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Chapter 2

Patients at Risk


2.1 NHS patients with bleeding disorders and medical and surgical patients requiring transfusion of blood or blood components formed small cohorts only of the total UK populations exposed to risk of infection with Hepatitis C and HIV/AIDS. Reports from 2014 estimated that there were 214,000 chronically infected individuals with HCV, and 107,800 with HIV/AIDS in the UK.[1] The numbers of NHS patients infected in Scotland are discussed in Chapter 3, Statistics. In summary, around 2500 individuals are thought to have been infected with HCV by transfusion and a small number of transfusion patients, estimated at 18 minimum, with HIV. 478 bleeding disorder patients are thought to have been infected with HCV, and 60 with HIV.

2.2 As this Report will discuss, there was research of unprecedented intensity into the aetiology and natural history of AIDS and into the development of forms of therapy for infected individuals, resulting in the effective treatment of HIV and control of its progression to AIDS. AIDS appeared to be a genuinely new disease when it was first reported and commitment by governments, public sector scientists and the pharmaceutical industry in response to it achieved these results in a very short time, reflecting the common perception that the disease threatened to achieve pandemic proportions, with high mortality. HCV proved to be a more intractable problem but, in that context also, the efforts of researchers led to the identification of enough of the genetic structure of the virus to allow for the development of tests for infection, a developed understanding of the natural history of the disease and, in due course, treatment of those infected.

2.3 The NHS patients with whom this Report is primarily concerned benefited from these scientific and technological developments, as did other groups at risk, and it has been necessary to discuss them at some length in later chapters of this Report. The common element affecting the various groups exposed to risk was that infection was transmitted by blood. That applied as much to intravenous drug users as to blood disorder patients receiving blood component or blood product therapy. It is important to bear in mind that the medical and other scientists conducting research and developing technology for identifying infection in blood, for example, were often concerned with the interests of the larger populations at risk and were not narrowly focused on blood disorder and transfusion patients.

2.4 In this chapter, the focus is on the groups of people who were potentially at risk from infection and the procedures that gave rise to risk. The patient groups exposed to risk were:

  • Patients receiving transfusions of blood or blood components in the course of medical care or surgical procedures.
  • Patients with bleeding disorders, such as haemophilia, who received whole blood, blood components and products manufactured from human plasma in the course of therapy for their primary disease.

2.5 The topic was discussed in Chapter 3 of the Preliminary Report. Since the writing of that chapter, subsequent investigation and the oral evidence led at the public hearings, particularly from experts in the field, have added significantly to the Inquiry's understanding both of the scope of the risks and of the impact of infection on individuals and on their families. The account which follows is therefore fuller than the account in the Preliminary Report and varies from it in part.

2.6 This chapter discusses, with the benefit of hindsight, the causes of risk and the practices that gave rise to risk generally, without reference to a time line of developing knowledge. The chronology of the developing knowledge of individual diseases is discussed later.[2]

Patients receiving transfusions of blood and blood components

Historical overview

2.7 As noted in the Preliminary Report[3], safe transfusion, in the broadest sense, is a relatively modern procedure. Dr Derek Norfolk, a Consultant Haematologist practising mainly in Leeds, provided oral evidence and a witness statement on the use of blood components in clinical medicine.[4] Dr Norfolk developed a particular interest in blood components and patient safety and, in 2006, took up a joint appointment with NHS Blood and Transplant and Leeds Teaching Hospitals NHS Trust. He is a member of the National Blood Transfusion Committee of the Chief Medical Officer for England and Wales. In the last decade he has written frequently on transfusion medicine.[5]

2.8 Dr Norfolk gave an insight into the hazards of nineteenth century transfusion practice:

Following early, but often ill-fated, attempts at blood transfusion in the 17th century, the first well-documented successes were those of the Edinburgh and London obstetrician Dr James Blundell ... who '... appalled at my own helplessness at combating fatal haemorrhage during delivery...', reported 10 direct donor to patient transfusions between 1819 and 1829. However, the equipment was primitive, the volumes transfused were small and, with no knowledge of blood groups, serious reactions were common.[6]

2.9 Direct transfusion involved connecting the donor and the recipient by a tube as they lay or sat together. In obstetric practice, the donor was usually the husband of a woman bleeding in childbirth.[7] The procedure was inherently hazardous and, in 1873, the Obstetrical Society of London concluded that transfusion should be used only as a last resort.[8] Real progress began only in the twentieth century.

2.10 Karl Landsteiner, a biologist and physician working in Vienna, discovered the ABO blood group system in 1901, although it took some time before his discovery began to influence clinical practice.[9] Transfusion using donor blood advanced little until it was introduced into military practice towards the end of the First World War, although it was not used very much in civilian practice for another two decades. It was only during the Second World War that voluntary blood donation was established generally in the UK. It appears that war has always been a major promoter of advances in transfusion technology and medicine and that continues in modern conflict zones.[10]

2.11 Until transfusion in medical and surgical practice came into general use, the risk of transmission of viral infection was relatively low. There were other risks associated with blood transfusion, such as haemolysis (the breakdown of red blood cells), that tended to have more immediate consequences.

Blood transfusion in the reference period

2.12 In the middle of the twentieth century, the relatively high risk of haemolysis was reduced by the development of sophisticated blood matching technology. With that reduced risk, however, the transmission of viral infection became more significant as transfusion became more common and as clinical practice tended towards the use of blood components. The use of continuous flow techniques (apheresis) that return unwanted components to the donor and collect only targeted components ensured an approach to collecting donations that was safer for the donor and clinically and economically more sensible,[11] although it appears that the procedure was not extensively used over much of the reference period for this Inquiry.[12] That change in technology did not, in any event, have a direct impact on the risk of transmission of any infection in the donor's blood, since such infections affected the component also.

