Landmarks in haemophilia care

The Babylonian Talmud, written in the 5^thcentury and recording a ruling made in the 2^ndcentury, is acknowledged as the source of the first documented mention of a bleeding disorder that may have been haemophilia.

The reference comes in the form of advice in the Yevamot tractate,¹in a section that primarily addresses inconsistency in rabbinical statements – specifically, whether an event should occur two or three times before being accepted as proof. Rabbi Judah the Patriarch stated:

If a woman circumcised her first son and he died as a result of the circumcision, and she circumcised her second son and he also died, she should not circumcise her third son, as the deaths of the first two produce a presumption that this woman’s sons die as a result of circumcision.

However, Rabbi Simon ben Gamaliel affirmed a general point of Talmudic law: that three events are required:

She should circumcise her third son, as there is not considered to be a legal presumption that her sons die from circumcision, but she should not circumcise her fourth son if her first three sons died from circumcision.

In the 11^thcentury, Rabbi Isaac Alfasi confirmed Rabbi Judah’s view.²

The 12^thcentury physician Moses Maimonides, in a commentary again focusing on the risks of circumcision, noted that children may be at risk through their mother, even when they have different fathers; transmission of the risk (not haemophilia) via the father was recognised in the 16^thcentury by Rabbi Joseph Karo.²

The first description of haemophilia is credited to the surgeon Al-Zahrawi (936‒1013 AD), also known as Albucasis.^3-5He described a fatal ‘blood disease’ affecting only males, in which minor trauma provoked prolonged bleeding. Observing the pattern of occurrence in one village, he deduced that the disorder was inherited.

The Book of Matthew in the New Testament of the Bible mentions a woman with a lifelong bleeding disorder who was healed by Jesus. The King James Bible states:⁶

And, behold, a woman, which was diseased with an issue of blood twelve years, came behind him, and touched the hem of his garment:

For she said within herself, if I may but touch his garment I shall be whole.

But Jesus turned him about, and when he saw her, he said, Daughter, be of good comfort; thy faith hath made thee whole. And the woman was made whole from that hour.

The first description of a bleeding disorder that affected only males is usually attributed to John C Otto (1774‒1844), an American physician working in Philadelphia, Pennsylvania.¹ However, there seem to have been several reports documenting transmission within a family around that time:

…the anonymous obituarist of Isaac Zoll, writing in 1791 (qu. McKusick 1962), Consbruch in 1793 and 1810, Rave in 1796 (qu. Bullock and Fildes, 1911), and Otto in 1803 all described families in which males suffered abnormally prolonged post-traumatic bleeding. In the Zoll family, six brothers bled to death after minor injuries, but their half-siblings by a different mother were unaffected; in Consbruch’s family, a man and two of his sister’s sons were affected; Rave himself was affected, with his three brothers…²

Otto’s account is a model of scientific caution and precision. He begins by describing a woman named Smith of Plymouth, New Hampshire, who transmitted an ‘idiosyncrasy’ to her descendants, the Smiths and the Shepards: ‘If the least scratch is made on the skin of some of them, as mortal a hemorrhagy will eventually ensue as if the largest wound is inflicted.’ He goes on to describe how persistent bleeding, despite partial healing, rapidly disables the individual and ‘death, from mere debility, then soon closes the scene.’

Otto adds: ‘It is a surprising circumstance that the males only are subject to this strange affection, and that all of them are not liable to it… Although females are exempt, they are still capable of transmitting it to their male children…’

The Smiths were not the only family known to have the condition. Otto cites reports of similar cases described by several of his colleagues and, with great insight, adds: ‘When the cases shall become more numerous, it may perhaps be found that the female sex is not entirely exempt…’

The 1803 report includes a description of the many medicines offered as treatment, including bark, astringents (topically and internally), strong styptics and opiates. Only one worked for Otto’s patients: sulphate of soda (sodium sulphate) ‒, ‘An ordinary purging dose, administered two or three days in succession, generally stops them [haemorrhage]; and, by a more frequent repetition, is certain of producing this effect.’What the mechanism of action could be is a matter for speculation (possibly dehydration and hypotension, secondary to bleeding and purgation). Otto did not understand how this medicine acted but he did not dismiss the family’s experience of treatment, noting that it had worked too often for this to be coincidence and his ignorance was not a good reason to disbelieve them. And, as he pointed out, ‘In every case, however, a doubtful remedy is preferable to leaving the patient to his fate.’

The Philadelphia physician John Otto is credited with the first record that haemophilia causes a bleeding disorder only in men. In 1803, he wrote:

‘It is a surprising circumstance that the males only are subject to this strange affection, and that all of them are not liable to it … Although females are exempt, they are still capable of transmitting it to their male children…’¹

In the years that followed, accounts were published of several families affected by haemophilia in what was then the 13 British colonies on the east coast of the Americas. Among the most important was a lengthy description of the Appleton-Swain family by John Hay, a physician in Reading, Massachusetts.² His interest was both professional and personal. Jonathan, his eldest son, married a descendant of Oliver Appleton, the first family member known to be affected, who had lived 100 years previously. Jonathan had eight children, three of whom were sons; at the time of Hay’s report, none had shown signs of exceptional bleeding but he feared that the youngest, at eight years old, ‘has the exact complexion of the bleeders’.

Hay’s description of the fate of the Appletons and Swains makes grim reading. Oliver Appleton died in old age from bleeding from a pressure sore and the urethra. The death of Oliver Swain, one of his grandsons, is recorded in full. Oliver was kicked by a horse, producing a leg wound three inches long and open to the bone. He initially bled profusely, then intermittently rapidly and slowly as physicians tried to stem the flow. He took 19 days to die, in severe pain and ‘in the greatest distress of body’, often lucid but sometimes delirious. Attempts to apply a ligature above the wound failed: ‘the blood has burst out above the ligatures, which caused extreme distress’. Oliver was attended by his brother Thomas, who was a doctor; he later died of a pulmonary haemorrhage. In all, 16 male members of the family were known to have haemophilia, of whom five were known to have died from bleeding.

Though he never explicitly states that Oliver Appleton’s female descendants were carriers, Hay’s painstaking account clearly identifies the women whose sons have haemophilia when they themselves had not apparent bleeding disorder. According to Bulloch and Fildes’ definitive 1911 review of what was known about haemophilia,³ Hay’s report does not provide definitive evidence of haemophilia in all the cases he described (for example, some deaths may not have been related to haemophilia and some family members had no recorded bleeding until adulthood). However, they conclude that his description ‘…bears the stamp of accurate observation. Hay was immediately acquainted with many of the cases and even related to them. Under these circumstances it is highly probable that he forbore to multiply instances.’

It may have been Freidrich Hopf, a German student, who first coined the word haemophiliain his doctoral thesis Über die Hämophilie [About Haemophilia] in 1828. Or perhaps it was his supervisor, Professor Schönlein, because some sources say that Hopf’s new word had actually been haemorrhaphilie and it was deemed too cumbersome. Whichever it was, the journey from conception to widespread use could not have been plain sailing, as other writers at the time suggested many alternatives.

Dr J Whickam Legg, a casualty physician at London’s St Bartholomew’s Hospital, provides a singular account of the acceptance of haemophiliaas the word of choice in his A Treatise on Haemophilia,Sometimes Called the Hereditary Haemorrhagic Diathesis (1872):¹

‘In England this disease is often called the haemorrhagic diathesis, or tendency … On the continent, the disease is universally called haemophilia, or haemarrhaphilia. The former of these is the more commonly used; neither is good, but it is now too late to attempt to change.’

Earlier terms had included the German Bluterkrankheit, Blutsuchtand Blutungssucht and the French diathèse hémorrhagique, hémorrhagie constitutionelle and purpura constitionel.

Legg resorts to footnotes for grumpy elaboration:

‘Various other names have been proposed: haemorrhophilia, haematophilia, haemorrhagophilia, idiosyncrasia haemorrhagica and morbus haematicus. A name proposed by Uhde… is amychaemorrhagia… perhaps it is the worst yet suggested.

‘Haemorrhaphilia is the name used by Schönlein in his Vorlesungen (third ed. 1837). Virchow seems to think that Schönlein was the author of the word haemophilia. I am unable to say from my own observation by what writer the name was first used. Die Hämophilie is said to be the title of an inaugural dissertation by Hopf, at Würzburg, in 1828. The word is so barbarous and senseless that it is not wonderful that no one should be proud of it.’

So, with Legg’s grudging acceptance, the term haemophilia – by far the best of the options available ‒ has stuck.

In 1839, the eminent German surgeon Johann Dieffenbach developed a new procedure to treat strabismus (squint) that involved dividing the muscles around the eye, so as to reduce their effect on one side and rebalance the tension of opposing muscle groups. It was such a success that, in 1840, the London surgeon Samuel Lane considered it an unremarkable procedure to offer 11 year-old George Firmin. Unfortunately, George was a far from unremarkable child and the complications that followed his operation led to the first recorded use of blood transfusion to treat bleeding due to haemophilia.¹

There was more bleeding than usual during surgery, Lane noted, but it subsided and George was able to walk home afterwards. But he soon started bleeding again and the family eventually called the surgeon out that evening, when they belatedly revealed that George had a history of life-threatening bleeding after minor trauma that had resulted in four hospital admissions.

On this occasion, George’s wound continued to bleed for six days and five nights ‘despite the usual remedies, both general and local’. These included applying gum tragacanth mixed with beaver hair to promote coagulation; this was initially successful but the clot formed was weak and soon displaced. By the fifth day, George had lost so much blood that he was unconscious, vomiting and fitting. Lane resolved the boy would not die and he would attempt a blood transfusion at 7pm on the sixth day.

Transfusion was, by contrast with Dieffenbach’s procedure, a rare event at the time due to its poor track record: early attempts at transfusing blood from lambs and calves had, unsurprisingly, proved fatal. Fortunately for George, the obstetrician James Blundell had realised the importance of using human blood and had carried out the first successful transfusion in 1829. He personally explained the procedure to Lane.

Lane describes the procedure in great detail. He collected blood from ‘a stout, healthy young woman’ into a funnel which, via a stop-cock, fed directly into a syringe. Initially the donated blood clotted quickly, a problem solved by excluding air from the syringe chamber. Blood was infused and the syringe rewashed five times in total, after which about half a pint of blood had been donated. Over the next one to two hours, George sat up in bed and drank a glass of wine and water from his own hand. ‘The contrast between life and death could scarcely be greater,’ Lane commented. George recovered fully over the next three weeks (and his strabismus was corrected).

