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Bleeding disorders
Bleeding Disorders
C. R. R i z z a
questioning wherever possible and to ask specific questions. The patient should be asked about his responses to mild knocks and scratches and whether or not he feels he bleeds longer than normal or bruises abnormally. Some patients have difficulty in deciding what is normal and what is abnormal, in which case it may be necessary to ask them very specifically if bruising after sporting injuries was much different from that of their colleagues in the team or if bleeding from cuts is different from that in school friends or workmates. Questions about bleeding following minor operations such as dental extractions or more major surgery such as tonsillectomy, give invaluable information. Whether or not blood transfusion was required should always be recorded. Questioning about dental extraction will give more valuable information if the patient can specify the number and type of teeth removed. Tonsillectomy is a particularly useful test of the haemostatic mechanism and if the patient did not bleed following tonsillectomy, it is unlikely that he was suffering at the time from a significant haemorrhagic disorder. The site and nature of bleeding may give valuable information about the underlying defect. Platelet and vascular defects and von Willebrand's disease may cause petechial haemorrhages or ecchymoses in the skin, nosebleeds and bleeding from the mucous membranes of the mouth, gastrointestinal tract and genitourinary system. On the other hand intramuscular, intra-articular and retroperitoneal haemorrhages are seen chiefly in the severe blood coagulation defects, in particular haemophilia A and haemophilia B. A history of recurrent epistaxes is of limited diagnostic value as nosebleeds are not uncommon in childhood and may be associated with upper respiratory tract congestion. Haematuria may be due to haemophilia, anticoagulant therapy or thrombocytopenia. Bleeding
Assessment
Patients with bleeding disorders, no matter how mild, are at risk of bleeding excessively following injury or surgery and may present the clinician with a difficult problem in diagnosis. When faced with a patient who is thought to have a bleeding disorder, the clinician must ask himself two questions 1) Does the patient have a bleeding disorder? and 2) What is the nature and severity of the disorder? The first question can only be answered by taking a careful clinical history and carrying out a full clinical examination. The second question is answered by examination of the patient's blood in the laboratory to see if there is any deficiency in coagulation factors or platelets (Fig. 1) and to assess the severity of the deficiency. The importance of the clinical history cannot be stressed too much and the failure to demonstrate an abnormality in laboratory tests in the face of a strong history of haemorrhage does not rule out the diagnosis of a bleeding disorder; it suggests that the tests used were inappropriate or not sensitive to the patient's defect. Similarly, abnormal laboratory tests in a patient who has recently undergone major surgery without haemorrhage suggests that the test is reflecting some deficiency which is of little or no importance in normal haemostasis. An example of this latter situation is seen in patients suffering from factor XII (Hageman factor) deficiency who have grossly abnormal activated partial thromboplastin times but do not bleed abnormally.
Clinical history When asking a patient about his history of bleeding, it is desirable to follow the same procedure of Dr C. R. Rizza FRCP, Consultant Physician, Oxford Haemophilia
Centre, Churchill Hospital, Headington, Oxford,OX3 7LJ. Current Orthopaedics (1987) 1,299 309 © 1987 Longman Group UK Ltd
299
300
BLEEDING DISORDERS Anionic
Surface
HMWK
Kallikrein Vll
Xlla
Xll
I Tissue Factor XI
Vlla
~ Xla
Ca2+[ IX
..... ~ V l l l
mVllla
Ca 2
X
~ PL
.......... ..,..• ..... .O,~V
I~Va Ca 2+
•
Pro thrombin
ionian •
~ Th rombin
(II)
p
'l'l
(lla)
~
ii•...•...........n.mmmn........n...mm•.I ••'e••'~• ••'~'°°'~•
XIII
~Xlla
;,Fibrin
Fibrinogen
Stabilised
Fibrin
Fig.
