotting time in a patient after several infusions. He mentioned that, according to literature, this could be the result of the formation of a clotting inhibiting factor in the blood.

In 1962, it was decided to give Roman figures to the different clotting factors. At the end of the 1960s, a dozen factors were known, they were numbered I-XIII, with number VI deleted. The theory, developed in the early 1960s, was that these factors are activated in a cascade of reactions. The cascade can be compared with a waterfall or the collapse of a row of domino stones.

This research did not offer much improvement for treating people with hemophilia. In the early 1960s, treatment of bleedings still consisted of transfusions with whole blood or plasma, followed by bedrest and plaster casts to prevent contraction. Boys with severe hemophilia like me spent a larger part of the year in the pediatric ward of a general hospital.

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Chapter 2 • Growing up – looking for opportunities

Hemophilia care in the 1960s

During the years at the HBS, I had to cope with frequent absentia because of my hemophilia. I did not study that hard either, I spent too much time on leisure-activities for school; for instance, writing for the school magazine. It took me eight instead of the ideal five years to pass my exams. Without the support of my parents and my schoolteachers, I would never have succeeded. Also, the nurses and physicians at the Centraal Ziekenhuis (Figure 8) helped me where they could. Often, I got a quiet room for myself or with two other patients. These were mostly people who had had a motorcycle-accident and needed quite some time to recover. Generally, I had time for my schoolwork and my friends from school could come to visit me outside the normal visiting hours. In the final year before the exams, the nurses occasionally created space for my whole class with whom I followed some extra courses. I must say that certainly this integrated care concept – parents and caregivers both responsible for all aspects of my young life – highly contributed to my HBS diploma. Integrated care in the 1960s! Who thought it was a 21st century concept?

Figure 8. The Central Hospital in Alkmaar where I was nursed

Referral to the Hemophilia Clinic

In the summer of 1967, my pediatrician Hofstra was worried about my future possibilities. He wrote a letter to Professor Van Creveld asking him for advice. This letter to Van Creveld, which is kept in my patient files at the Van Creveld Clinic, mentions my hemophilia A and my treatment with fibrinogen and AHF. Before AHF was available, I had received transfusions with whole blood or plasma donations. Commonly, fresh frozen plasma (FFP), which contained Factor VIII and Factor IX, was used. However, because of the risk of volume overload, there were limits to the volume of FFP infusion. It was further mentioned that I had regular joint bleeds as well as pain in my joints and abdominal pain. Hofstra also sought advice for my dental problems. Because of a cycle-accident the year before, my teeth were severely damaged. I had lost several teeth and I had asked for treatment.

Van Creveld had established a specialized Hemophilia Clinic where boys could receive the best care and where they also had possibilities for education and therapy. This clinic was in Huizen, a small village close to Amsterdam, and had been officially opened by Her Majesty Queen Juliana on June 26, 1964 (Figure 9). It was a unique clinic, and nothing like it existed elsewhere in the world, as Van Creveld proudly mentioned giving a tour to the participants of the second WFH meeting in Amsterdam in August 1964.

My admission to the Hemophilia Clinic occurred just a week after Hofstra had written to Van Creveld. I got a serious knee bleed, but it was Hofstra’s locum, the pediatrician Willy E. Naessens, practicing in the other hospital in Alkmaar, who decided to transfer me immediately from Alkmaar to the Hemophilia Clinic. This meant that for a month, I stayed seventy kilometers away from my parents and my sister. It was terrible being so far away from home and school. I remember that I longed to go home, back to my own hospital where they knew me. My parents and sister could only visit me during the weekends. I missed them and my schoolfriends. In fact, I was lucky I had to stay only for a month. Some boys stayed there for half a year and returned regularly.

Figure 9. Opening of the Hemophilia Clinic in Huizen in 1964. Her Majesty Queen Juliana performs the opening act. Professor Simon van Creveld is the man most to the right on the front row

Peanuts

As a treatment for my hemophilia, I had been prescribed raw peanuts. In the Hemophilia Clinic the peanuts were replaced by peanut extract. Today, I understand that I was taking part in Van Creveld’s research into the effects of raw peanuts. It was an experiment based on a publication by an American entomologist, H. Bruce Boudreaux, who had hemophilia himself. His finding was published in Nature in 1960, and got some attention in the national press with headings like “Peanut may help hemophilia fight” and “Peanut called a hemophilia aid”. Van Creveld used a peanut extract specially prepared for him by the Unilever factory in Vlaardingen. He tested the effect of this extract and of raw peanuts on the occurrence of bleedings and fibrinolysis. It seemed that a “peanut factor” improved the formation of the hemostatic plug by diminishing fibrinolysis, causing a shift in the equilibrium of build-up and breakdown of fibrin. Fourteen patients ate three times per week 20-40 grams raw peanuts or consumed two times a day a teaspoon of peanut extract. I was one of them.

Van Creveld might have believed in peanuts, but he did not believe in DES. In the old patient records I read that I had used DES from my fifth year on. In the Hemophilia Clinic I had to stop using DES immediately, but harm was already done. My patient record from 1967 shows that at age 16 my length was 1.45 meters and my weight 37 kg.

Treatment and life in the Hemophilia Clinic

On admission, my right knee was four centimeters thicker than the left one. After a few days, when the doctors expected that the bleeding should have stopped, they put my leg in a brace. After a knee bleed, one had to stay in bed, where a construction of weights on a pulley was used to gradually straighten the affected leg by increasing the weight. This took a couple of days. Treatment with plaster casts and braces was the usual treatment (Figure 10). Prophylaxis or continuous infusion were not yet part of the treatment, so sometimes the bleeding recurred.