Management of the - BMJ

Personal Practice

Archives of Disease in Childhood, 1972, 47, 451.

Management of the Haemophilic ChildC. R. RIZZA and J. M. MATTHEWS

From the Oxford Haemophilia Centre, Churchill Hospital, Oxford

Haemophilia is a hereditary and lifelong bleedingdisorder which affects males and is transmitted byapparently normal females. Bleeding commonlyoccurs after trauma, and in the severely affectedpatient may occur apparently spontaneously. Thehaemostatic defect is due to total or partial defi-ciency of factor VIII (anti-haemophilic factor,anti-haemophilic globulin, AHG, AHF) and theseverity of the bleeding is fairly well correlated withthe level of the factor in the blood (Table I).Complete deficiency of factor VIII is found insevere classical haemophilia and is associated withspontaneous haemorrhages into muscles and jointswith crippling. The patient with only partialdeficiency of factor VIII is usually spared haemarth-roses and may bleed only after injury or surgicaloperations.

TABLE IRelation of Observed Blood Levels of Factor VIIIto the Severity of Clinical Manifestations of

Defective Haemostasis

Blood Level ofFactor VIII Level of Haemostatic Efficiency(% of normal)

50-100 Normal25-50 Tendency to excessive bleeding after

major trauma; often not diagnosed5-25 Severe bleeding after minor trauma or

surgical operations1-5 Gross bleeding after minor injuries; some

haemarthroses and 'spontaneous'bleeding

0 Severe haemophilia; haemarthroses andcrippling; deep tissue haemorrhages

IncidenceHaemophilia is by far the commonest of the

hereditary haemorrhagic disorders (Table II),though the total number of haemophiliacs in the

*In the Personal Practice series of articles authors are invited togive their own views on some current practical problem.

community is small. There are thought to beapproximately 3000 to 4000 severely affectedhaemophiliacs in the United Kingdom, and theremay be as many again who are mildly affected withthe condition. The age distribution of the 224haemophiliacs treated at the Oxford HaemophiliaCentre during the year 1969-1970 is shown inTable III. Approximately 25% of the patientsare less than 10 years of age and 40% are less than15 years of age.

TABLE IIPatients with Bleeding Disorders Registered at

Oxford Haemophilia Centre (June 1969)

Diagnosis No. of Patients %

Haemophilia 623 61Christmas disease 120 12von Willebrand's disease 183 18Others:

Afibrinogenaemia 1Circulating anticoagulant 27Factor XIII deficiency 1Factor V deficiency 3Factor VII deficiency 2Factor X deficiency 4Factor XII deficiency 2 9Factor IX deficiency 14Qualitative platelet defects 37Combined clotting factor deficiencies 5

Total 1022 100

InheritanceHaemophilia is transmitted in a sex-linked

recessive manner. This mode of transmission isillustrated in the Fig. It can be seen from thisdiagram that in the case of a haemophiliac, all hissons are normal but all his daughters are carriers ofthe condition. In the case ofthese carrier daughterstheir sons have an equal chance of being normal orhaemophiliac and their daughters have an equalchance of being normal or carrier.

Approximately one-third of haemophiliacs haveno family history of the condition and presumablyin these people the condition has arisen as a result

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Rizza and MatthewsTABLE III

Age Distribution of 224 Haemophiliacs Treated atOxford During 1969-1970

Age Group (yr) No. of Patients

0-5 196-10 3611-15 3516-20 2721-30 4931-40 2541-50 1451-60 1261-70 371+ 4

Total 224

of a gene mutation in the patient or his mother.The alternative explanation is that the defectivegene has been present in previous generations,passing down through the female members withoutmanifesting itself in the male. This situationcould come about if previous generations werecomposed mainly of females.

In general, haemophilia runs true to type in agiven family with regard to plasma factor VIIIlevel and clinical severity.

Factor VIIIIt is generally accepted that the haemostatic

and coagulation defects in haemophilia are due toabsence of an essential clotting factor from theblood. This factor is variously known as anti-haemophilic factor (AHF), anti-haemophilic globu-lin (AHG), or factor VIII. Factor VIII is thoughtto be a glycoprotein with a molecular weight of atleast 2,000,000. Its site of synthesis in the body isnot known but it is made probably throughout thereticuloendothelial system. The factor is labile onstorage and deteriorates at a variable rate in bloodstored at +4 'C. The half-life of factor VIIItransfused into a haemophiliac is of the order of12 hours. This fact must be remembered whenplanning transfusion therapy for a patient under-going surgery.

Clinical Manifestations of HaemophiliaA child affected by haemophilia is born with the

condition and the diagnosis of the clotting factordefect may be made by examination of blood takenby careful venepuncture from the umbilical cord.The liability to bleed excessively is therefore presentfrom birth, but, in spite of this, bruising at birth isunusual as is excessive bleeding from the umbilical

1 2

I I1 2 3 n

IIIQ1 2 3 4 5 6

1 2 3 4 S 6

II

111

III

IV

Transmission through an affected male (1, 1) and carrier females (11, 1 and 1lt, 4),

Haemophilic Male

Normal Male

Carrier Female

Normal Female

FIG.-The pattern of hereditary transmission of haemophilia and Christmas disease.