1 - - A schematic representation of the b l o o d coagulation cascade: H M W K = High molecular w e i g h t kininogen FL = p h o s p h o l i p i d a = A c t i v a t e d factor . . . . > = Feed b a c k mechanisms
from the gastrointestinal tract m a y be a complication of any haemorrhagic disorder and enquiries should be made about the ingestion of drugs, in particular aspirin and oral anticoagulants. A history of exposure to toxic chemicals should also be sought. When enquiring about past history the patient should be asked about jaundice, hepatitis and the use of alcohol. In women attention should be paid to menorrhagia although this by itself is of little value as a diagnostic symptom. Excessive bleeding after childbirth and the need for blood transfusion should also be enquired after. Family history is important and details of haemorrhagic symptoms in other family members should be sought. This information by itself m a y give a strong hint as to the possible diagnosis. Haemophilia A and B are both sex-linked conditions. Von Willebrand's disease is autosomal dominant and the rest of the inherited disorders are autosomal recessive.
Laboratory tests All patients suspected of having a bleeding disorder should have estimation of haemoglobin, white cell count and platelet count. The bleeding time should be measured using the Ivy method or a modification which standardises the depth of incision by using a template. An automated device which produces a
standard cut is commercially available. The bleeding time is prolonged in quantitative or qualitative platelet deficiencies, von Willebrand's disease and following ingestion of aspirin. At present there is no simple and reliable screening test of haemostasis but there are several simple tests of clotting function which when carried out together can give a good indication of the likely diagnosis and suggest which factor should be assayed (Table 1). The definitive diagnosis will require a specific assay of the appropriate clotting factor. 1 Resultsof prothrombin time and activated partial thromboplastin time in different coagulation factor deficiencies
Table
Deficiency
Prothrombin time
APTT
Fibrinogen (factor I) Prothrombin (factor II) Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII High molecular weight kininogen Prekallikrein Factor XIII
+ + + + N N + N N N N N
+ + + N + + + + + + + N
N = Normal + = Prolonged
CURRENT ORTHOPAEDICS 301 Those assays are not easy and should be carried out by experienced staff who know how to interpret the results and provide the necessary quality control of assay and reagents. Bleeding disorders may be inherited or acquired. In general the inherited bleeding disorders are due to deficiency of one factor whereas acquired bleeding states usually show a deficiency of several coagulation factors with platelets also occasionally being involved. Table 2 shows some in vivo characteristics of blood clotting factors. This paper deals with inherited bleeding disorders and in particular classical haemophilia (haemophilia A) and Christmas disease (haemophilia B). Both these conditions can cause serious damage to the musculo-skeletal system and their management requires close collaboration with orthopaedic experts.
Classical Haemophilia (haemophilia A) and Christmas Disease (haemophilia B) Haemophilia and Christmas disease are inherited bleeding disorders which affect males and are transmitted as X-linked recessive conditions. Some female carriers may have bleeding symptoms. Bleeding in haemophilia is due to complete or partial deficiency of factor V I I I coagulant activity; in Christmas disease the bleeding is due to deficiency of factor IX. The genes for factor V I I I and factor IX lie on the X chromosomes and have recently been cloned. The factor V I I I gene is the largest known to date and is approximately 186 x 103 bases in length. The active factor V I I I produced by the gene is a glycoprotein
containing 2332 amino acids. In the case of factor IX the gene is approximately 34 x 103 bases long and codes for a mature protein containing 423 amino acids. Factor V I I I and factor IX are essential for the conversion of factor X to factor Xa, the active enzyme which converts prothrombin to thrombin in the clotting cascade. In the absence of factor VIII or IX the coagulation process is greatly delayed and thrombin generation is poor.
Prevalence Classical haemophilia is the commonest of the inherited severe bleeding disorders. In the United Kingdom the condition is present in 90 per million of the population, approximately 40% being severely affected with factor VIII level. In the case of Christmas disease the prevalence is 15 per million of the population with 30% being severely affected.
Inheritance Haemophilia and Christmas disease are passed on as X-linked conditions but it should be remembered that approximately 30% of sufferers have no previous family history of the condition. Both conditions run 'true' in a family so that all affected members of a given family will suffer from the same severity of the condition. This is important information for women carriers who are considering whether or not to have children. Because of the mode of inheritance a haemophilic male cannot pass the condition to his sons but all of his daughters will be
Table2--Some in vivoproperties of the differentclotting factors
Factor
Deficiencystate
I Afibrinogenaemia Defibrination syndrome II Prothrombindeficiency Coumarin anti-coagulanttherapy Liver disease V FactorV deficiency VII FactorVII deficiency Coumarin anti-coagulanttherapy Liver disease VIII Haemophilia von Willebrand's disease IX Christmasdisease Coumarin anti-coagulanttherapy Liver disease X FactorX deficiency Coumarin anti-coagulanttherapy Liver disease XI PTA deficiency XII Hagemandefect XIlI Fibrin stabilising factor deficiency * Higher levelsmay be required during surgery.
