Back to Contents page

CHAPTER 3

NHS PATIENTS AT RISK

Synopsis

Haemophilia and von Willebrand disease discussed – genetics of disorders – progress in treatment – prevalence of blood disorders – life expectancy and quality of life in patients with genetic blood disorders – incidence of HCV infection and HIV/AIDS in haemophilia patients – mortality data related to HIV/AIDS and HCV infection in haemophilia patients – blood transfusion and HCV transmission – mortality from liver disease in HCV infected patients – organisation of haemophilia care – UKHCDO – the Haemophilia Society – milestones in haemophilia.

Introduction

3.1 The Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV), described in the last chapter, are both blood-borne viruses. Consequently, NHS patients who were at risk of infection with HCV or HIV or both viruses as a result of their treatment fell into three broad groups: (i) individuals with haemophilia and related diseases who received whole blood, blood components and products manufactured from blood and blood components; (ii) patients receiving blood transfusion; and (iii) patients receiving other blood components or products manufactured from blood or blood components, such as immunoglobulin preparations.

3.2 The mechanisms of exposure to risk that are material for present purposes are: (i) intravenous infusion of therapeutic blood products, notably in the treatment of haemophilia patients; and (ii) blood transfusion, for example in surgery, following childbirth or consequent to severe anaemia, or in the treatment of haemophilia. In addition to NHS patients, clinical and laboratory staff, and other hospital workers and researchers who may have had contact with blood components in processing materials, or with infected patients or samples obtained from them, were at risk.

3.3 Transfusion was, and is, required during certain types of surgery or following childbirth to compensate for loss of blood, in particular loss of haemoglobin. Transfusion involves units of whole blood or red cells, each collected from a single donor. Transfusion of over ten units of whole blood, from ten individual donors, is rare. The use of single units of fresh frozen plasma (FFP) did not increase exposure to risk. In contrast, the use of products manufactured from plasma immediately increased the exposure of the patient to risk because of the numbers of donors contributing to the series of pools from which the plasma was derived. It would be impossible to identify any particular procedure as typical of the whole class of surgery requiring blood transfusion. But open heart surgery provided opportunities for follow-up studies of a distinct class of patients and provided data on infection that came to be illustrative of the risk of infection following blood transfusion at certain periods.

3.4 Safe transfusion, in the broadest sense, is a relatively modern procedure. In the nineteenth and early twentieth centuries, blood transfusion was potentially hazardous for a number of reasons not related to transmission of viral disease. Until matching by blood group was developed from about 1938 to ensure matching of source blood to the patient’s blood group, there was a relatively high risk of haemolysis. This is a destructive attack on transfused red cells by the patient’s antibodies, which can be serious or fatal, when incompatible blood is transfused. Viral infection came to be recognised as an added complication as the twentieth century progressed.

3.5 In the case of clinical and laboratory staff, and other hospital workers and researchers, the risk of viral infection might be casual: an accidental ‘needle stick’ incident, for example. Alternatively, it might relate to exposure, sometimes prolonged, in laboratory conditions to blood components or to aerosols produced in the course of processing those components. Dr Edward Shanbrom, of Hyland the pharmaceutical manufacturer, reported that laboratory staff working on the development of Factor VIII developed jaundice after breathing plasma mist in the cold rooms of the laboratory.[1] Risk was inherent in the manufacturing process.

3.6 Haemophilia patients have been and remain a particularly exposed group, though the risks to which they have been exposed have varied over time. At an early date, whole blood was transfused in the treatment of haemophilia patients. More recently, they were prescribed treatment with pooled plasma products derived from human blood, thereby increasing exposure. Exposure might be frequent and persistent over long periods of time, because of the need for control of the bleeding caused by their underlying condition, and each exposure involved multiple sources of blood or its components.

3.7 Inevitably, the literature has dealt with some groups, and haemophilia patients in particular, more than others, and provided a particular focus for public interest that will be reflected in this report. For a proper understanding of the developing picture, however, each of the groups mentioned is important.

3.8 Before the development of therapeutic blood products, haemophilia patients were exposed to pain, suffering and disability, and, depending on the severity of their condition, premature death. It is appropriate to set out in some more detail the characteristics of these conditions in order fully to appreciate first the beneficial impact of the new treatments, and then the damage done to confidence in, indeed faith in, the clinicians and scientists on whom haemophilia patients depended.

Haemophilia and von Willebrand’s disease

3.9 The general characteristics of the main types of genetic disorders of clotting were known long before the reference period for this Inquiry. The first written account of haemophilia dates back to the second century. A number of baby boys died following excessive bleeding after circumcision.[2] It was realised that the condition appeared to run in families.[3] However, the most significant scientific and medical advances arose in the nineteenth century. One of the first scientific papers on haemophilia was published by Dr John Conrad Otto in 1803,[4] detailing the haemorrhagic predisposition of males within a family. He recognised that the condition was hereditary, only affected males and appeared to be passed on maternally via healthy females.[5] A further account was published by John Hay in the New England Journal of Medicine in 1813[6] in which it was noted that affected males could pass the trait on to unaffected daughters.[7] The term haemophilia was first used in 1828 by Friedrich Hopff at the University of Zurich.[8]

3.10 During the twentieth century, Drs Patek and Taylor (1937)[9] discovered that a protein contained within blood and essential for blood-clotting (Taylor later named this protein antihaemophiliac globulin (AHG)) was missing from haemophilia patients. Further developments occurred in 1947, when Pavloasky discovered the apparent difference between what is now known as Haemophilia A and Haemophilia B.[10]

3.11 Haemophilia A and Haemophilia B (also known as Christmas disease) are genetic coagulation disorders. Among the range of coagulation disorders, clinically significant haemophilia is more common in the United Kingdom than in most other western countries. It is an inherited defect of blood clotting and, in most cases,[11] is present from birth. Haemophilia A is due to a deficiency in the blood component Factor VIII. Haemophilia B is due to a deficiency in Factor IX. The process of blood clotting involves the interaction of over a dozen clotting ‘factors’ created by the liver and released into the circulation along with other components of blood. In the case of a bleeding injury suffered by a person who is not affected by haemophilia, the process of clotting was classically described as a cascade. Initially, the damaged blood vessel or vessels narrow (the process of vasoconstriction). The vessel walls constrict to slow the flow of blood into the injured area. Platelets then migrate to the site of injury and pile up. They provide a scaffold or plug on which other factors build. Another protein component, fibrinogen, also moves to the location of the injury and helps clot the blood. Each of the clotting factors activates another in the chain. If one is missing, there is a break in the chain, and the others cannot contribute effectively to the clotting process. For example, if Factor VIII is missing, not only is there at that stage a failure of the process, but also Factors IX, X and XI are not engaged. More recent research (from the 1980s) has disclosed that haemostasis, the clotting procedure, is initiated by the release of tissue factor (Factor III) from the walls of the blood vessel which binds to Factor VII. Factor VII auto-activates tissue Factor VIIa which in turn triggers the coagulation network. However, a clot may still be regarded as a combination of platelets and other adhesive components which must act cumulatively to be effective.

3.12 In haemophilia patients, there is a deficiency of the Factor VIII or Factor IX required to contribute effectively to the clotting process and stop bleeding. Classification in terms of severity has changed over time. At present, the classification for both conditions is:

Mild – between 5% and 30% of normal levels of clotting factor

Moderate – between 1% and 5% of normal levels of clotting factor

Severe – less than 1% of normal levels of clotting factor.[12]

3.13 Effectiveness in haemostasis or clotting varies in proportion to the degree of deficiency. A mild haemophiliac may have serious bruising from a knock. If a severe patient suffers injury without the benefit of treatment, bleeding will occur, and it will not be stopped because clotting will not occur: even a mild injury exposes the patient to risk. Some individuals with severe haemophilia suffer what appears to be spontaneous haemorrhage from time to time. An individual with haemophilia does not bleed more profusely than a normal person, they simply bleed for longer.[13] The inherent risk is increased in surgery or serious trauma.

3.14 There are other genetic disorders of the blood, for example several forms of the genetic condition thalassaemia, which impair synthesis of haemoglobin leading to anaemia, and there are several immune disorders, for example common variable immune deficiency. Von Willebrand’s disease, which affects both sexes, is closer to the two forms of Haemophilia, A and B, than other genetic conditions and enters into the narrative of events with which the Inquiry is concerned.

