Haemophilia , Past and Present

INTRODUCTION The term haemophilia, meaning “lover of blood", was coined comparatively recently in the long history of bleeding disorders, having been first used in the early 19th century. Then it defined a bleeding disorder which was transmitted by certain unaffected females to some of their sons. Now, as a result of the enormous increase in scientific knowledge developed in the interim, haemophilia can be defined more precisely as a coagulation disorder transmitted in a sex-linked recessive manner and primarily expressed in males, in which the level of factor V I II clotting (or biological) activity in the blood is reduced below normal because some of the precursor molecules, (named immunological factor V III), are functionally abnormal and cannot be converted to clotting factor V III. The clinical grade of severity of the disorder breeds true and correlates well with the amount of circulating clotting factor V III, severely affected haemophiliacs having less than 1%, moderately affected between 1 and 5% and mildly affected between 5 and 50%. The normal range is 50 200%. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, New Series No.2, 1980: 24-29 doi:10.2218/resmedica.v0i2.926 PRINCIPLES AND PRACTICE HAEMOPHILIA, PAST AND PRESENT

The term haemophilia, meaning "lover of blood", was coined comparatively recently in the long history of bleeding disorders, having been first used in the early 19th century.Then it defined a bleeding disorder which was transmitted by certain unaffected females to some of their sons.Now, as a result of the enormous increase in scientific knowledge developed in the interim, haemophilia can be defined more precisely as a coagulation disorder transmitted in a sex-linked recessive manner and primarily expressed in males, in which the level of factor V I II clotting (or biological) activity in the blood is reduced below normal because some of the precursor molecules, (named immunological factor V III), are function ally abnormal and cannot be converted to clotting factor V III.The clinical grade of severity of the disorder breeds true and correlates well with the amount of circulating clotting factor V III, severely affected haemophiliacs having less than 1%, moderately affected between 1 and 5 % and mildly affected between 5 and 50%.The normal range is 50 -200%.

H A E M O P H IL IA IN H IS T O R Y
The first recorded references to haemophilia in man are probably to be found in Jewish writings of the 2nd Century A.D. where families are mentioned in which more than one male child died of excessive bleeding following ritual circumcision.The disorder also occurs in animals and probably first began in placental mammals through genetic mutation about 50 million years ago.
The severely affected patient bleeds 'spont aneously' in response to the 'microtrauma of living' and this grave gene deficiency was usually lethal in olden times before the reproductive age was reached.We therefore believe that the severe grade of the disorder was maintained in man by spontaneous genetic mutation and the mutation rate has been estimated at about 2 x 10-5 (W.H.O., 1972).
The history of haemophilia makes fascinating reading and the reader interested in a more detailed study of the subject is advised to read the excellent article by Ingram (1976).Apart from the methodic early clinical studies on the subject and the more recent scientific investigations recorded by Ingram, it is interesting to speculate on the role the disorder has played in European and Russian political history.Queen Victoria is thought to have acquired a carrier state at conception through genetic mutation, which was first recognised with the birth of her eighth child Leopold who was a severe haemophiliac.More significantly she produced at least two carrier daughters in her large family.One of these, Beatrice, transmitted the carrier status to her daughter Victoria Eugenie who married Alfonso X III, King of Spain, and at least two of their five sons were severe haemophiliacs.Through Alix, whose daughter Alice married Tsar Nicholas II of Russia, was born in 1904 the severely affected haemophiliac, and only son, Alexis.The inability of doctors to prevent, or even alleviate, the repetitive painful joint bleedings associated with this disorder in the boy, may have contributed to the evil influence that the monk Rasputin acquired over the unhappy Royal parents for the Tsarina had great faith in his healing powers.Isolated from everyday affairs by their preoccupation with their son's disability, the Royal parents may well have contributed to the tragic downfall and death of the family in the Bolshevik revolution.The drama of haemophilia is vividly portrayed in two novels by R.K. Massie ("Nicholas and Alexandra", 1968) and Dorothy Sayers ("Have his Carcase", 1932).