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Management of the Haemophilic Childstump. Commonly, there are no signs of haemo-philia until several months after birth unless ofcourse the child undergoes circumcision or someother surgical procedure. This is possibly due tothe fact that the child is not exposed to trauma in theearly months of life. In the majority of cases ofsevere haemophilia the first signs of the conditionare excessive bruising of the skin or persistentbleeding from the mouth after trivial injury. Oneor other of these signs has usually appeared by theage of 18 months and sometimes as early as 3 to 4months. Excessive bruising may take the form ofa lump or patch, and on occasion may track widelythrough the subcutaneous tissues and result inconsiderable loss of blood from the circulation.Such bruises usually involve the buttocks or thehead in the region of the forehead or occiput.Lips, gums, or tongue may be injured by teeth orforeign objects and may bleed persistently andseriously. The occurrence and site of haemor-rhages are usually related to the child's mobilityand activity and exposure to dangerous situations.Increased activity may produce a fall from bed orsettee, and attempts at standing and walking mayresult in bruises on buttocks and forehead shouldhe fall. Very occasionally a fall on to the head mayproduce intracranial haemorrhage.From the time of learning to walk, the joints and

muscles are liable to strains and haemorrhage.In the young child the ankles are most commonlyaffected but later the knees take precedence (TableIV). In schoolchildren the elbows may suffer ascommonly as the knee, perhaps as a result of leaningon them while writing.

TABLE IVIncidence of Joints Affected at 440 ConsecutiveAttendances for Treatment of Haemarthroses in 88

Haemophiliacs

Knee Elbow Ankle Shoulder Other Joints

38% 26% 19% 9% 8%

Muscles are the next most common site ofhaemorrhage after joints, and bleeding into themmay be spontaneous or may arise after some loco-motory strain or as a result of direct injury. Musclehaemorrhages involving in particular the forearmand the calfmay result in scarring and contracture ofthese muscles with consequent limb deformity.Furthermore, muscle haematomas, if large enough,may produce dangerous pressure effects on nearbyvessels and nerves. Bleeding involving the iliacusmuscle is a common and particularly important

form of muscle haemorrhage and may presentwith many of the features of acute appendicitis.Careful clinical examination in these patients mayreveal a mass in the region of the iliacus musclepalpable just inside the pelvic brim and evidence offemoral nerve compression on that side. Inaddition there may be a progressive fall in thepatient's haemoglobin if he continues to bleed intothe muscle. These features, along with the rapidimprovement of symptoms after AHG therapy, areimportant in differentiating between haematomaand appendicitis.

Bleeding of any severity from the gut, nose, orurinary tract is uncommon in childhood, though inadolescence and adulthood haematuria is the thirdmost common form of bleeding.The sites of haemorrhage which have been

mentioned are those which are commonly encoun-tered, but it should be borne in mind that in thesevere haemophiliac, bleeding is possible intopractically any site and any unexplained pain,swelling, loss of function, or indeed any obscureillness, should be considered as being possibly dueto haemorrhage unless there is clear evidence tothe contrary.

Excessive postoperative haemorrhage may followany operation, and even the simplest procedure,such as removal of a loose deciduous tooth, withoutadequate replacement therapy may be followed bydangerous haemorrhage. Tonsillectomy is acommon operation in childhood and because ofthis is sometimes regarded lightly. It should beremembered that tonsillectomy is a particularlysevere test of haemostatic function not only insevere haemophilia but in the mildest form of thecondition.The life of the young severely affected haemo-

philiac is punctuated by a succession of bleedingepisodes. These may be frequent, or few and farbetween; they may be severe, or not so severe.They may lead to marked crippling in some casesand surprisingly little crippling in others. Fre-quently they disrupt home and school life to aconsiderable extent so that there may be increasingdisability not only physically but also socially andeducationally.Many factors influence the occurrence and out-

come of bleeding episodes.

Haemostatic mechanism. The process ofhaemostasis is still not fully understood and themechanism may be more effective in one severehaemophiliac than in another or in the samehaemophiliac at different times, depending on thestate of the vessels, the platelets, or some other as

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Rizza and Matthewsyet undefined plasma factors. There may be insome severe haemophiliacs traces of factor VIIIdifficult to detect, which are sufficient to decreasethe incidence and severity of bleeding as comparedwith other severe haemophiliacs.

Physique. The boy who is naturally thin andwhose joints are perhaps ill protected by musclesmay be more liable to strain and bleeding than hissturdier haemophilic brother. And yet if the boyis overweight his knees will be more prone to stressand therefore more likely to bleed.

Accident proneness. Through temperamentor by lack of education the boy may expose himselfto potentially dangerous situations and as a resultaccidents may occur which result in bleeding.Accident proneness may be acquired in that anexisting disability will increase the chances ofaccident, as when a sore, stiff, or weak knee causesa fall. Conversely, the boy who maintains goodjoint and muscle function may be more agile,better co-ordinated in his movements, and morelikely to avoid and extricate himself from potentiallydangerous situations.

Life and environment. Changes in environ-ment may explain an alteration in the pattern ofbleeding disorders. The family may move to ahouse with stairs, the affected child may start totravel by school bus, or he may be given a bicycle, orbe studying for examinations, and in each case it ispossible that a change in the pattern of bleeds mayoccur.

General Management of HaemophiliaHaemophilia is due to the absence of factor VIII

from the blood and management consists primarilyofreplacing this missing factor by giving transfusionsof normal plasma or plasma derivatives rich infactor VIII. Though replacement therapy is avery important aspect of treatment, managementof haemophilia in the broadest sense requires muchmore than factor VIII replacement and involvesconsideration of the problems of education, recrea-tion, employment, and other socioeconomic aspectsof life. Presumably the problems of loss of timefrom school and work and the limitation enforcedby haemophilia on the patient's interests and activi-ties will become less as more potent preparationsofAHG become more widely available.The aim of management of the haemophilic

child is to treat and control haemorrhage into anysite, particularly into joints and muscles, as early aspossible after the onset of bleeding. In this way

