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HAEMOPHILIA AND RELATED CONDITIONSBy R. G. MACFARLANE, M.D.

Clinical Pathologist, Radcliffe Infirmary; Radeliffe Lecturer in Haematology, University of Oxford

IntroductionUntil recently haemophilia could be cited as an

excellent example of a clearly defined clinicalcondition. Its symptomatology, inheritance andpathological findings were striking and charac-teristic, and diagnosis seldom presented anyserious difficulties. But now the situation haschanged; new methods of investigation haverevealed the fact that the term ' haemophilia,' asusually applied, may cover more than one, perhapsseveral, distinct entities which differ from eachother in the mechanism of their causation, andtheir response to specific treatment. These find-ings have, of course, necessitated a completerevision of ideas, and have thrown the existingsystem of terminology into confusion. There are,moreover, indications that further revisions areimpending and it may be some years beforeanother period of comparative stability in thisfield is reached. This article is at best an interimreport on a rapidly changing situation, and itmust be recognized that what are thought to befacts and valid conclusions now may soon beconsidered fallacious.

HistoricalThe evolution of the concept of haemophilia

has followed a course which has many parallelsin medical history; there are, for instance, strikingsimilarities in the development of ideas on per-nicious anaemia. At the beginning of the lastcentury it became generally recognized that certainpatients were liable to bleed uncontrollably fromquite trivial injuries. Descriptions of individualsor of whole families affected in this way werepublished with increasing frequency, but for manyyears there was no uniform terminology, nor anyclear ideas as to the possible causes of the abnor-mality. Many terms, such as ' haemorrhoea,'' pernicious haemorrhage,'' haemorrhaphilia ' and' idiosyncrasia haemorrhagica' were used to de-scribe these cases. The name ' haemophilia ' wasappart ntly introduced by Hopff in I828, but itdid not become widely applied until some zo or

3 years later. Even then it was by no meansrestricted to the sort of cases that would be labelledh iemophilia today; it was used to d scribe con-ditions now recognizable as purpura haemor-rhagica, scurvy, telangiectasia and many cases ofhaemorrhage caused by some organic disease.The modern concept of haemophilia as a clinical

entity probably originated from the work ofNasse (i820), who pointed out among the hetero-geheous descriptions of bleeders many instancesof a hereditary condition, affecting only males andtransmitted only by apparently normal femal s.Such a peculiar inheritance attracted considerableattention and the use of the term ' haemophilia'became more ani more restricted to those cases inwhich a family history conforming to ' Nasse'slaw' could be obtained. The monumental surveyof Bulloch and Fildes (i i i), covering the wholeof the availablh literature, finally established theterm' haemophilia ' in this sense.

Until the end of the igth century the diagnosisof haemophilia rested entirely on clinical andgenetic findings. The persistent liability to bleedoccurring in a male from early infancy, the periodicswelling of the joints and evidence of a similarcondition in brothers, maternal uncles or cousinsprovided the diagnostic criteria of that time. Anyideas on the cause of the condition were necessarilytheoretical. It was usually supposed that thetissues or blood vessels were unduly fragile;though it was noted by Liston (I839) that theblood of a haemophilic patient coagulated slowlyand incompletely, the haemostatic importance ofefficient clotting was not widely appreciated. Itwas not until I893 that Wright established that thecoagulation time of the blood was characteristic-ally prolonged in haemophilia, and not until 19I0was it shown by Addis that defective clotting isthe only demonstrable cause of the haemorrhagictendency.

Meanwhile, there had been a growth of interestin the mechanism of blood coagulation and it wasnatural that many who worked on this subjectshould try to determine the cause of the delayed

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clotting of haemophilic blood. The fact that thisobjective was unattained for more than 30 yearswas an indication that the normal process ofcoagulation was only partially understood. Aseach factor of the clotting mechanism was iden-tified, its deficiency was thought to be the basicdefect in haemophilia. In turn a deficiency offibrinogen, calcium, prothrombin, platelet factorand thromboplastin was postulated, and refuted.

