Back to Contents page



1.1 On 23 April 2008, the Deputy First Minister and Cabinet Secretary for Health and Wellbeing, Ms Nicola Sturgeon, announced to the Scottish Parliament that there would be a judicially led public inquiry, under section 28 of the Inquiries Act 2005, into the transmission of Hepatitis C and HIV from blood and blood products to National Health Service patients in Scotland. She informed Parliament that the Rt. Hon. Lady Cosgrove would chair the inquiry. Lady Cosgrove subsequently withdrew for family reasons. The inquiry was set up as the Penrose Inquiry on 13 January 2009 with twelve terms of reference.

Terms of reference

1.2 An amendment to the terms of reference for the Inquiry was announced on
13 November 2009. The terms of reference as amended are:

1. To investigate the systems in place in Scotland for the collection, treatment, licensing, testing, preparation for supply and supply for use by the NHS of blood and blood products with particular reference to the risks of transmission of the Hepatitis C virus and HIV to patients treated by the NHS in Scotland, including the role of government in regulation and setting guidelines and standards.

2. To investigate the systems in place for informing patients treated by the NHS in Scotland of the risks associated with the use in their treatment of blood or blood products with particular reference to the risks of infection with the Hepatitis C virus and HIV.

3. To investigate the systems in place in Scotland for obtaining consent from, and testing for infection with Hepatitis C and HIV, patients treated with blood or blood products, and informing patients found to be so infected.

4. To investigate the systems for recording and monitoring the numbers of NHS patients in Scotland treated with blood and blood products, with particular reference to the numbers exposed to risk of infection with the Hepatitis C virus and HIV and the numbers contracting either or both such infections as a consequence of such treatment.

5. To examine the circumstances generally in which patients treated by the NHS in Scotland became infected with Hepatitis C, HIV, or both, through the use of blood or blood products in the course of their treatment, taking account of the development of scientific and clinical understanding and evidence internationally.

6. To investigate the deaths of the Reverend David Black, Mrs Eileen O’Hara, Alexander Black Laing, Neil Mullen and Victor Tamburrini, with particular reference to the circumstances in which they became infected with the Hepatitis C virus, or HIV, or both.

7. To investigate the steps taken by those involved in, and those responsible for, the NHS in Scotland, including NHS boards and the Scottish National Blood Transfusion Service (SNBTS), their officers and employees and associated agencies, once Hepatitis C and HIV were identified; to trace individuals who might have become infected with one or both of them as a result of receiving blood or blood products; and to identify any other or further steps that might reasonably have been taken to trace such individuals.

8. To investigate the steps taken by those involved in, and those responsible for, the NHS in Scotland including NHS boards and SNBTS, their officers and employees and associated agencies, to prevent the provision of infected blood and blood products.

9. To investigate the steps taken by those involved in, and those responsible for, the NHS in Scotland including NHS boards and SNBTS, their officers and employees and associated agencies: to inform individuals who might have received infected blood or blood products of the risks associated with their treatment for themselves and their families; to offer treatment to any individual at risk; and to identify any other or further steps that might reasonably have been taken to inform and to treat such individuals.

10. To examine any particular adverse consequences for patients treated by the NHS in Scotland and their families of infection through blood and blood products with Hepatitis C and HIV, including the treatment offered.

11. To identify any lessons and implications for the future, and make recommendations.

12. To report as soon as practicable.

Scope of the preliminary report

1.3 This report sets out evidence and facts that may assist in resolving the issues focused in the terms of reference. It is not comprehensive: there is other material that will be taken into account before a final report can be prepared, and there will be further procedure to carry out. That procedure will include the gathering of further written evidence, and written submissions, hearing oral evidence and hearing oral submissions. The nature and extent of further procedure will be determined in the light of the issues that emerge from this report and from the representations of interested parties. Some topics, for example those arising from Terms of Reference 2 and 3, may be highly contentious, and will depend on the assessment of all of the evidence ultimately available. Comment on the evidence touching on such matters, so far as it is available to date, has been avoided.

1.4 In preparing this preliminary report, the Inquiry team has examined a large volume of documentary material, published and unpublished, and has had the advice and assistance of independent experts in relevant fields of medical science and technology as well as the assistance of many patients and relatives of patients who have agreed to be interviewed by the Inquiry staff.

1.5 The objectives of this preliminary work were to define, so far as practicable, a framework within which the contentious issues that arise from the terms of reference could be identified and defined; to provide parties with an exposition of factual material which could properly be held to be uncontroversial; and to assist in the specification of the issues that require examination in public, with the benefit of oral evidence and argument.

1.6 This report does not deal with the specific deaths referred to in Term of Reference 6. Investigation of the relevant circumstances has commenced, but at this stage protection of sensitive personal data relating to family and other material witnesses is an important consideration. The results of the preliminary work on this aspect of the Inquiry will be communicated in the first place to the families of the deceased, to the clinicians involved in their care, and their respective legal representatives.

1.7 Age and the ravages of time do not spare those patients who were infected with Hepatitis C or HIV/AIDS nor the clinicians who provided them with care. Reasonable expedition in reaching conclusions on the disposal of the terms of reference was and remains desirable.