P R E S E N T A T IO N A N D N A T U R E
Classical haemophilia (factor V III deficiency) has to be distinguished from von Willebrand's disease, and particularly from Christmas disease (factor IX deficiency) with both of which it shares some common clinical and laboratory features.The distinction, made as recently as 1952 in the case of Christmas disease, is important not least because modern clotting factor replacement therapy is reasonably specific for each disorder and the products used are not interchangeable.
The hallmark of a bleeding disorder is the per sistence rather than the rate of blood loss.The typical haemophiliac is therefore a male in whom the clinical symptoms correlate well with the degree of his clotting factor deficiency.The severely affected patient, with less than 1% factor V III, bleeds 'spontaneously', that is without appar ent injury, the moderately affected in response to minor injury, but not spontaneously and the mildly affected in response to minor injury, but not spontaneously and the mildly affected only to moderate injury.More than 90% of bleedings in the severely affected patient occur into joints, and the knees, ankles and elbows are most frequently affected, though the reason why these particular joints should be involved is not known.The unpredictability of such bleedings in the severe haemophiliac with apparent normality in between episodes had a profound psychological effect on him in the days before modern factor replacement therapy became available to abort the bleeds in an early stage.Such joint bleeds, if un treated, produce intense pain and immobility and will eventually, when repeated sufficiently often, result in joint damage, permanent limitation of movement and finally crippling haemarthritic deformity.Less commonly occurring bleeds into muscles and tissue compartments can likewise, by their pressure effects, cause muscle necrosis or nerve damage and hence loss of function.Haemorrhage into a closed cavity such as the skull can cause brain damage and often death.Intracranial haemorrhage is now one of the commonest causes of death in this group of patients.
Classical haemophilia is the commonest of the single clotting factor disorders in Great Britain and has an approximate incidence of 6 per 100,000 in the population.About half of these patients are severely affected and the remainder are about equally distributed in the moderately and mildly affected grades.Whilst there is reason to believe that even some severely affected haemo philiacs have not yet been diagnosed and recorded, there is even stronger evidence that more of the moderately and mildly affected patients have escaped the net.These latter groups do not mani fest their disability so obviously as the severely affected patients, particularly as the accepted blood loss due to trauma in normal males varies widely.
Christmas disease (factor IX deficiency) is about one fifth as common in the population as haemo philia.

M A N A G E M E N T
The factor V III molecule is unstable in solution; it and factor V, only rarely congenitally deficient, are known as the 'labile' clotting factors.It has a half-life at blood heat in vitro and in vivo of 8 -12 hours, whereas that of factor IX is 18 -24 hours.It is ofen not appreciated that primary normal wound healing which, depending on the size of the wound, the presence or absence of infection and the nutritional state of the patient, may take up to 14 days to complete requires adequate levels of factor V III and the other clotting factors in the blood throughout.Failure to meet these needs will result in immediate or delayed wound bleeding according to the time in the healing process that it occurs.The quantity of factors needed is roughly proportional to the size of the wound.Less explicable is the fact that 'spontaneous' injury needs less clotting factors for healing than does overt trauma of apparently similar degree.The mildly affected haemophiliac w ho has some endogenous production of factor V III can therefore cope unaided with mild trauma as can the moderately affected patient with minimal trauma, but the severely affected haemophiliac will often bleed abnormally in response to the occult trauma 'o f being'.The principle of treatment of injury in these patients is to raise the deficient clotting factor to a safe blood level by exogenous means and to so maintain it until healing has been achieved.
In the 'spontaneous' joint bleed this may mean obtaining a 'once only' peak of 2 0 % whereas for more severe trauma, for example operative surgery, a pre-operative level of at least 6 0 % will usually be required, and thereafter the trough level must not fall below 2 0 % until late in healing.To achieve this goal repetitive infusions of factor V III as often as six-hourly may be necessary for much of the healing period.The greater the threat of re-bleeding, for example in intracranial injury, the longer is it wise to sustain a haemostatic level of the clotting factor in the blood.Meticulous surgical haemostasis together with wound rest by splintage etc. minimises factor V III requirements and is always advocated in the management of injury in haemophilia.
The improved management of severe haemo philia is the result of four main factors: (i) precise diagnosis, (ii) early treatment of bleeding episodes, (iii) a better understanding of factory V III require ments as discussed above and (iv) the availability of stable, concentrated preparations of clotting factor V III.Clearly it is impossible to raise and maintain the factor V III level of a severe haemo philiac from less than 1% to at least 6 0 % with whole blood or even plasma without causing circu latory overload and heart failure.The availability of such concentrated factor V III products has therefore revolutionised the management of haemophilia.