crippling may be prevented or minimized, and thechild allowed to attend school to acquire thestandard of education of which he is mentallycapable. For this policy of early treatment to besuccessful it is essential for the patient to be ableto get to hospital as soon as possible and to be givenhis dose of AHG as soon as possible thereafter.At the Oxford Haemophilia Centre the practice isfor the patient to telephone the Centre to reportthat he is bleeding, then to telephone the ambulanceservice direct if he does not have his own car, andarrange for his own admission. In our experiencemost general practitioners with haemophiliacs undertheir care agree to this arrangement and the ambu-lance service for their part are usually prepared toaccept calls from patients providing they havereceived a letter from the general practitioner or thehospital concerned explaining that the patient is ahaemophiliac. The patient should be seen andtreated as soon as possible after reaching hospital.He should not be expected to take his place in aqueue in casualty department and end up by beingseen by an inexperienced casualty officer. Ideallyhe should go to the ward or treatment area wherehe is to be given his dose and should be seen andtreated by a doctor experienced in the managementof haemophilia. In the case of children it isparticularly important for the child to see the samefaces at each visit. In this way the child soon loseshis fear of attending hospital and may even requestto be taken there as he comes to associate it withrelief of pain in friendly surroundings.

Education. Because of his proneness to bleed-ing after minor injury the severely affected haemo-philiac should not be employed in jobs which putsevere strains on his muscles and joints. He shouldtry as far as possible to find employment whichrequires him to use his brains rather than hismuscles. A good education is essential if he is tofind himself such a job. Unfortunately because ofthe recurrent episodes of haemorrhage the haemo-philic child may lose much time from school. Hisproblems are further added to by the fact that manyhead teachers are not willing to accept a haemophilicchild into their schools because of the responsibilityof supervising him and the fear that the child mightsuffer a severe haemorrhage while at school. Thislatter difficulty can usually be overcome by explain-ing to the head teacher that the boy is no morelikely to bleed to death in the classroom than anyother boy and that the commonest manifestationof the condition is bleeding into a joint or lesscommonly a muscle, and that the teacher's chiefresponsibility on such occasions is to arrange to

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Management of the Haemophilic Child

have the child admitted to hospital as soon as sucha haemorrhage takes place. Having decided to takea haemophilic boy into the school most teachers are

surprised at how little concern they cause.

The alternatives for the haemophilic boy are thathe may attend an ordinary state school or itsprivate school counterpart, or attend a school forphysically handicapped boys, or have tuition athome. Attendance at an 'ordinary' school has thegreat advantage that the child mixes with normalboys and girls of his own age and starts to learn froman early age how to live and play with normalchildren. In addition, he starts to learn fromexperience the type and amount of physical activityhe can undertake while living in a normal environ-ment and the extent to which he must limit oravoid harmful activities.For the boy who is severely crippled early in life

and requires to use crutches or a wheel chair to getabout there are advantages in his attending a

school for handicapped boys provided there is easyaccess to a Haemophilia Centre for factor VIIIreplacement therapy. The Lord Mayor TreloarSchool near Alton in Hampshire is one suchschool. It deals with 150 physically handicappedboys from the age of 11 years and upwards of whom50 have haemophilia or Christmas disease.

Games and other recreational activities.The type and amount of physical exercise a haemo-philic boy can take vary greatly from boy to boyand are best learned by the boy from personalexperience. Attempts to limit a boy's physicalactivity by laying down strict rules almost invariablylead to frustration on the part of the child and theparents. The child with spirit will go and playrough games no matter what rules have been laiddown. Unfortunately, if he does sustain a haemor-rhage as a consequence of playing forbidden gameshe may tend not to mention this until it is quiteadvanced and he is in severe pain, for fear of beingreprimanded. It is probably wiser and less stress-ful for all concerned to allow the child more freedomin his activities than has been the custom in the past.If the child then reports any injury or haemorrhageas soon as it occurs so that he can have early treat-ment the consequences are not likely to be tooserious. Though games such as football, rugby,and boxing should be avoided, there is no reason

why the haemophilic child should not swim or

cycle if these activities are within his capabilities.Well-developed muscles about the various jointsare an important factor in joint stability. This isparticularly so in the case of the knee joint wherewasting of the quadriceps muscle leads to weakness

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of the knee with consequently increased dispositionto bleed into the joint. The importance of exer-cises to regain quadriceps function after a periodof immobilization is discussed later.

Management of Bleeding in HaemophiliaIn this section we shall discuss the principles of

replacement therapy, the therapeutic materialsavailable for the control of bleeding in haemophilia,and the management of the commoner types ofbleeding.

Principles of Replacement TherapyThe aim of replacement therapy in haemophilia

is to raise the patient's blood factor VIII con-centration by transfusion to a level which willpromote haemostasis in the lesion being treatedand to maintain this level until healing is welladvanced. Lesions of different severity usuallyrequire different levels of factor VIII in the blood.For example, the level of factor VIII required toattain and maintain haemostasis after major abdomi-nal surgery is higher than the level required forspontaneous haemorrhage into a joint. Table Vshows the different levels of factor VIII regardedas necessary for the control of bleeding from dif-ferent lesions. These recommended levels areintended only as rough guides and may be higherif the injured part is infected or being constantlymoved, or conversely may be lower if the part canbe easily immobilized.

TABLE VBlood Levels of Factor VIII Required to Control

Bleeding in Different Lesions

Level of Factor VIIIRequired in BloodLesion Immediately After

Transfusion(% normal)

Spontaneous bleeding 5-20 (0-5)*Dangerous haematomas, post-

traumatic haemarthrosis, multiple 20-40 (5-10)dental extractions

Major surgery, serious accidents 80-100 (25-40)

*The figures in parentheses are the approximate levels to whichthe patient's factor VIII level will have fallen 24 hours after the dose.

Therapeutic materials available for treat-ment of haemophilic bleeding.

Whole blood. Because of the lability of factorVIII on storage at +4 °C, whole blood may bepoor in factor VIII activity and should not be usedfor factor VIII replacement therapy. In additionto being low in factor VIII activity, whole bloodcan rarely be transfused fast enough to attain areasonable haemostatic level in the patient's

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Rizza and Matthewscirculation. In the treatment of haemophilia wholeblood should be given only to replace blood lostand not as a source of factor VIII.