2.13 A change of practice that did have an impact on the spread of risk was the separation of whole blood into its major components after donation.[13] The major components are red cells, white cells, platelets and plasma. Plasma is the straw-coloured liquid portion of blood. It contains, in suspension, proteins, such as albumin, antibodies and clotting factors, as well as hormones, fats and dissolved salts and gases.[14] Blood cells are suspended in plasma and can therefore be removed by centrifugation.[15] The separation and use of blood components served a number of purposes. Most patients needing transfusion require the replacement of only one particular blood component, such as red cells for anaemia. Separation into components allows several patients to benefit from a single donation. Storage requirements vary: red cells survive for at least 35 days at 4°C while platelets are damaged by refrigeration and have to be stored at room temperature. Separation allows the different requirements of safe storage to be accommodated. The practice made and continues to make clinical and economic sense.[16]

2.14 All of these blood components were in use in Scotland throughout the reference period and each of them, the red cell units and platelet and plasma preparations used in clinical practice, may transmit infection. Red cells contain a small amount of plasma and platelets are suspended in plasma and even the relatively small amount of plasma involved would be capable of transmitting a viral infection.[17] As the practice of component use increased during the reference period, the numbers of recipients correspondingly at risk of transmission of infection from a single donor increased.

2.15 The clinical application of blood and blood components has changed over the reference period and it will be possible to identify only significant points of transition towards modern practice. The Preliminary Report traced the growing use of red cell concentrates between 1975 and 1990.[18] Between 1975 and 1981 use increased threefold. Growth continued until 1989, by which point it had reached almost five times its 1975 level. Simple partition into the components most frequently used in clinical practice, without further virucidal treatment, would not have increased the risk of introducing infected blood into the system: the proportion of blood donors who were carriers of infection would not have been altered by the sub-division of donations into blood components. On the other hand, the components of a single infected donation had the capacity to infect more patients than transfusion of the donation as whole blood from one individual donor to a single recipient, and risk overall increased.[19] In that sense, changing clinical practice did change risk.

Red cell transfusions

2.16 The clearest indication for a red cell transfusion is in patients who have dangerous bleeding after trauma, surgery or childbirth. In those cases, the urgent transfusion of red cells may be required. The body replaces platelets and plasma much more quickly than red cells and the production of red cells may fall short of what is required to replace those lost or consumed in coagulation.[20] In many of these cases transfusion of red cells is essential to maintain life and the prompt replacement of red cells can be life-saving in some cases.[21]

2.17 There are many causes of anaemia (decreased red cells in the blood), not associated with bleeding, that require medical intervention. The bone marrow may fail to produce enough healthy red cells or the cells produced may have a shortened lifespan in circulation. Genetic diseases such as thalassaemia and sickle cell disease, a lack of essential nutrients such as iron or vitamin B12, serious bone marrow diseases such as leukaemia or aplastic anaemia and anaemia due to inflammation or cancer, all require transfusion of red cells.

2.18 Particular types of patient receive more transfusions than others. Recent studies have shown that, in the case of red cell transfusions, there is an early peak in sick newborn babies, mainly in the first month of life. In the 20-40 age group red cell transfusion is more common in females than in males because of obstetric and gynaecological indications. All studies have shown that the transfusion of red cells increases sharply over the age of 60: the median age of patients receiving red cell transfusion in one study was 69 years.[22] In a later study, carried out in 2004, it was found that 62% of all red cell transfusions were received by medical patients; 33% by surgical patients; and 5% by obstetric patients. The most common surgical indications were orthopaedic surgery, gastrointestinal and liver surgery and cardiac surgery (16.7% in aggregate). A further 5.9% of red cell tranfusions were used in treating trauma patients. These percentages are not absolute, as between 2000 and 2004 the number of red cell transfusions used in surgery fell by around 25% despite significant increases in orthopaedic and cardiac surgery. The percentages given do, however, provide an indication of the order of magnitude of the use of the component.[23]

2.19 In modern practice, red cells remain the most commonly transfused blood component.[24] Improvements in surgical and obstetric techniques in western countries have reduced the use of blood for surgery and during childbirth. Some orthopaedic procedures, such as knee replacements, involve a lot of bleeding during surgery. Modern clinical practice, however, uses technology to re-infuse the patient's own blood, collected during an operation by 'cell saving' techniques, so reducing dependence on transfusion.[25] When liver transplantation was first carried out it was not uncommon for patients to need massive blood transfusions, up to 50 or even 100 units of red cells, to support the patient during the procedure. Re-infusing the patient's own blood has reduced transfusion in many cases to two or three units of blood.[26] With these new techniques, such residual risk of the transmission of infections, like the Hepatitis C virus (HCV) and HIV, as subsists notwithstanding modern screening techniques, was reduced. The emerging risks of transmission of as-yet unidentified viruses were also reduced. The use of transfusion in surgery has now reduced to the extent that in most modern hospitals more than half of all red cells are transfused to medical patients (those not undergoing surgery), typically patients with anaemia.[27]

Platelet transfusions

2.20 Platelet transfusion became readily available in the UK from the late 1970s.[28] Significant quantities were produced by Regional Transfusion Centres (RTCs) in Scotland before the beginning of the reference period. Production increased after the mid-1970s. Patients with very low platelet counts are at increased risk of bleeding and, at extremely low levels, may die of serious internal bleeding. Low platelet counts (thrombocytopenia) are a feature of bone marrow diseases such as leukaemia and are often a temporary effect of cancer chemotherapy or cardiac bypass surgery. The condition is also commonly seen in patients in intensive care and in sick newborn babies, often caused by serious illness. In modern practice prophylactic platelet transfusions are used to try to avoid bleeding.[29] The pattern of usage of platelets is broadly similar to the pattern of red cell usage.[30]

Other components and products

2.21 Clinical use of plasma and products derived from plasma predates the reference period. Plasma for clinical use is separated from the cellular components of blood soon after collection and quickly frozen as fresh frozen plasma (FFP). The pattern of usage of FFP is broadly similar to the pattern of red cell usage.[31] The main use of FFP is in the treatment of patients who are bleeding as a result of major tissue trauma, as occurs in road traffic and other serious accidents, military trauma or obstetric complications, when the natural clotting system cannot produce new clotting factors fast enough to replace those consumed in clotting. This condition, disseminated intravascular coagulation, is also a potentially life-threatening complication of many acute illnesses, and is commonly seen in very sick newborn babies and in patients with cirrhosis.[32]