The Clotting Defect in HaemophiliaThe first indications of the true nature of the

defect in haemophilia came from the work ofAddis (i9ii). He showed that a small proportionof the globulin fraction of normal plasma whenadded to haemophilic blood caused it to clotwithin the normal time. Unfortunately he con-cluded that this effect was due to prothrombinand thus that a deficiency of prothrombin was thecause of haemophilia. When it was later shownthat the prothrombin concentration of haemophilicblood was normal, Addis's work was discreditedand forgotten. It was not until I937 that Patekand Taylor again demonstrated the correctiveeffect of a normal plasma globulin fraction onhaemophilic blood and suggested that this effectwas due to an ' antihaemophilic factor' presentin normal blood but lacking in haemophilia.From this work came the recognition of a clottingfactor, hitherto ignored by the classical theory ofcoagulation, which became known as ' antihaemo-philic globulin.' It is found in the globulinfraction of the plasma associated with fibrinogen,and in fractions I, III2 and III3 of Cohn (Minotand Taylor, I947); it is consumed or inactivatedduring clotting and is not present in serum; it isnot absorbed by BaSO4 or AI(OH)3. This recog-nition of the basic defect allowed the definition ofhaemophilia to be expanded to include a deficiencyof antihaemophilic globulin as an essential feature.Attempts were then made to determine the

importance of this factor in the normal clottingmechanism. In 1947 both Quick and Brinkhousshowed that it was concerned with the platelets,and after contact with a foreign surface, in theactivation of prothrombin. Quick suggested thatantihaemophilic factor was the precursor ofthromboplastin being activated by platelets; herenamed it 'thromboplastinogen' and haemo-philia 'hypothromboplastinogenaemia.' Brink-hous suggested that the platelets released thrombo-plastin after being lysed by the action of theantihaemophilic factor which he therefore named' thrombocytolysin.' There was little experimentalevidence available to favour either of thesehypotheses.

Further information on the first stages ofcoagulation has been provided by the experiments

of Dr. Rosemary Biggs and her colleagues (1953).It is now apparent that normal clotting is initiatedby the generation within the blood of an extremelypowerful, but labile, thromboplastin. Thisthromboplastin, when formed, is capable ofclotting plasma in eight seconds or less, but theprocess of its formation, which is initiated bycontact with a foreign surface, takes severalminutes. It is this interval which constitutes themain part of the normal ' clotting time ' of theblood. Several factors, including the plateletsand antihaemophilic globulin, are concerned inthe generation of thromboplastin, and the con-centration of the latter directly affects the time atwhich thromboplastin first appears in the blood,and also the speed of its generation, once thisbegins. Thus when there is a deficiency of anti-haemophilic factor the clotting time may beprolonged and, even when coagulation begins,fibrin formation is slow and incomplete. Itappears that the intrinsic thromboplastin of theblood is of prime importance in physiologicalcoagulation and it is likely that ' tissue thrombo-plastin,' once thought to be essential, is relativelyunimportant. Haemophilic blood is coagulatedin normal time by the addition of either normalor haemophilic tissue extracts (Brown, 1952), yethaemophilic patients notoriously suffer extensivebleeding into the tissues, indicating that tissuethromboplastins can have little effect in limitingthe spre'ad of extravascular blood by promotingcoagulation.

The Changing Definition of HaemophiliaClearer understanding of the cause of haemo-

philic haemorrhage led to changes in the criteriaby which the condition was usually defined. Ithad become accepted, for instance, that a longclotting time was an essential diagnostic finding.How then should one classify cases in which theclinical and genetic manifestations resembledthose of haemophilia but in which the coagulationtime was almost or completely within normallimits? Merskey (I95I) was able to show in suchcases that, though the clotting time of the bloodas ordinarily measured might be normal, theclotting efficiency as measured by the moresensitive prothrombin consumption test wasabnormal. He demonstrated a deficiency of anti-haemophilic factor in these patients, showing thattheir plasma was much less effective than normalin correcting the clotting defect of blood from a' classical' haemophilic. Merskey classified thesecases as ' mild haemophilia,' though in someinstances the term '-mild' was more related tothe prolongation of the clotting time than to theclinical disability, which might be very severe.It is clear, from this, that the simple clotting time

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of the blood is not a sensitive index of a deficiencyof antihaemophilic globulin, or of the liability tobleed. An interesting point is that ' mild haemo-philia' breeds true, short clotting times beingfound in all affected members of the differentfamilies examined.

Other developments were concerned with thegenetics of haemophilia. Bulloch and Fildes(i9ii) had maintained that the condition was nottransmitted in any way by the affected male, thatit did not occur in females, and that isolated cases,without family history, should not readily beaccepted as instances of haemophilia. None ofthese restrictions would be applied now. It isknown that the affected male passes the conditionto his daughters, all of whom are potential trans-mitters capable of producing both normal andaffected sons, and normal and carrier daughters.These observations are in concordance with thetheory that haemophilia is inherited as a sex-linkedrecessive character, carried by a gene located onthe X chromosome. Acceptance of this impliesthat a female heterozygous for haemophilia, adaughter of an affected male and a carrier female,should exhibit active haemophilia. Three suchcases have been recorded within the past few years,in two instances (Merskey, I95I; Pinniger andFranks, 195I) affected females having been pro-duced by cousin inter-marriage in haemophilicfamilies, and in the third (Israels, Lempzrt andGilbertson, 195I) because the daughter of ahaemcphilic was so proficient in nursing herfather that she was regarded as an eminentlysuitable wife for a haemophilic.