It’s possible that blood transfusion may have been proposed as a treatment for bleeding due to haemophilia as early as 1832 by the German physician Johan Schönlein (who gave his name to Henoch-Schönlein purpura),²but Lane’s is the first definitive account. He and George were fortunate that the donor had compatible blood and that bacterial contamination was somehow averted. Such problems brought a temporary stop to blood transfusion until, at the turn of the century, blood groups were discovered. Subsequent research revealed that blood fractions contained the necessary clotting factors and, in the mid-1930s, the therapeutic potential of plasma precipitate was demonstrated.

Haemophilia was unusually prevalent among European royalty in the 19^thcentury ‒something that is attributed to its emergence in Queen Victoria’s family and the practice of arranging marriages between royal houses to secure power and influence.

Prince Leopold George Duncan Albert, the fourth of Victoria’s nine children, was born on 7 April 1853. He was diagnosed with haemophilia in childhood and was reputedly a delicate child. He died in 1884, probably of a cerebral haemorrhage following a fall. At least two of Victoria’s daughters, Alice and Beatrice, were haemophilia carriers, as was Leopold’s daughter Alice. Their marriages and those of their children resulted in the emergence of haemophilia in the Spanish and Russian royal families. In total, nine or ten of Victoria’s male descendants were known to have had haemophilia; the true number of women who were carriers is not known as some died without having children.

Victorian society did not deal with the issue well. Britain in the mid-19^thcentury was, like much of Europe, experiencing revolutionary fervour. In 1848, the Queen was sent to the Isle of Wight to protect her from the Chartist marchers in London. During her reign, she survived six assassination attempts. Haemophilia was seen as a weakness by an establishment that could not afford to yield an inch to republicanism.

In 1868, the medical and lay press carried reports of Leopold’s bleeding episodes. One commentator suggests ‘the disease was an embarrassment to the monarchy, who generally kept as quiet as possible about it …’¹ With careful media management, some papers reported public sympathy for the family’s plight, but the republican press ‘argued that the disaffected working classes resented the hyperbole connecting the health of royal individuals with the political future of the entire nation.’¹ The ensuing political manoeuvring meant that the public acquired an unusually deep understanding of ‘the royal disease’ ‒but arguably one that, by virtue of turning haemophilia into a political football, may have contributed to the stigmatisation that people experience to this day.

It is believed that haemophilia among British royalty emerged with Victoria’s father, Prince Edward, via a random mutation. In 2009, gene sequencing of bone samples of the Russian royal family identified the IVS3-3A>G mutation in the factor IX gene; this results in a causal substitution in the splice acceptor site of exon 4 ‒something that would cause severe haemophilia B.^2,3

The dawn of the 20^thcentury shed little light on how best to treat haemophilia. Medical and scientific journals had published several accounts of generations of families affected by haemophilia and, when treatment was mentioned, most had reported great difficulty – or failure – in controlling bleeding.

In 1803, for example, the Philadelphia physician John Otto listed bark, astringents (topically and internally), strong styptics, opiates and oral sulphate of soda (sodium sulphate) as the measures employed to stem bleeding.¹ Only sodium sulphate proved effective – a finding that others confirmed.

In 1840, the London physician Samuel Lane recorded how he had tried to promote the formation of a clot by applying ‘gum tragacanth and beaver gathered from a hat’.² Success was temporary: the clot was soft and broke away with renewed bleeding.

It is thanks to the efficiency of the army and its enthusiasm for record-keeping – or that of its librarians, at least ‒ that we have a picture of the remedies in vogue at the turn of the century. The 1901 index-catalogue of the library of the Surgeon-General’s Office, United States Army, lists the publications about haemophilia held by the library.³ The titles reveal the variety of interventions that doctors considered worth reporting. They include lime (calcium oxide and/or hydroxide), oxygen, thyroid gland or extract, injection of serum, hydrogen peroxide, gelatin (including by injection), suturing, compression, calcium chloride and bone marrow.

The London medical historian G.I.C. Ingram observed that more treatments were listed in the following years, some topical to promote clot formation, others systemic.⁴ They include injection of sodium citrate, calcium lactate or of Witte’s peptone (a protein hydrolysate), anaphylaxis, splenectomy, the ‘galvanic needle’ (passage of electric current via a wire), animal and human serum, adrenaline, the ‘muscle jostles’ of a bird, x-rays, transfusion of the patient’s own blood, oral tissue fibrinogen, female hormones, oxalic acid, a ‘bromide extract of egg white’ and the venom of Russell’s viper (which promotes thrombosis by activating factor X). Ingram notes that viper venom was the only treatment to undergo systematic evaluation. Robert MacFarlane, a junior demonstrator of pathology at London’s St Bartholomew’s Hospital (who would go on to describe the enzyme cascade underpinning coagulation and to identify haemophilia B), and Burgess Barnett, curator of reptiles at the Zoological Society of London, showed that a very dilute solution of the venom stopped bleeding immediately when applied topically.⁵

Although the first successful use of blood transfusion to treat bleeding due to haemophilia was published in 1840,² it was not until 1926 that the Surgeon General’s catalogue included publications documenting its use.

Often described as the most famous person with haemophilia, Alexei Nikolaevich, the Tsarevich of the Russian empire at the beginning of the 20^thcentury, had the misfortune to be born into the royal Romanov family at a time when inherited wealth and privilege became distinctly unpopular.¹

Alexei was born in 1904, the son of Alexandra Feodorovna, a German aristocrat and the granddaughter of Queen Victoria, and Tsar Nicholas II. He was their fifth child and first son ‒ and, as late-arriving heir to the crown, bore the considerable weight of the empire’s hope and expectation on his shoulders. Alexandra, as a result of her descent from the British royal family, was a carrier of haemophilia. She had not been a popular choice for Nicholas and, with the risk of haemophilia well known at the time, the marriage was opposed by others in the royal family.

It was apparent shortly after birth that Alexei had haemophilia. This would have been perceived by the population as a judgement from God for some failing of the ruling class, and every attempt was made to keep the fact secret. He grew up cosseted and protected, but many accidents and bleeding episodes are documented, at least one of which resulted in Alexei receiving the last rites. Partly to cope with this, Alexandra removed herself from public life, increasing her unpopularity.

Conventional medicine had little to offer, and it is believed this was one factor behind the family’s attachment to Grigori Rasputin. The peasant healer is reputed to have achieved several miraculous cures when Alexei was ill, including one via a telegram sent from Siberia. Rasputin’s closeness to the family and his growing political influence caused resentment among the aristocracy, resulting in his murder in 1916.

In 1917, as Russia suffered during the First World War, public unrest stoked by food rationing culminated in the February Revolution. The army sided with the Bolsheviks and Nicholas was forced to abdicate. The new government wanted him to hand power to Alexei, who they believed would be easily controlled. However, Nicholas knew the boy was not strong enough and abdicated in favour of his less pliable brother, Michael. For his part, Michael knew he could not keep power and soon abdicated himself.

The family were imprisoned in Yekaterinburg, a city about 1,600 miles from St Petersburg, until April 1918, when victory by the anti-Bolshevik White Army threatened. Alarmed by the possibility that the royals might be reinstated, the government ordered their execution. It was a brutal and bloody affair: the family had sewn jewels into their clothing for safe-keeping, which prolonged the carnage by deflecting some of the bullets and bayonets. Even the 13-year-old boy with haemophilia wouldn’t die until he was shot in the head.

The bodies were buried before the White Army took the city eight days later. The remains were discovered in 2007 and identified by DNA testing a year later. It was then confirmed that Alexei had haemophilia B, just like the other affected royals.²

It is arguable that haemophilia was instrumental in the demise of the Russian royal family.¹Alexei’s haemophilia contributed to the Romanovs’ close relationship with Rasputin and to Alexandra’s withdrawal from public life; and it influenced Nicholas’s decision not to hand power to his son.

In April 1924, a five-year-old girl called Hjördis attended a clinic at the Deaconess Hospital in Helsinki, Finland. She came from the Åland Islands, situated about halfway between Helsinki and Stockholm, Sweden. She had a history of severe bleeding from the nose, after tooth extraction and from the ankle, and had been hospitalised for ten weeks at age three due to bleeding from a deep wound in her lip.

Hjördiswas one of 11 children, of whom seven experienced excessive bleeding and three had died. The physician she had seen at the clinic was the hospital’s physician-in-chief, Dr Erik Adolf von Willebrand, a well-regarded doctor with a long interest in haematology and in blood clotting in particular. He found that Hjördis’s blood count was normal, as was her clotting time (an indicator of thrombin formation); she had slight anaemia and slight thrombocytopenia. But, unusually, her bleeding time (which depends on vasoconstriction and platelet function) was two hours – at least ten times longer than expected.Von Willebrand concluded that her disorder was the result of platelet dysfunction, combined with a defect of the vascular wall.

Von Willebrand obtained the co-operation of a local teacher to document the family history, and discovered that the bleeding disorder affected 23 of 66 family members. By contrast with haemophilia, the disorder affected both women and men. Bleeding did not affect muscles and joints, but mostly the mucosae, causing epistaxis, oral bleeding, bruising, heavy menstrual bleeding and excessive bleeding after childbirth. His findings, published in 1926, described a disorder he labelled pseudohaemophilia.Hjördis died from menstrual bleeding, aged 13.

Von Willebrand wasn’t the first to describe a bleeding disorder affecting both women and men – the earliest account seems to have been in 1852, though the cases were labelled haemophilia. However, he provided the best early scientific description, and went on to collaborate with other Scandinavian physicians and publish distinguished research. In recognition of this work, the disorder was named von Willebrand disease between the late 1930s and early 1940s, by which time more cases had been reported.

It was not until 1971 that the disorder was attributed to dysfunction of a large protein that acts as a carrier of factor VIII; the protein was christened von Willebrand factor (VWF). Further research in the 1970s and 1980s identified several subtypes of von Willebrand disease, characterised by different molecular defects. The VWF gene was cloned in 1985.

In 1947, Alfredo Pavlovsky (1907–1984), a haematologist from Buenos Aires, Argentina, reported that a mixture of blood from two people with haemophilia had a shorter coagulation time than unadulterated blood from either individual.¹

For some time, there had been a suspicion that haemophilia was not a single entity, but Pavlovsky is credited with the first recorded observation leading to the recognition of two types of haemophilia: one due to a deficiency of factor VIII, later labelled haemophilia A; the other, less common, caused by a deficiency of factor IX, and first known as Christmas disease before being relabelled haemophilia B.

When Pavlovsky combined blood from a person with haemophilia A and from another with haemophilia B, the mixture contained sufficient factor VIII and factor IX to clot normally. However, he did not interpret his findings in this way. Pavlovsky believed that haemophilia was likely to be caused by an excess of ‘anticoagulant substances’ rather than ‘a deficit in the globulin fraction’, though he did not exclude that possibility, or that the two might coexist.