3.15 Von Willebrand’s disease (vWD) was first described in 1926 by Dr Erik von Willebrand.[14] It was termed hereditary pseudo haemophilia.[15] During the early twentieth century treatment for the condition was very limited. In 1953 an association between von Willebrand disease and the coagulation Factor VIII was discovered.[16] This association initially led to confusion within the medical community regarding the protein abnormality responsible for von Willebrand and Haemophilia A.[17] But in time it was realised that the deficiency could be treated by the administration of plasma fractions.[18]

3.16 Von Willebrand’s disease is the most common of the inherited coagulation disorders.[19] It is characterised by reduced levels of von Willebrand protein in the blood. The protein serves two main functions. It is a carrier protein for Factor VIII and it has an adhesive role in vessel wall platelet interaction. Von Willebrand defects result in longer blood clotting time.[20] It has been estimated that one per cent of the general population suffer from the condition.[21] However, the proportion of those affected who are categorised as having a clinically significant bleeding disorder is small.[22] The number of patients registered and treated has been growing. In 2009 the number of patients in the UK registered with vWD was 9,265: 981 of those registered required treatment for the condition in that year.[23] Severe forms of the condition are detected in early childhood, whilst mild versions may go undetected for many years.[24]

3.17 Von Willebrand’s disease is now sub-divided into three major categories:[25] type 1, type 2 and type 3. Type 2 is further sub-divided into 2A, 2B, 2M and 2N.[26] Type 1 is the most common form and accounts for 80% of recorded cases.[27] An individual with type 1 has low levels of vW Factor but what they produce functions properly. In type 2, the vW Factor produced does not work efficiently. The sub-divisions reflect varying levels of severity of the deficiency. Type 3, the rarest form of the condition, is classed as severe. It affects one to three per million of the population.[28] Individuals may experience soft tissue and joint bleeds.[29] A person with type 3 usually lacks vW Factor altogether and will have low amounts of Factor VIII. The patient will experience regular bleeding problems, clinically similar to severe Haemophilia A, including spontaneous internal and external bleeds.[30]

Symptoms

3.18 Haemophilia is typically discovered during childhood in patients with moderate or severe forms of the condition. Children will often bruise easily or bleed profusely from what appear to be minor wounds. Children with mild haemophilia may go undiagnosed for several years.[31] Often the condition only becomes apparent after an accident or dental procedure where the child bleeds for a prolonged period of time.[32]

3.19 Haemophilia is frequently associated with external bleeding. Wounds, such as deep cuts in areas around the mouth and other parts of the body which are abundant in blood vessels, can be particularly troublesome and an individual may suffer prolonged bleeding.[33] However, a much more common and serious symptom is internal bleeding into joints and muscle tissues. While bleeding into the soft tissues may occur without serious adverse consequences, bleeding into the joints results, in general, in swelling and may leave behind scar tissue that starts to destroy the joint. Arthritic type pain is a common, and serious, complication of the condition.[34] In severe haemophilia, a patient who does not have the benefit of treatment with clotting factors might have painful joints by the age of five. The most common sites for joint bleeds are knees, elbows and ankles; but any joint with a synovial membrane can be affected.[35] Individuals with severe haemophilia can experience other spontaneous internal bleeds. A serious complication of haemophilia is intracranial haemorrhage, bleeding into the brain.[36] Another is bleeding into the gut. Serious morbidity and mortality may occur.

3.20 Current research into haemostatic disorders involves developing therapy aimed at gene replacement as a means of resolving the deficiencies in the liver’s production of Factors VIII and IX in particular. At the date of this preliminary report clinical trials are imminent. Knowledge of the genetic deficiencies arising with Haemophilia A and Haemophilia B, associated with the technical capacity to modify the individual’s genetic characteristics, may free the patient from the risks that have arisen with the current generation of treatments.

Genetics

3.21 Human DNA is contained within units of chromosomes. Each person contains 23 pairs of chromosomes, one set inherited from each parent. The sex of an individual is determined by the presence or absence of the X and Y chromosomes. Females have XX and males XY chromosomes respectively. Haemophilia is inherited in an X-linked recessive manner which results in the deficiency of a coagulation factor. It is passed down maternally from mother to male child via the X chromosome. Males only have one copy of the X chromosome, and for that reason if they are passed a copy of the haemophilia gene from their mother this gene will be expressed. Hence the condition predominantly affects males. However it is possible, albeit extremely rare, for women to suffer from the condition. In the case of males there is often a family history that initiates enquiry, and antenatal screening tests are now available.

3.22 A proportion of cases, perhaps up to one half, occur in patients with no family history of haemophilia.[37] This is due to spontaneous mutation of the gene responsible for Factor VIII or Factor IX production on the maternal X chromosome.

3.23 Individuals can either be sufferers or carriers. In circumstances where a female child is passed one copy of the haemophilia gene from one parent and one normal copy of the gene from the other parent, haemophilia will not be expressed as the normal gene is dominant. In such circumstances the female will become a carrier. The normal copy of the gene will facilitate the production of the necessary clotting factors which takes place in the liver.

3.24 The gene coding for von Willebrand Factor is located on chromosome 12, which is common to men and women, and the disease affects the sexes equally. Unlike haemophilia, types 1 and 2 von Willebrand are inherited in a dominant manner. One copy of the gene is required from either parent in order for it to be expressed.[38] Type 3 of the condition, the most serious coagulation disorder, is inherited in a recessive manner. The abnormal gene is inherited from both parents.[39]

Treatment

3.25 In the 1950s, knowledge of haemophilia and the treatment of the conditions remained rudimentary. The treatment available comprised hospitalisation, local compression where possible, blood transfusion, pain killers and bed rest. Apart from immediate palliative care, from the early 1960s the principle behind the treatment of haemophilia was, and remains today, replacement therapy: blood and blood components and products replace the missing or deficient levels of clotting factors (either VIII or IX). Most coagulation defects have been treated in that way since then. Early treatment for haemophilia involved transfusing whole blood. Extremely large volumes of blood might be required to restore an individual’s clotting factor levels. A major risk with that treatment was of overloading the person’s circulatory system with too much fluid which could result in heart failure. The next major development in the treatment of haemophilia involved the infusion of plasma. Plasma was found to be rich in the essential clotting factors. However, like whole blood, large volumes were transfused and the risk of heart failure remained, albeit the risk was less than in the use of whole blood.

3.26 Until the late 1980s the characterisation of Factors VIII and IX, their identity and structure, were not known. Nevertheless, efforts were made to develop ways in which the clotting activity of whole plasma would be ‘concentrated’ into a much reduced volume. These led first to the production of Cryoprecipitate and then factor concentrates as therapeutic materials.

3.27 The development of Cryoprecipitate and of coagulation factor concentrates removed the need for whole blood, and plasma, transfusions and brought a level of relief that had previously been unknown. The development of Cryoprecipitate, a frozen blood product which contained soluble clotting factors, was a major breakthrough in the treatment of haemophilia. The product, prepared from many litres of plasma, was initially used to treat patients with Haemophilia A. From 1967 onwards, Cryoprecipitate was offered to patients suffering from Haemophilia A and von Willebrand’s disease. The Factor VIII-rich component of blood greatly reduced the volume of transfused fluid required. From the early 1960s, primitive concentration of Factor VIII activity was achieved by processes involving freezing and thawing to produce what was called antihaemophiliac globulin (AHG). Treatment with more developed Factor VIII concentrate, manufactured from hundreds or thousands of donations, later became available, and in many, but not all, cases supplanted the use of Cryoprecipitate. In some cases prophylactic applications, and later home applications, allowed a level of ‘normal’ life that was unprecedented, as well as dramatically increasing life expectancy. The subsequent discovery that, in many cases, the treatment exposed patients to new, debilitating, and potentially fatal illnesses had a devastating impact on them.

3.28 The clinical regime adopted has varied over time depending on the severity of the condition in the individual patient, and depending also on the judgment of the clinician in charge of the patient’s care. Major shifts in the use of therapeutic materials occurred in the period to 1980:[40]

Human Factor VIII and IX preparations used by UK haemophilia centres 1969 to 1980

Year

Haemophilia A

Haemophilia B

Plasma %

Cryoprecipitate %

Factor VIII Concentrate %

Plasma %

Factor IX Concentrate %

1969

17.17

68.09

14.74

69.68

30.32

1970

13.16

76.04

10.80

62.39

37.61

1971

6.78

67.25

25.97

34.79

65.21

1972

5.60

75.98

18.42

11.60

88.40

1973

4.20

74.80

21.00

2.35

97.65

1974

3.37

70.29

26.34

3.22

96.78

1975

1.43

65.45

33.10

0.48

98.33

1976

0.1

46.6

53.30

0.30

99.70

1977

0.1

35.1

64.80

0.40

99.60

1978

0.1

24.4

75.50

0.40

99.60

1979

0.1

18.1

83.00

0.10

99.90

1980

0.1

14.2

85.80

0.10

99.90

3.29 The data also indicate growing demand for blood products. In the case of Haemophilia B, Factor IX concentrates (NHS and commercial) had become for all practical purposes the sole therapeutic material in use. In the case of Haemophilia A patients plasma had all but ceased to be used, and the use of Cryoprecipitate had fallen. But total volumes increased significantly:

• Factor VIII consumption in international units in 1969 was 6.95 million units and in 1980 it was 57.27 million units;

• Factor IX consumption in 1969 was 1.44 million units and in 1980 it was 8.27 million units.

3.30 In the United Kingdom as a whole, Cryoprecipitate was the most widely used product until 1976. In terms of volume, its use peaked in the mid 1970s, then fell progressively until in 1980 usage was at its 1972 level, when the haemophilia population receiving treatment, and the amount of treatment received per patient, had been much smaller. Commercial Factor VIII began to be imported from the USA in 1972. Commercial and NHS Factor VIII concentrate consumption began to rise in 1974, following parallel growth patterns until 1977. Consumption of NHS Factor VIII then levelled off, while use of commercial products continued to rise rapidly. In 1980 in the UK:

• plasma accounted for 0.1% of therapeutic products used;

• Cryoprecipitate for 14.2%;

• NHS Factor VIII for 25.1%; and

• commercial Factor VIII for 60.7%.