1.8 Interested parties are invited to comment on the issues that have to be considered and resolved. It will be necessary for all participants to bear in mind the requirement that the Inquiry report be made available in as short a time as is reasonably practicable, and at a proportionate cost to public funds. This is a preliminary report, intended to assist in the formulation of issues and preparation for further investigation. Some parties will have an opportunity to give written or oral evidence and to make submissions in which any perceived errors or omissions or other deficiencies in this report can be addressed in the course of the next phase of the inquiry. There is produced with the report a statement of proposed topics for further investigation. All interested parties are encouraged to make representations on these. Only with their assistance will the Inquiry be fully informed of their concerns and be able to determine the scope of, and the approach to adopt to, the next phase of the Inquiry.

The approach of the Inquiry

1.9 The reference period for this inquiry begins on 1 January 1974. That date was selected by the Cabinet Secretary for Health and Wellbeing on the basis that the earliest reference in the scientific literature, identified in the Report of the Lindsay Tribunal, to the development of liver disease in haemophiliacs associated with the use of blood factor products was in that year. In the event, biological discoveries and medical and technological developments before 1974 have been reviewed in this report where that has been necessary, or has seemed appropriate, to provide context for events within the reference period.

1.10 It is beyond dispute that some National Health Service patients treated in Scotland became infected with Hepatitis C or HIV or both diseases as a result of transfusion or infusion of blood, blood components or blood products in the course of medical treatment in this country. It is unquestionably tragic that any National Health Service patient should have become so infected. It would have been impossible for any person involved in this inquiry to have been unaware of and to have remained untouched by the physical, mental and emotional suffering of the individuals and families affected by these serious and potentially fatal diseases.

1.11 Many patients have died, and in some cases the causes of death will be dealt with in the final report of the Inquiry. Many who survived have suffered and continue to suffer serious illnesses resulting from their treatment, and in some cases as a result of infection transmitted by NHS products. For many, there is a deep sense of betrayal: the initial infection is seen as having been inflicted by those they were entitled to trust, in the course of treatment intended to relieve suffering. They believe that the benefits intended were cancelled out by the viruses, the seeds of destruction of their lives and the lives of their families.

1.12 On the other hand, the burden of concern and responsibility carried by the clinicians who treated patients is equally apparent. They sought to manage illnesses or resolve serious conditions by medical or surgical procedures, only to find in the course of time that the treatment had inflicted further, but different, pain and suffering.

1.13 Subject to the representations of parties, the approach of the Inquiry is likely to involve collecting further evidence. It will include assessing all of the relevant evidence for veracity and reliability, with a view to seeking an objectively true and reliable account of the material facts in the history of these diseases and those who suffered them. It would be a disservice to all concerned to allow that process to be affected by sentiment. It has been and will be necessary to acknowledge sympathy for those affected and for their families, not least in order to set it aside in arriving at judgment on the facts.

1.14 The issues are complex. Hepatitis C, and HIV/AIDS are diseases that exist, and have existed, in the wider community and are and have been suffered by individuals who have never received blood or blood products produced by the National Health Service or by commercial pharmaceutical manufacturers. In the case of Hepatitis C, the disease appears to have affected some individuals long before the development of modern transfusion medicine or the introduction of therapeutic blood products, and long before the virus causing the disease was identified. The manifestations of disease, the signs and symptoms and the natural history of Hepatitis C or HIV/AIDS that are recognised by the medical profession, have not been finally resolved even now: inevitably they have changed over time. There are no simple answers to the issues raised by the terms of reference of this Inquiry.

1.15 Nevertheless, it is clear that certain patients and groups of patients were exposed to risk of infection. The focus for the Inquiry has largely been and will be to investigate the circumstances in which risk was created, understood and reacted to.

Developments in scientific knowledge about blood

1.16 Central to a proper understanding of the emergence and recognition of Hepatitis C, and HIV/AIDS among NHS patients will be the assessment of contemporary knowledge of the characteristics of blood and its components at the beginning of the reference period in 1974 and continuously thereafter. Blood had been studied scientifically before, and throughout, the twentieth century. By the early 1970s there had been significant developments in medical and scientific knowledge.

1.17 That there were different blood groups, and the classification of blood groups, were known facts, well established by then. It was known that the blood groups related to proteins (antigens) found on the surface of red blood cells. Red blood cells contain an A antigen or a B antigen or both or neither. People with blood group A were known to have antibodies against B antigen, and vice versa. It was known that, in administering blood for therapeutic or surgical purposes the compatibility of the source and recipient blood groups was essential to avoid adverse reactions.

1.18 The distribution of the principal blood groups within the population was known. It was known that:

Blood group O (the blood containing neither A nor B antigen) was present in about 44% of the population;

Blood group A (the blood containing A antigen) was present in about 42% of the population;

Blood group B (the blood containing B antigen) was present in about 10% of the population; and

Blood group AB (the blood containing both A and B antigen) was present in about 4% of the population.

It was known that the rhesus blood groups were different in character from the ABO groups. Apart from the main antigens, other minor red cell antigens were known to play a role in compatibility. These other types were known to become increasingly important in people who received many blood transfusions, because their bodies developed increasing resistance to blood from other people by the process of alloimmunisation: with increasing blood transfusions there were more likely to be additional antibodies and it could become harder to cross match the blood.