Haemophilia B was formally identified as a distinct disorder from haemophilia A in 1952. It was initially labelled Christmas disease, after the first patient described.²

The Haemophilia Society is the UK’s largest charity representing everyone affected by a bleeding disorder ‒ not only haemophilia, and not only people with the bleeding disorder, but their families and carers too. Its aim is: ‘to provide easy access to information and opportunities, influence national policy and practice to make the care and treatment of bleeding disorders consistent, effective and accessible to all and enable the voices of all people with bleeding disorders to be heard.’

Haematologist GIC Ingram has described how the Society came into being thanks to the sociability of people with haemophilia. He records how, during the 1940s, Frank Smith and Bob White started chatting about haemophilia while waiting for their clinic appointments at a London hospital. Together with four others who attended the same clinic, they began to meet informally at the Francis Galton Laboratory for National Eugenics. In 1942, together with others with an interest in haemophilia, they formed the International Haemophilia Society (IHS) and began to reach out to more people with haemophilia. The new society remained informal until the post-war years, when a channel of communication was opened up with Sir Weldon Dalrymple-Champneys, deputy chief medical officer at the Ministry of Health. With his support, the IHS registered as a charity with the London County Council in 1950.

The IHS was soon holding its committee meetings at the Hospital for Sick Children in Great Ormond Street, London, beginning a close relationship that survives to this day. Its position was consolidated over the next few years and, in 1954, the IHS worked with the Ministry of Health on establishing haemophilia centres (beginning with the Oxford centre), and addressing the challenges faced by people with haemophilia in education and employment, and with transport.

The IHS was reconstituted and renamed the Haemophilia Society in 1954, and local groups were formed throughout the country. Close contact with the Ministry of Health was maintained and Sir Weldon became the Society’s president in 1957.

Part of the Society’s purpose was to raise awareness about haemophilia – however, it faced a ‘chicken and egg’ problem when it came to fundraising as few people knew about bleeding disorders. Its first big boost came from the actor Richard Burton who, after visiting the Oxford haemophilia centre, pledged the proceeds from the royal premiere of his 1969 film Where Eagles Dare to the appeal that carried his name, raising a much-needed £4,000 (equivalent to well over £60,000 in 2019).

The Society played a significant part in establishing the World Federation of Hemophilia in the 1960s, and has been instrumental in the campaign to persuade the UK government to pay compensation to people with haemophilia who were infected with HIV by contaminated blood. Today, the Haemophilia Society is still run largely by volunteers and continues to vigorously promote awareness and support research. It campaigns on behalf of people with bleeding disorders and has a prominent role in the current public inquiry into the infected blood scandal. Membership is free and open to everyone.

The name ‘Christmas disease’ was coined in 1952 by a team of haematologists led by Rosemary Biggs from the Radcliffe Infirmary, Oxford.¹In a paper published in the British Medical Journal, they described seven people who appeared to have haemophilia but whose blood clotted more quickly when mixed with that from other people with haemophilia. They mentioned five earlier publications documenting the same phenomenon, including that of Argentinian haematologist Alfredo Pavlovsky, who first reported evidence of more than one type of bleeding disorder in people diagnosed with haemophilia.²

The first person Biggs and her colleagues described was Stephen Christmas, a five-year-old boy from London. At that time, haemophilia was believed to be caused by a failure or delay in blood thromboplastin formation caused by absence or deficiency in the blood of ‘antihaemophilic globulin’ (now known as factor VIII). If that was true, then Christmas disease must be a different disorder. Biggs’s team correctly identified a strong functional association between the ‘Christmas factor’ they suspected was deficient in their newly identified disorder and factor VII. Their work explained why, by contrast with most people with haemophilia, bleeding in a person with Christmas disease could not be treated by infusion of antihaemophilic globulin. It was surely no coincidence that their paper was published in the Christmas edition of the British Medical Journal.

Stephen Christmas contracted HIV from transfused blood in Canada and died from the complications of AIDS in 1993. Rosemary Biggs went on to have an illustrious career in haematology under the mentorship of Robert MacFarlane, who first described the coagulation cascade. In 1955, they co-authored the first British guideline on the treatment of haemophilia.³

By the late 1950s, the effectiveness of treating bleeds in people with haemophilia A with antihaemophilic fraction (AHF) was well established. AHF, which contained factor VIII, was a stable preparation (albeit crude by modern standards) prepared by sequentially precipitating the proteins in human plasma. One dose required up to 1.6 L of blood and contained 3 g of a mixture of proteins that included clotting factors. AHF was given on demand to treat bleeding episodes and to prevent bleeding during surgery.

In 1958, the Swedish haematologist Inga Marie Nilsson and her colleagues Margarita Blömback and Olof Ramgren described three boys with severe haemophilia A who were the first to be treated using a new approach: prophylaxis.¹ They showed that regular doses of AHF provided sufficient clotting factor to lower the risk of bleeding from severe to moderate, and this reduced the number of days spent being treated in hospital; in one boy it also prevented overt joint damage. The boys received half a dose of AHF once a month for 3.5 years, which maintained their own ‘AHF’ level at 1%‒3% almost until the next dose. The authors concluded: ‘Prophylactic treatment of haemophilic patients may be of value in decreasing the frequency of severe bleeding episodes.’

Nilsson reported further experience of prophylaxis after up to 13 years and up to 25 years.^2,3 By this time, modern factor VIII preparations were being given in a three times weekly regimen and the approach was used for people with severe haemophilia A or B. Nilsson’s thorough long-term follow-up studies provided the strong evidence on which current management strategies are based. She showed that initiating prophylaxis at an early age (1–2 years) to maintain factor VIII activity above 1% meant ‘it is almost possible to prevent bleedings and haemophilic arthropathy’ compared with a control group treated on demand. In 1992, following Nilsson’s account of 25 years’ experience, a commentator expressed concerns about the risk of poor adherence and the high cost of prophylaxis, but conceded ‘we must seriously entertain the possibility of a change in our treatment philosophy.’⁴

There was a downside. Although prophylaxis was remarkably well tolerated, five of the 66 people in Nilsson’s study developed inhibitors, 50 were infected with hepatitis C, 11 were infected with HIV and one died of the complications of AIDS.³

Inga Marie Nilsson had an illustrious career: she developed a treatment for inhibitors, contributed to the identification of von Willebrand disease (VWD) as a disorder distinct from haemophilia, and described genetic variants of VWD, as well as conducting research in other aspects of coagulation and thrombosis. She died in 1999 after a short illness, aged 66.

In 1960, Swiss haematologist François-Henri Duckert and his colleagues described a family affected by ‘a congenital haemorrhagic diathesis with slow and poor wound healing’.¹ Those affected rarely bled spontaneously but did so after trauma; bleeding onset was delayed by 24–36 hours but then persisted for several weeks. Clots formed but were ‘remarkably loose’ and healing was slow. The disorder affected both sexes and was probably inherited in an autosomal recessive pattern.

Duckert suggested the cause was probably a deficiency of fibrin stabilising factor, a component of the coagulation system proposed in 1944, confirmed in 1948 by Hungarian biochemists Kalman Laki and Laszlo Lóránd, and subsequently known as factor XIII (FXIII).^2,3

It is now known that FXIII is activated by thrombin and calcium ions to form cross-links between fibrin strands, strengthening a clot and stabilising it by slowing the degradation of fibrin by the anticoagulation system. It is a complex entity consisting of two pairs of proteins, A₂and B₂. It has many physiological functions in addition to its role in the coagulation system, including the formation of new blood vessels, endothelial cell proliferation and barrier function, modulation of the activity of cells involved in inflammation and promotion of atherosclerosis, and the development of bone.⁴

Laszlo Lóránd recounts his involvement, as a research student, in the discovery of FXIII deficiency with an enthusiasm only a scientist could muster:

‘Few biological phenomena evoke a more dramatic effect in an audience than seeing a large volume of Ca₂⁺‐chelated plasma turn into a clot by adding a drop of thrombin. As if by magic, the liquid is suddenly converted into a gel that can no longer be poured out of a flask, and it is immediately recognized that clotting would be life‐saving at wound sites, but could be deadly within the circulation.’⁵

Over 20 years later, Lóránd and his colleagues developed a quantitative test for FXIII that enabled geneticists to confirm Duckert’s view of the pattern of inheritance. FXIII is very rare, with a prevalence of 1–3 per million population (though regional differences are marked). To date, more than 100 gene mutations causing FXIII deficiency have been identified.⁶

The World Federation of Hemophilia (WFH) was established in 1963 by Frank Schnabel, a Canadian businessman with severe haemophilia A. He was a founding member of the Canadian Hemophilia Society in 1953 and had seen it grow from a small support group in Montreal to a national voluntary organisation. By the early 1960s, patient-led organisations had developed in many countries and, working with representatives from twelve national patient associations (Argentina, Australia, Belgium, Canada, Denmark, France, Germany, Japan, the Netherlands, Sweden, the UK and the USA), Schnabel convened the inaugural meeting of the WFH in Copenhagen, Denmark, on 25 June 1963. The Federation was formally constituted as a charity in 1964, with Schnabel as its first chair.

From the outset, Schnabel’s ambition was to create an organisation that could represent people with haemophilia the world over, and support collaboration between health professionals, researchers and people with haemophilia and their families. To promote an international network, raise awareness and share knowledge, the WFH initiated the bi-annual WFH congresses, which to this day are among the premier events in the scientific calendar for the haemophilia community. In 1969, the WFH was officially recognised by the World Health Organization.

It has long been clear to everyone in the haemophilia community that the most effective treatments are not equally accessible to everyone around the world. The WFH established the International Hemophilia Treatment Centre Program to help share knowledge between member societies in economically developed and developing countries through outreach training and fellowships.

Frank Schnabel died in 1987. Alan Tanner succeeded him as acting chair of the WFH, and Brian O’Mahoney was elected president at the WFH General Assembly in 1994. O’Mahoney renewed the Federation’s commitment to help redress the imbalance in access to modern treatments through initiatives including the a twinning programme between haemophilia centres in developed and economically developing countries. In Chile, the first ‘winning coalition’ of government support, pharmaceutical companies (which donated medicines) and the national patients’ organisation proved to be an effective model for capacity building and improving haemophilia care. This model has since been successfully implemented elsewhere.

Building on the success of the winning coalition concept, the WFH launched its Global Alliance for Progress (GAP) Program in 2003. This ten-year initiative put into effect all that the WFH had learned about building sustainable care in 20 economically developing countries, with the aim of tackling under-recognition of haemophilia by raising the number of people diagnosed to 50,000 ‒a figure more in line with the known prevalence of the disorder. GAP was followed by the Cornerstone Initiative, which is focusing resources on economically developing countries where standards of care are least advanced. Cornerstone currently serves eight countries in Africa, South and East Asia and Southeast Asia and the Western Pacific.