Further confirmation of the occurrence ofaffected females has been provided by the breedingexperiments of Brinkhous and Graham (1950),using haemophilic dogs. Concerning sporadiccases, it is now realized that haemophilia has ahigh mutation rate, and that from ZO to 30 percent. of otherwise ' classical' cases may have nohistory of haemophilia in previous generations.Mutation may arise in the female, causing anapparently normal woman to produce one or moreatfected children, or it may occur in the male, inwhich case a haemophilic boy is the only affectedmember of the family. There is unfortunately noreliable method for detecting the carrier state infemales (Merskey and Macfarlane, I95I). Theiridentitication would be of immense importance inreducing the incidence of haemophilia, but,despite many attempts, it has not yet provedpractical.

Acquired ' Haemophilia' and ChristmasDiseaseWith new methods available for studying defec-

tive coagulation, attention was naturally directed

towards the conditions which lie on the boundariesof ' classical' haemophilia. A number of caseswere discovered in which a deficiency of anti-haemophilic globulin was apparently the cause ofsevere haemorrhagic symptoms, but which wasacquired and not inherited. Joules and Mac-farlane (I938) demonstrated such an acquireddeficiency arising without obvious reason, in amiddle-aged woman, and called the condition' pseudo-haemophilia.' A number of observershave reported similar cases, but mainly in associa-tion with pr-gnancy, and in some of these ananticoagulant has been found to be present inthe blood, which has the effect of inhibiting ordestroying the antihaemophilic factor, and whichmay be an antibody produced by some antigenicupset associated with pregnancy. Similar anti-bodies have been observed in the blood of haemo-philics after transfusion or injection of antihaemo-philic globulin (Biggs and Macfarlane, I953).

It has thus been shown that conditions otherthan haemophilia may have a deficiency of anti-haemophilic globulin; it has also been shown,more disturbingly, that in many cases which hadbeen confidently diagnosed as haemophilia therewas no such deficiency. The usual methods forthe assay of antihaemophilic globulin are basedupon the ability of the sample to correct theclotting defect of blood or plasma derived froma ' classical ' haemophilic, the degree of correctionbeing determined by the simple clotting time, orby the more sensitive prothrombin consumptiontest. It would not be expected that blood fromone case of haemophilia would show any markedcorrective effect when mixed with the blood ofanother. Yet Pavlovsky (I947), Koller et al.(I950), Aggeler et al. (I952), Schulman andSmith (I952) and Poole (I953) all reported thatblood obtained from certain cases closely resemb-ling haemophilia had the ability to correct theclotting defect of blood from other haemophiliccases. This suggests that at least two basicallydifferent clotting defects exist within the con-dition commonly known as haemophilia. Furtherinformation was provided by the observations ofBiggs et al. (I952). These authors studied a groupof seven cases clinically resembling haemophilia,the blood from which corrected the deficiency inblood from a number of cases of 'classical'haemophilia. Since mixing blood samples derivedfrom these seven patients produced no mutualcorrection, it was considered tnat all were examplesof the same clotting defect. Investigation bymeans of the newly devised thromboplastingeneration test (Biggs and Douglas, 1953) revealedthe fact that these patients were d.ncient in aclotting factor not previously recognized, andwhich was essential for blood thromboplastin

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formation. This factor was shown to be normallypresent in serum and readily adsorbed by Al(OH)3,thus being sharply differentiated from the anti-haemophilic factor, which is not normally presentin serum and is not adsorbed by Al(OH)3. Underthe influence of the current practice of namingnew red-cell antigens after patients, and of theclose approach of December 25, the new factorwas called ' Christmas factor' and the condition' Christmas disease,' from the surname of the firstpatient investigated. It was shown that there wasno deficiency of antihaemophilic globulin inChristmas disease, nor of Christmas factor in' classical ' haemophilia, the two conditions appear-ing to be basically distinct.