1.19 Scientists knew that there were three types of blood cells, and knew their characteristics. It was known that red blood cells are manufactured by red bone marrow, and that their function is to transmit oxygen to all the cells in the body. Cells need oxygen for metabolism. It was known that a patient with a low red blood count was anaemic. It was known that anaemia was due to (i) bleeding, (ii) haemolysis (where the body destroys its own red blood cells, and they break down too quickly as, for example, in thalassaemia) (iii) low iron, which is the element required to make haemoglobin, low folic acid, or low vitamin B12, or (iv) rare conditions such as plastic anaemia caused by poor manufacture of red blood cells.

1.20 It was known that white blood cells fight infections; one type, neutrophils, attack particular bacteria and destroy them. In addition, other white blood cells (lymphocytes)modulate the immune function: that is, they use different ways of dealing with something that is foreign.

1.21 It was known that platelets clot the blood, and that if a patient’s platelet count is low, the patient might bleed too much during surgery, which might make the procedure too hazardous or it might not be possible to stop the bleeding. If there were a problem with the platelets, a platelets transfusion might be required.

1.22 The principal characteristics of plasma were known. The three constituents of plasma that are material for present purposes were known: (i) the clotting factors, including fibrinogen and Factors VIII and IX; (ii) immunoglobulins (Ig) needed in blood for a normal immune reaction to foreign bodies; and (iii) albumin, a normal protein in the blood which helps to build muscle tissue.

1.23 There had been significant developments in the technology available for separating whole blood into its basic component parts of plasma, buffy coat and red cells, and for further processing of those components. In 1940, the process of cold ethanol fractionation of plasma was developed by Dr Edwin Cohn, a professor of biological chemistry at Harvard University Medical School. Albumin was isolated along with gamma globulin and fibrinogen. Further fractionation produced a range of derivatives for clinical application. Initial separation at the point of collection isolated plasma and red cells in particular, and buffy coat as required. Buffy coat, which contains white cells and platelets, was processed according to need. Red cells were mixed with nutrient, refrigerated and stored pending use. Plasma was either used at or near source and was refrigerated pending use, or was frozen for further processing.

1.24 This brief, and superficial, comment is not intended to be a comprehensive statement of contemporary knowledge of blood and its characteristics: much more was known in 1974. It would be misleading to present scientific or technological knowledge in the early 1970s as having achieved a steady state, or as having become comprehensive so far as material for the purposes of this report. Knowledge was increasing. But much of the knowledge that is relevant for present purposes was not available: many of the issues could not have been the subject of responsible hypothesis, much less analysis and presentation in scientific literature. And, inevitably, much that would have been thought by a skilled medical scientist in 1974 to be established or generally accepted scientific fact has been undermined by later research and development.

1.25 By way of example only, it would be reasonable to assume an understanding of the mechanisms of haemostasis, as the body’s natural process for preventing extra-vascular blood loss, and its sub-division into primary and secondary phases. But as late as 1988 knowledge of the mechanics of the two stages in primary haemostasis, vascular constriction and the adhesion of platelets at the site of injury, immediately following vascular constriction, remained speculative.[1] Much of the basic research on platelet adherence was carried out in the 1980s.[2] Knowledge of the coagulation sequence in secondary haemostasis was refined during the same period. The role of Factor VIII was re-defined in the process. It was originally thought to act as an enzyme.[3] In research published in 1979 and 1981, it was shown to participate as a co-factor in the interaction between Factor IXa and Factor X leading to the formation of Factor Xa.[4] Knowledge of the interaction of Factor VIII and von Willebrand’s Factor as a complex circulating in the blood, and their contribution to blood coagulation, was developed at this time. However, this description of the function of Factor VIII, in terms of modern scientific understanding, would not have been recognised by those familiar with contemporary science in 1974.

1.26 The development of effective therapeutic products to counter deficiencies in coagulation factors, which is a major issue in this inquiry, took place at the same time as fundamental scientific knowledge was progressing. In relation to any issue that has to be discussed, it is essential to avoid attributing to the scientists, technicians and doctors involved knowledge that had not been established and made generally available prior to the reference date for the Inquiry, or the date as at which the issue has to be focused.

Blood products

1.27 At the beginning of the reference period, transfusion in surgery and other applications in the United Kingdom, including Scotland, typically used whole blood, and most blood donations were transfused in that form. Returns from Regional Transfusion Centres (RTCs) for the year ended 31 March 1975 showed that in Scotland 73% of all usable blood donations was issued as whole blood. The practice depended on the immediate availability of fresh blood, and in that respect, the United Kingdom was, and had to be, self-sufficient.

1.28 However, throughout the United Kingdom, the treatment of haemophilia patients progressed from the routine use of whole blood to fresh frozen plasma; thereafter, between 1966 and 1968,[5] to anti-haemophilic factor[6] and cryoprecipitate; and finally, and increasingly as a proportion of therapeutic materials used, to improved factor concentrates from about 1972.[7] The balance of the usable donations for the year ended 31 March 1975 was processed at RTCs to produce red cell concentrates, and 60% of those donations was also used to produce cryoprecipitate.[8]

1.29 The manufacture of factor concentrates, and in particular Factor VIII, proved to be technically difficult. Capacity was limited in the United Kingdom, including Scotland, and there was insufficient product to meet increasing patient demands.[9] It was necessary to rely on imported commercial products. It is unnecessary to trace the early history of these developments in any detail in this report. However, since scientific development tends to be based on the foundations of earlier research, identification of the milestones in the process informs medical history generally; and it is important in particular to have an understanding of the position reached at or near the beginning of the reference period.