Plasma concentration required for haemostatis (% normal) 10 25
Half-life of transfused factor 4-6 days
Recoveryin blood (as transfused dose) 5O
40 10 15
3 days 12h
40-80 80 100
5 10
4-6 h
80-100
10 40*
8 12h
50-80
10 40*
12.-24 h
30 50
10-15 ?3O
2 days 60-80 h 60 h ?6 10 days
50 90 100
15
50 100
302
BLEEDING DISORDERS
obligatory carriers. In the case of carrier women, there is a 50: 50 chance that their sons will be affected or be normal and a 50:50 chance that their daughters will be carriers or be normal. Women in haemophilic families may wish to know if they are carriers of the condition and many when pregnant go on to request antenatal testing of the foetus to find out if it is affected. This would only be proceeded with if the woman wished abortion of an affected foetus. With regard to discovering the carrier status of a woman, a probability assessment of carrier status can be given in approximately 75~ of possible carriers by using pedigree information and assay of factor VIII coagulant activity and factor VIII-related antigen. More recently it has been possible by means of gene probing and using D N A polymorphisms to discover the carrier status with a high degree of certainty in those families which carry an appropriate polymorphism. Similar genetic methods applied to D N A obtained from chorionic villus biopsy will allow antenatal diagnosis in a proportion of women at 8-10 weeks of pregnancy. In women in whom a useful polymorphism is absent, antenatal diagnosis can still be offered by carrying out factor VIII assay on blood obtained from the foetus by foetoscopy at 17-19 weeks of pregnancy. The disadvantage of this method lies in the lateness of the termination of pregnancy in those women found to be carrying an affected son.
Diagnosis The patient's clinical history and any family history may raise the suspicion of haemophilia or Christmas disease. Laboratory tests show the bleeding time and ,prothrombin time to be normal but the whole blood clotting time and activated partial thromboplastin times are prolonged. A definitive diagnosis is made by carrying out specific assays for factor VIII or factor IX. In severely affected patients the factor level will be < 1X of average normal. More mildly affected patients will have levels between 2 ~ and 25~ of normal.
Clinicalfeatures Haemophilia and Christmas disease have the same clinical features and are indistinguishable on clinical grounds. They are both characterised by prolonged bleeding, sometimes continuing for weeks, following accidents or surgery. The onset of bleeding after the injury may be delayed for hours or even days. The severity of bleeding experienced correlates well with severity of the coagulation factor deficiency (Table 3); patients with no detectable level of factor VIII or IX usually bleed severely after minor injury or even spontaneously whereas patients with levels greater than 4 - 5 ~ may lead a normal life unless they are involved in accidents or undergo surgery. Acute haemarthrosis. Bleeding into joints is a classical feature of severe haemophilia and Christmas disease (Fig. 2). On many occasions the joint bleeding seems to be spontaneous in so far as the patient cannot recall any definite injury. The onset of bleeding may be preceded by a variety of sensations in the knee including a feeling of warmth, prickling, tickling or a sensation of water trickling in the joint. If bleeding progresses those symptoms are followed in a short time by stiffness, then pain and swelling of the joint. In severe episodes pain is extreme and the joint is held in a semi-flexed position and cannot be flexed or extended. Muscle haemorrhage. Bleeding into muscles is common in severe haemophilia and Christmas disease and may sometimes be as damaging in terms of limb function as bleeding into joints. The flexor muscles of the forearm and the muscles of the calf are common sites of bleeding. In young children buttock haematomas are relatively common and are probably due to the child sitting down hard while learning to walk. In addition to destroying muscle tissue large muscle haematomas may cause pressure on neurovascular bundles and other structures. The iliacus haematoma is a particularly important type of muscle haemorrhage since it may compress the femoral nerve as it runs under the iliacus fascia and cause loss of muscle power in the quadriceps and instability of the knee (Fig. 3). The condition may be mistaken for appendicitis if it
Table 3--Relationship of plasma factor VIII level to the severity of bleeding Plasma level of factor VIII (iu/dl) >40 20 40 5 20 1-5 <1
Bleeding manifestations None Tendency to bleed after major injury. Often not diagnosed. Bleeding after minor injury and surgery. Severe bleeding after minor injury. Occasional haemarthroses and 'spontaneous' bleeding. Severe haemophilia. Spontaneous haemarthroses and muscle haemorrhages. Joint ankylosis and crippling.