Fresh frozen plasma. Plasma which is to beused for the treatment of haemophilia should beseparated from the blood cells as soon as possibleafter collection and preferably within 3 to 4 hours ofdonation. After separation from the cells theplasma is rapidly frozen and stored at -20 °Cto -30 'C. At this temperature there is very littleloss of factor VIII activity in the plasma over 2 to 3months. Plasma is effective in the control ofspontaneous haemorrhages into muscles and joints,especially if given soon after the onset of bleeding.A dose of 10-15 ml/kg body weight (i.e. 7-10 unitsof factor VIII*) infused over a period of 45 to 60minutes will raise the level of factor VIII in thepatient's plasma to 15-20% of normal. Whentreating babies or small children it is wiser to usecryoprecipitate or a freeze-dried AHG preparationrather than plasma which could more easily overloadthe circulation.

Cryoprecipitate. When frozen plasma is allowedto thaw slowly at +4 'C a proportion of the plasmaproteins remain insoluble in the cold. Thiscryoprecipitated fraction of plasma, which can berecovered simply by centrifuging the plasma afterthawing, has been shown to be rich in factor VIIIactivity (Pool, Hershgold, and Pappenhagen, 1964)and has been found to be effective in controllinghaemophilic bleeding (Pool and Shannon, 1965).

Cryoprecipitate is relatively easy to prepare andcan be produced by most Blood TransfusionCentres. It is dispensed either in plastic bagswhich contain on average 75 units of factor VIII orin blood transfusion bottles which contain approxi-mately 150 units of factor VIII. The material isstored deep-frozen and is reconstituted fortransfusion by thawing at 37 'C and adding ifnecessary a volume (10-20 ml) of citrate saline,to ensure that the cryoprecipitate remains insolution and is easily injected through anaverage-sized needle. In our experience a doseof 10 units of factor VIII per kg body weight raisesthe level of circulating factor VIII by approxi-mately 15% of normal. It follows that a boyweighing 30 kg will require 300 units of factorVIII, i.e. approximately 4 bags of cryoprecipitateto raise his factor VIII level to 15% of normal.As already mentioned, this level of factor VIII isusually sufficient to control an early spontaneoushaemarthrosis or intramuscular haemorrhage.

* Fresh frozen plasma contains on average 0 7 units of factorViII/ml.

Freeze-dried AHG concentrates. Until the intro-duction of cryoprecipitate the only concentratedhuman factor VIII preparations were the variousfreeze-dried protein fractions prepared from humanplasma by means of alcohol or ether fractionation.Though there has been a great increase in theproduction of lyophilized human AHG concen-trates, especially in the United States, this materialis still in very short supply and where availablecommercially is very expensive.

It has been our practice to reserve this materialas far as possible for use in children or for adultswho are allergic to plasma or cryoprecipitate.Animal AHG. Because of the shortage of

potent preparations of human AHG during theearly 1950's, Macfarlane and his colleagues soughtto prepareAHGfrom animal plasma. In 1955 (a, b)Bidwell described the preparation of potent AHGconcentrates from both porcine and bovine blood,and in 1957 Macfarlane and his colleagues reportedthe successful use of these preparations in con-trolling haemorrhage in haemophiliacs undergoingmajor surgery.Most patients become resistant to treatment with

a particular animal AHG preparation within 7 to10 days of starting treatment so that their factorVIII response after transfusion ofthe dose graduallydiminishes. This 'resistance' does not seem to bedue to the appearance offactor VIII antibodies sincesuch antibodies have not been found at this stage oftreatment. Moreover the patients still respond tothe alternative animal AHG preparation and tohuman AHG. Both preparations of animal AHGare potentially antigenic and in addition can causethrombocytopenia. Because of these drawbacks itis advisable to reserve bovine and porcine AHG foruse in life-saving surgery when there is no cryo-precipitate available or for the treatment of patientswith factor VIII antibodies who are bleedingdisastrously. Animal AHG preparations are par-ticularly useful in this latter situation since theyare commercially available and also because of thefact that porcine and bovine factor VIII are ingeneral less susceptible than human factor VIII tothe action of factor VIII antibodies.When considering replacement therapy to control

haemorrhage in a given patient the doctor mustassess the severity of the patient's lesion, decide onthe level of factor VIII required in the patient'sblood to obtain haemostasis, decide on the thera-peutic material to use, and then calculate the doseof material required to achieve the desired factorVIII level. In the case of a patient undergoingsurgery the doctor must also decide on the durationof replacement therapy.

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Management of the Haemophilic Child(1) Severity of lesion. In general, spontaneous

haemorrhages require a lower circulating level offactor VIII for their control than haemorrhagesafter obvious trauma. Most spontaneous haemor-rhages into joints and muscles, especially if seenwithin 2 to 3 hours of onset, respond satisfactorilyto plasma in a dose of 10-15 ml/kg body weight.This dose will raise the patient's level of circulatingfactor VIII to 15 to 20% of normal. If it isdesired to use cryoprecipitate, the same level offactor VIII can be achieved in the patient by givinga dose of cryoprecipitate containing 10 units offactor VIII per kg of the patient's body weight, orif one wishes to express the dose in 'bags of cryo-precipitate' the dose is approximately 1 bag/10 kgbody weight.The approximate levels of factor VIII required

in the blood to control bleeding in different lesionsare shown in Table V. These figures serve only asrough guides to treatment levels required. Ifhaemorrhage is not controlled, in spite of thecirculating factor VIII level being at the recom-mended level, then a larger dose must be given toraise the level still higher or some surgical cause forthe haemorrhage must be considered.