Early history of the manufacture of blood products

1.30 The process of separation of whole blood into components for use, or further processing, has a long history, reflecting the interaction of developing medical knowledge and technological progress. The primary stage procedure of separation into red cells, buffy coat and plasma depends particularly on the density differences between the corpuscular components and plasma.[10] Centrifugation of blood results in layering of components according to their density. From the 1950s sterile disposable plastic pack assemblies began to replace glass bottles in the collection of blood donations.[11] Centrifugation of the blood in that form of initial storage provided the starting materials for further processing.[12] That process was routinely performed at transfusion centres or by the blood component manufacturer.[13] Later developments have included the use of apheresis procedures at transfusion centres which allow for the continuous separation, by centrifugation on site, of the donor’s blood, extracting the desired component and returning the remainder of the whole blood to the donor. But the major developments are best understood by reference to the more basic procedure.

1.31 Initially, storage of whole blood or blood components was hampered by the coagulation that inevitably follows collection of blood from the body. Once the collection procedure begins, the blood is removed from the body’s natural metabolic sustaining environment, cools from body temperature, and is exposed to foreign substances.[14] Early in the twentieth century, it was discovered that various salts, and in particular citrates, in an unphysiological preservative anticoagulant solution, could maintain the fluidity of blood stored in containers. Citrate-based anticoagulants, usually with the addition of sugar, and heparin anticoagulants were developed progressively thereafter.[15] The blood collection procedures had to be rapid to avoid coagulation in the collection line. And the addition of the anticoagulant solution had to be prompt to prevent the development of foci of coagulation in the collection pack. The plastic collection bags provided for the easy introduction of the appropriate anticoagulant solution. Once bagged, the material had to be stored at the appropriate temperature, depending on the purpose for which the components were required.[16] Technology was required for the effective and efficient collection and storage of blood.

1.32 Apart from material required for the collection of platelets, donations were cooled rapidly to -20˚C. Refrigerated plasma was used clinically at or near the point of collection. Plasma for further processing was freeze dried (lyophilised) from about 1941.[17] Fresh frozen plasma was retained for further processing. It could be stored for up to three months without perceptible change.[18]

Cohn fractionation scheme

1.33 The procedures that followed initial separation also reflected the intended uses of the components. The collection and preservation of plasma enabled plasma volume replacement rather than the replacement of red cells in post-haemorrhagic resuscitation.[19] This became particularly important during the Second World War when there was a dramatic escalation in demand for blood and plasma. Since plasma could be dried, desiccated plasma, reconstituted at the point of use, became an important surgical tool.

1.34 It was against this background that the work of Dr Cohn came into prominence. It had been known from the nineteenth century that plasma proteins had a major role in maintaining circulatory dynamics. Among these proteins, albumin was the most oncotically active ingredient. The albumin molecule was relatively small and was highly concentrated. It was therefore selected as a candidate for purification and use for plasma volume expansion.[20] Dr Cohn and his colleagues[21] showed that plasma proteins could be separated and partially purified in a reaction medium in which hydrogen ion concentration, ionic strength, temperature, protein concentration, and the amount of added ethanol were all carefully controlled. A series of fractionation steps was devised for the major biological categories of plasma proteins: these were partitioned as precipitates or supernatants after each manipulative stage. Cohn fractionation exploited the physical changes induced in the frozen plasma by thawing under controlled conditions. Immersed in a water bath at 4-6˚C, thawing produced a liquid component (the supernatant) which could be extracted, leaving an illiquid residue.

1.35 Dr Cohn’s work was carried out on bovine plasma, but the methodology was readily adapted to human plasma. Transportable human albumin was the result.

1.36 In Blood Separation and Plasma Fractionation[22] (from which this summary is largely derived) the impact of Dr Cohn’s work is assessed as at 1990:

Among other products from the Cohn fractionation scheme there appeared fibrinogen (fraction1), which also contained a major proportion of plasma Factor VIII (anti-haemophiliac globulin), then γ-globulin in fractions 2 and 3, and prothrombin and related coagulation factors in fraction 3. With discoveries concerning the various clinical states in which deficiency in one or another of these blood constituents was the causative pathological abnormality, the possibilities of specific remedial therapy became evident. The development of the Cohn fractionation scheme was able to provide the basis for manufacture of the whole range of blood products available today.

1.37 For most of the period with which the Inquiry is concerned, therapeutic materials continued to be derived from human or porcine blood. Within recent years, Factor VIII and IX materials have been made using recombinant DNA technology. The products are synthetic.

1.38 The residue left by progressive thawing of frozen plasma, and the adsorption of proteins from the supernatant by the Cohn method, was slow to re-dissolve, but it contained a high concentration of fibrinogen and Factor VIII. The residue also contained von Willebrand’s Factor and other proteins, including fibronectin. In 1965, Pool and Shannon[23] devised a relatively simple procedure for separating this ‘cryoprecipitate’ from the supernatant plasma. Their process left a cryoprecipitate that was high in Factor VIII content, that was stable and soluble, and could be produced on a large scale.[24] This provided a relatively purified form of Factor VIII for haemophilia therapy. Attempts had been made to isolate Factor VIII for clinical use in the treatment of haemophilia in the 1930s.[25] But only now was there an effective procedure.