Fig. 2 - - A n acute knee haemarthrosis in a patient with clinical severe haemophilia.
CURRENT ORTHOPAEDICS
Fig. 3 - - A n iliacus bleed with a palpable haematoma in the left iliac fossa (cross hatched) and an area of numbness in the femoral nerve distribution (dotted).
occurs on the right side. The diagnosis is made by finding a palpable tender mass in the iliac fossa, a hip flexion deformity and altered sensation down the front of the thigh with a diminished knee reflex. Occasionally a large muscle haematoma fails to resolve completely and following a series of re-bleeds takes on the features of a haemophilic cyst or pseudotumour. Any muscle may be involved but the commonest sites are the pelvic region, thigh and calf. Such cysts may attain a great size and cause pressure on nerves and surrounding structures and may lead to fracture of the pelvis or femur. Ultrasound or CT scanning is of value in delineating the size of haemophilic cysts and in following their progress. In addition to pseudotumours which appear to arise from muscle some seem to have their origin in bone. Chronic arthropathy. Repeated joint bleeding results in joint damage with synovial thickening, loss of cartilage, osteoporosis and eventually fibrosis or bony ankylosis (Fig. 4). In addition to the loss of joint function and mobility chronic arthropathy is usually accompanied by pain which limits the patient's day time activities, disturbs his sleep and may be difficult to control with anything but the most powerful analgesics. Haematuria. This is common and in the majority of instances is painless and not associated with infection or any other underlying pathology in the urinary tract. Occasionally large clots may form in the renal pelvis causing obstruction to urinary flow and severe clot colic.
Gastrointestinal haemorrhage. This is often associated, as in the patient without bleeding diathesis, with gastric or duodenal ulceration or some other gut pathology. In a small proportion of cases no underlying lesion can be demonstrated by endoscopy or X-ray examination. Bleeding from oesophageal varices secondary to liver disease is in our experience becoming more common. Sometimes bleeding is related to aspirin intake. Intracranial haemorrhage. This is a serious complication of haemophilia and although it is relatively uncommon it is still the commonest cause of death in haemophiliacs, accounting for 20-25~ of deaths. Most cases of intracranial haemorrhage follow some minor injury to the head. Treatment of bleeding in haemophilia and Christmas disease Bleeding in haemophilia and Christmas disease can be controlled by giving transfusions of material containing the appropriate clotting factor; factor VIII in the case of haemophilia and factor IX in the case of Christmas disease. The level of factor required to achieve haemostasis will depend on the nature and site of bleeding and the severity of the injury or surgery (Table 4). The post-transfusion level in the circulation is fairly well correlated with the size of the dose given providing the patient's weight is taken into account and providing he does not have antibodies to factor VIII or IX. In general a factor VIII increase in the patient of 2 iu/dl can be expected for every iu/kg body weight administered. In the case of Christmas disease the factor IX level increases by 1 iu/dl for each iu of factor IX/kg body weight. Such simple formulae are useful for deciding the size of initial doses but there may be considerable variation in the response in different patients and it is important to monitor the patient's response by carrying out post-transfusion assays to be sure that the desired level is being achieved.
Materials used in replacement therapy 1) Plasma. Until 1964 fresh frozen plasma was the therapeutic material most widely used in the treatment of haemophilia and Christmas disease. Minor hae-.