3.31 For Factor IX treatment, plasma use fell to near zero and commercial Factor IX to minimal values. Demand was met by NHS Factor IX. The proportions in 1980 were:

• plasma 0.1%;

• commercial Factor IX 0.9%, and

• NHS Factor IX 99.1%.

3.32 Over the period home treatment increased. By 1980 44% of all haemophilia patients in the UK received home treatment; 60% of severely affected patients received home treatment.

3.33 In current clinical practice, mild Haemophilia A and von Willebrand patients are normally treated reactively following a prolonged bleed. The basic purpose behind current treatment techniques is to correct two abnormalities resulting from the disorder:[41] firstly prolonged bleeding episodes and secondly low Factor VIII in blood resulting in irregular coagulation.[42] The treatment employed is dependent on the type of disorder. Apart from factor concentrates, there are two main treatments offered to individuals: desmopressin or DDAVP, a product first utilised in 1977,[43] which increases plasma concentrations of factor VIII and von Willebrand protein.[44] DDAVP is a synthetic hormone which stimulates the body’s own production of Factor VIII and is administered by injection. Since its effectiveness depends on the individual having the capacity to generate Factor VIII, it is not suitable for severe haemophilia sufferers or those with Haemophilia B.[45]

3.34 For Haemophilia B patients prolonged bleeding can be treated by nonacog alfan, a synthetic drug made up from monoclonal antibodies. Administered intravenously, the monoclonal antibodies contain active ingredients which will replace the diminished or missing Factor IX.[46]

3.35 In the case of moderate to severe diseases, the trend towards home-based prophylactic treatment became well established from the 1980s. This led to a demand for ‘high-purity’ products, that is factor concentrates that were relatively low in fibrinogen and other aggregates, and quick to dissolve in regular ordinary use by patients or their families. Advances in research and technological development led to the commercial production in the late 1980s of virus-safe products of high purity that were preferred by some clinicians, to the disadvantage of products from Scottish public sector manufacturers in particular. By the end of the decade monoclonal products of unprecedented purity had become available, and recombinant Factor VIII was available for treatment of new, previously untreated, patients in particular.[47]

3.36 Working at the Royal Free Hospital, London, scientists led by Edward Tuddenham and Alison Goodall purified Factor VIII, and raised monoclonal antibodies of over 95% purity by 1982. The sequencing and cloning of the antibodies were produced in collaboration with Genentech Inc of San Francisco and led to production of a synthetic Factor VIII. Cutter Laboratories, San Francisco, carried out the work required to scale up synthetic Factor VIII production, and clinical trials of the product were successfully completed. Kogenate, the resulting product, was licensed for clinical use in 1988 and, along with other commercial products developed over roughly the same period, became the preferred treatment for Haemophilia A. These developments depended on demanding and inspired scientific research which would not have been possible at earlier periods, and would indeed have been absolutely impossible before the discovery of DNA sequencing.

3.37 Treatments for Haemophilia A and B using synthetic drugs have been very successful. It appears that the risk of hepatitis may have been removed, for all practical purposes, by avoiding dependence on human blood products. However, one complication with this form of treatment has been an increased risk of the development of inhibitors. In some cases the patient develops antibodies to the therapeutic material which ‘inhibit’ its operation by destroying the protein administered in treatment. The individual’s immune system attacks the replacement material as if it were ‘foreign’, in the same way as it would attack a virus for example. In these patients treatment is more difficult. It has been estimated that inhibitors develop in approximately one third of individuals with severe Haemophilia A.[48] Inhibitors can either be classed as high or low titre (level).[49] In an individual with a high titre, the immune system will attack the replacement clotting factor in a very short space of time rendering the treatment ineffective. Such individuals may now be prescribed an immune tolerance induction programme which aims to train the body to tolerate the clotting factor replacement drugs.[50] Individuals with low titre inhibitor levels are generally treated with a higher dose of the clotting factor concentrates.[51]

3.38 At the date of this preliminary report, the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) has reported increasing external pressures on the service. The foremost of these are: issues related to prophylaxis in adult patients; continuing and increasing demand for Factor VIII; and significant variations in the intensity of treatment offered by different centres. The UKHCDO Annual Report for 2009 notes that the need for clinicians to justify clinical practice is likely to become ever more acute, ‘particularly if the NHS is overwhelmed by a financial tsunami in the next year’. It is impossible to ignore the tensions between those involved in the care of coagulant disorder patients and the Health Departments of the United Kingdom and of Scotland, not only in the current financial climate, but over time. Over much of the reference period, those tensions arose from clinicians’ preferential selection of commercial therapeutic products (which were more expensive) as against those available from NHS sources. Currently, the scope for tension may be illustrated in a case study published in the first issue of the magazine ‘Inhibitors’ and used to support the case for immune tolerance therapy. The child in the study was a severe haemophiliac: in the three months prior to commencing immune tolerance therapy he had had 18 bleeds, with treatment costing £390,000. Against that background it was suggested that immune tolerance therapy was cost effective. The allocation of scarce NHS resources may arise for discussion.

Prevalence of haemophilia

3.39 The prevalence of reported haemophilia in the United Kingdom generally, and in Scotland in particular, has varied over the reference period. Reported cases of Haemophilia A in 1974 were 9.3 per 100,000 of the male population. In 2008, the equivalent figure was 21.5.[52] There is a strong trend of increasing Haemophilia A over time. This contrasts with the Unites States of America, where the prevalence reported fell from 20 in the early 1970s to eight per 100,000 in 2006. The gross figures for Canada also show a strong trend of increasing prevalence. But in Canada there has been increasing prevalence of severe Haemophilia A that is not reflected in the experience in the United Kingdom. The range of variation undermines the usefulness of international comparisons. In the United Kingdom, the reasons for increasing prevalence over time could reflect increased survival, improved diagnosis and classification, and improved access to care for haemophilia patients. The ratio of Haemophilia A to Haemophilia B patients is now about 4 to 1.[53]

3.40 In the United Kingdom as a whole, there were 6,480 Haemophilia A, 1,372 Haemophilia B patients and 9,265 von Willebrand patients registered with the UKHCDO in September 2009. Published data for the earliest years of the period are incomplete but, so far as available, show:[54]

Numbers of patients registered and treated at UK haemophilia centres 1969 to 1980

Year

Haemophilia A

Haemophilia B

von Willebrand

Registered

Treated

Registered

Treated

Registered

Treated

1969

1,022

142

1970

1,108

131

1971

1,154

132

1972

1,234

172

1973

1,434

204

1974

1,634

237

1975

2,839

1,670

463

275

1976

3,192

1,886

548

296

1977

3,546

1,975

621

312

1978

3,914

2,048

686

330

1979

4,122

2053

725

344

1980

4,321

2,117

777

355

3.41 The historical data for subsequent periods from UKHCDO reports are:

Year

Haemophilia A

Haemophilia B

von Willebrand

Registered

Treated

Registered

Treated

Registered

Treated

1987

5,195

2,277

982

416

2215

45

1990

5,339

2,404

1,055

416

2,688

382

1995

5,413

2,258

1,133

474

4,150

572

2000

5,385

2,162

1,165

471

5,955

654

2005

6,012

2,285

1,276

507

7,718

648

2009

6,480

2,783

1,372

596

9,265

981

3.42 The Scottish position as recorded by UKHCDO is set out in detail in the appendices. The Scottish totals for registered patients, at five year intervals, were:

Year

Haemophilia A

Haemophilia B

von Willebrand

Total

1970

159

17

2

178

1975

274

47

2

324

1980

409

88

44

541

1985

443

95

134

672

1990

462

102

184

748

1995

475

116

394

985

2000

398

107

616

1,121

2005

397

107

805

1,309

2010

405

112

900

1,417

3.43 The data on registered severe haemophiliacs recorded in the UKHCDO Annual Report 2009, Table 5, at September 2009, were:

United Kingdom

East of Scotland

West of Scotland

Scotland Total

Haemophilia A

1,510

51

66

117

Haemophilia B

315

4

20

24

3.44 Of 1,825 severe haemophilia patients in the United Kingdom as a whole, 141 were Scottish patients, just under eight per cent of the UK total. Although the data are not strictly comparable, the Scottish proportions of severe haemophilia patients registered at the present time can be derived approximately from the 2009 report and the 2010 data for Scotland provided by UKHCDO:

Haemophilia A 6.25%

Haemophilia B 8.16%

von Willebrand’s 9.71%

3.45 The number of patients with hereditary blood disorders registered with haemophilia centres in Scotland has never been large.

Life expectancy in haemophilia

3.46 In the days before treatment with clotting factor concentrates became available, both quality of life and life expectancy were seriously compromised for those who suffered from inherited blood disorders. In the 1997 edition of R. M. Titmuss The Gift Relationship[55] it is said:[56]

The median expectation of life for patients with severe haemophilia in Britain was estimated as near normal in 1980 in contrast to a life expectancy of thirty-seven years in 1962 ...[o]ne published testimony, that of Donald Bateman, gives a vivid impression of the pre-Factor VIII days:

For internal bleeding there was nothing on offer other than immobility and encasing the limb in a plaster cast. The pain from such a situation defies description and must in my boyhood have contributed to my mood of blank despair. When the plaster is removed, the muscle wastage is serious and restoration of movement becomes hazardous and painful. I have had my left thigh treated in such a manner three times in pre-Factor VIII days. Bleeds into muscles produce scar tissue which is devitalised and a permanently painful problem.[57]

The increase in longevity and in quality of life over such a short period was almost entirely due to the widespread introduction of Factor VIII concentrates.

