History of the West of Scotland Haemophilia Centre, Glasgow, 1950–2019

Introduction

Haemophilias are genetic bleeding disorders due to deficiency of circulating blood coagulation factors. Haemophilia A (factor VIII deficiency) is an X-linked recessive condition of variable severity, with a worldwide prevalence of 1 in 10,000 males, transmitted by female carriers. The understanding of haemophilia¹ was advanced in the 1930s by the discovery that the defective clotting could be corrected by transfusing a plasma fraction, later named antihaemophilic globulin, then factor VIII. This fraction also corrected the defect in a commoner (1 in 1,000), but milder genetic bleeding disorder: von Willebrand’s disease (VWD), whose inheritance is usually autosomal dominant and which affects males and females equally. VWD is due to deficiency of von Willebrand factor (VWF), the carrier protein for factor VIII. Haemophilia B (factor IX deficiency, Christmas disease) is clinically similar to haemophilia B, but about six times less common. Other clotting factor deficiencies are rarer.

Following the development of blood transfusion in the 1940s, infusions of plasma were used worldwide to treat bleeding in patients with haemophilias A and B and VWD. In the UK and other countries, regional specialist haemophilia centres were established from the 1950s for diagnosis and registration of patients with bleeding disorders, education of patients, families and healthcare professionals, and provision of timely treatment or prevention of bleeding episodes.¹ We describe the development of the West of Scotland Haemophilia and Thrombosis Centre which achieved a national and international reputation for research, practice and education. In this review we focus on haemophilias; the Centre’s contributions in thrombosis will be reviewed elsewhere.

1950–1959

The Glasgow Royal Infirmary (GRI) Haemophilia and Thrombosis Centre was a collaboration between the National Health Service in Scotland and the University of Glasgow. Leslie Davis, appointed to the University’s Muirhead Chair of Medicine at GRI in 1945, specialised in haematology. Stuart Douglas, Registrar 1949–1951, obtained a Medical Research Council Research Fellowship at its Blood Coagulation Research Unit in Oxford, with Glyn Macfarlane and Rosemary Biggs. Using a new blood test – the thromboplastin generation test – they differentiated Christmas disease (haemophilia B) from haemophilia A and published their findings in the Christmas edition of the British Medical Journal in 1952.² Douglas returned to Glasgow in 1953 as Lecturer, then Senior Lecturer and Reader.

During the 1950s, Douglas and Davis developed the West of Scotland Haemophilia Reference Centre as the regional clinical and diagnostic centre. Covering the western half of Scotland, it served the largest area of the UK regional haemophilia centres, and one of its largest populations (over 2.5 million). Douglas (Figure 1) studied suspected cases and their families, referred by local practitioners, established the type and severity of the disorder, registered them at the centre, issued haemophilia cards with the centre’s contact details, and educated patients, families and local practitioners about the prevention and management of bleeding.

Figure 1 Stuart Douglas, founder of the West of Scotland Haemophilia Centre

Patients could attend their local hospital and be managed by a physician with an interest in haematology, and the local blood transfusion service, who could order plasma from the Glasgow and West of Scotland branch of the Scottish National Blood Transfusion Service (SNBTS), with advice as required from the Reference Centre. Alternatively, patients could self-refer and attend the Centre, where advice and treatment was available at all times. Patients were seen at the Department of Medicine’s Wards 2 and 3 on the first floor of the Royal Infirmary, conveniently close to the hospital entrance and casualty department. Children in the Glasgow area were usually treated at the Royal Hospital for Sick Children (RHSC), Glasgow.

The classical feature of haemophilias was excessive bleeding after minor trauma into joints (haemarthrosis), which often led to chronic arthritis (Figure 2), and muscles (which could cause nerve compression). Prolonged treatment with plasma and bed rest, followed by physiotherapy, was often required. Prolonged bleeding after trauma or surgery, even minor surgery such as tooth extraction, was a major and sometimes fatal problem for patients with haemophilia of all severities. Dental extraction for teeth and gum decay was routine in the 1950s. Douglas and his colleague John Orr reported their experience and recommended limiting extractions to two teeth at a time, use of splints and sealants, transfusion of plasma immediately before extraction, and again if bleeding occurred, and antibiotic therapy.³

Figure 2 Haemophilic arthritis, 1970s

The UK Haemophilia Society started in 1954 and played a vital role in the education and support of patients and families. The Centre encouraged its patients and families to join and to attend meetings of the Scottish branch.