Table 4--Approximate levels of factor VIII required for haemostasis in different lesions
Lesion Minor spontaneous haemarthrosis and muscle haematomas Severe haemarthrosis and muscle haematomas, haematomas in dangerous situations Major surgery
303
Level of factor VIII desired in patient's blood immediately after transfusion (iu/100 ml)
Dose of factor VIII (iu/kg body weight)
15-20(0 5)
10 15
20-49 (5-10) 80-100 (or less if transfusion given 8-hourly or 6-hourly)
15 20 40-50
Figures in parentheses are the approximate levels to which factor VIII will have fallen 24 hours after dose.
304
BLEEDING DISORDERS
Fig. 4 ~ ( A ) and (B) AP and lateral radiographs showing chronic haemophilic knee arthropathy. Features, in addition to secondary degenerative change, are metaphyseal/epiphyseal widening (due to local hypervascularity during growth), widening of the intercondylar notch, squaring of the lower end of the patella, and generalised osteoporosis.
morrhages and early haemarthroses could be controlled by means of fresh frozen plasma but it was extremely diffficult to maintain haemostasis following surgery with this material because of the large volume required. Plasma is now rarely used in the treatment of haemophilia but is still used in the treatment of factor V deficiency and factor XI deficiency for which there are at present no factor concentrates available. 2) Cryoprecipitate. The introduction of cryoprecipitate in 19641 was a major advance in the management of haemophilia. It was shown that the cold insoluble protein remaining after gentle thawing of frozen plasma was rich in factor VIII. By separating this material by centrifugation, a potent concentrate of factor VIII was obtained. Cryoprecipitate contains approximately 50~ of the factor VIII activity of the original plasma and 50~ of the original fibrinogen content. In addition there are large amounts of fibronectin and factor XIII. Cryoprecipitate is of no
value in the treatment of Christmas disease. The advantages of cryoprecipitate are the ease and low cost of production. Since it is not prepared from large pools of plasma, it also carries a relatively low risk of transmitting hepatitis or HIV infection. It is therefore often used for treating mildly affected patients who have had few previous transfusions, and who are at particular risk of developing hepatitis. Clearly if large doses of cryoprecipitate are given over a prolonged period the patient's exposure to infection is increased. The disadvantages of cryoprecipitate are that reconstitution is laborious and time consuming; it must be stored at - 20°C or less which makes it unsuitable for home therapy; there is considerable variation in factor VIII content from bag to bag which makes rational replacement therapy difficult. 3) Intermediate and high purity factor VIII concentrates. These concentrates are prepared using cryoprecipitate as the first step in the purification process. Thereafter
CURRENT ORTHOPAEDICS
depending on the degree of purity further steps may be added including washing with buffer, adsorption with aluminum hydroxide and precipitation with polyethylene glycol, ethanol or heparin. High purity concentrates have a specific activity usually greater than 1 iu factor VIII/mg protein and are used at a potency of 20-30 iu/ml; intermediate purity concentrates have a specific activity of 0.2 0.5 iu factor VIII/rag protein and are used at a potency of 10 20 iu/ml. As expected the greater the purity sought the greater the factor VIII toss in the manufacturing process. Most of the factor VIII used in the U K at present is of intermediate purity. All intermediate and high purity concentrates whether produced by commercial companies or by NHS laboratories are prepared from blood donations tested for anti-HIV. In addition the finished freezedried product undergoes a heating process to inactivate any HIV which may be present. The heating regime varies with the different manufacturers. The material at present prepared by the NHS fractionation laboratories is heated to 80°C for 72 h. Hopefully this degree of heating will inactivate not only HIV but also the viruses which cause hepatitis. It is already known that less severe heating such as 60°C for 72 h is not sufficient to inactivate the virus of non A non B hepatitis. Although prepared from blood donations tested for anti-HIV it should be noted that cryoprecipitate cannot be heated. 4) Prothrombin complex (II, VII, IX and X) concentrates. The chief value of these preparations is in treatment of Christmas disease. Because of their chemical characteristics all four factors tend to fractionate together although it is possible with relative ease to separate factor VII from the other three and collect it as a separate fraction for treatment of factor VII deficiency. The prothrombin complex concentrates at present used in the U K are obtained from cryoprecipitate supernatant using DEAE cellulose chromatography. Because of the long half-life of prothrombin compared with factor IX it can be seen that a patient with Christmas disease receiving heavy treatment with prothrombin complex concentrate may develop very high levels of prothrombin which may be dangerous. As with factor VIII all prothrombin complex concentrates are now prepared from donors tested for anti-HIV and have undergone a heating stage.