1.39 Cryoprecipitate was applied clinically or further processed to produce Factor VIII concentrate. Both cryoprecipitate itself and Factor VIII concentrate were of importance in the treatment of Haemophilia A patients. The supernatant was processed to produce Factor IX concentrate, immune globulin, albumin and other more specialised products. Factor IX was used in the treatment of Haemophilia B patients. By the beginning of the reference period, concentrates could be and were freeze dried. However, while the technology required to produce therapeutic products had developed, scientific knowledge of their characteristics was relatively undeveloped.

1.40 During the 1970s Factor VIII was identifiable only by its ability to correct the defective coagulation of haemophilic plasma (its ‘biological activity’ known as FVIII.C). Little was known of its molecular, physical and chemical characteristics. It was known that it was contained in plasma along with other components that were necessary for normal blood clotting. Factor VIII was known to be present in plasma at very low concentrations. That fact, and, as discovered later, its susceptibility to proteolysis by thrombin, plasmin and other serine proteases (‘proteolytic degradation’),[26] made its purification and classification extremely difficult. In addition, Factor VIII activity was unstable and tended to co-purify with fibrinogen and fibronectin. These were particularly difficult proteins to deal with in pharmaceutical processing because of their poor solubility and their propensity to adhere to other proteins.[27] However, since deficiencies in these components, and Factors VIII and IX in the blood of Haemophilia A and B patients respectively in particular, were characteristic of the diseases, and since it was known that they had the ability to correct the defective coagulation of haemophilic plasma,[28] efficient isolation of the factors for therapeutic use was a major target of research.

1.41 Cryoprecipitation of Factor VIII from single units of fresh-frozen plasma was viewed as a simple, practical procedure that could be carried out by any blood bank.[29] Larger volume production of cryoprecipitate for therapeutic application involved tens of units. But, typically, and as practised by the United Kingdom blood transfusion services, production of factor concentrates was a commercial scale operation using multiple units or pools of donated plasma, and in time came to require thousands of units of plasma. Until the scientific developments that allowed the manufacture of synthetic Factor VIII and IX, the manufacturing processes affected the level of risk of viral transmission. The probability of transfused whole blood from a single donor transmitting viral infection reflected the incidence of infection in the general population. Pooled donations used in the manufacture of cryoprecipitate increased that risk by a factor in the tens. The use of concentrates increased the risk by a factor expressed in thousands.

1.42 Large scale preparation of Factor VIII concentrate was considered to be a highly specialised activity. It was initially attempted by only a small number of commercial pharmaceutical manufacturers, based largely in the United States of America, and some blood transfusion services. Technology developed in the public and private sectors. Commercial blood products appeared in various countries under a variety of trade names. The market in synthetic products has many of the same characteristics: there may be a number of products, with different names, that are essentially the same and have the same application.

1.43 In the period between 1940 and the reference period of this Inquiry, scientists pioneered the use of a range of chemical additives during the manufacturing process which modified the Cohn ethanol fractionation procedure, resulting in Factor VIII concentrates of varying purity, a function of the removal of proteins such as fibrinogen and fibronectin. By 1970, depending on the chemical agent introduced, low purity, intermediate purity, high purity and very high purity concentrates could be produced. Typically, at the beginning of the reference period, PFC Liberton (the Scottish NHS blood product processing centre in Edinburgh) produced an intermediate purity Factor VIII concentrate for the treatment of haemophilia patients. The concentrate was freeze-dried.

1.44 At the beginning of the reference period, the method of preparing Factor VIII concentrates used by PFC Liberton was based on work carried out during the 1960s at New York University Medical Centre under the direction of Dr Alan Johnson[30] (sometimes referred to as the Newman method from the name of the first mentioned worker in the seminal 1971 paper).[31] Dr Johnson and his co-workers developed methods for the production of Factor VIII concentrates of intermediate and high purity. In their 1971 paper, they traced the developments in technology based on increasingly sophisticated precipitation methods using chemical additives. They had published, in 1966 and later years, papers describing methods of producing clinically effective intermediate purity Factor VIII concentrate by simultaneous ethanol- and cryo-precipitation of Factor VIII from melting fresh-frozen plasma and adsorption of Factors II, VII, IX and X from the precipitate. The technology could be adapted to large scale production, and was the basis of the method used by PFC. The step forward in the 1971 paper was the introduction of polyethylene glycol in the precipitation of intermediate purity concentrate, resulting in a concentrate purified 125 to 350-fold which was effective in the treatment of haemophilia patients. The paper published in 1971 gave wide circulation to the methodologies involved.