3.47 In parts of Africa today, haemophilia patients continue to experience the pain and suffering described by Mr Bateman, in the absence of readily available treatment. The distressing images of severely swollen knee and ankle joints, and of distorted leg shapes, which have largely disappeared due to effective therapy in this country and elsewhere, remain visible in disadvantaged parts of the world. However, patients in the United Kingdom continue to suffer pain, and in some cases severe pain, both acute when a bleed occurs, and chronic day-to-day pain from damaged joints.[58] Chapter 4 ‘Patients and their Families’ sets out material on the experiences of Scottish patients that will be subject to examination in the second phase of the Inquiry.

3.48 The impact on life expectancy described by Titmuss is less easily demonstrated. It takes time to assemble data, and inevitably the data available from time to time were inconsistent and sometimes unreliable in detail. The data also appear to have differed from one country to another to a degree that suggests that comparison may be unreliable unless thoroughly researched.[59] The best available up-to-date analyses for the United Kingdom as a whole, referred to later, appear to be those prepared by the UKHCDO. But published material allows a general picture to be derived of the information that would have informed the perceptions of relevant clinicians from time to time.

3.49 A study of 98 UK haemophilia patients published in 1937[60] disclosed that 82 died in childhood or adolescence. Six percent of the total survived the age of 40. In the 1970s, Dr Biggs and other workers at the Oxford Haemophilia Centre studied data recorded at Oxford, and published tables covering a range of topics including the percentage age distribution of patients as against the general male population.[61] Dr Rizza and Dr Spooner brought the data down to 1980.[62] In each case, the population was most heavily concentrated in the age groups 10 to 39. However, there were changes in patterns and more changes were anticipated. The data were:

Percentage of population over 40 years of age

31 December 1974

31 December 1980

General Male Population

40.3%

40.3%

Haemophilia A

19.47%

25.2%

Haemophilia B

21.13%

24.2%

3.50 The percentages of patients surviving age 40 at 31 December 1974 showed a significant improvement over the six per cent in 1937. And as between 1974 and 1980 there was a further improvement in survivorship in both groups of patients while the position in the general male population appears to have been static. The tables noted, without further details, ‘unknowns’ and dead patients among the study group, and the data were therefore incomplete, but the information appears sufficiently reliable for present purposes. A higher proportion of haemophilia patients were surviving the age of forty in each group, though the percentage was still below the comparable percentage in the general male population.

3.51 In the Biggs papers, it was presumed that most patients in the 10 to 30 age group would live to be middle-aged and older and that there would be a substantial increase in the number of living patients. Rizza and Spooner reported that, as at 1980, the average ages of the patients who died were 46.7 years in the Haemophilia A group and 48.3 years in the Haemophilia B group. Comparable figures for the 1974 group were 42.3 years and 33.6 years respectively.

3.52 Thus, even on the superficial basis provided by these sources, survivorship was improving over the period, and it can reasonably be inferred that that would have informed professional opinion about the value of the therapeutic products prescribed. The 1983 paper contained life expectancy tables for Haemophilia A patients in the group studied. Taken at face value, the median life expectancy for these patients in the period 1977 to 1979 was (i) for patients with Factor VIII values <2% of normal 69.1 years; and (ii) for patients with Factor VIII values of 2–<10% of normal 79.2 years. The median life expectancy of normal males was 72.8 years.

3.53 The median life expectancy values set out above would have indicated to relevant clinicians a prospective experience for the surviving members of the two classes which was significantly different from the actual experience of those who had died during the study period. In the group of severe Haemophilia A patients 53% of deaths had occurred at or before 39, compared with 25% in each of the other groups. These were, by age, patients born in and after 1941 who had, for much or all of their lives, been treated with blood products, maximising both the benefits and the risks associated with those products. The projection of a life expectancy of 69 years for the whole surviving class might have been open to the objection that the database was perhaps too narrow to justify the generality of the conclusions, and the paper acknowledged some reservations about the validity of the estimates. But to the extent that the paper was accepted as valid, it appears to have been important in influencing opinion.

3.54 Dr Biggs’ conclusions were that there had clearly been a noticeable improvement in the management of haemophilia since Factor VIII had become widely available and bleeding to death from trivial injury – so common in the past – was by then rarely seen. It should not be a surprise if there was some increase in life expectancy at the time. There appears to be little doubt that the figures were accepted by clinicians and informed their views, which might not always have reflected the qualifications noted by the authors.

3.55 Thus, the same data on life expectancy were included without further development by Dr Peter Jones of the Newcastle Haemophilia Centre in an article in The British Medical Journal (BMJ) of 10 December 1983,[63] referring to the work of Biggs and co-workers on the treatment of Haemophilia A and B and von Willebrand’s disease.[64] With the benefit of hindsight there were two emerging factors that were not, and, it appears, could not have been, taken into account fully in the very early 1980s: the morbidity and mortality factors associated with Non-A Non-B Hepatitis and with AIDS.

3.56 During the period from 1960 onwards, there were improvements in the overall management of haemophilia. More dedicated centres were established, and there were more specialist haemophilia clinicians and allied support staff. Biggs’ data for 1969 were derived from 37 centres. In their 1983 paper, Dr Rizza and Dr Spooner reported that by 1980 the number of centres had increased to 10 reference centres and nearly 100 other centres. These improvements contributed to the quality of care, and must have had an impact on survivorship and life expectancy as well as on quality of life. However, the major candidate for credit for the improvement in life expectancy prior to the advent of HIV/AIDS appears clearly to have been the therapeutic use of Cryoprecipitate and factor concentrates during the study periods.

3.57 Over the period discussed by Dr Biggs, and subsequently by Rizza and Spooner, as tabulated above, when factor therapy was increasing throughout the United Kingdom, the numbers of patients registered and treated increased. In the case of Haemophilia A patients treated Dr Biggs’ data show a rise of 107%, and in the case of Haemophilia B patients treated the rise was 150%. There has been no indication to date of material increases in the birth rates for patients born with haemophilia. On the contrary, the proportion of total patients in the youngest age groups fell, as the details published by Dr Biggs and others demonstrated, with increasing numbers of patients surviving the age of 40.

3.58 It appears that it would have been a reasonable inference from the statistical data that, despite the risks inherent in their use, the increasing availability of blood products, and more convenient treatment (including prophylactic treatment) contributed greatly to the improved life expectancy of the patient and to the quality of life experienced. Mr Bateman’s experience, quoted above, provides direct evidence to support that inference. In numbers, far more haemophilia patients had access to treatment with modern products that improved the management of their condition.

3.59 Later data has tended to confirm a trend towards general improvement in life expectancy. By 1999, for those not infected with HIV, the average life expectancy for a patient with severe haemophilia was estimated to be 63 years. For a person with mild/moderate haemophilia the estimate was 75 years.[65] But HIV and Hepatitis C altered the picture. The Camelot moment reflected in Dr Jones’ 1983 paper was to pass.

3.60 The most up-to-date UKHCDO records of the incidence of HIV and Hepatitis C infection are set out in the appendices to this report, together with the organisation’s observations. The data recovered from the Scottish Centre for Infection and Environmental Health are also appended. The validity of the UKHCDO observations has not been tested at this stage in the Inquiry: there may be scope for alternative views and until that is explored with interested parties it would be inappropriate for a conclusion to be reached as to the explanation for the data. Similarly, the exact numbers of patients infected will only be resolved when the differences between the two sources are investigated. For present purposes, the UKHCDO data have been adopted for illustrative purposes. The data show that the numbers of patients registered with Scottish Haemophilia Centres with all bleeding disorders who tested positive for HIV between 1982 and 1995 were:

Haemophilia Centre

HIV positive

Aberdeen

7

Dundee

0

Edinburgh

29

Glasgow: RHSC

11

Glasgow: RI

23

Inverness

2

Total

72

3.61 The total number of patients registered at United Kingdom Centres outwith Scotland who tested positive for HIV was 1,310. Scottish patients represented 5.2% of the United Kingdom total.[66]

3.62 The UKHCDO data for patients registered at Scottish Centres distinguish between patients who were alive in 2010, and patients who died in the period 1969–2010 having been diagnosed as infected with Hepatitis C. The addition of the groups shows that the total numbers of deceased and surviving Haemophilia A, Haemophilia B and von Willebrand’s disease patients who tested positive for HCV in the period 1969–2010 were:

Haemophilia Centre

HCV positive

Aberdeen

54

Dundee

30

Edinburgh

135

Glasgow: RHSC

62

Glasgow: RI

166

Inverness

47

Total

494

Total corrected for double counting

410

3.63 The comparable corrected total for patients who tested positive for Hepatitis C, and were registered at non-Scottish Centres was 4,366. Scottish patients represented 9.4% of the United Kingdom total.