(2) Choice of therapeutic material. Formost practical purposes the choice of therapeuticmaterial rests between fresh frozen plasma andcryoprecipitate. Only rarely is lyophilized humanAHG available. At Oxford we still commonlyuse fresh frozen plasma for the treatment of spon-taneous or early haemarthroses or intramuscularhaemorrhages in patients of 10 years of age ormore. Plasma in a dose of 10-15 ml/kg of bodyweight is effective in the management of theseminor or early haemorrhages. The disadvantagesof plasma therapy are that it takes 30 to 45 minutesto thaw 450 ml of plasma at 37 °C, and a largevolume of fluid is administered, which may take45-90 minutes. The time factor may be of greatimportance to the patient sometimes and he maybe reluctant to have plasma if he has experiencedthe convenience of cryoprecipitate in the past.

(3) Calculation of dose. Having decided uponthe level of factor VIII necessary in the patient'sblood for haemostasis and having decided on thetherapeutic material to be used, it is possible bymeans of a simple formula to calculate the doseof factor VIII required. There are many formulaewhich may be used and the one which we havefound useful is:Patient's weight (kg) x Rise produced by dose in factor VIII

(Y% normal) KUnits of factor VIII in dose

The patient's weight is known, the level offactor VIII required in the patient's circulationhas been decided, and K is a constant which is 2if plasma is used, 1-5 if cryoprecipitate or lyo-philized human AHG are used, and 1 if animalAHG is used. The following example shows theuse of the formula. A haemophilic child with afactor VIII level of 5% and weighing 25 kg requiresa dose of cryoprecipitate to raise his factor VIIIlevel to 50% of normal. Using the above formula:

25 x 45 = 15x.. x = 750 units,

i.e. 750 units of factor VIII are required. If it isassumed that there are about 75 units of factorVIII in each bag of cryoprecipitate then 10 bags ofcryoprecipitate should be transfused.Formulae such as the one shown above are of

considerable value when calculating the first dose tobe given to a patient about to undergo surgery butsubsequent doses are best assessed on the basis ofthe patient's factor VIII response after his previousdose. The reason for this is that different patientsmay show different factor VIII responses after agiven dose of AHG even after allowance has beenmade for differences in body weight. By assayingthe patient's factor VIII level before and afterevery dose it is possible to 'tailor' replacementtherapy to his needs, giving neither too muchwhich is wasteful nor too little which is dangerous.

(4) Duration of antihaemophilic replace-ment therapy. The duration of factor VIIIreplacement therapy depends largely on the healingtime of the wound. Small to moderate-sizedhaemarthroses in relatively undamaged jointsrequire only 1 or 2 doses of plasma of the order of10-15 ml/kg to control bleeding and bring aboutresolution. In more severe haemarthroses or ifaspiration of the joint is undertaken, cryoprecipitateor freeze-dried human AHG concentrate should begiven for 2 to 4 days in the first place and 1 or 2further daily doses should be given when the patientstarts active joint movement. A similar regimenis usually suitable for the management of haema-tomas of the iliacus muscle, forearm, or calfmuscles.

For dental extraction it used to be the practiceat Oxford to give cryoprecipitate or freeze-driedhuman AHG daily for a period of 7 to 10 days.There is now strong evidence that this regimen isnot required providing epsilon-aminocaproic acid(EACA) is given in adequate doses. The manage-ment of patients undergoing dental extraction isdealt with more fully in a later section of this article.

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Rizza and MatthewsFor patients undergoing laparotomy, 8-hourly

dosage should be given for the first 3 to 4 days and12-hourly dosage for the next 8 to 10 days, sufficientto keep the patient's factor VIII level above 30 to40% of normal throughout the period of healing.

For operations involving much cutting of muscleor stripping of periosteum, or for the resection ofhaemophilic cysts, infusions may be required for3 to 4 weeks. Similar treatment may be requiredfor severe wounds and injuries complicated byinfection or haematoma formation. Reopening orexploration of a wound may require a return to day 1of a new course of treatment. On the other hand,if the site of operation or injury can be completelyimmobilized, a shorter period of infusion therapymay be safe.

Management of Some Specific ProblemsRecurrent haemarthroses with the danger of

crippling, and the need for dental extraction areperennial problems in haemophilia so that the careof joints and teeth is a very important aspect of themanagement of the haemophiliac. We shall there-fore discuss here in some detail the treatment ofacute haemarthroses and the care of the teeth inhaemophilia. Also, the question of immunizationand its hazards from the point of view of haemor-rhage often causes much concern to parents and todoctors looking after haemophiliacs. This prob-lem will also be discussed.

Acute haemarthroses. Because of the fre-quency of haemarthrosis, the severe pain whichmay be associated with the condition, the loss oftime from school, the danger of severe joint damageand permanent crippling, it is important to treatbleeding into a joint as soon as possible after itsonset, preferably within 1 to 2 hours of the childcomplaining of discomfort in the knee. Thetreatment of haemarthroses has 4 main objectives:(1) to stop bleeding into the joint; (2) to relievepain in the joint; (3) to maintain or restore jointfunction; and (4) to prevent chronic changes in thejoint.When the haemarthrosis is small, spontaneous,

and treated within 2 to 3 hours of onset, all of theseobjectives can be achieved by the transfusion offresh frozen plasma, cryoprecipitate, or freeze-dried AHG concentrate. The dosage of thesevarious therapeutic agents required to bring abouthaemostasis in such an early haemarthrosis hasalready been mentioned. Treatment of manyhaemarthroses may be carried out on an outpatientbasis. The child is given his transfusion, rests for1 to 2 hours, and may then return to school if the

pain in the joint has settled. The majority of earlyspontaneous haemarthroses respond well to thistreatment.