Other conditions similar to, and possibly iden-tical with, Christmas disease have been described.In the case studied by Aggeler et al. (1952) it wasshown that there was a deficiency of a factornormally present in serum, and which was called'P.T.C.' (plasma thromboplastin component).Two families containing in all I3 males affectedby 'P.T.C.' deficiency have been investigated byLewis and Ferguson (I953). It appears from thedata published that P.T.C. and Christmas factormay be one and the same. Cramer et at. (1953)describe also two families of a haemorrhagic con-dition they have called ' Haemophilia B,' andhave shown that the basic defect is probably adeficiency of Christmas factor. It is evidentfrom personal communications that a number ofother families previously reported as examples ofhaemophilia have now been found to be sufferingfrom Christmas disease. It is too early to assesswith any confidence the relative incidence ofhaemophilia and Christmas disease, but fromfigures so far available a rough estimate wouldsuggest that the ratio is about io to i.

Further complications may arise. Rosenthalet al. (1953) report three cases of haemorrhagicdiathesis occurring in one family in which theclotting defect appears to be due to the deficiencyof a new factor which is neither antihaemophilicglobulin nor Christmas factor. They have tenta-tively called this hypothetical agent ' P.T.A.'(plasma thromboplastin antecedent). Koller (I953)also has evidence that points to the existence ofyet another factor which he has called' Factor io,'antihaemophilic factor being called by him' Factor 8 ' and Christmas factor' Factor 9.' Buttime must elapse before the inter-relationship andeven the existence of these factors is established.

Deficiency of Factors 5 and 7In addition to haemophilia, Christmas disease

and the more hypothetical P.T.A. and Factor iodeficiencies, there are haemophilia-like states pro-duced by a lack of other factors which are con-

cerned in thromboplastin generation. Both Factor5 (pro-accelerin) and Factor 7 (pro-convertin) arerequired for the generation in the blood of thedirect activator of prothrombin. The naturallyoccurring deficiency of either factor is rare. Thefirst case of Factor 5 deficiency was described byOwren (I947) under the name ' parahaemophilia.'In Owren's patient a haemorrhagic condition hadexisted from early childhood, though there was nofamily history. Owren (I953) has also observeda further case, this patient's mother and sisterbeing affected. Other cases are described byFrank et al. (1950), Koller et al. (I950), Stohlmanet al. (I95I), Cosgriff and Leifer (1952). Factor 7deficiency as a congenital or hereditary conditionhas been described by Owren and Aas (I95I)under the name' hypoproconvertinaemia ' and byAlexander et al. (I95I). Owren (I953) describesa large family with at least I2 members affectedby Factor 7 deficiency, inherited apparently as asimple dominant.

Long-standing and severe deficiency of eitherFactors 5 or 7, whether inherited or acquired,results in symptoms closely resembling those ofhaemophilia. Temporary Factor 7 deficiency isnow deliberately produced by the administrationof drugs of the dicoumarol group, the resultingclotting defect and lengthening of the ' pro-thrombin time' being the aim of therapy designedto lessen the risk of thrombosis and embolism.In such cases, however, the deficiency should notbecome severe enough to promote bleeding.

The Diagnosis of Haemophiliaand its Related ConditionsFrom a clini-cal point of view, the separation of

haemophilia from its related conditions is impor-tant, because the basic defects are different, andany specific treatment must aim at replacing thefactor which is actually deficient. Yet this separa-tion cannot be made by clinical means, nor by theusual laboratory tests. The disorder common toall these states is a faulty production of bloodthromboplastin, and this defect, though it may beproduced in different ways, will produce the sameclinical effects. There will be the familiar pictureof prolonged bleeding from injuries, of massivetissue haemorrhages and, probably, haemarthroses.There is some indicatior% that patients with Christ-mas disease tend to be less severely affected thanthose with haemophilia, but this is too indefiniteto be of diagnostic value in individual cases.Christmas disease, like haemophilia, is inheritedas a sex-linked recessive character. That two suchclinically similar conditions should share this raretype of inheritance is unlikely to be mere coin-cidence, and it is probable that the two factorsinvolved, with perhaps others also concerned in

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I Pro-ThromboplastinCondition Defect Inheritance thrombin GnronbTest

Time Plasma Serum

Haemophilia A.H.G. deficiency Sex-linked recessive Normal Abnormal NormalChristmas disease Christmas factor de-

P ficiency Sex-linked recessive Normal Normal Abnormnal' Parahaemophilia Factor ; deficiency Non sex-linked Abnornal Abnormal Nornal' Hypoproconvertinaemia' Factor 7 deficiency Non sex-linked Abnormal Normal Abnormal

Ti4s DIFFERFNTI1ATION OF HAEMOPHILIA AND ITS RFLATED CONDITIONS.