3.64 The explanation of the incidence of HIV infection and Hepatitis C infection, and of the differences in the proportions represented by Scottish patients overall will arise during the second phase of the Inquiry. However, it may be noted at this stage that while UKHCDO believed (consistently with the major studies already referred to) that it is likely that a very high proportion, if not all, of patients with bleeding disorders who tested positive for HIV were registered with UK Haemophilia Centres and hence were recorded in the UKHCDO database, the completeness of the data for patients who were, and are, HCV positive is likely to be substantially less, and to suffer from regional variations.

Mortality data

3.65 In 1995 an influential group of workers, Darby et al, published a letter in Nature setting out mortality data before and after HIV infection in the complete UK population of haemophilia patients.[67] The letter brought out mortality rates that led to the conclusion that there was a large excess attributable to HIV/AIDS:

These are the first data to document that, in a complete population, mortality among those who by chance were infected with HIV increased more than tenfold while remaining unchanged over time in those who escaped infection. Assuming that the death rate during 1985–92 among infected patients would, in the absence of HIV, have been close to that for uninfected patients, 60 deaths would have been predicted, whereas 403 deaths in fact occurred, an excess of 343. Thus 85% of the deaths in HIV seropositive patients are likely to have been caused by HIV. This large excess, together with the temporal pattern of the increase in those who became infected, the similarity of the excess death rate associated with HIV infection regardless of the severity of haemophilia, and the large increase in mortality from conditions not usually associated with haemophilia, demonstrate particularly clearly the enormity and the specificity of the effect of HIV-1 infection on mortality in this population.

The data reflected in the quotation from Nature, above, calculated excess mortality due to AIDS. The number of deaths reported in the letter as certified due to AIDS was 235. Before 1985 one death only was certified due to AIDS.

3.66 Patients testing positive for HIV were again studied by Darby et al, and the results were published by UKHCDO, in 2004.[68] The data referred to 7,250 haemophilia male patients for the period 1977–1999, distinguishing those with severe haemophilia (defined as less than 1 IU/dl) from moderate and mild haemophilia patients. Individual data on HCV status were not available. However, study analyses were relied on for the view that close to 100% of patients treated before 1985 were infected with HCV, with a single exposure to large-pool concentrate usually causing infection. HIV-1 testing was available in late 1984, and the paper noted that virtually all haemophilia patients who had received potentially infected blood products were subsequently tested.[69] Stored blood samples were used to estimate dates of seroconversion. The methodology described gives a reasonable level of confidence in the study, though inevitably the paper acknowledged a number of limitations to the study which were thought to have little or no impact on the conclusions. The material conclusions were:

In the entire UK haemophilia population, annual mortality was constant during 1977–1984, at approximately 0.9% in severe haemophilia, and 0.4% in moderate/mild haemophilia. From 1985, mortality in those not infected with HIV remained essentially unchanged but, among the infected individuals, mortality rose progressively by large amounts. Among those infected, the timing of the increase was identical in the two severity groups, and in each calendar period mortality rates were similar in size in the two groups, despite the different proportions infected and their different mortality rates in the absence of infection. Survival was poorer in HIV-infected individuals than in uninfected individuals at all ages. However, a much larger proportion of individuals remained alive by the end of the follow-up period for those who were younger when infected, even after correcting for the mortality expected in the absence of HIV...

The impact of co-infection with HCV on mortality in HIV infection is hard to estimate precisely. Before 1997 it was probably proportionately small, because during this period liver disease was the certified cause of death for only 9% of the deaths in HIV-infected individuals. Studies comparing HIV-infected individuals in different exposure categories, some of whom would have had much lower HCV prevalence, have also found no appreciable effect of exposure category on survival before the HAART (highly active antiretroviral therapy) era.

During 1997–1999, mortality fell sharply in HIV-infected individuals, both in severe and in moderate/mild haemophilia. A similar fall, occurring shortly after the introduction of HAART, had been reported…and clearly demonstrates the impact of HAART. However, at the end of the present follow-up period, mortality in HIV-infected individuals still remained substantially higher than in HIV-uninfected individuals. Both the large increase in mortality up to 1996 and the subsequent fall were chiefly caused by changes in mortality from HIV-related causes….

3.67 Mortality from causes unrelated to HIV rose over time, with the value for 1991–1996 almost double that for 1985–1990, and no appreciable decline in 1997–1999. The paper attributed the rise almost entirely to an increase in liver disease, some of which was attributable to HIV/HCV co-infection.

3.68 In 2007, Darby and others published the results of a study of UKHCDO data relating to 6,018 people with Haemophilia A or Haemophilia B in the United Kingdom in the period 1977–98 excluding those who were infected with HIV.[70] The data in the Darby paper included details of all males diagnosed with Haemophilia A or Haemophilia B regardless of whether they required treatment, and had been updated annually, with patients followed up until 1 January 2000. The conclusions were:

Given disease severity and factor inhibitor status, all-cause mortality did not differ significantly between hemophilia A or hemophilia B. In severe hemophilia, all-cause mortality did not change significantly during 1977 to 1999. During this period, it exceeded mortality in the general population by a factor of 2.69…and median life expectancy in severe hemophilia was 63 years. In moderate/mild hemophilia, all-cause mortality did not change significantly during 1985 to 1999, and median life expectancy was 75 years. Compared with mortality in the general population, mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischemic heart disease it was lower, at only 62%...of the general population rates, and for 14 other specific causes it did not differ significantly from general population rates….

3.69 The detailed analyses tabulated provided a source of apparently firm information about cause of death, and of the risks to which the population had been exposed as at the end of 1999. The data are not consistent in point of detail with the reports of the Scottish Centre for Infection and Environmental Health.

3.70 Data contained in the UKHCDO annual reports from 1987–2009 (with the exception of 1991 and 1992 for which separate data are not available) enable a reasonably reliable estimate to be made of actual deaths from AIDS. Interpolating figures for 1991 and 1992 (of 55 deaths each year) based on the data for 1990 and 1993, the total for 1987–2008 was 544. That figure included 259 for the period 1987–90, and can be compared with the 236 certified cases for 1985–90. Making allowance for deaths before 1987, the total of 544 does not appear to be an excessively high estimate. The annual distribution of these deaths, and the relationship of AIDS-related deaths to all relevant deaths was:

UK AIDS-related deaths among patients with bleeding disorders and percentage of all deaths each year - 1987 to 2008

Year

Number of deaths

Percentage

1987

21

31

1988

29

38

1989

48

52

1990

51

53

1991

Estimated 55

not known

1992

Estimated 55

not known

1993

59

47

1994

71

48

1995

72

44

1996

36

32

1997

12

19

1998

9

14

1999

8

11

2000

5

6

2001

4

5

2002

4

4

2003

0

0

2004

1

1

2005

1

1

2006

1

1

2007

2

2

2008

0

0

3.71 Of note are (i) high absolute numbers of deaths from AIDS between 1989 and 1995, and the high percentages those represented of all deaths in the haemophilia population over that period; and (ii) the steady decline in deaths from AIDS after 1996.

3.72 Data for deaths from AIDS recorded by UKHCDO for Scottish patients, as set out in the appendices to this report, relate to patients also diagnosed with Hepatitis C infection and may not be comprehensive. But they show:

Haemophilia Centre

Death from AIDS

Aberdeen

8

Dundee

2

Edinburgh

22

Glasgow: RHSC

7

Glasgow: RI

14

Inverness

6

Total

59

3.73 The reasons for the apparent incompatibility between the tabulated deaths and the data for positive test results for HIV infection, for example in Dundee and Inverness, may have to be explored in the second phase of the Inquiry.

3.74 Again based on data published in UKHCDO annual reports, an estimate can be made of the number of haemophilia and von Willebrand patients exposed to risk of infection with Hepatitis C between 1969 and 1985. The data for patients who received Factor VIII concentrate or Cryoprecipitate therapy are believed to be reasonably comprehensive and accurate. Data have not been collated of patients who were in fact tested for anti-HCV or found to be HCV positive. Nor are there data recording the numbers who were treated for the disease, who received transplants or who died from HCV. The hypothesis relied on is that all patients who received therapy were exposed to risk. The published data available updated to 31 March 2009 can be summarised:

UK patients who received Factor VIII concentrate or Cryoprecipitate 1969 to 1985 who were assumed to have been exposed to HCV

Diagnosis

Alive at 31 March 2009

Dead by 31 March 2009

Total

Haemophilia A

1,906

1,546

3,452

Haemophilia B

526

187

713

von Willebrand

209

66

275

Total

2,671

1,799

4,400

3.75 Corrected for double counting, the UKHCDO data set out in the appendices distinguish between patients who were alive in 2010, and patients who died in the period 1969–2010 having been diagnosed as infected with Hepatitis C. The data for patients registered at Scottish Centres with Haemophilia A, Haemophilia B and von Willebrand’s disease can be summarised:

Haemophilia Centre

Alive

Deceased

Total

Aberdeen

36

18

54

Dundee

22

8

30

Edinburgh

77

58

135

Glasgow: RHSC

51

11

62

Glasgow: RI

86

80

166

Inverness

26

21

47

Total

298

196

494

Total corrected for double counting

256

154

410

3.76 The comparable data for patients diagnosed with Hepatitis C, and registered at non-Scottish Centres were: patients alive at 2010 – 2,584; patients who died in the period – 1,782. Deceased Scottish patients represented eight per cent of the United Kingdom total.