WFH now has 140 member organisations and is supported by all the major pharmaceutical companies involved in the development and provision of treatments for haemophilia. Although it is now an international organisation that commands respect on the global stage, it still relies on the efforts of volunteers to deliver change at a local level.

“After years of confusion, it seems that a relatively simple pattern is emerging from present theories of blood coagulation.”

So wrote Robert Gwyn MacFarlane in 1964, in a letter to the scientific journal Nature titled An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier.¹

It was indeed relatively simple but, much like a user’s manual for an electronic gadget, only when you understand it in the first place. Researchers had been struggling for years to work out how the various components of blood interacted to form a clot. MacFarlane described how a succession of studies stretching back to 1953 had revealed the various stages of coagulation. He summarised this in a simple diagram in which the proteins (i.e. clotting factors) were elegantly shown to be activated in a sequence of eight steps, each dependent on its predecessor.

MacFarlane described the cascade as a series of enzyme-proenzyme transformations, each regulated by positive and negative feedback mechanism. This explained how a single event could precipitate a rapid and marked increase in blood coagulability (the ‘amplifier’) and why coagulation did not continue to expand beyond the site of injury.

The cascade is very close to the current (slightly more complex) model of coagulation. The main differences are that MacFarlane included factors V and VIII as if they acted independently; they are now considered to be cofactors when in their activated forms (that is, they act in combination with another factor). Factor VIII, which is deficient in people with haemophilia A, is a cofactor for activated factor IX (which is deficient in haemophilia B); together they form a complex that contributes to the conversion of factor X to Xa.

MacFarlane died in 1987. He was a pathologist at Oxford’s John Radcliffe Hospital, and part of the team that first described haemophilia B in 1952, having carried out pioneering work on coagulation by studying snake venom. In 1988, the British government set up the Macfarlane Trust in his name to support people with haemophilia infected with HIV by contaminated NHS blood products. Its duties were taken over by the NHS in 2017 and its assets were transferred to the Terence Higgins Trust, which continues this work.

The management of haemophilia requires more than treatment for acute bleeding. It involves the prevention of bleeding and joint damage; prompt management of bleeding; management of complications (including joint and muscle damage and other sequelae of bleeding, inhibitor development, viral infection transmitted through blood products); and attention to psychosocial health.¹ All this is delivered by a package of services and resources known as comprehensive care.

The World Federation of Hemophilia defines comprehensive care as a process that ‘promotes physical and psychosocial health and quality of life while decreasing morbidity and mortality… to provide or coordinate inpatient (i.e. during hospital stays) and outpatient (clinic and other visits) care and services to patients and their family.’¹It is provided by a multidisciplinary team, the core of which comprises a medical director, a nurse coordinator, a musculoskeletal expert (e.g. a physiotherapist), a laboratory specialist, and a psychosocial expert (such as a social worker or psychologist). This team, which should be experienced in the management of bleeding disorders, calls on a wide range of other specialties when needed.

Comprehensive care represents the best model of care that a well-resourced health system can offer to people with a bleeding disorder and their families. An approach that was developed during the 1960s, two of the most prominent clinicians involved were Netherlands paediatrician Simon van Creveld (1894–1971)² and UK haematologist Katharine Dormandy (1926–1978).³

Van Creveld became director of the paediatric clinic at the University of Amsterdam in 1938. He retired from this post in 1964, having contributed significantly to research into clotting mechanisms at a haemophilia clinic he had founded near Amsterdam. In that year, the clinic was officially re-opened by Queen Juliana of the Netherlands as the first comprehensive treatment centre for people with haemophilia. Van Creveld said: ‘With the opening of the Hemophilia Clinic at Huizen, in 1964, the Netherlands became the first country in the world where hemophilic children could receive comprehensive treatment and be educated to take their place in the outside world.’

The centre subsequently focused on clinical work and, now affiliated with the University of Utrecht, it is known as the Van Creveld Kliniek. Van Creveld’s pioneering work influenced a generation of health professionals and established the primacy of the comprehensive care model in The Netherlands.

Katharine Dormandy was already an experienced researcher and an advocate of the emerging network of haemophilia centres in the UK when, in 1964, she joined the Royal Free Hospital in London. She established a haemophilia centre serving the North East Thames NHS region (in a caravan in the car park) where, for the first time in the UK, a full-time nurse provided on-demand factor infusions. Dormandy was a pioneer of holistic care for haemophilia, and helped to develop education resources for boys with haemophilia. In 1966, she wrote: ‘It is not enough for young haemophiliacs merely to survive, nor even for them to grow to manhood with good physique – they must also be able to take their place in society as well-integrated, independent individuals, able to earn a salary and support their families.’⁴

In 1970, Dormandy introduced a programme of home treatment with cryoprecipitate. By this time, with support from the UK Haemophilia Society, the centre had expanded and now delivered a comprehensive care programme in collaboration with other specialties at the hospital. In 1977, Katharine Dormandy was the first recipient of the RG Macfarlane Award, conferred by the Haemophilia Society for her outstanding contribution to the social and physical wellbeing of people with haemophilia and related disorders. The Royal Free centre was renamed the Katharine Dormandy Haemophilia and Thrombosis Centre in 1978.

Physicians in the 19^thcentury had shown that blood transfusion would correct the coagulation defect in people with haemophilia, a property believed to be due to the action of platelets. Transfusion offered an effective acute treatment for severe bleeding; however, due to the large volume of blood needed to provide sufficient clotting factor, it was not feasible for routine use.

It became clear during the 1930s that plasma was as effective as whole blood in stopping bleeding. The active component was one or more of the proteins that could be precipitated from plasma.^1,2 Initially, the precipitate was obtained by acidification, but by the mid-1940s it had been shown that this could also be achieved by freezing and slow thawing ‒though this had to be done with care because its clotting activity was readily lost. The protein mixture prepared in this way was termed ‘cryoprecipitate’.

In 1955, Emile Rémigy, a PhD student at the University of Nancy in France, showed that a plasma preparation concentrated by freezing could correct the coagulation defect when infused in people with haemophilia A as well as a larger volume of normal human plasma.³ However, as his research was published in French it remained unknown to the English-speaking scientific community.

Work continued on cryoprecipitate, but research was hampered by the challenges of producing a sterile preparation in sufficient quantities. In 1961, a commercial preparation became available in the United States, marketed as a source of fibrinogen.

In 1959, Judith Graham Poole, a physiologist at California’s Stanford University, had developed an assay for factor VIII. When assaying frozen plasma fractions, she and co-worker Jean Robinson knew the importance of slow thawing; however, when they tested the resulting liquid they found little FVIII activity. On testing the sludge left at the bottom of the container, they discovered why: the precipitate contained FVIII in a concentration 50 times greater than in plasma. In 1964, Poole reported the first successful use of cryoprecipitate to treat four people with haemophilia, noting that an injection of no more than 50 ml could raise clotting factor activity to 40% of normal.⁴

Poole realised she and Robinson had found a method for extracting FVIII from plasma that could be used by local institutions such as blood banks, and went on to describe this in a landmark publication in 1965.⁵ After freezing plasma, the liquid could be removed and the precipitate stored in a plastic bag for up to one year, then thawed when needed for administration. The process was so simple and inexpensive that it was rapidly adopted around the world. As cryoprecipitate also contained other factors, it also provided a convenient treatment for people with von Willebrand’s disease.

The development of plasma cryoprecipitate in 1964 and a system for large-scale production of a sterilised preparation in 1967 offered people with haemophilia and other bleeding disorders the prospect of routine factor replacement therapy. Whereas previously they had had to attend hospital for infusion of a large volume of plasma, they could now receive a high concentration of factor VIII or other clotting factors in a small volume of liquid. The use of frozen cryoprecipitate in the United States and of freeze-dried cryoprecipitate in Europe increased rapidly.

The new preparations were so easy and convenient to use that people with haemophilia were soon administering their treatment at home rather than attending a hospital clinic. Frozen cryoprecipitate required storage in a freezer at <20°C; the freeze-dried version could be kept in a fridge and reconstituted when needed, though the penalty for this convenience was a lower concentration of factor VIII.

By the early 1970s, home transfusions had become the preferred treatment for people with haemophilia. In 1972, one team from Chicago, US, described three years’ experience of home treatment for 32 people with haemophilia A.¹ They encountered ‘minimal technical problems and no serious transfusion reactions’. Compared with hospital-based treatment, they recorded more bleeds; however, there were also fewer hospital admissions, fewer severe joint problems and fewer days off school or work. They also noted – and considered these of equal importance to the physical benefits of home treatment – a positive psychological effect on patients and their families, with increased self-reliance, better mobility and freedom from fear. They concluded: ’…until a prophylactic regimen is feasible, home transfusion is the treatment of choice for haemophilia.’

A 1968 brochure of blood products and accessories includes a monochrome advert with the picture of a 6ml syringe lying on its side, needle in place. It is promoting Hemofil, the first commercially available preparation of freeze-dried concentrated antihaemophilic factor (AHF, factor VIII).

The point of using the syringe was to emphasise that this was a product with a lower volume than the older but nonetheless very successful cryoprecipitate, and one that could be given by intravenous injection rather than infusion. (Of course, the syringe pictured represented the smallest volume of Hemofil available – the vials ranged in size from 4ml or 125 units to 30ml or 1,000 units.) Further, the vial was labelled with the concentration of AHF measured by assay. This was another advantage over cryoprecipitate, which contained a variable dose of AHF.

The AHF concentration in Hemofil was 100–400 times greater than in plasma¹‒about six times greater than in cryoprecipitate ‒and it contained lower levels of extraneous proteins such as fibrinogen. It could be reconstituted and injected in a matter of minutes, whereas cryoprecipitate had to be thawed over 30 minutes and infused from a bag attached to a drip stand. It was undoubtedly a major improvement in convenience for people with haemophilia. Freeze-dried AHF concentrate was also available from blood transfusion services, but it contained about one-third of the AHF activity of Hemofil.²

Hemofil was manufactured by the Hyland Division of Travenol Laboratories, part of Baxter. However, it was prepared from pooled blood and, as was customary at the time, it was not treated to destroy possible viral contamination. It was withdrawn in 1975 after being associated with an outbreak of hepatitis B. Attempts to reintroduce a heat-treated formulation under the brand Hemofil T were discontinued when it was shown that this did not prevent transmission of hepatitis.

Erik Adolf von Willebrand described the bleeding disorder that was later to bear his name in 1926. He believed it was caused by dysfunction of platelets and the vascular wall. Only in 1971 was it discovered that the cause was an inherited deficiency of a protein that was associated with factor VIII and therefore christened factor VIII-related antigen.