thromboplastin formation, have a genetic as wellas a functional association for reasons not yetapparent. The practical point is that no dif-ferentiation between these conditions can be madefrom a study of the family histories. On theother hand, deficiency of Factors 5 or 7, whenhereditary, does not show a sex-linked inheritance.The differential diagnosis between haemophilia

and its related conditions therefore rests uponspecial pathological findings. In both haemophiliaand Christmas disease the platelet count, bleedingtime, tourniquet test and prothrombin time areusually normal, but the clotting time and pro-thrombin consumption tests are abnormal. Thetwo conditions can be readily separated by thethromboplastin generation test. In this test ismeasured the rate of thromboplastin productionin plasma treated with Al(OH)3 when mixed withserum and platelets; each component can bederived from normal (control) blood or from theblood of the patient under investigation. Inhaemophilia it is found that the plasma is abnormalin promoting thromboplastin generation, whereasin Christmas disease it is the serum which isabnormal.The laboratory differentiation of Factors 5 or

7 deficiency from haemophilia and Christmasdisease is provided by the fact that in the lattertwo conditions the ' prothrombin time ' is normal,whereas in both Factors 5 and 7 deficiencies it isprolcnged. This is because both Factors 5 and 7are required for the conversion to active thrombo-plastin of the brain extract used in the prothrombintime test, which is not a complete thromboplastin.Factor 5 deficiency may be distinguished fromFactor 7 deficiency by means of the thromboplastingeneration test, since Factor 7 is normally presentin serum and Factor 5 in plasma (see table).

TreatmentAs regards the treatment of these conditions,

there has been no major advance for the past ISyears. No consistently effective general treatmenthas yet been produced. It has long been recog-nized, however, that the transfusion of freshnormal blood often has beneficial effects in haemo-

philia, reducing the clotting time and helping tocontrol otherwise intractable haemorrhage. Theseeffects are probably due to the antihaemophilicfactor present in normal blood. But two pointsmust be recognized if transfusions are to be useful.Antihaemophilic factor may be rapidly consumed,even in citrated blood, by pre-coagulation reactionsfollowing contact with glass. To be effective,therefore, the blood must be used as soon aspossible, certainly not more than a few hours aftercollection. The second point is that probablymuch larger transfusions are required than wasoriginally supposed. It has been found that anamount of blood which will reduce to normal theclotting time of a haemophilic patient's blood willhave relatively little effect on the more sensitiveprothrombin consumption, thrombin generationor thromboplastin generation tests. In ' mild'haemophilia, patients may bleed severely, whilethe clotting time is almost normal, but thesesensitive tests always show a gross abnormality.It is probable, therefore, that the clotting time isa less reliable index of haemostatic efficiency thanthe latter tests, and therapy should aim at reducingall tests to normal, in cases of dangerous bleedingor before embarking on minor surgery. This mayrequire the transfusion of relatively large amountsof normal blood, perhaps 50 per cent. of theblood volume, and even then the effect may onlylast a few hours. It is obvious, therefore, thatmajor surgery should never be undertaken inhaemophilia unless it provides the only chance ofsurvival. Fresh blood transfusion will also tendto correct the defect in Christmas disease, and inFactors 5 and 7 deficiencies; information as tothe amount required is incomplete. Factor 7and Christmas factor, being much more stablethan antihaemophilic factor and Factor 5, areprobably active in stored blood for several days.Many attempts have been made to treat haemo-

philia by injections of antihaemophilic factorwhich has been concentrated and purified invarious ways. Specific .therapy of this sort hasmany advantages and has been successful in somecases, but many disappointments have alsooccurred. Patients have failed to respond, and

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in some cases have apparently developed anti-bodies to the factor and suffered reactions. Inany case, it is clear that, for such specific therapyto succeed, the diagnosis of haemophilia must becertain. A proportion of failures to respond toadministration of antihaemophilic globulin maybe due to the fact that the patients concernedlacked not antihaemophilic factor, but Christmasfactor, or some other component of the thrombo-plastin-forming system. A re-examination of thisaspect of the problem may have enlighteningresults.

Local treatment, though often useful, cannotbe relied upon to promote and maintain haemo-stasis. In the case of external haemorrhage, it ismost important to avoid making matters worseby drastic attempts to control the bleeding.Ligatures, sutures, and tight dressings are notonly useless in these haemorrhagic conditions,they may be positively dangerous. They maylead to wide extravasation of the blood into thetissues which, in the region of the throat ormediastinum, may be disastrous. Local measuresshould therefore be restricted to haemostaticapplications. Thrombin, which effectively co-agulates the blood in all the haemophilia-likestates, when combined with an absorbable dressingsuch as fibrin foam or oxidized cellulose andapplied with light pressure, provides the bestmethod for securing local haemostasis.

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