2.22 Current usage of all components and products reflects major changes over time. For example, cryoprecipitate, a derivative of FFP initially developed as a source of Factor VIII[33] for the treatment of clotting factor deficiencies, has been used over the last two decades primarily as a source of fibrinogen for the treatment of patients with major haemorrhage.[34]

Patients with Bleeding Disorders

Patients at risk

2.23 Individuals with haemophilia and related coagulation disorders who received whole blood, blood components and blood products were at risk of transmission of infection by treatment.[35] Haemophilia and its treatment were discussed in detail at paragraphs 3.9-3.82 of the preliminary report, and readers are referred to that discussion for more background on the condition and its effects. There is a broad relationship between the risk of transfusion-related transmission of viral infection and the severity of the patient's underlying condition. There are necessary qualifications of this statement which will emerge in the course of this chapter, but current classification criteria are inevitably part of the context in which risk to these patients has to be considered.

2.24 The World Federation of Haemophilia has graded the severity of Haemophilia A and B according to the quantity of clotting factor (Factor VIII for Haemophilia A and Factor IX for Haemophilia B) in a given patient's blood,[36] as follows:

  • <1 international unit per decilitre (iu/dl) - Severe
  • 1 - 5 (iu/dl) - Moderate
  • 5 - 50 (iu/dl) - Mild

2.25 Dr Brian Colvin, until 2007 Director of the Haemophilia Centre at Barts and The London Hospital, observed, however, that diagnosis at the edges of normality can be difficult.[37]

2.26 The normal range of Factor VIII is between 50 and 150 iu/dl. In practical terms, at below 50 iu/dl a degree of abnormal bleeding is found in haemophilia patients and in women who are carriers of haemophilia. Below this level people can have significant clinical problems at times of dentistry or surgery or following trauma.[38] There are other classifications, for example The International Society on Thrombosis and Haemostasis defines the upper limit of mild haemophilia at 30 iu/dl,[39] but for NHS purposes 50iu/dl is accepted.[40]

2.27 Traditionally, the classification of a patient's haemophilia as mild, moderate or severe has been based on the level of Factor VIII or Factor IX found on assay using the technology available at the time. Some patients who have extremely low levels of Factor VIII, including some who do not produce Factor VIII at all, do not bleed excessively, however, and therefore do not require replacement therapy as often as might be expected, or in a few cases do not require it at all. In some cases it has been discovered that the patient has acquired another gene that develops clotting. Dr Mark Winter, Kent and Canterbury Hospital, described the case of a child who had acquired a severe haemophilia gene from his mother and a thrombosis gene from his father. The clinical result was that, although the child had no natural Factor VIII, his father's thrombosis tendency made his bleeding less than expected. Clinically, he behaved like a patient with mild haemophilia.[41]

2.28 Quite apart from such exceptional cases, the level of Factor VIII or Factor IX in an individual case is not determinative of exposure to risk of bleeding: the level of physical activity of the patient is a much more common indicator.[42]

2.29 It is now possible to precisely identify the genetic defect responsible for haemophilia.[43] Generally speaking, haemophilia breeds true within a family: those who are affected within the family tend to be affected to a similar degree. However, people's characters do differ and individuals of a sedentary disposition are less likely to bleed than those who are physically active. Bleeding in the first years of life is a strong determinant of subsequent bleeding. An active child who falls off his bike from time to time is more likely to have trouble than a sibling who sits at home.[44] A child who is very active in the first few years of life and has had, by the age of two or three, multiple bleeds into one particular joint, may develop a 'target' joint. In that event, the child is much more likely than other children with haemophilia to get bleeds later on in life.[45] Lifestyle can also affect older patients. Playing football as goal keeper in a Sunday league, for example, can expose that individual to a greater risk of bleeding than other mildly affected haemophilia patients with the same factor levels.[46]

2.30 When patients suffer recurrent untreated haemarthroses (bleeding within a joint), the joints are rapidly destroyed by secondary osteoarthrosis.[47] When this occurrs in knee joints walking becomes slow and painful.

2.31 On the other hand, it is a mystery why some severely affected patients do not bleed more often. Dr Winter said:

We don't know why ... [severely affected haemophilia patients] don't bleed more often. They have no Factor VIII, so why do they only bleed naturally 30- to 40-ish times per year? We have evidence they are more likely to bleed when they are infected. That's probably because the infection affects the way their platelets work, which is the other part of the clotting mechanism apart from clotting factors.

We have evidence that bleeding is much more common in a joint when the joint has been previously damaged. I think that ... micro-bleeding is probably happening the whole time in joints and muscles, which is the site of main pathology in haemophilia.

But the patient ... can't actually work out whether the minor ache in his knee is due to his arthritis or is it due to a new bleed. Some of these episodes of bleeding will reach a greater threshold, where the bleeding is obviously very significant, but ... our suspicion is that a lot of episodes of bleeding are subclinical and attributed by the patient to the inflammation that he experiences day to day because of all the previous joint damage. Certainly if you go to an operation on somebody's joint ... you can see that the lining of the joint looks like mushroom risotto, for want of a better word, and that it is very bloody.

So one would expect that these joints have been damaged by bleeding early in life ... [T]he synovium, the lining of the joint, becomes much more friable and, like fronds of sea weed, waves in the cavity of the joint and, naturally enough, that can be a focus for very, very tiny episodes of bleeding.