1960–1969

During the 1960s, haematology developed as a clinical and laboratory specialty, and George McDonald was appointed Consultant in 1962. Thereafter the Haematology and Thrombosis Centre had two Co-Directors: Douglas (in charge of the University department’s wards where patients were reviewed and treated, and of its coagulation research laboratory), and McDonald (in charge of the NHS routine haematology laboratory and blood bank). They trained their successors Colin Prentice, Charles Forbes, John Davidson and Isobel Walker. At RHSC, Michael Willoughby was appointed Consultant Haematologist in 1963.

The University awarded Douglas a personal professorship in 1964. He was joined by George McNicol, Senior Lecturer. They had an interest in fibrinolysis – the process by which fibrin blood clots dissolve. Since the start of transfusion, blood and plasma were known to potentially transmit viral hepatitis, and patients requiring repeated transfusions were at increased risk. At the Haemophilia Centre, patients and staff were informed of the risks, liver function tests were performed routinely, and episodes of hepatitis reported to SNBTS for donor investigation.

To reduce this risk, McNicol, McDonald and Douglas sought to reduce the amount of blood products used. They pioneered randomised clinical trials of fibrinolytic inhibitor drugs in prevention of bleeding in patients with haemophilia. While ineffective in joint and muscle bleeding, tranexamic acid was effective in minimising plasma use and hepatitis risk after dental extraction and other types of minor surgery,⁴ and was subsequently recommended in guidelines.

In patients without haemophilia, the Centre later reported that activated fibrinolysis was associated with adverse outcome after acute gastrointestinal bleeding, and recommended trials of tranexamic acid.⁵ Subsequent trials showed that this drug reduced mortality in such patients and reduced bleeding and mortality in patients with major trauma or in childbirth. Use of tranexamic acid has therefore reduced transfusion requirements worldwide.

In 1965 Pool and Shannon in the USA reported that freezing and thawing of fresh plasma produced cryoprecipitate – the first Factor VIII and VWF concentrate, and a more effective treatment of haemophilia and VWD. The GRI Centre reported their experience and its advantages and disadvantages, one of which was that viral hepatitis could still occur.⁶

The UK Haemophilia Centre Directors Organisation (UKHCDO) was established in 1968, recognising regional haemophilia centres, including GRI for the west of Scotland and Edinburgh Royal Infirmary for the east of Scotland.

1970-79

From 1970, a staff nurse and senior house officer in haemophilia were based in the GRI Centre during normal working hours, to deal with enquiries and arrange treatment. Douglas moved to Aberdeen in 1970 and McNicol to Leeds in 1971. They were succeeded by senior lecturers Colin Prentice (Co-Director) and Charles Forbes. In the haematology department John Davidson was appointed Consultant in charge of the Blood Transfusion and Products laboratory, ordering treatments from SNBTS or commercial manufacturers.⁷ Isobel Walker was appointed Consultant in 1978, with a remit for perinatal haematology at Glasgow Royal Maternity Hospital and GRI.

Comprehensive care haemophilia centres were developing, including specialist medical and nursing staff liaising with a team of relevant hospital and social work colleagues. In GRI close liaison continued with the dental service. Renal complications (haematuria and ureteric obstruction) were common, reflecting the importance of fibrin to urinary tract integrity⁸ and were managed with renal physicians and urologists. Gastrointestinal bleeding was also common⁹ and was managed with the department of surgery and gastroenterologists. Haemarthroses and intramuscular bleeds were managed with physiotherapists, rheumatologists and orthopaedic surgeons. Social and psychological issues were studied by Forbes with Professor Ivanna Markova of the Department of Psychology, University of Stirling.¹⁰ These included family issues, education, sport, control of pain from haemarthroses and arthritis, and unemployment. The Centre social worker linked to community services.