Ifthe haemarthrosis is more severe, either becauseof trauma or because there was some delay inseeking treatment, there may be marked sweLlingof the knee with severe pain, muscle spasm, andloss of joint function. Such cases require thecombined care of the haemophilia and orthopaedicservice and should be admitted to hospital.Replacement therapy with cryoprecipitate orfreeze-dried AHG is required and should be givendaily for 2 to 3 days or until pain and musclespasm diminish. In addition, immobilization ofthe joint is advisable and this alone often leads torapid diminution of pain. In a small proportionof cases with very tense, swollen, painful joints,aspiration under full AHG 'cover' may be required.Immobilization of the knee, elbow, ankle, and wristis obtained by means of padded plaster of Parissplints. The joint in the first instance is immobi-lized in the position of maximum comfort. Within24 to 48 hours the acute pain has usually settled,and it is then possible to dispense with this tem-porary splint and start to encourage periodicjoint movements or if necessary continue immobili-zation with another splint with the limb in a morefunctional position. In this latter situation staticmuscle exercises should be started as soon as thechild is free of pain. It is especially important inthe case of haemarthrosis of the knee to startstatic quadriceps exercises as soon as possiblesince the quadriceps muscle atrophies very quicklyafter a haemarthrosis, and prolonged immobiliza-tion leaves the knee unstable and prone to furtherbleeding. From static quadriceps exercises thechild should proceed to straight leg raising, then togentle flexion exercises, and then to partial and fullweight bearing. It is probably wise to give factorVIII replacement therapy during the first 2 or 3days of weight bearing, especially if the haemarthro-sis has been severe and there has been muchmuscle wasting.With patients now seeking treatment for haemar-

throses early and with effective therapy with cryo-precipitate and AHG concentrate becoming morewidely available, aspiration of blood from the jointis rarely required. The following factors should beconsidered before carrying out joint aspiration.(1) Size of haemarthrosis and degree of pain andtension in it. A large, tense, and very painfulhaemarthrosis should probably be aspirated if onlyto relieve the severe pain in the joint. (2) Timeinterval between onset of haemorrhage into joint andadmission to hospital. If there is a delay of more

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Management of the Haemophilic Childthan 24 hours, aspiration of the joint is oftendifficult and it is seldom possible to empty the jointcompletely. This is presumably due to the bloodin the joint having clotted. (3) Type of jointinvolved. The knee joint is the joint most com-

monly affected by haemorrhage and may containup to 200 ml of blood. Such large volumes ofblood may take many weeks to be reabsorbed andeven then resolution may not be complete. Forthis reason the knee joint is the joint most frequentlyaspirated. Haemarthroses in the elbow or anldejoints are usually relatively small, are absorbedrapidly, and so rarely require aspiration. (4)Presence or absence of antibodies to factor VIII in thepatient's circulating blood. Aspiration should never

be carried out if it is known that the child's bloodcontains factor VIII antibodies. The risk ofserious haemorrhage as a consequence ofpuncturingthe joint are high and more harm than good may bedone.

Care of teeth. The main aims of dentalmanagement in haemophiliacs are: (1) to preventgingival disease and dental caries and so preserve

the teeth; (2) to carry out dental extraction whenthis becomes necessary, as safely as possible.The prevention of gingival and dental disease is

based on educating the patient from an early age

about the necessity for oral hygiene. Heshould be instructed to brush his teeth regularlyand at least twice each day, to avoid sweets andexcess carbohydrates and to make 6-monthlyvisits to his dentist to have dental inspectionand any necessary fillings carried out. Theseprocedures can be undertaken by the familydentist without factor VIII therapy and inmost instances without any local anaesthesia.If local anaesthesia is required this should beachieved by papillary infiltration. Anaesthesia bymeans of nerve block should never be attemptedbecause of the danger of bleeding into the softtissues of the neck and floor of the mouth.When the preventive measures fail and dental

extraction is required the child should be admittedto hospital to have this carried out. Dentalextractions are carried out under general anaesthesiawith the patient intubated via the mouth. Withregard to factor VIII replacement therapy it was

our practice until recently to give the patient a

transfusion of cryoprecipitate or AHG immediatelybefore dental extraction sufficient to raise his bloodfactor VIII level to 30 to 40% of normal and there-after to give daily doses of cryoprecipitate for 7 to10 days until healing was complete. During thepast 4 to 5 years there have been reports that the

antifibrinolytic agent epsilon-aminocaproic acid(EACA, Epsikapron) is effective in reducing bloodloss after dental extraction in haemophiliacs(Tavenner, 1968). We have confirmed this work(Walsh et al., 1971) and our regimen of treatmentfor haemophiliacs undergoing dental extraction isnow as follows.On the morning of operation the patient is given

a transfusion of cryoprecipitate sufficient to raisehis factor VIII level to 50% of normal. This isfollowed by intravenous EACA in a dose of 0-Ig/kg body weight. After extraction the patient isgiven EACA by mouth in a dose of 0 1 g/kg every6 hours for 7 to 10 days. The patient is also givenpenicillin by the oral route in a dosage of 250 mg6-hourly for 7 to 10 days. No further doses ofcryoprecipitate are given unless the patient bleeds.This regimen of treatment has proved very effectivein controlling bleeding and has led to a great savingof cryoprecipitate and AHG. In addition the risksof the patient getting transfusion hepatitis arereduced.

Deciduous teeth are commonly shed withoutexcessive bleeding. If a deciduous tooth isforcibly loosened, persistent bleeding, which isaggravated by movements of the tooth, may occurfrom the gum and the tooth should be extracted.A single dose ofAHG followed by oral Epsikapron0 1 g/kg body weight, 6 to 8 hourly for 4 or 5 days,should control bleeding.

Extraction of firmly fixed deciduous teeth shouldfollow the plan used for permanent teeth.