Management of acute haemarthroses Bleeding into joints can be an acutely painful condition. Treatment aims at controlling the bleeding and relieving the pain. Clotting factor concentrates should be administered in a dose of 10 15 iu kg/body weight as soon as possible after the onset of bleeding. For an early mild haemarthrosis a single dose may be sufficient but for severe haemorrhage, especially following injury it may be necessary to give larger doses and repeat the dose daily for several days. If pain is severe,
305
analgesic drugs such as pethidine, morphine or dextromoramide should be given, always bearing in mind the risk of inducing drug dependency. Immobilisation of the joint in a light plaster of Paris back splint also helps to diminish the pain. The majority of haemarthroses respond quickly to these simple measures and the patient can start mobilisation gently within a few days. Bleeding into muscles should be treated in a similar way. Mobilisation after haemorrhage into muscle should be gradual and gentle because of the risk of re-bleeding.
Home therapy In view of the delay and great inconvenience often caused to the patient by going to hospital for transfusion therapy, many centres have started programmes of home therapy or self-therapy for their severely affected patients. The coagulation factor is administered by the patient or a close member of his family and there seems little doubt that bleeding episodes are being treated earlier and thus loss of time from school or work has been reduced. It is too early to know if there has been a significant reduction in chronic arthropathy in patients on home therapy.
Management of chronic arthropathy Treatment of chronic arthropathy is aimed at reducing pain and improving joint and muscle function. Cooperation with orthopaedic specialists and physiotherapists is essential. The mainstays of management are: l) Physiotherapy 2) Splinting of the joint 3) Correction of joint deformity by non-surgical means, e.g., reversed dynamic slings 4) Analgesics 5) Reconstructive surgery including arthroplasty 1) Physiotherapy. The function of a joint with only slight structural damage may be improved considerably by exercise aimed at improving muscle strength and range of movement. In the case of severely damaged joints with flexion contractures, physiother-. apy seems of less benefit. 2) Splinting. Damaged joints are often unstable and as a consequence prone to recurrent bleeding. Calipers will give some support to the knees and ankles. More recently splinting by means of light plastic 'supports' have been found of value for knees, ankles and elbows. Firm boots lacing above the ankles are often sufficient to reduce pain or haemorrhage in the ankles. 3) Reverse dynamic slings. A system of dynamic slings has been described 2 which has proved of value in treatment of fixed flexion contracture of the knees. The method is gentle, does not require factor replacement and may produce benefit within a few days. 4) Analgesics. Pain is common in haemophilic arthro-
306
BLEEDING DISORDERS
pathy and may be severe, disrupting the patient's day time routine and his sleep. Aspirin and aspirincontaining preparations should not be used. Paracetamol, pentazocine or dihydrocodeine should be given in the first instance. Non-steroidal anti-inflammatory drugs may give some relief but it may be necessary for the patient and his doctor to explore the various possibilities to see which suits the patient best. More powerful potentially addictive drugs such as pethidine, dextromoramide and morphine should be used with great care and only in short courses. 5) Reconstructive surgery. If all of the above measures fail to give benefit and especially if pain is severe, it may become necessary to relieve deformity and pain by surgical means. Procedures which have been found of value in the management of haemophilic joint disease include synovectomy (Fig. 5), total hip replacement, corrective osteotomy, patellectomy, knee replacement, arthrodesis of knee and ankle.