Theodore Zimmerman and his colleagues from Cleveland, Ohio, applied the new science of immunoelectrophoresis to the problem.¹ They developed an antiserum to antihaemophilic factor (AHF, now known as factor VIII) and used it to assay blood taken from people with ‘classic haemophilia’, von Willebrand disease (VWD), and controls who did not have a bleeding disorder. They found a protein antigenically similar to AHF in normal levels in controls and in people with haemophilia, but not in those with VWD. The test could therefore distinguish between haemophilia and VWD.

At the time, it was not known that the protein, then labelled AHF-like antigen (and today known as VWF:Ag), was von Willebrand factor (VWF), and that it occurred in blood as a complex with factor VIII as well as in platelets and the walls of blood vessels. VWF acts as a chaperone to factor VIII, preventing its rapid degradation. The factor VIII/VWF complex is split by the action of thrombin as part of the coagulation cascade.

Together with Italian haematologist Zaverio Ruggeri, Zimmerman later described ten forms of VWF with different physiological properties, providing the molecular basis for identifying subgroups of VWD.² He died in 1988, aged 51.

Von Willebrand disease is the most common inherited blood disorder, affecting about one per 1,000 people. The identification of von Willebrand factor (VWF) transformed scientific understanding of this disorder, paving the way for the development of specific treatments.

In 1973, Harvey J. Weiss and his team at Columbia University, New York, reported that the antibiotic ristocetin caused platelets from ‘normal’ blood to coagulate but did so weakly or not at all in blood from people with von Willebrand disease.¹ They speculated that this was due to ‘a deficiency of a plasma factor necessary for platelet function’ that was somehow associated with factor VIII. In a second study, they concluded that what they were now calling von Willebrand factor was a protein associated with ‒ but distinct from ‒ factor VIII, and that a deficiency in this factor was the cause of von Willebrand disease.²

Subsequent research demonstrated the presence of VWF in the walls of blood vessels and platelets, and showed that it is released by the action of shear forces on the vascular wall. VWF was found to occur in blood as a chaperone bound to factor VIII, acting to prevent its rapid degradation in blood. In the coagulation cascade, the factor VIII/VWF complex is split by the action of thrombin; VWF then binds to platelets to promote aggregation. If there is a lack of VWF, or it does not function correctly, blood levels of factor VIII are reduced and platelets do not properly contribute to clot formation.

Changes in VWF are now the basis for the classification of von Willebrand disease into three main types. Type 1, which accounts for about 85% of cases, is due to a partial deficiency of VWF. Type 3, which is the rarest, affects about one per million people and is caused by an almost complete deficiency of VWF. Type 2 (of which there are four subtypes) is caused by abnormalities in function. It is believed that small variations in VWF function occur in the general population, giving rise to mild bleeding symptoms in some people who do not meet the diagnostic criteria for von Willebrand disease.

Depending on the severity of the bleeding risk, von Willebrand disease can be treated with desmopressin, a synthetic hormone that increases VWF levels, or with a concentrate of human plasma containing VWF and factor VIII. A recombinant form of human VWF was approved for marketing in Europe in 2018.

Monoclonal antibodies have transformed modern medicine. They provide a way to target a specific molecule, such as a hormone, protein or its receptor, and block its actions. This means that a key component of a physiological pathway or a specific cell function that contributes to a disorder can be interrupted without directly affecting other parts of the body (though there are indirect effects). For example, tumour necrosis factor alpha is a major driver of inflammation in rheumatoid arthritis; when its actions are blocked by a monoclonal antibody, the severity of inflammation is greatly reduced and sometimes abolished. The symptoms of arthritis are greatly decreased and the progression of the disease is arrested. Monoclonal antibodies have proved so effective in the treatment of rheumatoid arthritis that they are now the medicines of choice for moderate or severe disease.¹

The discovery of how to make monoclonal antibodies in quantities sufficient to be therapeutically useful was recognised by the 1984 Nobel prize in physiology or medicine.² The prize was shared by Danish immunologist Niels Jerne (1911–1994), German biologist George Köhler (1946–1995) and Argentinian biochemist César Milstein (1927–2002) ‘for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies.’

Jerne’s theories of systems biology led to the development of the clonal selection theory, which describes how the body’s B cells produce multiple identical copies of a single antibody (a ‘monoclonal’ antibody). He also developed an assay that enabled researchers to quantify the number of B cells producing antibodies.

B cells cannot be maintained for long in a laboratory environment, leading researchers to look for a more stable source of antibodies. Milstein and his colleagues developed a technique through which B cells could be fused with myeloma cells (bone marrow cancer cells) to create lines of ‘hybridoma’ cells that replicated repeatedly in the laboratory, producing large quantities of antibodies. However, the antibodies had no specific target.

Milstein described his work in a presentation at the Basel Institute, where George Köhler sat in the audience. Köhler subsequently joined Milstein’s team and worked out a way to target the antibodies. He activated B cells in mice by immunising them with an antigen, collected the B cells from the spleen and fused them with a myeloma cell line. Using Jerne’s assay technique, he then showed that the hybrid cells were producing identical antibodies targeted against the antigen. This is the basis of modern production techniques for monoclonal antibodies.

Monoclonal antibodies are used in many fields of medicine, with around half accounted for by cancer treatment, haematology, rheumatology, dermatology and gastroenterology. Potential therapeutic applications now being developed include their use in obesity, diabetes, coeliac disease, Alzheimer’s disease and bacterial infection. It is estimated that the global medicines market for these agents will be worth $130‒200 billion by 2022.

In 1974, a team from the Regional Blood Transfusion Centre in Edinburgh’s Royal Infirmary published the first evidence that desmopressin, a synthetic analogue of the hormone vasopressin, increased blood levels of factor VIII and plasminogen activator in healthy volunteers.¹ There was a clear relationship between the dose of desmopressin and the level of factor VIII, and the response was ‘sustained and without side effects’.

It was not until 1977 that a study testing this observation in clinical practice was published.² A team of haematologists from Milan, Italy, administered infusions of desmopressin to patients with mild or moderate haemophilia or von Willebrand disease (VWD) shortly before and soon after dental extraction surgery. They observed a two- to three-fold increase in factor VIII activity in the blood, which prevented bleeding in two patients and limited bleeding to oozing from the gums in two others (for which they needed clotting factor replacement). A higher dose increased factor VIII activity up to normal levels in another six people with mild haemophilia and two with VWD.

That study was timely. In the late 1970s, clotting factor was in short supply and what little was available was reserved largely for on-demand treatment. Furthermore, blood products had become contaminated with hepatitis virus and their use could not be justified for people with mild bleeding disorders whose greatest risk was from trauma and surgery rather than spontaneous bleeds. Desmopressin was a safe, predictable option. Its widespread use in Italy is believed to have been a factor in the low prevalence of HIV infection among people with mild haemophilia A compared with those with mild haemophilia B, who required treatment with plasma products because desmopressin does not increase levels of factor IX.³

However, early studies did not detect the adverse effects of desmopressin that are now recognised. These include flushing, hypotension and fluid retention, which requires restriction of liquids intake for 24 hours after a dose. The response is variable and a test dose is administered to determine how useful it will be in individual cases.⁴

Desmopressin increases levs of factor VIII and von Willebrand factor levels by stimulating their release from the endothelial cells of blood vessels.⁴ It is effective in people with VWD and mild or moderate haemophilia, but not in those with severe haemophilia or type 3 VWD as they have little or no stores of factor VIII or von Willebrand factor. It has many advantages: it is less expensive than treatment with a clotting factor and avoids the risk of developing inhibitors; it appears to be safe during pregnancy; and it is administered subcutaneously (or intranasally), offering greater convenience. It is therefore preferred to blood products for treating and preventing bleeds in people with mild or moderate haemophilia A or VWD, and for symptomatic carriers of haemophilia A.⁵

We hear a lot about disruptive therapies these days – innovations so radical that they have the potential to bring about a drastic change in treatment and also in the way care is organised and funded. Extended half-life clotting factors and gene therapy are two recent examples of disruptive therapies. But it is not widely known that the Haemophilia Nurses’ Association (HNA) was founded in response to a disruptive therapy that fulfilled its potential to fundamentally transform haemophilia care.

Clotting factor concentrate, introduced in the 1960s, was a disruptive therapy. It made life much easier for people with haemophilia, as bleeds could be treated with a low volume infusion rather than large volumes of plasma. Patients would normally visit hospital to have the drip set up and venepuncture carried out. However, it soon became evident that this was a simple procedure that could be done at home by the patients themselves, with training and support from the clinic. By 1970, leading centres in the United States were strongly advocating this approach.¹

In the UK, people were still attending hospital to get treatment for bleeds, usually receiving their infusion of concentrate as an outpatient. At the time, the nurse’s role did not even include taking bloods or setting up intravenous infusions, but forward-thinking individuals were starting to change practice. Maureen Fearns, a haemophilia sister in Newcastle upon Tyne, was one such pioneer. The Newcastle haemophilia centre was progressive: the director had recently established a comprehensive care team to deliver holistic care to patients and their families. Maureen was keen to learn about clinical practice in other centres: “Initially, I sent out a one page newsletter to nurses working with haemophilia patients at other centres, asking them what they were doing and how they were doing it, and whether they’d be interested in sharing information – and we just took it from there.”²

That letter led to the first meeting of haemophilia nurses in London in 1976, at which Maureen described her experience of setting up a home treatment service for adults and children with severe haemophilia. That event and the meetings that followed were such a success that, in 1981, she and Patricia Turk from the Treloar School and College for young people with disabilities formally established the HNA. Its first meeting was held in Newcastle’s Airport Hotel over two days in September 1982, with home therapy training as the first presentation.

From its inception, the HNA aimed to improve patient care through nurse education and training, promoting communication and support within the specialty, building links with professional societies and other disciplines, and developing professional standards. The experience of caring for patients with HIV and their families during the 1980s, and again for those affected by hepatitis in the 1990s, reinforced the bonds within the HNA, demonstrating that its network, meetings and peer support were highly valued by its members. The role of haemophilia nurses has since greatly expanded and now includes every aspect of the organisation and delivery of care, with specialist haemophilia nursing posts now formally recognised.

Today the HNA has around 120 members. In partnership with Haemnet, it provides courses on clinical practice and leadership and is developing a new competency framework. It is actively strengthening links with other healthcare professionals, such as physiotherapists, and reaching out to haemophilia nurses throughout Europe. Maureen was invited to address the HNA Annual Meeting in Birmingham on 30 March 2019, where she recounted how the experiences of its members over more than three decades had made the Association even more relevant to nursing practice, providing a stronger voice for nurses and patients alike.