The History of Replacement Therapy
The history of blood transfusion in man is much shorter than that of haemophilia.It began in the 17th century, initially with the use of animal as well as human blood, and usually in either case with disastrous results to the patient.It was mainly due to the discovery, first by Landsteiner of the A B O blood groups, and then by Weiner of the Rhesus (Rh) groups, in the last fifty years that blood transfusion has become safe and practicable.
The management of bleeding battle casualties in World War II soon brought an appreciation of the urgent need for early restoration of the intravascular deficit by an isosmotic, colloid containing fluid even without red cells, at least until the loss of these became very severe.The separation of plasma from whole blood by centrifugation followed by the preparation of a dried, and hence stable, product met this need.Such a product was also easy to reconstitute and administer in forward battle areas, and did not require the skilled tech nical compatibility matching which is always desirable, and often essential, when whole blood is used.By this time Macfarlane in Oxford and other workers elsewhere, had also realised that only intravenous factor replacement therapy would satisfactorily and safely control bleeding in the haemophiliac.
The knowledge gained during the War years in the preparation, handling and use of plasma stimu lated further exploration of this product for its more specific component fractions.This had two main objects, namely (i) to produce more specific products of high potency which would make possible sustained, intensive replacement therapy in patients, and (ii) to make more economic use of blood which, in Great Britain, is obtained from voluntary donors who have to be allowed a mini mum period of four months to make good the deficit produced by the giving of one whole blood donation.
Factor V III requirements at that stage, because of the instability of the molecule in vitro, were best met by using fresh plasma (within no more than four hours of blood donation) which was inconvenient.However, the factor V III activity in such plasma could be preserved for at least three months either by immediately deep freezing it to not less than -20° C or by freeze drying it.
Unfortunately neither of these measures solved the problem of the unacceptable volume it was necessary to transfuse to achieve and maintain an adequate haemostatic level of factor V III in a severe haemophiliac for other than trivial bleeds.
The next logical sequence was plasma fraction ation.After the pioneer work in this field of Cohn et al (1946), crude concentrates of human and animal products were produced in various European and American centres in the early 1950's and used w ith increasing success in the management o f the more serious and major bleeding episodes in haemophiliacs whether they were spontaneous or traumatic, accidental or elective in origin.The species specificity o f the highly potent concentrates obtained from the pig and the cow lim ited their use in man because of the sensitisation and thence severe reactions they eventually induced in the recipient, but they fu lfille d an im portant interim role where large dosage o f factor V III was needed u ntil the human product could be adequately refined.This latter achievement dates from a chance observation made in America by Judith Pool and her colleagues (1965).She noticed th a t when human plasma was deep frozen at -20°C and then slowly thawed, the large plasma protein molecules, factor V III (m.w t about 2 x 10 6 ) and to a lesser degree fibrinogen (factor I, m. w t 560,000), would at 4°C remain fo r a tim e as a sludge or cryoprecipitate w hilst the other plasma proteins w ent into solution.By careful removal o f most o f the liquid supernatant the sludge could be harvested and then stored stable deep frozen at not less than -20°C in the little remaining plasma until required fo r use.It could then be dissolved as required in the retained plasma by controlled thawing at blood heat (37°C) and injected intravenously at once.Comparatively high doses o f factor V III could thus be obtained in an acceptably small plasma volume by pooling as many o f these cryoprecipitate donations as were necessary.
The theoretical and practical disadvantages of such cryoprecipitate were (i) the tim e consuming skill needed in preparation o f each individual pack, (ii) the variability o f factor V III levels in the normal donors and the manipulative loss in preparation, (iii) the need fo r controlled temperature thawing (37°C) to avoid factor V III loss immediately prior to use and (iv) the need to enter several packs w ith its attendant infection risk to obtain a sufficient dose o f factor V III fo r therapeutic use.
On the other hand despite the technical, organ isational and economic difficulties o f harvesting large quantities o f whole blood, separating and deep freezing the plasma immediately, storing and transporting it deep frozen to a central large scale fractionation unit, and the technical difficulties o f large scale fractionation w ith o u t loss o f potency o f the components, cryoprecipitate has been an im portant interim advance in the treatm ent o f haemophilia and it still remains so today.Never theless, at various centres in Britain (O xford, Elstree, Edinburgh) large scale plasma fra ctio n ation is a reality and the quality and quantity o f the products, available, not least o f factor V III, are increasing and in some cases (e.g.factor IX ) do meet all the present day requirements.The freeze dried factor V III so produced has many advantages over the stalwart cryoprecipitate.'First, it is produced from a large, pooled, plasma batch and equal aliquots o f the finished product are freeze dried in individual vials; thus the dose is constant in each vial from any batch.Secondly, by standard random sampling the vials can be checked fo r potency and sterility and duly labelled w ith this inform ation.T h ird ly, the product is stable fo r a considerable tim e if kept at 4°C, and it can be re constituted in a small volume of sterile water immediately prior to use to give a known factor V III dose which usually has a potency o f at least tw enty times that o f an equal volume o f fresh plasma.
The present aim is to produce dried products of ever greater potency w ith acceptable recovery loss in manufacture and in such quantities that they w ill meet all needs o f haemophiliacs fo r factor V III.