The position in Scotland

1.45 So far as Scottish workers were concerned, the work of Dr Johnson and his colleagues appears to have been crucial in the early 1970s. SNBTS and PFC in particular collaborated with Dr Johnson in order to introduce the American technology into the UK.[32]

1.46 Despite assistance from Dr Johnson, the product was found to be extremely difficult to manufacture because of the instability of Factor VIII activity and the poor processing characteristics of the other proteins present. Consequently processing was always problematic, Factor VIII yields were low, capacity was very limited and there was insufficient Factor VIII available to meet patient needs.[33]

1.47 Manufacturers worldwide experienced similar problems. However, commercial companies increased their output by purchasing increasing quantities of plasma from paid donors. This practice was favoured in the USA where limits on the volumes of plasma that could be taken from an individual donor were much more lenient than in Europe. As a result, the NHS requirement for Factor VIII concentrate was met increasingly by commercial products imported from the USA.[34]

1.48 This was a time when demand for blood products for the treatment of haemophilia patients in Scotland, as elsewhere, continued to grow annually.[35] The SNBTS had difficulty in planning to meet the demand because of the dramatic changes in the way Factor VIII concentrates had been used since the introduction of on-demand and prophylactic treatment. In terms of the total number of donations processed, there had been a major increase in demand in 1964 due to the introduction of reconstructive surgery for haemophilia patients, and then steady and steep growth from about 1971 due to the introduction of on-demand therapy. In the south-east of Scotland region, demand in 1961 had been expressed as 1,326 donation-equivalent units. Peak demand in 1973 was 10,835 units. Analysis by product showed the use of fresh-frozen plasma increasing slowly until 1970 after which it fell dramatically. Use of anti-haemophilic fraction (AHF, Factor VIII) fluctuated. Cash and Spencely published information in rough graph form in 1976[36] to which it will be necessary to return. The data are discussed below in Chapter 5 ‘The Organisation of Blood Transfusion in Scotland’. In general terms the data reflected growth in the use of Factor VIII products. However, they did not distinguish the production of AHF by Cohn technology from the development of ‘intermediate (New York) Factor VIII’ based on later technology.

1.50 At the same period, in relation to the production of Factor IX concentrate, two scientists at the PFC in Scotland, J K Smith and S M Middleton, participated in a collaborative project with Dr Johnson and other scientists at New York University. This was the ‘Supernine Project’, which aimed to replace the then-current Factor IX preparation, DEFIX, with a concentrate that would be three to five times more potent, and have a reduced Hepatitis B surface antigen (HBsAg) content.[37] They produced a Mark I version of this product which was used in clinical trials in 1973, finalized a Mark II version in 1976, and were prepared for routine production in 1977.

1.51 It would be misleading to present the position at 1 January 1974 as reflecting a settled stage in the development of the technology of blood products: scientific and technological development was rather in a continuing state of change. There was increasing sophistication in the manufacture of products. There was increasing understanding of the uses to which specific products could be put. That would be the position going forward.

The position in England and Wales

1.52 In England and Wales, similar products were developed, but the approach appears to have been different. Different technological procedures appear to have been well established in several centres.

1.53 In 1961, Rosemary Biggs and other workers at the Blood Coagulation Research Unit at Oxford published a method of extracting Factor IX from the residual material derived from the plasma fractionation process used by the Blood Products Laboratory of the Lister Institute.[38] In 1967, Edith Bidwell and other workers from the same team took the technology further.[39] The paper they published on their work set out some relevant background. From the early 1950s it had been known that Factor IX could be adsorbed from serum and from plasma. All early work depended on the adsorptive properties of Factor IX, the distinguishing features being related to the selection of the starting material, which could be either unfractionated plasma (serum) or an unwanted residue of an established large-scale fractionation procedure. They discussed the disadvantages of each source material, setting out in some detail the work of others in the 1950s and 1960s, before referring to the work of Biggs:

In the meantime the residue of the large-scale ether fractionation of plasma developed in England by Kekwick and Mackay (1954) had been used as a starting material for a successful preparation of a Factor IX concentrate (Biggs & Others). The preparative procedure was similar to that used by Soulier and co-workers,[40] ie the adsorbent was tricalcium phosphate and heparin was used as stabilizer. Factor-IX concentrates for therapeutic use have now been produced regularly in Oxford for more than six years during which the method has been much simplified by technical improvements described by Bidwell and Dike (1966) and in the present paper.

1.54 The work depended materially on the use of alcohol fractionation which permitted the preparation of both Factor VIII and Factor IX from the same batch of plasma. So far as Factor IX was concerned, the result was a very high-purity product.

1.55 The impression left by these sources is that Scottish workers tended to collaborate with American workers rather than their English counterparts, who pursued their own lines of research, and, as a result, developed a product (generally described as ‘NHS Factor VIII’) which depended on technology developed by Kekwick and Mackay rather than the Newman techniques used in Scotland.

Viral infection of blood products

1.56 Throughout the 1970s, a major focus of research was on attempts to remove the risk of hepatitis transmission by removing viruses from the factor concentrates in the manufacturing process.[41] The development of techniques for heat-treatment procedures changed that focus, but it is important in understanding what was happening.