In July 1982, the United States Centers for Disease Control (CDC) reported that three people with haemophilia A had developed a rare form of pneumonia due to the fungus Pneumocystis carinii(now known as Pneumocystis jirovecii). All died.^1,2

The organism responsible typically causes infection in people whose immune system is compromised, such as in the severe immune deficiency syndrome in homosexual men and intravenous drug users that had been reported in New York and California in 1981. ‘The clinical and immunologic features these three patients share are strikingly similar’ to the cases reported in people with immune deficiency, the CDC noted, adding that the cause was unknown but ‘the occurrence among the three hemophiliac cases suggests the possible transmission of an agent through blood products.’

By December 1982, it was clear that the three men with haemophilia had what was now known as Acquired Immune Deficiency Syndrome (AIDS). Five similar cases had also come to light: three were children and two adults were already dead. The only risk factor common to them all was treatment with factor VIII concentrate or other blood products.

Lymphadenopathy-associated virus, later renamed human immunodeficiency virus (HIV), was eventually confirmed as the cause of AIDS in 1983.³Isolated cases had been reported for many years without understanding the role of the virus, but since 1980 its increasing frequency in high-risk groups had attracted medical attention.

HIV had entered the blood supply in the United States because donations were accepted from people in high-risk groups. Public health authorities warned people who used blood products of the risk, but encountered resistance to their proposal that blood should not be accepted from high-risk individuals – including the already stigmatised gay community, which accounted for a high proportion of donations.⁴Scepticism among representatives of the haemophilia community, the US medicines regulator and the blood industry also delayed progress. Blood banks refused to provide donors’ details, obstructing attempts to connect transfusion and transmission. However, in December 1982, the CDC proved the link when it reported that a 20-month‐old infant had developed AIDS after receiving a transfusion of platelets derived from the blood of a man later found to have AIDS.

Doubt and denial persisted but, in March 1983, the CDC recommended that blood donations should not be accepted from high-risk groups.⁵By this time, over 1,200 cases of AIDS had been notified and 450 people had died; 11 cases were known among people with haemophilia, which increased to 26 by August. Attempts were already underway to develop methods to destroy HIV in blood products, and by October 1984 it could be shown that heat treatment removed the virus completely. The new year saw an almost complete switch to heat-treated blood products.

Between 1981 and 1984, more than half of all people with haemophilia in the United States had been infected with HIV. By 1998, 2,254 people with haemophilia had died of AIDS-related complications.⁶

During the 1980s, the UK was not self-sufficient in blood products and imported supplies from the United States. Between 1979 and 1986, 1,227 people with haemophilia were infected with HIV.⁷Between 1985 and 1992, 403 HIV-positive people died ‒the expected number had been 60. It was estimated that 85% of the excess deaths were due directly to the complications of AIDS. In 2017/18, one person registered on the National Haemophilia Database died of AIDs.

In September 1982, a research team from Oxford University reported that they had partially cloned the human gene for factor IX.¹ Concluding the densely-packed description of their work, the authors commented, ‘It is hoped that the genomic clone reported here will be similarly useful for the diagnosis and understanding of the mutations in patients with haemophilia B, as well as of heterozygote mothers who are carriers of the factor IX mutation.’

Within two months, researchers from the University of Washington, Seattle, described the complete cloning of the factor IX gene, known as pHfIX1.² It is sobering to see the gene’s sequence of amino acids typed out on a single page in this short scientific paper (available free online) and realise that this was the discovery that transformed the lives of people with haemophilia B.

Cloning the factor IX gene opened the way for the development of recombinant factor IX for replacement therapy, giving people with haemophilia B a safe source of replacement clotting factor. It also marked the point at which gene therapy for haemophilia B became a reality.

What is less well known is that cloning the factor IX gene also led to groundbreaking experiments with cloned sheep. Following the successful cloning of Dolly the sheep in 1996, researchers at Edinburgh’s Roslin Institute cloned two more: Molly and Polly. Like Dolly, they were created from a single cell of an adult sheep, but they were also transgenic – that is, their cells had been altered to express a non-native gene that would cause human factor IX to be expressed in their milk. This was the first experiment to show that transgenic animals could be used as a source of complex proteins to treat human disorders. The technique, known as pharming, is now used to manufacture recombinant human antithrombin (ATryn) from the milk of transgenic goats and the recombinant C1-inhibitor conestat alfa (Ruconest) from the milk of transgenic rabbits. Pig milk appears to offer the best prospect of transgenic production of recombinant clotting factors for therapeutic use.

The human factor VIII gene was fully cloned in 1984 by researchers working at US biotech startup Genentech, based in San Francisco. This was the step that opened the way for production of recombinant human factor VIII, providing a safer alternative to the plasma-derived products then in use. Jane Gitschier, one of the team leaders, has given a colourful and very detailed account of the planning and research that led to the discovery.¹

In the early 1980s, Genentech was an unlikely setting for such prestigious research. Gitschier recalls that the company ‘operated like a boy’s locker room, and the place reeked of testosterone. No prank was too outrageous, no poker bet was too high, and no woman was part of the inner circle. The head of organic chemistry came out of the building one day to find his car had been painted pink.’ Such boisterousness does not seem to have interfered with the serious business of research.

Despite Gitschier’s clear account, the explanation of how the Genentech team overcame the many practical and theoretical problems in their path requires a good understanding of gene biochemistry: the work was complex, technical and involved several teams investigating complementary lines of research, including researchers from the Haemophilia Centre at London’s Royal Free Hospital. The project started in 1981; as the end of 1983 approached, Genentech had sequenced almost all of the factor VIII gene.

But Genentech had a rival. Genetics Institute (GI), based in Washington, had been studying porcine factor VIII. In December 1983, the company shocked Genentech when it announced to the press that it had cloned the human factor VIII gene. It turned out that GI had actually only partially cloned the gene, though this did not deter the company from filing a patent based on what it knew of the sequence.

Genentech fully achieved its objective in April 1984, sequencing the entire gene and also expressing the gene from recombinant DNA. A patent was filed on the same day that this achievement was announced to the world.

The research was published in three papers in a single issue of the journal Nature,^2-4 together with a paper from GI describing their work.⁵ GI marketed its recombinant factor VIII (Recombinate) in 1992; Genentech launched Kogenate in 1993. The two companies entered what was to become a patent dispute lasting five years.⁶ This was eventually settled in Genentech’s favour and the two companies agreed a cross-licence arrangement. GI was later taken over by Wyeth, which introduced a modified recombinant factor VIII under the brand ReFacto in 2000.

Following the successful cloning of the factor VIII gene in 1984, the first recombinant factor VIII to be marketed in Europe was Kogenate. The recombinant protein was produced in hamster kidney cells and there were concerns that residual animal antigens might provoke an immune response ‒in particular, the neutralising antibodies known as inhibitors. On the other hand, manufacturing clotting factors by recombinant technology avoided the risk of viral contamination of plasma products (this was by now more theoretical than real, but memories of HIV and hepatitis transmission were fresh).

The first clinical trial of Kogenate began in Europe and the United States in 1988.¹ It involved three phases: a comparison of the pharmacokinetics of recombinant factor VIII with a plasma-derived product in 17 people; a study of the feasibility of home treatment involving 26 people; and the efficacy and safety of the recombinant factor as on-demand treatment for serious bleeds and to provide cover during surgery in 76 people (some of whom had participated in the preliminary studies). Twenty infants and children who had not previously received a clotting factor were treated with the recombinant product on demand or as prophylaxis.

The pharmacokinetics of recombinant factor VIII were found to be similar to those of the plasma product. Home treatment for almost two years showed that average infusion frequency was once per week and the average annual bleed rate was 24.4 (equivalent to one bleed every 14–15 days). Haemostasis was rated ‘excellent’ as cover for surgery. Inhibitors were found in eight patients; they predated recombinant therapy in one but were high-level (and therefore likely to reduce the effectiveness of replacement factor VIII) in two patients.

The Kogenate trial suggested that recombinant factor VIII was about as safe and effective as the plasma-derived products it might replace, though the authors acknowledged that questions remained about inhibitor risk. This debate rumbled on until, in 2016, the SIPPET study showed that recombinant products were associated with a 69% greater risk of causing high-level inhibitors than plasma products in previously untreated patients.² Why this should be so remains unclear, but the conclusion has withstood criticism about its design and possible confounding factors.³

The Royal Victoria Hospital (RVI) in Newcastle upon Tyne has made (at least) two valuable contributions to the development of professional care in NHS haemophilia services. The first was the founding of the Haemophilia Nurses’ Association (HNA) by Maureen Fearns in 1982. The second was the Haemophilia Chartered Physiotherapists Association (HCPA), which held its first meeting in 1990 (albeit in London), organised by Brenda Buzzard, a physiotherapist at the RVI, and her colleagues Karen Beeton, Ruth Bolton, Fiona Hall and Fiona McChesney.

The original aim of the HCPA was to provide a forum for communication via meetings and a newsletter ‒ an ambition that was soon met through a series of meetings in haemophilia centres throughout the UK. It was clear that there was great enthusiasm within the profession for improving the quality of care by developing practice standards and collaborating with agencies such as the World Federation for Hemophilia (WFH).

With support from Bayer, HCPA was able to develop its own continuing professional development (CPD) training and liaise more widely in the international forums. In 2007, an annual meeting was established to promote research, facilitate networking and provide peer support. Since then, the Association has established standards of care for child and adult haemophilia care. It has formed a clinical studies group to provide support and mentorship for researchers, and has strengthened relationships with the HNA. There is also a web-based peer-support forum on Haemnet (www.haemnet.com), where members can meet and share problems and issues. HCPA represents physiotherapists at the NHS England Clinical Reference Group by helping to develop the service specification for England, and is a member of the outcomes and musculoskeletal working parties of the UK Haemophilia Doctors’ Organisation. Further afield, HCPA members are represented on the physiotherapy groups of both the European Association for Haemophilia and Allied Bleedings Disorders (EAHAD) and the WFH.

The HCPA has, in a relatively short period, established the profession’s credentials and created the foundation on which physiotherapists working with people with haemophilia can further improve care by promoting research and good clinical practice. It provides professional leadership and a forum for exchanging ideas within the profession and with colleagues working in haemophilia care.

The UK Haemophilia Centres Doctors’ Organisation (UKHCDO) was founded in 1968 to ‘improve haemophilia care, research into bleeding disorders, their treatment, epidemiology and complications, and to facilitate healthcare planning.’ Ten years later it had established the UK’s registry of people with bleeding disorders, the National Haemophilia Database (NHD). It became a registered charity in 1991.