3.77 The overall data for deceased patients in Scotland do not record the numbers for HCV-related deaths. The causes of death among patients who tested positive for HCV were many and varied. Table 16 of the UKHCDO annual report for 2009 summarised the United Kingdom deaths from liver disease between 1969 and 2009. Examination of the annual reports within that period has disclosed variations, and possible additional deaths, in some years. Hepatocellular cancer (HCC) was recorded in some years, but omitted from Table 16. Adjustments have been made to find a maximum figure for each year. As before, data for some individual years are not available. The following pattern emerges for the United Kingdom as a whole:

Estimated maximum UK deaths of haemophilia patients from liver disease
1969 – 2009

Year

HCC

Liver failure

Liver failure + alcohol

Maximum total

1969

2

2

1970

2

2

1971

1972

2

2

1973

1

1

1974

1

1

1975

1

1

1976

1977

1978

1979

1

1

2

1980

1

1

1981

1982

1983

2

2

1984

1

2

3

1985

4

4

1986

7

7

1987

2

3

5

1988

1

1

1

3

1989

2

3

5

1990

3

1

4

1991

9

9

1992

9

9

1993

1

14

1

16

1994

4

10

3

17

1995

3

3

6

1996

4

8

2

14

Year

HCC

Liver failure

Liver failure + alcohol

Maximum total

1997

1

10

11

1998

1

9

10

1999

1

4

5

2000

15

15

2001

6

6

2002

5

4

4

13

2003

3

1

4

2004

2

3

1

6

2005

1

1

1

3

2006

6

2

2

10

2007

4

3

7

2008

6

8

14

3.78 The total UK deaths from liver disease amounted to 220 in the years for which published data are available. This is a worst case position in terms of total deaths. Assuming that the total number of 4,776[71] who may have been exposed were infected, 220 deaths would indicate total mortality from liver disease of 4.6% over this period. Within the total, six or seven deaths were attributed to HBV: it appears likely that liver failure deaths until 1972 were related to HBV. Thirty were associated with alcoholic liver damage. Between 20 and 40 appear to have HCV/HIV co-infection. There were about five cases in which liver disease was associated with other causes. The annual mortality statistics show no evidence that other causes of death were related to HCV. It is not clear from the data how many deaths post-liver transplant have been included. Twelve such deaths in total have been noted elsewhere in the reports.

3.79 Among the 154 deaths from all causes of Scottish patients, adjusted to exclude double-counting, in the table above, 20 died from liver disease. Of these, four died from alcoholic liver disease.

3.80 The UKHCDO data, unadjusted, are set out in the appendices which record one additional death in 2010.

3.81 Co-infection with HIV and HCV has not been disclosed consistently in the published data. Where the numbers have been disclosed, they indicate that in approximately 40% of cases co-infection was a factor. The hypothesis that all patients who received factor therapy up to 1985 were infected may be too extreme, but the probability is that in any event a very high proportion were infected. The risk that the mortality rate is seriously distorted by this factor is not great. Although the final figures are approximate, and based on incomplete data, they have been cross-checked between two sources, and appear reasonably robust. The results do not as yet indicate a systemic increase in overall liver deaths in recent years. But it appears possible that deaths from hepatocellular cancer have been increasing in the most recent years.

3.82 There are no comparable data for surgical use of blood and blood products or for the numbers of patients receiving blood and blood products in the course of surgical procedures. Having regard to the total volumes of blood used in the NHS, it appears that the total numbers exposed to risk, particularly of HCV, may have been very much larger than in the haemophilia population. However, as noted in Chapter 1, it has been reported that 12 patients only contracted HIV as a result of blood transfusion.

HCV infection acquired from blood transfusion

3.83 Although the information concerning acquisition of HIV and HCV infection among United Kingdom and Scottish haemophiliacs, derived from the UKHCDO and its NHD database, appears to be authoritative and is likely to be reasonably complete, subject to the reservations already noted, the same is not true for information concerning acquisition of HCV following blood transfusion in the UK, including Scotland. There are two sources of information available. The first comprises data collected in the four months following the introduction in September 1991 of routine screening of every donation of blood or plasma in the UK with second generation ELISA, and with supplemental RIBA and PCR testing to define the true prevalence of HCV positivity. The prevalence of HCV positivity in the donor population was found to be 0.066% in England and 0.088% (159 HCV positive from 180,680 donors) in Scotland.[72] The second source is derived from studies carried out on the basis of data available from the UK Hepatitis C look-back exercise and the HCV National Register derived from it, and from information gathered by Health Protection Scotland concerning people diagnosed anti-HCV positive. These data have formed a basis for estimation of the numbers of individuals infected by transfusion of blood and blood products.

3.84 With the above information, and extrapolating from the data recovered, it was estimated by Soldan and others that around 13,500 individuals would have been chronically infected with HCV from blood or blood products in England between 1980 and 1991. Of these individuals, it is estimated that fewer than 5,200 could have been assumed to have been alive by 1995. Mortality from an underlying condition was assumed to be about 50% at two years following blood transfusion.[73]

3.85 The HCV look-back programme in England, 1995–98, traced patients transfused before September 1991 with blood from donors who were found to be positive for anti-HCV after testing was introduced in 1991. Using those data Soldan and colleagues derived values for the probability of blood from infected donors resulting in infected (and hence chronically infected) recipients. Then, knowing the total number of units of blood collected in the period 1980–91, and using the prevalence of HCV positivity in the English donor population at the outset of HCV testing, they estimated the total number of transfusion-transmitted HCV infections for that period, 1980–91. Following the introduction of screening of donors for anti-HCV there have been very few additional cases of post-transfusion HCV acquisition recorded in the UK (two between 1995 and 2001 for example).

3.86 Soldan and her colleagues state that they may have underestimated or overestimated the infections transmitted from January 1980 to September 1991. This is because they used the prevalence of HCV positive testing donors, without accounting for the selective removal of infected donors during the 1980s (for example donors from prisons), or conversely, the accumulation or prevalence of anti-HCV positive individuals (as intravenous drug abuse increased) over time. The latter difficulty may be illustrated by the finding that prevalence of anti-HCV positivity among Scottish donors fell from 0.088% in 1991 to 0.008% by 2003.[74]

3.87 The above uncertainties make accurate estimates of likely numbers of recipients of blood and blood products infected with HCV in the 1970s even more difficult. However, assuming the same level of anti-HCV positivity among English blood donors for the 1970s as the 1980s, Soldan and colleagues suggested that a further 10,000 individuals could have been infected in the 1970s, with a smaller proportion – say 3,000 – still alive in 1995.

3.88 Dr Soldan was afterwards asked by Dr Brian McClelland of the Scottish National Blood Transfusion Service (SNBTS) to prepare a similar estimate of the number of individuals who might have been infected by blood/blood components in Scotland, excluding haemophiliacs.[75] This study would employ the same methodology as the English estimates but using the Scottish look-back data and the prevalence of anti-HCV among Scottish donors–0.088%. She estimated that 3,498 individuals were infected with HCV by blood transfusion in Scotland in 1980–91, of whom, 1,886 were known or expected to be dead by 1995, and 1,612 were not known to be dead. Dr Soldan stated that: ‘many assumptions were used to generate these estimates – some of uncertain validity’. Bearing in mind all these uncertainties, and extrapolating from the English estimates for the period 1970–80, she estimated that around 2,600 individuals may have been infected in Scotland by HCV following blood transfusion in the 1970s, of whom perhaps a maximum 850 remained alive in 1995.

3.89 Using information from all Scottish HCV testing centres, record linkage and surveillance, survey and statistical modelling, Hutchinson and colleagues have produced data on behalf of Health Protection Scotland.[76] This group also searched all literature pertaining to the epidemiology/prevalence of HCV in Scotland in the period January 1989–December 2004. They estimated that there were around 400 diagnosed and up to 1,000 undiagnosed individuals with chronic HCV infection from transfusion of blood or blood products in Scotland in 2004. It is not clear whether they included infected haemophiliacs in the overall numbers.

3.90 Extrapolation of Soldan’s data therefore suggests that in 1995 there were perhaps about 2450 (1612 + 850) individuals alive in Scotland who had been infected with HCV by blood or blood products. This cohort would undoubtedly have dwindled very considerably by 2004 since the median age of almost all the above (had they survived) would have been 82 years or more by 2004. In comparison Hutchinson and colleagues, using some of the same assumptions but rather different methodology, suggested that about 1400 individuals, chronically infected with HCV from blood/blood products, were living in Scotland in 2004. Given the different reference periods, these estimates do not appear to be widely inconsistent. Estimates of HCV liver-related mortality, as opposed to overall (very largely non HCV-related) mortality in England and Scotland in these modelled groups is unobtainable, and at present can only be extrapolated from elsewhere or from smaller studies.

3.91 In the largest and best conducted study of long-term mortality and morbidity of transfusion-associated Hepatitis C, Seeff and colleagues in the USA have been reporting results, now extending to more than 30 years follow-up, on over 200 patients with post-transfusion Hepatitis C. They were studied alongside control patients, transfused at a similar time, who did not develop raised liver enzymes post-transfusion and were subsequently shown to be HCV negative.[77] By 2001 (after an average 25 years of follow-up) liver-related mortality in the 222 HCV positive cases had, for the first time, become significantly greater than in the 377 HCV negative controls (4.1% in cases versus 1.3% in controls).[78] However, overall mortality in the two groups – 67% in the HCV negative group, 65% among the controls – showed no difference. Liver deaths among the HCV positive group were from hepatocellular cancer or complications of cirrhosis.