Injections and immunization. A skilfullyperformed venepuncture which does not undulytraumatize the surrounding tissues is generally freefrom bleeding complications in the severe haemo-philiac if pressure is afterwards maintained on thepuncture site for a continuous period of 3 to 4minutes. After a venepuncture at the elbow thelimb should be kept straight and not flexed over aswab.The main problem in venepuncture is often

related to whether one attempt, or 3 or 4 attemptsat venepuncture are necessary, since this can involvea difference in the time the child is upset from afew minutes up to half an hour or even longer.In difficult cases it is helpful to sedate them ade-quately, say with trimeprazine, and occasionally itmay even be necessary to give a short anaestheticto provide ideal circumstances for successfulpuncture. On the whole these measures areuncommonly used, and for an experienced operatorwho is prepared to look carefully at all the possiblepuncture sites beforehand and then to immnobilize

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Rizza and Matthewsthe part concemed, there is usually little trouble.The obese haemophilic infant is not always asdifficult to transfuse as might be anticipated sincesuitable veins for the short duration infusionswhich are used in treatment may often be foundon the foot, the back of the hand, or the scalp.Where repeated venepunctures are necessary fortreatment one may find that with time one becomesfamiliar with the child and with the veins whichhave been used with success, so that the procedurebecomes easier. The converse may of courseoccur and it may become more necessary to sedatethe child as time goes on.

Medications may be given by mouth, or byintravenous or subcutaneous injection, applyingpressure on the injection site and keeping thevolume of drugs given by the subcutaneous routeto a minimum. Intramuscular injections com-monly produce serious haematomas and are notrecommended. Subcutaneous injections shouldbe made horizontally into the base of a fold of skinand subcutaneous tissue raised between forefingerand thumb, thus avoiding damage to underlyingmuscles.

Immunization can be carried out safely inhaemophiliacs using intracutaneous or deep sub-cutaneous injection which, in most instances, isquoted as an alternative to intramuscular injection.

Home treatment of haemophilia. Someseverely affected haemophiliacs attend hospitalvery frequently for treatment of bleeding episodes.They spend much time in travelling, lose time beforetreatment can be started, and occupy the servicesof ambulance and hospital staff to a disproportionateextent. If a suitable AHG preparation is availableand a child's parents have the necessary intelligenceand aptitude to learn to carry out venepuncturesefficiently, they may be able to treat their childsuccessfully at home at the earliest sign of trouble.In other cases, the general practitioner may bewilling to give the child his injections. Hometreatment can be much less traumatic psychologi-cally than treatment in hospital and may prove tobe more economical in terms of material usedsince a smaller dose of AHG than would be usedin hospital, given early, will often arresthaemorrhage.

Rabiner and Telfer (1970) have recently des-cribed their experiences with a home transfusionprogramme involving 18 patients. They concludedafter 18 months that treatment at home withcryoprecipitate was practical and safe and thatthe number of days lost by the patient from workor from school was diminished. There was,

however, an increase in the amount of antihaemo-philic factor used. We have recently embarkedupon a programme of home treatment in certainseverely affected haemophiliacs using freeze-driedAHG as the therapeutic material. So far only 7patients are receiving this form of treatment but ifit proves to be useful and enables the patients tolead a more normal life it seems reasonable, provid-ing enough AHG becomes available, to extend theprogramme to include as many patients as mightbenefit from this form of treatment. At presentour criteria for giving home treatment are asfollows. The patient must be severely affected;must be having frequent haemorrhage, i.e. at leastonce every 2 weeks; must be co-operative: musthave a co-operative parent or relative who shows anaptitude for carrying out venepuncture; must havegood veins; must live at a considerable distancefrom the Haemophilia Centre or have difficulty ingetting there for treatment; and must not havefactor VIII antibodies.

Certain safeguards should be enforced when apatient is receiving treatment at home. A carefulrecord is kept ofmaterials issued, used, and returned,of adverse reactions to treatment, and of bleedingepisodes and their time of recovery. Periodicassays are carried out to check that the patient'sresponse after a dose is adequate, and that he isnot developing an antibody to factor VIII.

Ideally, the parent should phone the doctor atthe Haemophilia Centre to report a suspectedbleed and ask permission to give a dose, or in somecircumstances to check whether it would be betterto proceed to the Centre for further assessment.Parents treating their child should ensure before-hand that their general practitioner can be contactedfor advice in the unlikely event of a reaction to theAHG preparation.

Possible complications of factor VIII re-placement therapy. Transfusions of plasma orAHG concentrate are not entirely without dangerthough in general the risks of therapy are slightcompared with the danger to life or limb of uncon-trolled haemorrhage. The complications of re-placement therapy are here briefly discussed.

Hypervolaemia. This complication rarely ariseswhen concentrated AHG preparations are used butis a well-known complication of treatment withwhole plasma. Plasma in a daily dose of 10 to 15ml/kg body weight is usually well tolerated.Larger and more frequent doses of plasma tend tocause overloading of the circulation.

Pyrogenic and allergic reactions. In a proportion

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Management of the Haemophilic Child 461of patients infusion of AHG concentrate, cryo-precipitate, or plasma is followed by a reactionwhich may produce headache, backache, rigor, andpyrexia, or an urticarial eruption, occasionallyaccompanied by breathlessness and bronchospasm.

In general, pyrogenic reactions come on an hourto an hour and a half after starting the dose andthough they may be unpleasant for the patient andworrying to the observer they are not usuallydangerous. A strong narcotic analgesic may berequired for control of severe headache. Allergicreactions usually occur while the dose is beinggiven though sometimes they may be delayed forseveral hours. On the whole, the earlier they occurthe more seriously they should be regarded. If areaction occurs during a dose, the rate ofadministra-tion is reduced and an antihistamine such aschlorpheniramine maleate is given intravenouslyin the maximum dose recommended for thepatient's weight. If the reaction is more severe,and especially ifthere is breathlessness and broncho-spasm, the infusion should be changed for one ofnormal saline, and if necessary subcutaneousadrenaline and intravenous hydrocortisone shouldbe given.