Obviously, if the patient then has trauma - about half of our patients would come in and say, 'I have a bleed. I know why. I banged my elbow coming down the stairs.' About half of them would say, 'I woke up this morning, I have a bleed and I don't know why.' So these things are by no means as well understood as you might think.[48]

2.32 The bleeding patterns in haemophilia are complex because they are variable. Although it is reported that patients get around of 30-40 bleeds a year, an absolute characteristic is that whole weeks might pass with no problems and there might then be a run of several bleeds over a few weeks. A particular precipitating factor, especially in children, is a concurrent infection, such as an ear infection, with bleeding more likely to happen in that situation.[49]

2.33 In the case of mild haemophilia, factor levels may vary from time to time. Factor VIII is an acute phase protein, a protein the levels of which fluctuate, even in healthy patients, in response to tissue injury. This variability is seen more often in mildly affected patients, depending both on how the test is done and on the general health of the patient. For example, patients who have developed arthritis in older age, and therefore have ongoing inflammation, may show an increase in background Factor VIII from 20 to 30 iu/dl. Classification might change permanently if a patient with mild haemophilia develops an inhibitor to factor therapy: that would convert the individual into a more severely affected patient.[50] Illness of any kind might cause a transient increase since inflammation or infection may increase the general activity of several acute phase proteins. A patient's normal Factor VIII level of 20 iu/dl might transiently go up to 30 if he gets pneumonia, for example. In addition, Factor VIII assays are not necessarily the easiest test to carry out and different laboratories testing the same sample might produce different results.[51] The figures for Factor VIII levels in any particular case can give an impression of precision which is not achieved in clinical practice.

2.34 Fluctuation in factor level is less likely in people with severe haemophilia. In a significant percentage of patients there is the deletion of a gene responsible for Factor VIII production so that they cannot make any Factor VIII at all and their Factor VIII level will not increase as an acute phase protein because, even if they have an illness such as pneumonia, the liver cannot make any Factor VIII under any circumstances.[52]

2.35 Dr Colvin explained some common situations:

Children with severe haemophilia usually present, in the first 18 months of life, particularly at the time when they begin to get up and run around or crawl around and bump into things. So the little child with severe haemophilia gets bruises on the shins and may develop haemarthrosis, particularly in the knees and ankles, or when they are trying to put toy soldiers into their mouths, they may cut the mouth and get bleeding from the mouth.

So many children with severe haemophilia who don't have a family history may find - or their parents may find - that they are accused of non-accidental injury, which of course is extremely upsetting for someone who later proves to have a significant blood disorder. But when you are dealing with children with mild or moderate haemophilia ... spontaneous bleeding or bleeding after minor injury is not quite so common, so that you may need quite a significant injury in order to cause bleeding. For example a dental extraction, a classical injury which would cause trouble, or if there is a more important injury, where ... there is a twisted ankle or a twisted knee that may lead to bleeding or at the time of a major contusion like falling off your bicycle or having an operation.

So the person with mild to moderate haemophilia may remain undiagnosed for quite a long time, and being diagnosed at the age of 5 or 6 or 7 years is pretty routine and I have seen patients being diagnosed with mild haemophilia in their 60s and 70s. So it just depends on the level of trauma to which you are subjected. But ... to be diagnosed with haemophilia perhaps after dental extraction at the age of 7 is absolutely typical of the condition.[53]

2.36 It was suggested to Dr Colvin that people with severe haemophilia may experience bleeding without a trigger. He said:

That's true, although the majority of bleeding in severe haemophilia takes place into the joints and muscles, which are the moving parts. However, it is the case that people with haemophilia, particularly severe haemophilia, may have spontaneous [bleeding] - intracranial haemorrhage is the best example - where there is clearly no discernible trigger. Maybe somebody might have bumped their head, but there is no doubt that some people with haemophilia, particularly severe haemophilia, have truly spontaneous bleeding. Of course, it is still possible that there might have been some minor defect in the circulation within the brain that pre-disposes to this spontaneous bleeding. So the word 'spontaneous' is certainly valid in everyday speech; whether it is completely valid at a scientific level is less clear.[54]

2.37 Dr Winter's views on the prevalence of sub-clinical bleeding have been noted at paragraph 2.33. Professor Christopher Ludlam, Director of the Edinburgh Haemophilia Centre, commented on bleeding into the brain in particular:

It is likely that ... we all have a small amount of bleeding in our brains from time to time. We all have good - or most of us have good clotting systems and it stops very quickly and heals up. The problem in haemophilia is that once bleeding starts, it takes a long time to stop. You do not necessarily get a greater flow of blood but it just goes on and on and on and on, and if that happens in the brain, then it often has catastrophic consequences.[55]

2.38 Mild haemophilia does not imply mild bleeding. Once a person with mild or moderate haemophilia begins to bleed after an event such as a tonsillectomy, he will go on bleeding until something is done. A tonsillectomy could be life threatening because a large amount of material is removed from the throat and the airway is critical: death from bleeding could very easily take place.[56]

2.39 Because the severity of haemophilia in an individual may not correlate with the frequency of treatment with blood products, it is not possible definitively to associate the severity of haemophilia with the risk of infection from blood products. Perhaps the most one can say is that there is a broad relationship between risk from replacement therapy and the individual's history of bleeding that required replacement therapy.

Impact of haemophilia

2.40 The balance of risk and benefit in the use of blood, blood components and blood products in general medical and surgical practice may often be relatively uncomplicated. In extreme cases, without a transfusion the patient may die in the course of treatment for the condition requiring medical intervention. Lifelong treatment for an incurable condition, which haemophilia generally is (short of liver transplantation), raises more complex questions. The forms of therapy available for managing the condition change over time, and with those changes come changes in the benefits and in the risks associated with them. Choice of therapeutic materials may become an issue, and any risk/benefit analysis is inevitably complicated by that. The patient's response to therapy may also change. Throughout, however, there is one factor in the balance of risk and benefit that is relatively stable: the risk of progressive illness and death that is inherent in blood coagulation disorders. It is clear that those risks, reflected in morbidity and mortality rates, influenced patients, the Haemophilia Society and haemophilia clinicians. It is important to take note of these risks as the history of treatment and increasing knowledge of risk developed.