1.57 By the beginning of the reference period, the risk of viral infection transmitted by blood and blood products was known. Clinicians, scientists and technicians interacted, responding to developments in their parallel fields in response to the risk. Techniques developed to deal with one perceived threat were adapted to respond to emerging threats. What could be achieved technically, however, was often limited by the state of scientific knowledge at the time. Human albumin had never been reported to transmit a virus. Prior to the reference period, the preparation of human albumin for therapeutic application involved heat treatment with specific stabilisers in the liquid phase. The heat treatment process (pasteurisation of the solution at 60ºC) whereby human albumin products could be made hepatitis-safe had been developed in the 1940s in the USA.[42] Human albumin was first produced by SNBTS in 1965. The Scottish product was heat treated by pasteurisation at 60ºC for 10 hours,[43] using the American process.[44]

1.58 The background to and use of albumin was reported in 1977 in the context of growing American concerns about excessive use of the product.[45] The principal indications for its clinical use had been in relation to its oncotic action as a plasma volume expander, and there were concerns that its use was being extended beyond appropriate limits. The incidental information in the report is more interesting for present purposes:

The safety of albumin is so high that it rarely warrants discussion. The reaction rates for various side effects….are low….Fortunately, even these reactions, for the most part, are ephemeral…As a result of the unusual stability of albumin, it is possible to heat it routinely during processing to 60˚C for ten hours, thus achieving inactivation of hepatitis viruses.

As a result, infectivity for hepatitis B virus is so infrequent as to constitute a reportable item. The only established cases have apparently come from a breakdown in equipment wherein 60˚C treatment for ten hours was not uniformly achieved in a lot of material. Studies on hepatitis B antigen contamination of albumin products formerly showed wide variability on the basis of the type of donor from which the plasma pools were obtained. Since the advent of radioimmune assays for the accurate screening of donor sources, however, a dramatic fall in potential anti-genicity for even that inactive virus has occurred.

1.59 However, at first, albumin was considered to be unique amongst plasma products in its ability to withstand heat to this degree.[46] The emphasis on the stability of the albumin molecule may explain the belief that its capacity to tolerate heat treatment was thought to be particular: the relative instability of Factor VIII was referred to frequently.

Issues for consideration by the Inquiry

1.60 By the beginning of the 1970s there were experimental programmes aimed at applying heat treatment procedures in the manufacture of other products. In particular, many manufacturers first used heat treatment to try to make other blood products, including factor concentrates, virus-safe. However, it is important to avoid investing workers generally with knowledge of the developments achieved and discoveries made by leaders in the field before the results had been published. Progressive developments in blood product technology during the Inquiry’s reference period provide a focus for investigation generally.

1.70 The Inquiry is already aware of a number of issues raised by interest groups and individuals. Generally, these issues fall into five broad categories:

The criteria for the selection or rejection of blood donors.

The steps taken to screen donated blood for viruses.

The techniques developed and applied to inactivate viruses in donated blood.

The dispensing to patients of products containing infective material.

The information given to patients and their families about viral contamination and about infections resulting from such contamination.

The Inquiry team has prepared a draft list of topics for examination at oral hearings. The list is set out in the schedule to this Introduction. The preparation of this list has involved an attempt to focus more specific areas within the categories outlined above. These appear to the team to be areas in which there is controversy meriting critical examination by questioning of witnesses in public. Responses to the report which suggest other topics, or which highlight a particular aspect of any topic which is considered to be particularly important, will be welcomed.

Schedule - Draft list of topics for examination at oral hearings


1. The efforts made to discourage ‘higher risk’ donors from giving blood (by the dissemination of information, including leaflets); whether these efforts went far enough and began early enough.

2. The use of commercial products in Scotland, including the continuation of such use after:

a) international realisation that these carried a risk of AIDS;

b) the proposal by Dr Galbraith of the Public Health Laboratory Service in May 1983 that use in the UK should be stopped; and

c) significant progress towards self-sufficiency in the manufacture of blood products by the NHS in Scotland had been made.

3. The implementation of heat treatment against LAV/HTLV-III by the Protein Fractionation Centre in Scotland in December 1984, and the technological background to such implementation, including the history and exploration of methods of heat inactivation by the Scottish National Blood Transfusion Service.

4. The decision not to use kits from the United States of America for testing donated blood for the virus as soon as they became available but, instead, to follow a process of evaluation of the kits before any such use.

5a) The information given to patients (or their parents) about the risk of
AIDS before their treatment with blood or blood products;

5b) the tracing and testing of patients who might have been exposed to
the virus through their treatment with blood or blood products; and

5c) the information given to patients who might have been infected, or
who were found to be infected, and their families.

6. The effects of infection with HIV, including the effects of treatment, on patients and their families.

Hepatitis C

7. The acceptance of blood from ‘higher risk’ donors, in particular:

a) prisoners; and

b) donors who had a history of jaundice, and who were negative for
Hepatitis B when the existence of Non-A Non-B Hepatitis was known
and its presence could not be excluded.

8. The non-introduction in Scotland of surrogate testing for Non-A Non-B Hepatitis.

9. The implementation of heat treatment sufficient to inactivate Hepatitis C in blood products by the Protein Fractionation Centre in Scotland in 1987, and the technological background to such implementation, including the achievement of this objective by the National Blood Transfusion Service in England and Wales in 1985.

10. The interval between the availability of tests for the Hepatitis C virus in 1989 and the introduction of screening of donated blood for the virus in the United Kingdom in September 1991.

11a) The information given to patients (or their parents) about the risk of
non A non B Hepatitis before their treatment with blood or blood

11b) the tracing and testing of patients who might have been exposed to
the virus through their treatment with blood or blood products; and

11c) the information given to patients who might have been infected, or who were found to be infected, and their families.