Transfusion hepatitis. Most severely affectedhaemophiliacs receive large numbers oftransfusionsof blood or blood derivatives and are thereforeexposed to the risk of transfusion hepatitis. Therisk of hepatitis is probably greater with freeze-dried AHG concentrates than with plasma orcryoprecipitate since the dried concentrates areusually prepared from pools of plasma obtainedfrom several hundreds of donors. A patientreceiving a single dose of a given batch of AHGconcentrate may therefore have 'contact' with400 to 500 donors. Because ofthis risk it is advisablewhen planning to give a course of freeze-driedAHG to a patient, to try as far as possible to givehim material from the same batch of AHG and notto mix batches.During the year 1969, 228 patients with haemo-

philia or Christmas disease were seen at Oxfordand of these, 208 were treated with plasma, cryo-precipitate, freeze-dried human AHG, or, in thecase of the Christmas disease patients, factor IXconcentrate. Of the 208 patients transfused, 7(3 4%) developed clinical jaundice. The incid-ence of subicteric hepatitis in those patients is notknown. The figure of 3-4% for the incidence ofjaundice may seem large but when one considersthat on average each ofthe 208 patients had 'contact'with 630 blood donors during the year it is not sosurprising.

Factor VIII antibodies. Approximately 6% ofthe haemophiliacs registered at the Oxford Haemo-philia Centre have antibodies to factor VIII intheir blood. These antibodies make the treatmentof haemophilia extremely difficult since they rapidlydestroy factor VIII transfused into the patient.The antibodies presumably appear as a consequenceof treatment with factor VIII-containing materialsbut at present there does not seem to be any clearrelation between the development of antibodies andthe type or amount of factor VIII used in thereplacement therapy.

In many patients, the level of antibody in theblood diminishes spontaneously over the course of1 to 2 years providing factor VIII-containingmaterial is not given to the patient. Unfortunately,the antibody usually reappears within 5 to 7 daysof the giving of factor VIII.With regard to the management of haemo-

philiacs who have factor VIII antibodies it is thepolicy at Oxford to withhold replacement therapyin cases of minor haemorrhage. In the case ofmuscle haemorrhages which are threatening tocompress nerves or blood vessels, or in the case ofhaemarthroses which are large, tense, and painfuland presumably causing serious joint damage,large doses of cryoprecipitate are given in an attemptto achieve haemostasis and promote healing. Forexample, a child might be given up to 1 bag ofcryoprecipitate per kg body weight twice daily.A similar regimen might be used in the managementof life-endangering haemorrhage but in this situationif there was no improvement within 12 to 24 hoursof starting treatment or if the patient's conditiondeteriorated, it would be justified to use bovine orporcine AHG. Both preparations are availablecommercially* and in large amounts, and have theadded advantage that bovine and porcine factorVIII are usually much less susceptible than humanfactor VIII to the action of factor VIII antibodies.

REFERENcEs

Bidwell, E. (1955a). The purification of bovine antihaemophilicglobulin. British Journal of Haematology, 1, 35.

Bidwell, E. (1955b). The purification of antihaemophilic globulinfrom animal plasma. British Journal of Haemarology, 1, 386.

Macfarlane, R. G., Mallam, P. C., Witts, L. J., Bidwell, E., Biggs,R., Fraenkel, G. J., Honey, G. E., and Taylor, K. B. (1957).Surgery in haemophilia: the use of animal antihaemophilicglobulin and human plasma in thirteen cases. Lancet, 2, 251.

Pool, J. G., Hershgold, E. J., and Pappenhagen, A. R. (1964).High-potency antihaemophilic factor concentrate prepared fromcryoglobulin precipitate. Nature (London), 203, 312.

*Maws Pharmacy Supplies Ltd., Cromer Road, New Barnet,Herts.



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462 Rizza and MatthewsPool, J. G., and Shannon, A. E. (1965). Production of high-

potency concentrates of antihemophilic globulin in a closed-bagsystem. New England Journal of Medicine, 273, 1443.

Rabiner, S. F., and Telfer, M. C. (1970). Home transfusion forpatients with hemophilia A. New Englandjournal of Medicine,283, 1011.

Tavenner, R. W. H. (1968). Epsilon-aminocaproic acid in thetreatment of haemophilia and Christmas disease with specialreference to the extraction of teeth. British Dental Journal,124, 19.

Walsh, P. N., Rizza, C. R., Matthews, J. M., Eipe, J., Kernoff,P. B. A., Coles, M. D., Bloom, A. L., Kaufman, B. M., Beck, P.,Hanan, C. M., and Biggs, R. (1971). Epsilon-aminocaproicacid therapy for dental extractions in haemophilia and Christmasdisease: a double blind controlled trial. British Journal ofHaematology, 20,463.

ADDITIONAL READING

Biggs, R., and Macfarlane, R. G. (Editors) (1966). Treatment ofHaemophilia and Other Coagulation Disorders. Blackwell,Oxford.

Duthie, R. B., Matthews, J. M., Rizza, C. R., and Steel, W. M.(1972). Management of Musculo-Skeletal Problems in theHaemophilias. Blackwell, Oxford. (To be published.)

Hardisty, R. M., and Ingram, G. I. C. (1965). Bleeding Disorders:Investigation and Management. Blackwell, Oxford.

Rizza, C. R. (1970). The management of haemophilia. Practi-tioner, 204, 763.

Correspondence to Dr. C. R. Rizza, Oxford Haemo-philia Centre, Churchill Hospital, Headington, OxfordOX3 7LJ.



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