2.41 The extent to which patients' lives and life expectancy were compromised before clotting factor concentrates became available was noted in the Preliminary Report and reference was made to reported studies.[57] According to the studies referenced, life expectancy was increased by the use of factor replacement therapy until a position was reached, in 1977-79, when median life expectancy in moderately affected haemophilia patients was estimated to exceed by several years that of the general male population. Median life expectancy for severely affected haemophiliacs (defined as <2% Factor VIII at this stage) remained a little below the median for the general population. The oral evidence led at the Inquiry was more direct and emphasised the adverse consequences for patients of bleeding episodes over time.

2.42 In his written submission to the Archer Inquiry,[58] Dr Winter wrote about life for the haemophilia patient before effective treatment was available:

Without treatment we know that life expectancy is very limited. The Birch report in the 1930s disclosed that only 20% of patients with severe Haemophilia could expect to live beyond twenty years. A Finnish study in 1960 showed that the average life expectancy for patients with severe Haemophilia was twenty five years. The commonest cause of death was internal bleeding, particularly into the brain or gastro intestinal tract. Although Haemophilia appears to have been around for a very long time, no treatment was available until the early 1960s because factor VIII circulates in the blood in only tiny amounts and no way had been found of concentrating factor VIII from blood.[59]

2.43 Dr Winter commented in oral evidence on the natural history of haemophilia:

I think it may be relevant to say that if you ... want evidence of what happens when somebody with severe haemophilia doesn't get treated, you don't only need to look back to these retrospective studies, which were a long time ago and not many of them, you can go to one of the developing countries because the cost of concentrate is so significant, there are many developing countries where, as in Pakistan, they have got very nice hospitals, experienced doctors, good nurses, they are a nuclear power, but they have no concentrate. In the centre in Islamabad, where we visited twice, there are upward of 250 children with severe haemophilia, of which one of them lived beyond the age of 18.

So that remains the natural history of haemophilia. Without treatment, as happened to members of the Royal Family, the likely thing by far is that you will have some life-ending event of serious and spontaneous internal haemorrhage before the age of 20 or so years. That is the natural history of severe haemophilia.


You can look at the old footage of the Tsarevich being carried round Moscow at the age of 8 and he is completely crippled and can't walk, and in Pakistan hardly any of the children we were doing clinics with, hardly any of them - certainly none of them had normal joints and most of them were bedbound.[60]

2.44 Untreated, haemophilia has always been, and remains, a serious, debilitating and potentially fatal disease. It is clearly this factor that has, throughout the reference period, driven the search for therapeutic materials and methods intended to reduce exposure to risk of bleeding or to treat the patient for bleeds when they occur, which has for much of that time involved the risk of transmission of viral infections.

Treatment of haemophilia and risks

2.45 By the commencement of the reference period, the main preparations used in the treatment of haemophilia were early forms of factor concentrates and cryoprecipitate. The history of production and use of these materials in Scotland is discussed in Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s and Chapter 21, Haemophilia Therapy - Use of Blood Products.


2.46 Cryoprecipitate was the first effective treatment for bleeding that was readily available throughout Scotland.[61] It was prepared, mainly at RTCs in the opening years of the reference period, from individual blood donations.[62] In use, it was a high-volume product. Typically, doses used in treatment required a number of units to be administered at the same time. In Glasgow and the West of Scotland, an 'empirical daily dosage scheme' was adopted from the mid-1960s: 10 packs were used for minor bleeding episodes and 20 packs for major episodes, with further infusions as required. A patient treated at the Glasgow Centre in accordance with the empirical dosage scheme might have 20 bleeds in the course of a year, each requiring treatment for four days with 20 packs of cryoprecipitate per day. In the course of the year the patient would have been exposed to 1600 units (20 x 4 x 20) derived from up to 1600 donors.[63]

2.47 At the levels of usage implied, for patients requiring frequent treatment, cyroprecipitate exposed the recipient to a large number of donors. It was soon recognised that cryopecipitate might be associated with transmission of virus infection. In 1966, Vincent del Duca and R. Bennet Eppes reported the transmission of hepatitis following use of cryoprecipitate.[64] Two Glasgow patients were reported in 1969 to have had jaundice after infusion.[65] They also had received blood and FFP and the report was tentative in respect of any relationship between infusion and infection. Dr Judith Pool[66] responded to del Duca's 1966 report of transmission:

We are not aware of this complication after the administration of more than 3000 cryoprecipitates in our own institution, but know of no reason why such preparations should be any more free of transmissible hepatitis than other single donor units given in large numbers.[67]

2.48 Dr Pool's response acknowledged the risk inherent in multiple treatments with cryoprecipitate. While each unit of cryoprecipitate had a single donor origin, the accumulation of units for any one treatment and of repeated treatments over time exposed the recipient to increasing risk. At the level of use suggested by the empirical dosage scheme in Glasgow and the West of Scotland, the risk of transmission in the course of a year was as great as would have arisen from use of the large pool concentrates eventually produced in Edinburgh.

2.49 The administration of cryoprecipitate involved some problems. It was very laborious to prepare, taking two people up to an hour to prepare a dose from about 20 frozen bags, which had to be removed from deep freeze, thawed in a water bath and then reconstituted. Given the nature of the production processes involved, the Factor VIII activity in each bag was not measured and was not known, and clinicians could not scientifically calculate the dose required for the patient. It was difficult to inject and particularly difficult to administer to children.[68]

2.50 Cryoprecipitate could also have quite significant side effects.[69] Some patients who had multiple previous transfusions, which included most haemophilia patients receiving treatment, might react against protein impurities in the cryoprecipitate and that could make the administration of the cryoprecipitate quite an unpleasant experience for the patient. Over the period of an hour the patient might shake and shiver, run a fever, have muscle aches and feel generally unwell.[70]

2.51 The difficulties in administering cryoprecipitate and the practical problems sometimes associated with access to treatment in hospital out-patient departments are discussed in Chapter 21, Haemophilia Therapy - Use of Blood Products. Dr Winter emphasised that it was a very harrowing experience for the patient. He had never, in all his years of haemophilia practice, heard a patient say, 'I went to casualty with a bleed and everything went well'. He said that never happened. Not only was cryoprecipitate not a very good medical treatment for the patients, having to go to hospital to have that treatment was 'a dreadful experience'.[71]

2.52 The incentive to use concentrates when they became readily available was clear. The introduction of concentrates, and increase in their supply in the mid-1970s, heralded a major revolution in haemophilia care. Before then, schooling in particular had been so variable an experience for children with haemophilia that there was a dedicated boarding school in Hampshire, the Lord Mayor Treloar School, for patients with haemophilia. When concentrates became available, boarding provision was no longer required.[72] Concentrates were much easier to use than cryoprecipitate and in particular, unlike cryoprecipitate, they did not need to be stored deep-frozen.