Major surgery Major surgery in a patient with haemophilia or Christmas disease can be extremely hazardous and requires close collaboration between surgeon, physician, haaematologist and laboratory staff. Before undertaking surgery it is essential to check that the patient does not have antibody to factor VIII or IX. In most instances the finding of antibody is a contraindication to surgery. A transfusion of clotting factor concentrate is administered immediately before surgery. The dose should be sufficient to raise the clotting factor level to 80-100 iu/100 ml. In the case of haemophilia this will require a dose of 40-50 iu factor VIII/kg body weight and in the case of Christmas disease a dose of 80-100iu/kg body weight. Assays are carried out immediately after the dose to make sure that a satisfactory level has been achieved. Further doses are given according to the level of factor VIII or IX in the patient's blood, the aim being to maintain the level above 40 iu/100 ml. Factor replacement is given 8hourly or 12-hourly and this is continued until wound healing is well advanced, usually 7-14 days.
Von Willebrand's Disease After haemophilia A, yon Willebrand's disease is probably the next commonest inherited bleeding disorder. There is a wide range of clinical and laboratory features and it is difficult to be sure of the prevalence of the disease. Estimates range between 30 and 100 per million of population. The condition shows autosomal dominant inheritance and affects males and females equally. It is characterised by a tendency to bleed from mucous membranes especially of the gastrointestinal tract, nose and uterus. Bleeding into muscles and joints is very uncommon and this helps to distinguish it from severe haemophilia. The skin bleeding time is prolonged and examination of the blood shows a variable reduction of the factor VIII coagulant activity and factor VIII-related antigen. There is also reduced aggregation of platelets on addition of the antibiotic ristocetin, yon Willebrand's disease has been classified into several types depending on the relative levels of factor VIII coagulant activity, factor VIII-related antigen and ristocetin co-factor, on the electrophoretic mobility of factor VIII-related antigen and analysis of the multimers of factor VIII-related antigen. The patient with yon Willebrand's disease who is undergoing major surgery will require to have his factor VIII level raised. This may be achieved by giving transfusion of cryoprecipitate or intermediate purity factor VIII concentrates. Alternatively if the level of factor VIII complex is > 10 15% of normal, the vasopressin analogue, desmopressin (DDAVP) may be used in a dose of 0.2-0.5 ~tg/kg administered by the intravenous route. Cyklokapron should be given to counter the increase of plasminogen activation brought about by DDAVP. The factor VIII response to the D D A V P may vary from patient to patient and it is therefore important to assay the patient's factor level after administration of the drug. In patient's undergoing major surgery it is desirable to maintain the level of factor VIII above 40-50% of normal until wound healing is well advanced. If blood products are used a dose of 15-20 iu/kg body weight should be given immediately before operation. Thereafter further doses are given depending on the level of factor VIII found by daily assay.
Rare Coagulation Factor Deficiencies Inherited deficiencies of coagulation factors other than factor VIII complex and factor IX are very uncommon and will be mentioned here only briefly.
Plasma thromboplastin antecedent (Factor X I PTA ) deficiency
Fig. 5--Haemophilic synovium removed at surgery. The pannus is blood and haemosiderin stained.
This condition is inherited as an autosomal recessive trait. Homozygotes tend to bleed excessively. In the majority of cases bleeding is mild and usually follows injury. Epistaxis and menorrhagia may be trouble-
CURRENT ORTHOPAEDICS
some. Laboratory testing shows a prolonged activated partial thromboplastin time and a normal prothrombin time. Specific assay for factor XI is necessary to confirm the diagnosis. Treatment of bleeding consists of giving transfusion of fresh frozen plasma.
Factor X (Stuart-Prower factor) deficiency This condition is transmitted as an autosomal recessive disease and is extremely rare. Bleeding may be severe especially in the homozygotes. The prothrombin time and activated partial thromboplastin times are prolonged as is the recalcification time in the presence of Russell's viper venom. Plasma is an effective method of treatment although for severely affected patients undergoing major surgery it may be necessary to use a prothrombin complex concentrate.
Factor VII deficiency This condition is rare and is probably transmitted as an autosomal recessive trait. The prothrombin time is prolonged but the activated partial thromboplastin time is normal. Specific assay of factor VII is required for the diagnosis. Bleeding from the gastrointestinal tract, epistaxis and menorrhagia may be troublesome. Severely affected patients may suffer haemarthroses and severe crippling. Treatment consists of giving fresh frozen plasma, a prothrombin complex concentrate or a factor VII concentrate. The factor has a short half-life ( ~ 6 h) and it may be necessary to give transfusions three times daily.