Despite its name, UKHCDO is concerned with all bleeding disorders. Its objectives are defined as:

• to preserve, protect and relieve persons suffering from haemophilia and other inherited bleeding disorders;
• 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 inherited bleeding disorders and their treatment;
• to promote or assist in the promotion of audit and research into the causes, prevention, alleviation and management of haemophilia and other inherited bleeding disorders and to disseminate the useful results of such research.

The NHD (http://www.ukhcdo.org/nhd) is a treasure trove of information about people with haemophilia in the UK and their care. The UKHCDO is required by the Department of Health to collect data from haemophilia centres to help to plan haemophilia care and determine spending commitments, and to facilitate research. The NHD is mainly funded by the NHS, with additional support from the pharmaceutical industry for research and information for medicines regulators. Annual reports from the NHD are publicly available at http://www.ukhcdo.org/home-2/annual-reports.

The UKHCDO has 11 working parties and task forces, focusing on many aspects of haemophilia and its management and publishing authoritative management guidelines. It also liaises with other professional groups, including the Haemophilia Nurses’ Association, the Haemophilia Chartered Physiotherapists’ Association, the Haemophilia Society and the Clinical Molecular Genetics Society. It maintains a register of UK haemophilia centres and operates the Haemtrack system, through which people with haemophilia monitor their treatment and coordinate with their treatment centres.

The biotech company Genetic Industries (GI) was – just – beaten to the line by Genentech for the first sequencing of the entire factor VIII gene. However, it was the first to bring to market a recombinant human factor VIII. Recombinate was introduced in the United States in 1992, where it is still available.

Recombinant factor VIII marked the final move away from using human blood as a source of clotting factor ‒a necessary change following the contamination of donated blood supplies by HIV and hepatitis virus, and a shortage of blood from safe sources. Newer formulations of clotting factors had been heat-treated and cleared by ultrafiltration, so the risk of viral transmission was negligible by this time. However, the risk of previously unrecognised pathogens could not be ruled out – the UK outbreak of bovine spongiform encephalopathy had raised concerns that prions might be potential contaminants. Confidence in human blood sources therefore remained low; recombinant products offered safety and greater certainty about supply.

The early recombinant clotting factors were not entirely free of human blood products. Recombinate (antihaemophilic factor [recombinant], later available in Europe as Helixate), the only example of a ‘first generation’ recombinant factor VIII, contains human albumin as a stabiliser and, unlike later products, was not treated to remove viruses. Second generation agents, such as Kogenate (octocog alfa) and ReFacto (moroctocog alfa) have a different stabiliser. but may contain traces of human albumin from the cell culture medium in which the compounds are synthesised. The third generation recombinant factor Advate (octocog alfa), licensed in Europe in 2004, is a modified formulation of Recombinate from which all animal and human products have been removed during fermentation and manufacture.

With the advent of gene therapy, it is remarkable that it is now possible to talk – however tentatively – about a cure for haemophilia. But this further highlights the acknowledged disparities in the care for people with bleeding disorders available in wealthy developed countries and economically developing countries. The World Federation of Hemophilia (WFH) has been working for over 50 years to close this therapeutic gap, and one of its most effective approaches is the twinning programme.

The idea of a twinning programme was first proposed by Guglielmo Mariani, now a professor of haematology at the Università LUdeS, Lugano, Switzerland. His original plan has changed little: twinning is a formal, two-way collaboration or partnership between emerging and established treatment centres or organisations, and builds personal and organisational relationships that encourage the sharing of knowledge and experience to the benefit of both partners. WFH is adamant that this is not a one-way process by which the wealthier twin gives and the other takes, noting that relationships in which one centre views itself as ‘the expert’ are at risk of being unbalanced. Over the past 20 years, the WFH Twinning Programme has established 215 partnerships in 113 countries.

Types of twinning activities include exchange visits, training, sharing expertise on complex cases, swapping information resources, supplies of equipment, reagents and factor concentrates, special projects such as advocacy and outreach, and research and networking. Both twins benefit from capacity building, sharing best practice and collaborative working.

In 2016, WFH launched a new twinning initiative to help improve and strengthen youth groups in developing partner countries, with the specific aim of fostering leadership.

The twinning programme is funded exclusively by Pfizer.

On 11 February 1997, US medicines regulator the Food and Drug Administration notified biotech company Genetics Institute that it was now authorised to ‘manufacture and ship for sale, barter or exchange in interstate and foreign commerce Coagulation Factor IX (Recombinant).’¹

The protein, now known as nonacog alfa, was synthesised using a stable line of Chinese hamster ovary cells and was free of animal and human products. Factor IX was marketed under the brand BeneFIX. In Europe, BeneFIX was licensed on 27 August 1997. Children and adults with haemophilia B now had their first recombinant clotting factor.

Prior to 1997, factor IX products were derived from human plasma. Initially, these were extracts that contained only low levels of factor IX, but also factors II and VII; they were therefore known as prothrombin complex concentrates. These crude products were associated with a potential risk of thrombosis and were replaced by high purity alternatives that had undergone heat treatment and ultrafiltration to remove possible viral contamination. But as recently as 1996, US patients had been warned of a possible risk of hepatitis A transmission associated with high purity products.²

In the UK today, 69% of factor IX products prescribed for people with haemophilia B are high purity recombinant proteins.³ BeneFIX still dominates the market, accounting for 98% of recombinant factor IX products, but its use is now declining with the advent of extended half-life factors. This next generation of recombinant proteins has been modified to reduce the rate at which factor IX is eliminated from the body. Introduced in 2016, they made up 23% of all factor IX products prescribed in 2017/18.

The 1990s were a time of feverish activity as researchers struggled to develop a gene therapy for haemophilia. The concept had been demonstrated in experimental models, but proof was needed that it would work in humans. The first clinical trial to attempt that began in 1998.¹ By current standards the results were disappointing.

The trial was a Phase I study; that is, it was designed to assess dosage and side effects. A team from Boston, Massachusetts, working with biotech company Transkaryotic Therapies, took fibroblasts from the skin of six people with severe haemophilia A, transfected them with parts of the gene for factor VIII, cultured the cells and reinjected them into the peritoneum.

After one year, no serious adverse effects were detected. Factor VIII activity increased in four participants, coinciding with a reduction in bleeding frequency and use of clotting factor. However, the highest factor VIII activity was only 4%, and that was recorded in only one person after three months; after one year, factor VIII activity had returned to baseline levels in all participants.

Transkaryotic Therapies was not the only player in an area of research that offered huge prizes for success.²It was clear that gene therapy could work if only the person’s cells could be persuaded to take up the gene in a way that ensured it would survive and produce factor VIII. Researchers turned to viruses to use as vectors deliver the gene. Chiron Inc tried intravenous administration using a mouse leukaemia virus; it failed. GenStar Therapeutics Inc tried using an adenovirus, but this provoked an immune reaction that destroyed the cells carrying the gene. 1999 saw the start of a trial of intramuscular injection of the factor IX gene using an adeno-associated virus (AAV) vector.³It demonstrated that the gene had been successfully transferred, but factor IX levels did not increase. The authors concluded that the doses needed for success were too high to be delivered by intramuscular administration, and began work on developing administration into the liver. This proved successful, but the transplanted genes were destroyed by an immune response to the AAV vector.⁴

This apparently disappointing outcome was, in fact, a milestone. It showed that delivery of the virus into the liver was the route of administration of choice, and also that AAV was an effective vector. Treatment to suppress the immune response to the AAV vector was needed to preserve the gene, but it was soon found that oral prednisone was enough to do this – the immune response was transient and only a short course was needed. The principles for conducting future gene therapy trials had been established.

As of 2019, there are 13 clinical trials of gene therapy for haemophilia A or B under way, all using an adenovirus vector (though other viral vectors are also being evaluated). Three are Phase III trials designed to provide definitive evidence of efficacy and safety. Results so far show that factor VIII and IX activity after gene therapy is high and sustained, and that freedom from bleeding and its complications is now a realistic prospect.^5,6

People with haemophilia who have repeated episodes of bleeding into joints develop disabling arthritis and experience constant pain ‒but for many years there was no way to prevent joint bleeds. Until the 1960s, factor replacement therapy required the infusion of large volumes of plasma and was feasible only for on-demand treatment of a bleed. The advent of factor concentrates allowed the use of much lower volumes. Small studies suggested that regular infusions (prophylaxis) could prevent bleeds, and that this might be a better strategy than waiting for a bleed to occur then treating it.

This promising approach was foiled by the contamination of blood products with HIV and hepatitis, and it wasn’t until the introduction of recombinant clotting factors (not derived from human blood and therefore free of viral contamination) that prophylaxis again became a serious option.

In 1991, a trial in Sweden showed that starting prophylaxis at age three was associated with less joint damage than starting at age five, and suggested that it would be even better to start at age one to two.¹ Three years later, an American team showed that prophylaxis reduced the daily impact and complications of haemophilia by reducing joint bleeds.²

Definitive evidence of the benefits of prophylaxis, and of starting early in life, was first provided in 2007 by the Joint Outcome Study.³Sixty-five boys aged less than 30 months were randomly assigned to have standard on-demand treatment with recombinant factor VIII when a bleed occurred, or prophylaxis with infusions of recombinant factor VIII on alternate days. By six years of age, only 55% of boys treated on-demand still had normal joints, compared with 93% of those who received prophylaxis. The risk of joint damage detectable by an MRI scan was found to be six times greater in the on-demand group. There was a concern that regular exposure to factor VIII might increase the risk of inhibitors, and this occurred in two of the 32 boys using prophylaxis. On the other hand, three of the boys treated on-demand experienced a life-threatening haemorrhage during the study period.

Perhaps surprisingly, the Joint Outcome Study showed that joint damage did not correlate well with clinical signs of joint bleeding. The authors speculated ‘that chronic microhemorrhage into the joints or subchondral bone in young boys with hemophilia causes deterioration of joints without clinical evidence of hemarthroses and that prophylaxis prevents this subclinical process.’ And they were right. Prophylaxis from an early age ‒before the onset of joint damage, meaning before or soon after the first joint bleeds ‒is now the treatment of choice for haemophilia.⁴

Many young people and adults with a bleeding disorder now administer their treatment themselves at home or, if they are young children, their parents do it for them. Their medication and syringes arrive by courier, they reconstitute the factor and they give themselves the injection.

Most people prefer home treatment to visiting a hospital clinic several times a week. The downside is that there is less contact between the healthcare team and the person with the bleeding disorder and their family, so each treatment centre has procedures in place to ensure that patients have access to help and support when they need it, in addition to their regular clinic appointments. in the UK, week-by-week monitoring of treatment with clotting factor is managed via Haemtrack.