Factor concentrates

2.53 Early Factor VIII concentrate, known as Cohn Fraction 1, was prepared in Edinburgh from the 1950s, using plasma from about a dozen donations. Cohn Fraction 1 was reported to be associated with the transmission of hepatitis in the 1960s.[73]

2.54 As far as the patient was concerned, risk was a function of the number of units infused, in the case of cryoprecipitate and early small-pool concentrates. In the course of the reference period, progressive technological development increased the volume of plasma used to produce a single batch of factor concentrates to a point where many thousands of donations were pooled together by some manufacturers. Before effective virucidal treatment of blood products became available, that inevitably increased the number of recipients exposed to risk from a single batch of product. However, there was an incentive to use the newer products in light of the advances they brought in clinical management of the patient.

2.55 In the case of later concentrates, risk was primarily a function of the number of units used in their production. At about the beginning of the reference period, batches of fractionated product produced at the Royal Infirmary of Edinburgh Royal Infirmary had already involved hundreds of donation units and, with the move to Liberton, 1000 units was the initial batch quantity. Very few infusions of concentrate were required to raise the risk of virus transmission to levels approaching 100%.

Changes in patient management

2.56 Factor concentrates opened the door to home therapy as clinicians could issue concentrate that was small in volume and could be kept in a domestic refrigerator. The concept of comprehensive care evolved. Usually from the age of about three, depending on the state of the child's veins and the competence of the parents, the family would be taught how to inject and the patient would go on home therapy for the rest of his life. The patient would then attend clinic every two to three months, depending on the severity of the disorder, for a comprehensive clinical review.[74] The breakthrough brought a 'golden interval' that lasted from about 1973 until the years of viral contamination problems began some five or six years later. Dr Winter said that haemophilia patients were having better attendance rates at school, getting decent jobs and receiving early treatment at home for their bleeds. There were fewer joint problems.[75]

2.57 In its initial phase, home therapy, like earlier hospital treatment, was used in response to need when the patient had or anticipated a bleed. Some adult haemophilia patients reported an early and brief phase of a few minutes when they had an 'aura' that indicated that not all was well. That would be followed very soon by obvious clinical signs of the bleed, wherever in the body it might be. For joint bleeding, the major clinical indicator would be pain or swelling. Patients were taught that, because the joint was very hot due to the blood in it, they should rub the back of the hand over the affected joint, such as the knee, and compare the good joint with the bad. If the bad knee was a lot hotter, that was a very good sign of an acute episode of bleeding. If the patient were a child, he might be in distress, in particular if the parent passively tried to move the joint, by straightening the knee and the ankle. The child would resist because it was painful, as well as it being hot. In day-to-day home life it was usually obvious that the child did have a bleed, if it was into a joint or a muscle.[76]

2.58 For many years cerebral bleeding was the leading cause of death in haemophilia patients. It has not been eliminated even today but its incidence is very much lower than it was 30 years ago. Identifying major risks was a significant focus for teaching families before a patient went on home therapy. Instruction included the identification of times when it was of the utmost importance that the centre should be contacted immediately, day or night, for assistance. Those included cases in which a child had a significant head injury, lost consciousness or started to vomit after a head injury. Another major area of concern was bleeding into the mouth. If any of these things were to happen, patients and parents were taught to get in touch right away because the centre would wish to administer clotting factor concentrate very quickly and to assess the child clinically.[77]

2.59 In theory, home treatment in response to a bleed might not have been expected to increase the risk of viral infection: the availability of home treatment did not increase the risk of a bleed. Patients did not, however, always seek treatment at hospital before the advent of home therapy. Having regard to Dr Winter's evidence, there was an incentive to put up with the pain and inconvenience of a minor bleed rather than go to hospital. It would be reasonable to infer that there would be an increase in use of concentrate because of the convenience afforded by home treatment and, therefore, an increase in viral infection risk overall.

2.60 The next stage in the development of practice was the introduction of prophylaxis in the 1980s. A practice pioneered by Swedish physicians, it followed the observation that, if a child with severe haemophilia was given Factor VIII or Factor IX regularly (three times a week in this study), then, although their factor levels were not normalised, a baseline zero per cent level of Factor VIII would be changed into a baseline of five per cent. Although the patient would still bleed on even minor trauma, he would not bleed spontaneously. Prophylaxis became widespread practice in Europe.[78]

2.61 Superficially, it might seem reasonable to infer that increasing use of factor concentrates, with home treatment and with prophylaxis, was accompanied by increasing risk of viral infection. However, there was evidence, referred to in Chapter 21, Haemophilia Therapy - Use of Blood Products, that early treatment helped prevent bleeds from developing and that had a beneficial effect on total consumption of factor concentrates.

2.62 Commercial concentrate production, on which English haemophilia practice in particular was heavily dependent, had by the mid-1970s come to involve the processing of very large plasma pools. Before effective virus inactivation, the risk inherent in the product itself had increased. Dr Winter said:

That was my understanding, that by the time concentrate production was well underway by the mid 1970s, the pool size would be at least 20,000 and sometimes higher.


The mathematics is actually quite straightforward. There are studies showing that the incidence of the virus that we now know as Hepatitis C in US donor plasma in the 1970s was of the order of 1 per cent. So if you were giving somebody with haemophilia a treatment that came from 20,000 donors, and one in 100 of them had Hepatitis C, each time the patient had a treatment they were getting a couple of hundred, at least, different Hepatitis C infections, and of course this treatment was being given to them maybe 30 to 50 times a year, or even more often than that.