12. The effects of infection with Hepatitis C, including the effects of treatment, on patients and their families.

[1] V.S. Hornsey: Studies on Monoclonal Antibodies to von Willebrand Factor and Coagulation Factor VIII: PhD Thesis, Heriot-Watt University

[2] A.L. Bloom (Ed): Methods in Haematology, 1982, Churchill Livingstone Edinburgh

[3] E.W. Davie & O.D. Ratnoff: (1964) Waterfall sequence for intrinsic blood clotting. Science 145 1310-1312 [LIT.001.1023].

[4] G.G. Neal & S.I. Chavin (1979): The role of factors VIII and IX in the activation of bovine blood coagulation factor X. Thromb Res 16, 473 -184 [LIT.001.1072]. G. Van Dieijen, G. Tans, & Others (1981): The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem 256, 3433-3442 [LIT.001.1084].

[5]Blood Separation and Plasma Fractionation: Harris Ed. 1990 page 19, based on the work of Pool & Shannon, 1965, New Eng J Med 273:1433-1447

[6] In England and Wales referred to as ‘NHS FVIII’

[7] Rizza & Spooner: Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-80: 1983; BMJ 286:929 – 933 [LIT.001.0234]

[8] Total usable blood: 212,061 donations; whole blood issued 153,877 donations; red cell concentrates 58,175 donations; and cryoprecipitate 35,048 donations.

[9] Foster PR and McIntosh RV: The development of hepatitis-safe Factor VIII Concentrate: 9 December 1999 [SNB.001.6647]

[10]Blood Separation and Plasma Fractionation: Harris Ed. 1990 page 49

[11] Ibid page 49

[12] Ibid page xi

[13] Ibid page 6

[14] Ibid page 48-9

[15] Ibid 28 and 44

[16] Ibid page 44

[17] Dr Peter Foster: Plasma Fractionation in Scotland: Blood Letter Spring 2008.

[18] Newman J, Johnson AJ, Karpatkin MH, and Puszkin S: Methods for the Production of Clinically Effective Intermediate- and High-Purity Factor VIII Concentrates: British Journal of Haematology, 1971. 21. 1 [SGF.001.1913]

[19] Blood Separation and Plasma Fractionation: Harris Ed. 1990 page 44

[20] Ibid page 45

[21] Cohn EJ, Strong LE, Hughes WL et al (1946) Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. Journal of the American Chemical Society, 68, 459 [LIT.001.0948].

[22] Harris Ed. 1990 page 45,

[23] Pool & Shannon, 1965, New Eng J Med 273:1433-1447 [LIT.001.0967]

[24] Newman J, Johnson AJ, Karpatkin MH, and Puszkin S: Methods for the Production of Clinically Effective Intermediate- and High-Purity Factor VIII Concentrates: British Journal of Haematology, 1971. 21. 1 [SGF.001.1913]

[25] Ibid

[26] V. Atichartakarn, V.J. Marder & Others (1978) Effects of enzyme degradation on the subunit composition and biologic properties of human factor VIII. Blood 51, 281 -297 [LIT.001.1148].

[27] Foster PR and McIntosh RV: The development of hepatitis-safe Factor VIII Concentrate: 9 December 1999 [SNB.001.6647]

[28] Ibid.

[29] Newman J, Johnson AJ, Karpatkin MH, and Puszkin S: Methods for the Production of Clinically Effective Intermediate- and High-Purity Factor VIII Concentrates: British Journal of Haematology, 1971. 21. 1 [SGF.001.1913]

[30] Foster PR and McIntosh RV: The development of hepatitis-safe Factor VIII Concentrate: 9 December 1999 [SNB.001.6647]

[31] Newman J, Johnson AJ, Karpatkin MH, and Puszkin S: Methods for the Production of Clinically Effective Intermediate- and High-Purity Factor VIII Concentrates: British Journal of Haematology, 1971. 21. 1 [SGF.001.1913]

[32] [SNB.001.6647] at SNB.001.6650

[33] Ibid

[34] Ibid

[35] Cash and Spencely: Haemophilia A and the blood transfusion service; a Scottish study BMJ 18 September 1976 682. [LIT.001.0255]

[36] Ibid

[37] Foster P R: Methods for Preparing Non-Infective Blood Products, 8 March, 1983 [SNB.007.3503]

[38] The preparation and Assay of a Christmas-Factor (Factor IX) concentrate and its Use in the Treatment of Two Patients: Biggs & Others Brit Jnl Haemat. 1961, 7, 349 [LIT.001.1332].

[39] The Preparation for Therapeutic Use of a Concentrate of Factor IX Containing also Factors II, VII and X. Brit Jnl Hamat 1967; 13; 568 [LIT.001.0084]

[40]Preparation d’une fraction serique riche en convertine (VII) facteur… Nouv Rev franc Hemat 2 27 [LIT.001.0942]

[41] Foster PR and McIntosh RV: The development of hepatitis-safe Factor VIII Concentrate: 9 December 1999 [SNB.001.6647]

[42] Edsall, “Stabilization of serum albumin to heat, and inactivation of the hepatitis virus”, 1984, Vox Sang, 46, 338-340 [SNB.008.5701]

[43] [SGF.001.1439] page 5.

[45] Tullis: JAMA Jan 24 1977 vol 237 no 4

[46] Foster & McIntosh Submission to Scottish Executive 9 December 1999 [SNB.001.6647]

Back to Contents page