Haemtrack is an electronic diary accessed via a mobile phone app or website in which the patient (or parent) records details about the doses of clotting factor used, such as the day of administration and the batch number, and events such as bleeds. The app/website connects with the treatment centre and automatically transfers data so that it can be reviewed by the haemophilia nurse or doctor. Data can also be recorded on paper forms when the app/website are not suitable. Currently, about 90% of patients in the UK use Haemtrack.¹

It is a condition of NHS home treatment that a patient’s treatment data are recorded using Haemtrack. Further, treatment with newer agents, such as extended half-life factors, is available only to individuals who adhere closely to the requirement for monitoring treatment with Haemtrack (that is, they record at least 75% of all infusions).

In addition to monitoring treatment, anonymised data from Haemtrack are used to support research about the use of clotting factors. For example, Haemtrack provided data for the THUNDER study, which revealed that people with moderate haemophilia may be undertreated with prophylactic clotting factor.²

During the early 2000s, success with gene therapy for haemophilia was increasing incrementally rather than in leaps and bounds. By the middle of the decade, it was known that the genes should be targeted at the liver, encapsulated in a viral vector that could promote its uptake into the patient’s cells, from where it would start to produce clotting factor. The best viral vector was identified as adeno-associated virus (AAV) which, in its natural state, causes a benign infection in humans.

This, of course, raised the problem that individuals who had in the past had an AAV infection would have antibodies against the AAV vector and would not be eligible for gene therapy. There are several subtypes of AAV; they have some antigens in common, so that immunity against one may also confer protection against others. However, they are not equally prevalent in the population and the level of cross-sensitivity varies between subtypes.

The breakthrough trial of gene therapy for haemophilia B was published in 2011.¹ A joint research team from the UK and the US developed an approach that they said was different from earlier attempts in three ways. First, they modified the vector to increase gene expression. Second, they used the AAV8 virus subtype, one of the less common naturally occurring subtypes in humans and therefore associated with a lower rate of background immunity. The AAV8 subtype also has an exceptionally strong affinity for liver cells, which enabled the third innovation of administering the gene/vector via a peripheral vein rather than directly into the liver.

The trial involved three pairs of people with severe haemophilia B (FIX <1%), who received low, medium and high doses. After 6–16 months, FIX activity levels were 2%‒11%. Four participants were able to discontinue factor IX prophylaxis completely and had no more bleeds; the other two were able to reduce their factor dose frequency. The two who received the highest dose had evidence of an immune response to the AAV8 vector; this was treated with a short course of steroids.

The trial was published on 22 December 2011  in one of the most prestigious medical journals, The New England Journal of Medicine, accompanied by a commentary wittily titled ‘Merry Christmas for haemophilia B patients’ (haemophilia B was originally known as Christmas disease, after the family name of the boy in whom it was first formally described). This commentary referred to the trial as ‘truly a landmark study’ and answered the question ‘Should the practicing hematologist rush to order this gene therapy vector if it is approved by the Food and Drug Administration?’ with the reply: ‘The answer is probably yes, but the risks of this procedure are not yet totally clear.’ This more or less sums up the state of knowledge several years later, in 2019.

Haemnet supports a vibrant and interactive community of nurses, physiotherapists and allied healthcare professionals, sharing knowledge and experiences, and engaging in research that enables people affected by bleeding disorders to live well.

Haemnet began as an online professional network for the nurses and healthcare professionals who look after people with haemophilia and inherited bleeding disorders. Before Haemnet, when a haemophilia nurse needed advice or encountered a ‘difficult-to-manage’ patient, he or she would phone a friend for advice. Now, those conversations also take place on Haemnet with more voices contributing, to the benefit of the whole community. What began as a UK-wide initiative quickly spread across the global haemophilia community: now more than 550 nurses and physiotherapists from around the world are registered on Haemnet, along with a growing number of psychologists and social workers.

In 2013, in response to the views of members of the Haemophilia Nurses Association (HNA), Haemnet became a registered charity, overseen by a board of trustees, with the aim of providing education and collaborative research opportunities for all members of the haemophilia multidisciplinary care team. Day-to-day management of Haemnet is the responsibility of the director, Mike Holland, with strategic development support from Sandra Dodgson.

Haemnet runs the annual HNA conference alongside a growing number of haemophilia-specific and professional development courses. The courses are the result of listening to members in the context of the future of haemophilia care and identifying areas for development. They include the Contemporary Care of People with Bleeding Disorders course, a four-day residential training course for healthcare professionals, and ASPIRE, a leadership development programme followed over six to eight months.

The outputs and outcomes of Haemnet’s projects are shared with practitioners on the Haemnet website (which also provides CPD opportunities and a forum for HNA members), and through The Journal of Haemophilia Practice (JHP). Haemnet launched JHP as an open-access, online journal for haemophilia care professionals in 2014, and has now published over 100 articles. The journal is currently supported by charitable donations from Sobi, CSL Behring, Octapharma, Pfizer, Novo Nordisk and Grifols.

Prophylaxis with clotting factor replacement therapy has been a tremendous leap forward for people with haemophilia: it greatly reduces bleeds and lowers the risk of joint damage compared with on-demand treatment. But it comes at the considerable cost of frequent infusions. As a result of pharmacokinetics ‒or the rate at which a substance is cleared from the body ‒most people with haemophilia A have to inject themselves with factor VIII on alternate days or two to three times per week, with some needing daily injections.^1,2 This is time-consuming, and parents find it stressful having to administer infusions to their children.

Reducing the frequency of infusions would therefore be a major step forward ‒one that could make a big difference to a person who has to inject daily or every other day. Extended half-life (EHL) factors promise exactly that.

Half-life is a measure of how quickly factor is cleared from the body, measured as the time taken for its concentration in blood to fall by half. EHL factors are clotting factors that have been modified by adding side chains to the molecule, slowing the rate at which they are cleared from the body. This means that a dose lasts longer, prolonging the time until the next injections is needed.

On 19 November 2015, the first EHL factor VIII was approved for use in Europe. Efmoroctocog alfa, better known as Elocta, was developed in the United States by Biogen and marketed by Sobi. It is essentially a modified recombinant factor VIII (its B domain is removed, as in the conventional product ReFacto AF) that is fused to part of a protein (human immunoglobulin). Its half-life averages 19–21 hours in adults and 12–18 hours in children. This compares with 11–12 hours and 9 hours respectively for a conventional factor VIII. In clinical trials, efmoroctocog alfa was administered every three to five days and still maintained factor VIII activity above trough level for longer than a conventional product. In February 2018, the Republic of Ireland announced that all people with haemophilia would be switched from a conventional factor VIII to an EHL product.

To date, clinical trials have compared EHL factors with historical experience with conventional factors. These data suggest they reduce the frequency of bleeds with less frequent injections. However, the question for each individual switching from a conventional to an EHL factor is whether to aim for the same trough factor VIII activity level and have fewer injections, or to have a higher (and safer) trough level and keep injection frequency the same.

As of April 2019, one other EHL factor VIII product had been licensed in Europe: rurioctocog alfa pegol (Adynovi) is a factor VIII combined with a polyethylene glycol (PEG) side chain. Novo Nordisk’s turoctocog alfa pegol (Esperoct), which combines factor VIII with PEG, has been licensed in the United States.

Three EHL factor IX products are available: eftrenonacog alfa (factor IX fused to immunoglobulin; Alprolix), nonacog beta pegol (factor IX combined with PEG; Refixia); and albutrepenonacog alfa (factor IX fused to albumin; Idelvion).

Clotting factors are large proteins. When they are infused, there is a risk that they will provoke an immune reaction that will lead to the formation of antibodies, which bind to the clotting factor, neutralising its activity. In the management of haemophilia, neutralising antibodies are known as inhibitors.

Inhibitors are more frequently a problem for people with haemophilia A than those with haemophilia B as the factor VIII molecule is larger and more immunogenic than factor IX. Inhibitors may occur at a low or high level. Low-level inhibitors can be overcome by increasing the dose of clotting factor; high-level inhibitors render a clotting factor useless. A person who develops high-level inhibitors needs additional treatment with a preparation that circumvents the need for factor VIII or IX. This may be factor VII or a preparation of mixed factors known as FEIBA (factor eight bypassing activity). Alternatively, they can undergo immune tolerance induction with very high doses of clotting factor designed to overwhelm their immune response. However, this can take months of daily infusions and is very expensive. Emicizumab has changed all that.

Emicizumab is a monoclonal antibody that takes the place of factor VIII in the coagulation cascade by acting as a bridge between factor IX and factor X. It does not resemble factor VIII in structure and does not induce neutralising antibodies. It makes factor VIII redundant and inhibitors irrelevant.

In 2017, emicizumab (Hemlibra, Roche) was approved by the US medicines regulator, the Food and Drug Administration (FDA), for routine prophylaxis in children and adults with haemophilia A with inhibitors. It was approved for use in Europe on 23 February 2018.

On 23 February 2018, emicizumab was approved by the European Medicines Agency as routine prophylaxis for bleeding episodes in children and adults with haemophilia A with factor VIII inhibitors. It is an alternative to the burdensome and expensive approaches to managing inhibitors previously available: treatment with a bypassing agent (factor VII or FEIBA (factor eight bypassing activity)) or immune tolerance induction, an intensive regimen of daily infusions of high-dose clotting factor designed to overwhelm the immune response.

Treatment with emicizumab is an altogether different prospect. It is administered by subcutaneous injection, initially weekly; but after a month this can be reduced to every two weeks or monthly. All other treatment with a clotting factor can be stopped. Furthermore, emicizumab proved more effective than bypassing agents at preventing bleeds: in the key clinical trial providing the evidence for its authorisation, weekly emicizumab was associated with a 79% lower bleeding rate than had been achieved through prophylaxis with bypassing agents.¹

In 2018, emicizumab was also approved as prophylaxis in people with severe haemophilia A who did not have inhibitors, thereby replacing the need for 90–365 intravenous infusions every year with only 12–52 subcutaneous injections.

In July 2018, NHS England announced that every patient with haemophilia A with inhibitors and poorly controlled bleeding would be eligible for treatment with emicizumab. On 11 March 2019, the European Medicines Agency approved emicizumab for the treatment of people with severe haemophilia A whether they had inhibitors or not.

In an era where new technologies promise radical change, emicizumab is a truly disruptive innovation. Real-world experience of its use is currently limited; however, if the evidence of efficacy and safety is borne out in day-to-day clinical practice, it could transform care for people with haemophilia A. Its use does not need the close support that is customary with clotting factor replacement, which has implications not only for patients but also for haemophilia treatment centres. Emicizumab’s future depends on how cost is balanced against effectiveness and potentially improved quality of life, compared with the familiar options that have served the haemophilia community well for the previous 20 years.