So our understanding, as haemophilia doctors, is that it was absolutely inevitable that if you had Factor VIII concentrate in the 1970s, particularly from US donor plasma, it was absolutely inevitable that you were getting a number of different Hepatitis C infections, and clinically quite an interesting observation that has been made is Hepatitis C comes in different genotypes, six different genotypes - I say quite often, there have been quite a few experiences in my centre and in a number of other centres that we have treated a patient with a known genotype, say genotype number 1, and we have cleared that genotype and retested him to be then told by the viral laboratory we have now found another genotype. So our understanding based on this mathematics is that these patients were multiply infected with Hepatitis C, as we now call it.[79]

2.64 There was less extensive use of imported concentrate in Scotland generally. Imported, commercially-produced Factor VIII was used, however, especially in Edinburgh and Glasgow, from time to time, and specialised imported products were used more widely.[80] The use of domestic Scottish products was believed to carry less risk because the pool size was smaller and the prevalence of infection in the donor population was thought to be lower than in the USA. The differences were not sufficient to eliminate risk in Scotland, however, and in time it came to be understood that the general position remained the same as elsewhere: the move to concentrates increased the risk of transmission of viral infection. Regular prophylactic rather than reactive treatment may have increased exposure and risk further, whether Scottish or imported products were used, at least as far as Hepatitis C was concerned.

2.65 By the mid-1970s, many UK patients with haemophilia had liver function blood test results which, with the benefit of hindsight, were suggestive of a hepatitis-like pattern. The patients were, by and large, very well. It was possible to demonstrate that maybe 5%, perhaps slightly higher than that, had circulating levels of Hepatitis B; a small number could be demonstrated to have had Hepatitis A, so-called infectious hepatitis; and about 20% could be shown to have antibodies against Hepatitis B (and had therefore been exposed to Hepatitis B). However, for the majority of the other patients who had a hepatitis-like picture on their liver function blood tests, all the standard Hepatitis A and Hepatitis B markers were negative. Most were infected with 'non-A, non-B Hepatitis' as a result of the use of factor concentrates, which only unusually gave clinical symptoms. That was not understood at the time.[81]

Risks of transmission: HCV

2.66 The risks of transmission of HCV by administration of therapy for coagulation disorders in Scotland were largely eliminated by the introduction for clinicial use of effective virus inactivated concentrates (Factor IX in October 1985 and Factor VIII in April 1987).[82] Until those dates, all patients in treatment were exposed to risk of infection.

Risks of transmission: HIV

2.67 As with HCV, the risks of transmission of HIV were substantially eliminated by the introduction of effective virus inactivation of factor concentrates (December 1984/January 1985).[83] Patients were exposed to risk of infection throughout the early 1980s, though that did not become apparent until 1984. It is now clear from the phylogenetic analysis of retained samples that very few HIV-infected individuals donated blood during the few critical years before effective viral inactivation was introduced.[84]

Other people exposed to risk

2.68 As noted in the Preliminary Report, other people were exposed to the risk of transmission of viral infection in a National Health Service context, specifically clinical and laboratory staff and other hospital workers and researchers.[85] They were exposed to all of the consequences of infection to which those presenting as patients were exposed. These people became patients as a result of participation in treatment and other operations.

2.69 In Edinburgh, the risk was illustrated in the transmission of 'infectious jaundice' (in this case Hepatitis B) in the Medical Renal Unit at the Royal Infirmary and the Nuffield Transplantation Surgical Unit at the Western General Hospital between June 1969 and May 1970. There had been two previous cases but, in this short period, 18 cases of infection occurred in dialysis patients and six in people who had had contact with dialysis patients. Four of the contacts were members of staff and two were relatives of patients. In the same period four of the 18 patients had died. One member of staff had died and an additonal member of staff, a clerk in the haematology department at the Western General Hospital, had also died.[86] Though not within the Terms of Reference, these examples show that the classes at risk from time to time were wider than those who came into NHS care as patients in the first instance.


2.70 Successive developments in clinical practice reduced risks to patients, although, on the whole, they did not change patients' needs for treatment. As with all innovations aimed at patient safety, they removed or reduced the risk, or some of the risk, that was known to be inherent in previous practice. Other risks remained. All red cell therapy, for example, continued to carry a risk of transmission of HCV, until routine screening of blood for antibodies to Hepatitis C was introduced in the UK on 1 September 1991.

2.71 Throughout the reference period there was significant use of human blood and blood components, FFP and cryoprecipitate in surgical and medical practice. Patients receiving transfusions have been among those exposed to the risk of transmission of virus infection. Estimates of the numbers of patients who may have been infected are discussed in Chapter 3, Statistics, and a summary has been noted in paragraph 2.1 above. Taken together, transfusion patients represent the largest cohort of NHS patients relevant for the purposes of this Report.

2 Chapters 8-11 and 13-16

3 Preliminary Report, paragraph 3.4

4 Dr Norfolk's Report [PEN.010.0048]

5 Dr Norfolk - Day 7, pages 57-59

6 Dr Norfolk's Report [PEN.010.0048]

7 Dr Norfolk - Day 7, page 59

8 Dr Norfolk's Report [PEN.010.0048]

9 Dr Norfolk - Day 7, page 60. (Landsteiner was also, with Alexander S Wiener, responsible for the discovery of the Rhesus factor in 1937. These two discoveries - ABO and Rhesus - were essential to the possibility of blood transfusion as currently practiced.)

10 Dr Norfolk's Report [PEN.010.0048]

11 Dr Norfolk - Day 7, page 64

12 The reference period for this Inquiry begins on 1 January 1974, the date selected by the Cabinet Secretary for Health and Wellbeing at the outset of the Inquiry's work. There is no specified end-date for the reference period, it having been necessary to consider aspects of the Terms of Reference which continue to operate until the present day.

13 The use of blood components was promoted by SNBTS from the beginning of the 1970s: see Chapter 17, Blood and Blood Products Management, paragraph 17.55.