3.92 Since 2002, while information concerning overall mortality, and liver-related mortality, among Scottish and UK subjects with chronic HCV infection following blood transfusion, is incomplete, there are two contributions which provide relevant important evidence.

3.93 Using the UK national look-back programme for post-transfusion HCV, via the HCV National Register, Harris and colleagues updated their description of the natural history of post-transfusion HCV to a minimum 16 years after exposure.[79] They studied survival in 921 HCV-infected transfusion recipients and 475 anti-HCV negative transfusion recipient controls. While all-cause mortality was not significantly different between cases and controls,[80] risk of death directly from liver disease was higher in the HCV-infected individuals than in the controls.[81] It should be remembered, however, that this was a ‘selected’ group in that the individuals were identified as still alive at the end of the look-back study (1998), and by the nature of the study, most had been transfused during the later part of the 1980s.

3.94 In a recent Japanese, community based, prospective cohort study of 1125 anti-HCV positive individuals, of whom 758 were chronically infected HCV carriers, and 367 were HCV virus negative non-carriers, overall mortality was higher in the HCV carriers than the non-carriers.[82] Liver-related deaths were much more frequent in the carriers.[83] But there was no excess of non liver-related deaths.[84]

3.95 In summary, the weight of evidence now suggests that individuals chronically infected with HCV following blood transfusion are more likely to die of liver disease, including hepatocellular cancer, than those not infected with HCV. It has taken up to 35 years following infection for these data to emerge. However, it is still unclear whether, as suggested in the Japanese Community Study, the weight of liver deaths in post-transfusion chronic HCV infection will ultimately affect overall mortality.

3.96 Finally, evidence is now beginning to emerge that successful treatment of HCV with antivirals does lead to good long-term outcomes. George and colleagues have shown that, of 150 chronic HCV carriers, with sustained virological response after treatment, when followed up for five years, virological relapse was not seen. Only two patients developed hepatocellular cancer, of whom one died.[85] This points the way to more effective look-back studies since treatment can now be shown to be increasingly likely to be effective and to carry long-lasting benefit. But the outcome of such studies cannot be anticipated.

The organisation of haemophilia care

3.97 There were 48 haemophilia centres in 1975, and 71 in 1976.[86] The number of patients on or in training for home treatment increased from 267 to 488 in the two years, and a further 241 haemophiliacs were considered suitable for home therapy by the end of 1976. Apart from a small (but increasing) number of haemophiliacs on prophylactic treatment, most patients were on low-dose (250–500 units) on-demand regimes, using a mean of 20,000 Factor VIII units per patient per year in 1976. This picture, painted by Dr Peter Jones, was the introduction to a demand that was sustained throughout the reference period for increased provision for the care of haemophilia patients. But it captures the broad range of the NHS service. The Haemophilia Centre grew into a comprehensive care centre, providing a range of services for patients with haemophilia, von Willebrand’s disease and other coagulation factor deficiencies and platelet disorders. Provision of the service extended beyond the centres in the case of prophylactic and home treatment regimes. The centres came to include clinics for the diagnosis and management of bleeding disorders and the provision of specialist services with access to other services across different disciplines.

3.98 Typically, in a haemophilia centre, there is a specialist nursing team, now often led by a nurse consultant. The team may be responsible for some or all of the following:

• coordinating haemophilia services in the unit and in the community;

• liaising with other hospitals and haemophilia centres;

• providing a telephone help line;

• training in home treatment and general education, including home and school visits;

• management of the delivery of concentrates required for home treatment; and

• management of treatment of bleeding episodes, dentistry and surgical procedures in hospital.

3.99 There are therapists and welfare officers who provide psychological support and welfare advice. The unit will have or have access to orthopaedic and physiotherapist services, focused on regular assessment of joint and muscle function for patients; and identifying patient needs for specialist care in these fields. The centre will also have or have access to expertise in liver care, including assessment, counselling and treatment of patients with liver disorders, access to expertise in the management of patients with HIV, and to specialised dental services. In addition antenatal clinics may be provided for women with bleeding disorders.

3.100 As at the date of this report, considerable change in the organisation of haemophilia care is in progress. The UKHCDO Annual Report for 2009 reflected significant variation in the intensity of treatment offered by different centres, and material new developments in the structure of the services provided in England and Wales. Though not directly applicable in Scotland, these new developments reflect health care objectives that are likely to have general application, for example centre networking to ensure that centres have working relationships with comprehensive care centres, in order to improve access to care and the quality of care.

United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO)

3.101 The UKHCDO was established in 1968 and is composed of members of the medical profession who work within the haemophilia centres throughout the United Kingdom. The aims of the organisation are as follows:

1. To preserve, protect and relieve persons suffering from Haemophilia and other inherited bleeding disorders.

2. To advance the education of the medical profession, the nursing profession, professions allied to medicine and the general public in the knowledge of haemophilia and other bleeding disorders and their treatment.

3. To promote or assist in the promotion of audit and research into causes, prevention, alleviation and management of haemophilia and other inherited bleeding disorders and to disseminate the useful results of such research.[87]

3.102 The association was established to improve haemophilia care and facilitate health care planning. The UKHCDO is the custodian of the national haemophilia database set up in 1968.[88] The database is a register of patients residing in the UK who suffer from bleeding disorders. The confidential database collects information from the regional haemophilia centres. Such information includes: nature of diagnosis, date of birth, types and amounts of treatments administered, details of adverse reactions such as inhibitors and cause of death.[89] The data are used for planning and research to follow trends on bleeding disorders, their treatment and adverse reactions to treatment.[90]

The Haemophilia Society

3.103 In and after the 1950s there was considerable progress in haemophilia care. The United Kingdom Haemophilia Society was established in 1950 and since then has provided a forum for discussion of patient needs, and support for haemophilia patients in explaining and pursuing their interests.[91] It is an independent organisation, run by haemophilia sufferers and serves those people whose life has been affected by haemophilia.[92] At present the society consists of 17 support groups located throughout the UK. The function of the support groups is to provide self-help centres and to raise funds for both local and national schemes.[93]

3.104 In 2007 the Haemophilia Society launched the Scottish Development Project. The project was established with the aim of raising awareness of haemophilia, von Willebrand’s disease and other coagulation disorders.[94]

[1] Starr, Blood: an epic history of medicine and commerce p 290

[3] Ingram, ‘The history of haemophilia’, Journal of Clinical Pathology, 1976; 29:469-479 [LIT.001.1348]

[5] Ingram, ‘The history of haemophilia’, Journal of Clinical Pathology, 1976; 29:469-479 [LIT.001.1348]

[6] Ibid

[7] Webb and Dixon, ‘Haemophilia and Haemophilic Anthropy: An Historical Review and a Clinical Study of 42 Cases’, Annals of the Rheumatic Diseases, 1960; 19:143-157

[9] Ingram, ‘The history of haemophilia’, Journal of Clinical Pathology, 1976; 29:469-479 [LIT.001.1348]

[11] An exception is acquired haemophilia, an extremely rare autoimmune bleeding disorder which usually develops in later life. It occurs when the immune system develops antibodies against the body’s own clotting factors, and inactivates them.

[16] Ginsburg et al, ‘Molecular genetics of von Willebrand Disease’, Blood, Vol 79 No. 10. (May 15) 1992: pp 2507-2519 [LIT.001.1392]

[17] Ginsburg et al, ‘Molecular genetics of von Willebrand Disease’, Blood, Vol 79 No. 10. (May 15) 1992: pp 2507-2519 [LIT.001.1392]

[19] [www.haemophilia.org.uk/uploads/vwillebrandsgeneral.pdf]

[20] Laffan et al, ‘The Diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation’ Haemophilia (2004) 10, 199-217[LIT.001.1478]

[21] Editorial ‘Molecular basis of Von Willebrand disease and its clinical implications’, Haematologica 89 (9): 1036

[22] Laffan et al, ‘The Diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation’ Haemophilia (2004) 10, 199-217 [LIT.001.1478]

[23] UKHCDO Annual Report for 2009

[24] Laffan et al, ‘The Diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation’ Haemophilia (2004) 10, 199-217 [LIT.001.1478]

[25] Acquired vWD can occur. This form of the disorder is an autoimmune disorder where the body attacks its own vW as if it was a foreign substance.