Management today
How has the management o f haemophilia changed and kept pace w ith the blood product development?First, it has become more aggressive; that is treatm ent o f spontaneous bleeding, com m only into joints, is given earlier and is more effective so that bleeding is arrested before distention and pain occur, and temporary disability, permanent damage and d eform ity are minimised or prevented.This results in less tim e lost from school, w ork or leisure activities.Secondly, major surgery, whether fo r disorders that may beset us all, such as the complications of peptic ulcer or extensive dental caries, or fo r those peculiar to the haemophiliac, such as jo in t deformities from past haemarthroses, has been made much safer and can now be undertaken electively and not only as a desperate life-saving measure.For these aims to achieve fruition other associated developments have been necessary.Haemophilia Centres have been established and developed in major hospitals so that precise diagnoses can be made and patients counselled, advised and instructed.A t these Centres specialised out-patient treatment is available on a 24-hour basis and the haemophiliac can report direct to the Centre using the Ambulance Service or his own 'car for the disabled' to get there.Joint bleeds etc. can thus be treated at a very early stage and the haemophiliac, if sufficiently competent, can be taught self-injection of the factor V I II made available at the Centre 'on demand'.When he is fully trained, and when adequate dried factor V I II supplies are available, he can change to the Home Treatment programme.He will then be issued with a limited supply of dried factor V III with which he can treat joint bleeds -the bugbear of the severe haemophiliac's life -at home and thus save time and trouble and gain independence.Since 9 5 % of all factor V III used by a severe haemophiliac is for such bleeds, the advantages of home therapy are obvious.For bleeds other than into joints, out-patient manage ment at the Centre, or occasionally in the Ward, is still advisable and the haemophiliac must not attempt such treatment at home.

The future
Whilst present progress has revolutionised the life of the severe haemophiliac, given him selfconfidence and a much greater degree of independence, it has not cured him.A t present we know of no means of achieving this.Perhaps as supplies of factor V III improve still further, we will be able to offer him prophylaxis, but the short factor half-life would probably necessitate twice daily self-infusion of factor V I II rather like an insulin-dependent diabetic though using the intra venous route.However, about 10% of haemo philiacs develop a neutralising 'a ntib o d y'to factor V I II which is not dose related, and at present is causally not understood.In some it persists in the plasma indefinitely and in others it wanes if not provoked by further therapy, but in all it con stitutes a bar to replacement therapy, either totally or save in urgent circumstances.Manage ment of these patients is at present not very satis factory even though blood products with 'factor V I II bypassing activity' have some beneficial use.We can, however, hope for a radically different approach to the problem of haemophilia.
It is possible even now to sex the foetus in utero accurately in early pregnancy, and where the mother is a known or potential carrier of the disorder this may be advisable; however, the procedure is associated with a small abortion loss.Hopefully in the near future it will be possible to measure the factor V III level in the foetus accurately and thus offer therapeutic abortion of an affected male foetus if desired.
The investigation of suspected female carriers of haemophilia is becoming more specific, based upon the dissociation of the levels of clotting and immunological factor V III in the blood of those positive for the trait, but it is not yet wholly reliable.A n entirely new approach to the manage ment of haemophilia depends upon using an exogenous stimulus to induce a temporary increase in endogenous production of factor V III.Deamino-D-arginine vasopressin (D D A V P ) given intra venously or as snuff is used for this purpose but is effective only in the moderately or mildly affected patient (Mannucci et al, 1975).And so the search for better products, more effective and simpler treatment, prophylactic rather than therapeutic, goes on.Selective abortion as a preventative measure is never likely to overcome the perpetuation of the disorder through spon taneous genetic mutation and hence the goal must ultimately be to find a cure.This still seems to be a long way off, but progress towards it accelerates.

The Haemophilia Society
What have haemophiliacs done to help themselves?In the early 1940's in Britain they formed their own Haemophilia Society and this is now linked with other similar societies elsewhere in the world in the World Federation of Haemo philia.Through their Society, and as a minority group in the population, they have helped to dispel fear and ignorance of the disease and this has improved their opportunities for better medical care, schooling, employment and leisure.The Society has, through organised meetings and its literature, helped parents of newly diagnosed haemophiliacs and the effected children themselves, to adjust and adapt to the disability and to lead a fuller, more balanced life.It has provided funds for research and has agitated and helped to make Governments understand the needs of all handicapped people, and of those with haemophilia in particular.
A n d so whilst haemophilia and its problems are so much better understood and managed than in those far off days o f the Rabbinic references to exsanguination of ritual circumcision, there is still much to be done and the contributions made in this field in the future, as in the past, will add to as much as they derive from, the advances made in medicine in their widest sense.