Identification of female carriers of haemophilia was important for genetic counselling. Prior to identification of genetic mutations, Prentice and Forbes measured plasma factor VIII antigen and activity in normal and known carrier populations, and calculated predictive odds to inform counselling.¹¹ They also reported high premature mortality in haemophilia, despite treatment with plasma and cryoprecipitate.¹²

Hepatitis B (HBV) came to public attention in 1970, due to an outbreak in Edinburgh. At haemophilia centres, patients and staff were regularly tested for HBV, in addition to hepatitis risk warnings and Dangerous Specimen labelling of blood samples. HBV testing of blood donors from 1969 reduced the risk of transmission, although there remained a significant infection rate in patients who received SNBTS products.¹³ Vaccination was introduced in 1985, and recommended to all healthcare workers at risk, including Haemophilia Centre staff and to Centre patients who were not naturally immune. By 1996 the prevalence of HBV surface antigen positivity in haemophiliacs in developed countries was less than 3%.

Freeze-dried clotting factor concentrates of factors VIII, and IX, were developed in the early 1970s at the SNBTS Protein Fractionation Centre in Edinburgh and by commercial manufacturers. Their advantages over cryoprecipitate and fresh frozen plasma were: assay of factor content resulting in a predictable dose, stability for refrigerator storage, injectability by syringe in a small volume, and few allergic reactions. Concentrates were therefore much more suitable for treatment of major bleeds, trauma and surgery, and for self-administration and home treatment.¹⁴ Disadvantages were: a higher number of plasma donors per batch of concentrate, hence a potentially higher risk of hepatitis, and cost. Forbes and Prentice calculated that provision of home treatment to the 20% of patients who used 80% of the treatment (for frequent bleeds, usually into joints) would cost only 16% more, improve quality of life, enable return to work, and reduce chronic arthritis and hence longterm care costs.¹⁴

The GRI Centre used concentrates initially for major surgery and major bleeds,^15,16 including the use of prothrombin complex concentrate.¹⁵ For patients with factor VIII inhibitors, which rendered factor VIII concentrates ineffective, porcine factor VIII was used. In RHSC Glasgow, Willoughby, who reviewed home treatment in his textbook of 1977,¹⁷ introduced home treatment for children with severe haemophilia who had frequent bleeds, especially those distant from Glasgow. He reported in 1983 that this had led to a marked reduction in delayed treatment and improved quality of life. To monitor, plan and coordinate increasing use and NHS costs of concentrates, as well as safety issues, annual meetings of SNBTS, the Scottish Home and Health Department (SHHD) and Haemophilia Directors in Scotland were held from 1979, with more frequent meetings of its Coagulation Factor Working Party Subcommittee.

In 1974, John Cash (SNBTS Director) reported that intravenous infusion of the synthetic vasopressin analogue desmopressin raised blood levels of the factor VIII: von Willebrand factor complex, by releasing VWF from vascular endothelium.¹⁸ Such elevations were later shown to be sufficient to treat minor bleeding and to prevent bleeding following dental extractions or other minor surgery in patients with mild haemophilia A or VWD, reducing the use of blood products and the risk of viral hepatitis. After commercial manufacture, it was adopted from 1977 by the GRI Centre, who reported as a side effect symptomatic cerebral oedema from hypo-osmolality due to the drug’s antidiuretic effect.¹⁹

1980-89

During the 1980 Annual General Meeting of UK Haemophilia Centre, Directors at the Royal College of Physicians and Surgeons of Glasgow, Forbes and Prentice organised its first scientific open meeting. International speakers highlighted growing areas of haemophilia care and research, including increasing awareness of non-A non-B hepatitis.

The GRI Haemophilia Centre expanded from two to four rooms, allowing increases in patient waiting, assessment and treatment areas. A haemophilia sister was appointed and trained patients for home treatment (Figure 3). A review of 23 adults and 20 children at the GRI and RHSC Haemophilia Centres reported that the ability to treat themselves was perceived by patients as a great improvement.²⁰

Figure 3 Home treatment training, 1980s

While home treatment reduced the frequency of musculoskeletal bleeds, many patients remained crippled by chronic arthritis, especially of the knees, for which the only effective treatment was joint replacement surgery, made feasible by use of concentrates. Total knee replacement was performed in five patients with frequent bleeds, severe pain and limitation of movement. Review after 24–48 months showed dramatic lessening of pain and maintenance of a satisfactory level of movement. The frequency of haemarthroses diminished markedly, and the requirements for factor concentrate in the years after operation fell substantially. Two patients returned to employment (Figure 4).²¹

Figure 4 Knee joint replacement surgery, 1980s