[26] Saddler et al, ‘Update on the pathophysiology and classification of von Willebrand disease: a report of the subcommittee on von Willebrand factor’ J Thromb Haemost., 2006; 4: 2103-2114 [LIT.001.0920]

[33] Jones (1984) Living with Haemophilia, 2nd Edition, MTP Press Ltd, Lancaster

[35] Jones (1984), Living with Haemophilia, 2nd Edition, MTP Press Ltd, Lancaster

[37] Other figures are quoted, for example, up to 30% is the range published by the Haemophilia Society: [www.haemophilia.org.uk/index.php?content_id=87&parent=278]

[39] Laffan et al, ’The Diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation’ Haemophilia (2004) 10, 199-217 [LIT.001.1478]

[40] Data derived from:

Biggs, ‘Haemophilia Treatment in the United Kingdom from 1969 to 1974’; Br Jnl Haem 1977,35,487, Tables VI and IX for 1969 to 1974;

Haemophilia Centre Directors’ Annual; Statistics for 1975 Br Jnl Haem 1977, 36,447.[LIT.001.0159] Table VI, for 1975; and

Rizza .C.R., Spooner R.J.D., ‘Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976 0 80: report on behalf of the directors of haemophilia centres in the United Kingdom’ Brit. Med. Jnl. Vol 286; 19 March 1983. 929 – 933. [LIT.001.0234] Tables VIm and VIIm for 1976 to 1980

[41] Mannucci, ‘Treatment of von Willebrand Disease’ Int Clin Lab Res (1998) 28: 211-214 [LIT.001.1305]

[42] Mannucci, ‘Treatment of von Willebrand Disease’ Int Clin Lab Res (1998) 28: 211-214 [LIT.001.1305]

[43] Mannucci et al, ‘1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrand’s diseases’ The Lancet 1: 869–72 [LIT.001.0354]

[44] Mannucci, ‘Treatment of von Willebrand Disease’ Int Clin Lab Res (1998) 28: 211-214 [LIT.001.1305]

[47] The Rome conference 18–19 January 1990: ‘Factor VIII Concentrates and Treatment of Haemophilia: State of the Art in 1990’ [SNB.007.7009]

[49]Mitchell, J., Phillott, A., ‘Haemophilia and inhibitors 1: diagnosis and treatment’ Nursing Times, 2008; 104: 26–27 [www.nursingtimes.net/nursing-practice-clinical-research/haemophilia-and-inhibitors-1-diagnosis-and-treatment/1677719.article]

[50]Mitchell, J., Phillott, A., ‘Haemophilia and inhibitors 1: diagnosis and treatment’ Nursing Times, 2008; 104: 26–27 [www.nursingtimes.net/nursing-practice-clinical-research/haemophilia-and-inhibitors-1-diagnosis-and-treatment/1677719.article]

[51]Mitchell, J., Phillott, A., ‘Haemophilia and inhibitors 1: diagnosis and treatment’ Nursing Times, 2008; 104: 26–27 [www.nursingtimes.net/nursing-practice-clinical-research/haemophilia-and-inhibitors-1-diagnosis-and-treatment/1677719.article]

[52] Stonebraker et al, ‘A study of variations in the reported haemophilia A prevalence around the world’ Haemophilia, 2010; 16:
20-32 [LIT.001.1200]

[53] Appendix 1: UKHCDO data

[54] Data derived from: (1) Biggs, ‘Haemophilia Treatment in the United Kingdom from 1969 to 1974’ British.Medical.Journal,1977; 35: 487–504 [LIT.001.0159]. Tables VI and IX - for patients treated 1969 to 1974; (2) Biggs and Spooner, ‘Haemophilia Centre Directors’ Annual Statistics for 1975’ British Journal of Haematology, 1977;36:447 [SNB.001.7011]. Tables VIII and IX for patients treated in 1975; and (3) Rizza .C.R., Spooner R.J.D. ‘Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976–80: report on behalf of the directors of haemophilia centres in the United Kingdom’ British Medical Journal, 19 March 1983; 286:929–933 [LIT.001.0234]. Tables 1m and VIIm for patients registered 1975 to 1980 and patients treated 1976 to 1980.

[55] Titmuss, R, The Gift Relationship: from Human Blood to Social Policy (1997) ed Oakley and Ashton

[56] Ibid page 19

[57] Bateman, D, ‘The good bleed guide: a patient’s story’ Social History of Medicine, 1994; 7(1):115–133

[58] For a contemporary published description of life quality in a patient see Inhibitors Issue 1 Spring 2008 [www.inhibitorsupportgroup.org/UserFiles/INHIBITOR NEWSLETTER final.pdf].

[59] For example, a comprehensive study in Finland of mortality among severe Haemophilia A patients over the period 1930 to 1979 cannot be reconciled with UK data. During the period of 50 years studied, the mean age at death of the patients increased from 7.8 years in 1930-39 to 25.5 years in 1970-79: Ikkala et al, ‘Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930 – 79’ British Journal of Haematology, 1982;52:7–12.

[60] Birch, Haemophilia, Clinical and Genetic Aspects, 1937

[61] Biggs, ‘Jaundice and Antibodies Directed against Factor VIII and IX in Patients treated for Haemophilia or Christmas Disease in the United Kingdom’ British Journal of Haematology, 1974;26:313–329 [SNB.001.4837]; Biggs, Haemophilia Treatment in the United Kingdom from 1969 to 1974, 1977;35:487–504 [LIT.001.0159]; Biggs and Spooner, ‘Haemophilia Centre Directors’ Annual Statistics for 1975’ British Journal of Haematology, 1977;36:447–449 [SNB.001.7011]

[62] Rizza .C.R., Spooner R.J.D., ‘Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976 0 80: report on behalf of the directors of haemophilia centres in the United Kingdom’ British Medical Journal, 19 March 1983; 286:929–933 [LIT.001.0234]

[63] Jones, ‘Acquired immunodeficiency syndrome, hepatitis, and haemophilia’ British Medical Journal, 1983; 287 (6407): 1737–1738 [LIT.001.0243]

[64] Biggs R, ed. The treatment of haemophilia A and B and von Willebrand’s disease. Oxford: Blackwell Scientific Publications, 1978:25

[65] Darby, S.C., Kan, S.W., Spooner, R.J. et al. (2007) Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood, 110: 815-825.

[66] The Scottish Centre for Infection and Environmental Health data record 87 HIV+ve haemophiliac patients to 30 September 1999. The different reference periods may help explain the difference.

[67] Darby S C. & Others: Mortality before and after HIV infection in the complete UK population of haemophiliacs: Nature Vol 377, 79; 7 September 1995.

[68] Darby et al: The impact of HIV on mortality rates in the complete UK haemophilia population: AIDS. 2004; 18:525-533

[69] The paper states that they were tested ‘very shortly afterwards’, but many, though infected by 1985, were not tested until 1986 and 1987, affecting the chronological distribution of data in the UKHCDO table of years of HIV diagnosis.

[70]Blood, 1 August 2007. Vol. 110, no. 3 815 - 825

[71] Scottish patients 410; non-Scottish surviving patients 2,584; and non-Scottish deceased patients 1,782.

[72] Crawford RJ et al Prevalence and epidemiological characteristics of hepatitis C in Scottish blood donors. Transfusion Medicine 1994, 4, 121-124.

[73] Soldan K, Ramsay M, Robinson A, et al. The contribution of transfusion to HCV infection in England. Epidemiology & Infection 2002. 128, 587-591.

[74] Dow BC. HPS Weekly Report 2005 39, 21-22

[76] Hutchinson SJ. Roy KM Wadd S et al Hepatitis C virus in Scotland. Scottish Medical Journal, 2006. 51, 8 -15

[77]Seeff LB, Hollinger FB, Alter HJ. Long Term Mortality and Morbidity of Transfusion - Associated Non – A, Non – B and Type C Hepatitis: Hepatology 2002. 33, 455-463

[78] P-value 0.05. The p-value is a measure of the probability that a cause has no effect on the variable being measured.

[79] Harris HE, Ramsay ME, Andrews NJ. Survival of a national cohort of hepatitis C virus injected patients, 16 years after exposure. Epidemiology & Infection, 2006, 134. 472-477

[80] Hazard ratio 1.17. p = 0.21. The hazard ratio (HR) in survival analysis is the effect of an explanatory variable on the hazard or risk of an event.

[81] HR 2.71. p = 0.03.

[82] HR 1.53 CI 1.13–2.07). A confidence interval (CI) is an estimate of a population parameter. Thus, confidence intervals are used to indicate the reliability of an estimate. How likely the interval is to contain the parameter is determined by the confidence level. Increasing the desired confidence level will widen the confidence interval.

[83] (HR 5.94 CI 2.5–13.7).

[84] Uto H, Stuver SO, Hayashi K et al. Increased rate of death related to presence of viraemia. Hepatology 2009 50. 393-399

[85] George SL, Bacon BR, Brunt EM et al. Clinical, Virologic, Histologic and Biochemical outcomes after successful HCV therapy. Hepatology 2009. 49. 729-738

[86] P Jones et al. Haemophilia A home therapy in the United Kingdom 1975 – 76 Br Med J 1978;1:1447-1450 (3 June) [LIT.001.0528]

[87] [http://www.ukhcdo.org/aboutUs.htm?]

[88] [http://www.ukhcdo.org/docs/YourQuestionsAnswered_v2.pdf]

[89] [http://www.ukhcdo.org/docs/YourQuestionsAnswered_v2.pdf]

[90] [http://www.ukhcdo.org/docs/YourQuestionsAnswered_v2.pdf]

[91] [http://www.haemophilia.org.uk/information/About+the+Haemophilia+Society]

[92] [http://www.haemophilia.org.uk/information/About+the+Haemophilia+Society]

[93] [http://www.haemophilia.org.uk/index.php?content]

[94] [http://www.haemophilia.org.uk/index.php?content]

Back to Contents page