14 Dr Foster's paper [PEN.013.1125] at 1127

15 Dr Norfolk's Report [PEN.010.0048], section 2 from 0049 and section 3.3.1 from 0051.

16 Ibid [PEN.010.0048] at 0049

17 Dr Norfolk - Day 7, pages 65-66

18 Preliminary Report, paragraph 5.52 and Figure 1.

19 An extreme example was reported from Italy where a single donation divided into 31 aliquots and administered as mini-transfusions infected 18 neonatal patients with Hepatitis. Castiraghi et al 'Long term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth', Hepatology 2004 (39:90-96) [LIT.001.4027] See Chapter 13, Knowledge of Viral Hepatitis Now, paragraph 13.70

20 Dr Norfolk's Report [PEN.010.0048] at 0051

21 Ibid [PEN.010.0048] at 0050

22 The Epidemiological and Survival of Transfusion Recipients (EASTR) study discussed in Dr Norfolk's Report [PEN.010.0048] at 0053

23 Dr Norfolk's Report [PEN.010.0048] at 0053

24 Ibid [PEN.010.0048] at 0049

25 Dr Norfolk - Day 7, pages 82-83

26 Day 7, pages 83-84

27 Dr Norfolk's Report [PEN.010.0048] at 0050

28 Ibid [PEN.010.0048] at 0051

29 Dr Norfolk's Report [PEN.010.0048] at 0051

30 Ibid [PEN.010.0048] at 0055

31 Ibid [PEN.010.0048] at 0056

32 Ibid [PEN.010.0048] at 0052

33 Factor VIII is a protein essential for the normal clotting of blood. Haemophilia A is a deficiency of this 'clotting factor'.

34 Dr Norfolk - Day 7, page 73

35 Preliminary Report, paragraph 3.1

36 Dr Colvin - Day 2, page 80; Witness Statement of Dr Winter [PEN.015.0292]

37 Ibid, page 82

38 Dr Winter - Day 15, pages 58-59

39 Ibid, pages 69-70

40 Some NHS clinicians continue to prefer older formulations, while conforming to the official policy: see, for example, Professor Ludlam's Witness Statement [PEN.015.0385] at 0388 and Professor Ludlam's evidence on Day 18, Pages 23-25. For present purposes it is not necessary to resolve these differences.

41 Dr Winter - Day 15, pages 61-62

42 Ibid page 62

43 Dr Colvin - Day 2, page 81

44 Ibid page 87; Dr Winter - Day 15, page 62

45 Dr Winter - Day 15, pages 62-63

46 Ibid page 65. The example was not hypothetical.

47 Professor Ludlam explained the difference between osteoarthrosis and osteoarthritis (Day 18, page 28). He advised that most of the chronic changes in bones are osteoarthrosis whereas osteoarthritis refers more to an inflammatory component.

48 Dr Winter - Day 15, pages 66-67

49 Dr Winter - Day 15, page 63

50 Ibid, pages 63-64

51 Ibid, page 59

52 Ibid, page 60

53 Dr Colvin - Day 2, pages 78-79

54 Ibid, pages 83-84

55 Professor Ludlum - Day 18, pages 22-23

56 Dr Colvin - Day 2, page 88

57 Preliminary Report, paragraphs 3.46-3.49, noting that the Birch Report was a study from Illinois.

58 The Archer Inquiry was an independent, non-statutory Inquiry on 'NHS Supplied Contaminated Blood and Blood Products' chaired by Lord Archer of Sandwell which reported in 2009.

59 Dr Winter's submission to the Archer Inquiry [PEN.015.0283]

60 Day 15, pages 56-57

61 Cryoprecipitate is the solid residue which remains after the thawing of frozen plasma. It contains most of the Factor VIII from FFP.

62 Paragraph 3.27 of the Preliminary Report is inaccurate in stating that units of the product were prepared from many litres of plasma.

63 As noted in paragraph 2.64 below, Dr Winter said that some patients had treatment 30-50 times a year or even more. Evidently, such patients would have been exposed to yet more units (and donors) than in the example given above.

64 Del Ducca and Eppes, 'Hepatitis Transmitted by Antihaemophilic Globuin' New England Journal of Medicine, 1966; 275:965 [PEN.018.1455]

65 Forbes et al, 'Cryoprecipitate Therapy in Haemophilia' Scottish Medical Journal 1969, 1: 1 - 9 [LIT.001.4018]

66 Dr Pool was a physiologist at Stanford University who, in 1964, discovered cryoprecipitate.

67 Judith Pool, Letter to the Editor in Response to Del Duca and Eppes (q.v.) New England Journal of Medicine, 1966; 275: 966 at 1456 [PEN.018.1455] at 1456

68 See Professor Ludlam's descriptions of use of cryoprecipitate - Day 18, pages 32-38

69 Dr Winter - Day 15, Page 79

70 Ibid Pages 81-82

71 Ibid Pages 79-81

72 Ibid Page 73

73 Marder and Shulman, 'Major Surgery in Classic Hemophilia Using Fraction I' American Journal of Medicine, 1966; 41:56-75 [PEN.018.1432]

74 Dr Winter - Day 15, Pages 72-73

75 Ibid Page 73

76 Ibid pages 75-76

77 Ibid pages 76-77

78 Ibid pages 73-74

79 Dr Winter - Day 15, pages 83-84

80 SNBTS paper 'Resources Required for Adequate Treatment of Scottish Haemophiliacs' [SNB.001.4943] at 4944

81 Day 15, pages 86-87

82 See Chapters 22 and 23.

83 See Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy, paragraphs 24.8-24.9 and Chapter 3, Statistics, paragraph 3.43

84 The Edinburgh Cohort of eighteen patients who were found to have acquired HIV infection in 1984 were associated with two (possibly three) donors. See Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/Aids 2, paragraphs 10.121-10.122. Phylogenetic analysis, which enables the definition of genetic relationship among samples from several sources, was vital to this discovery and is discussed in that chapter.

85 Preliminary Report, paragraph 3.2

86 SHHD background note on infections [SGH.002.3818]

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