Factor V deficiency This is an autosomal recessive condition. It is very rare. Bleeding symptoms are usually mild and include epistaxis, gastrointestinal haemorrhage, menorrhagia and bleeding from cuts and scratches. Associated congenital abnormalities involving the kidneys and heart have been found. The patient's prothrombin time is prolonged and the skin bleeding time may be abnormal. Treatment consists of giving transfusions of fresh frozen plasma.
Prothrombin deficiency This is inherited as an autosomal recessive condition and is very rare. Bleeding is from mucous membranes and after injury. The prothrombin time is prolonged. Treatment consists of giving transfusions of fresh frozen plasma. There is a long half-life of prothrombin in the circulation (3-4 days) and transfusions twice weekly are therefore sufficient even for major surgery.
Congenital afibrinogenaemia This is an autosomal recessive condition. There is often a history of consanguinity in the family. Surprisingly, despite having very low levels of fibri-
307
nogen and blood which is completely incoagulable, affected people may have only slight bleeding problems. Bleeding usually follows injury and surgery. Females may suffer menorrhagia. Haemarthrosis is extremely uncommon. The whole blood clotting time, activated partial thromboplastin time, prothrombin time and thrombin time are infinitely prolonged and fibrinogen cannot be detected in the plasma. Bleeding responds to transfusions of plasma or cryoprecipitate. Transfusions need be given only once or twice a week because of the long half-life of fibrinogen (4-6 days).
Dysfibrinogenaemia This is a qualitative abnormality of fibrinogen and is rare. Many variants have been described. In general, bleeding is very mild, and many sufferers have experienced thromboembolism rather than bleeding. The thrombin time, prothrombin time and activated partial thromboplastin time are all prolonged. If treatment is necessary plasma should be given.
Factor XIII deficiency This is one of the more common of the rare bleeding disorders. Factor XIII is a precursor of plasma transglutaminase and is necessary for stabilisation of the fibrin clot. The mode of transmission of the deficiency is not known for certain. Homozygotes suffer lifelong bleeding which may be severe. Typically there is excessive bleeding following separation of the umbilical cord, prolonged bleeding after injury or surgery, bruising and muscle haematomas. Delayed wound healing is common as is bleeding into the central nervous system; there is a tendency to abortion. The diagnosis is made by finding the patient's fibrin clots soluble in 5M urea or 1% monochloracetic acid. Normal fibrin clots are resistant to those agents. Treatment of bleeding consists of giving transfusions of plasma, cryoprecipitate or one of the factor XIII concentrates now available. In view of the high risk of intracranial haemorrhage, severely affected patients should be given prophylactic treatment. Because of the long half-life of factor XIII (6-10 days) a dose of cryoprecipitate every 2-3 weeks should suffice.
Complications of Transfusion Therapy Transfusion with blood or blood products carries the risk of several possible complications. Until recently these were considered to be relatively unimportant compared to the benefits of treatment and so were rarely considered as contraindication to therapy. The emergence of hepatitis and infection with HIV has meant that this point of view has had to be modified and careful thought must be given to the balance of benefits and risks before administration of any blood products, especially to mildly affected patients.
308
BLEEDING DISORDERS
Hypervolaemia This is a well-known and potentially life-threatening compiication of treatment with whole plasma, especially when large volumes are transfused rapidly. With the advent of potent factor concentrates it is now rarely seen. If large volumes are to be used it is wise to give a diuretic prophylactically.
Allergic reaction Allergic reactions following transfusion with plasma or plasma factor concentrates are uncommon but may be severe and life-threatening. Reactions may occur during or within 1-2 h of administration of a dose and consist of backache, headache, rigor, tightness of chest, wheeze, urticaria and itching. If a reaction occurs the dose should be stopped and an antihistamine given intravenously. For more severe reactions steroids or subcutaneous adrenaline may be required. If a patient is known to have adverse reactions to plasma concentrates he should be given antihistamine prophylactively following which the factor concentrate should be given cautiously.
Haemolysis Most factor VIII concentrate contains small amounts of blood group isoagglutinins which seem to be of little significance when average size doses are used in treatment. If large doses of concentrate are given, for example in the management of patients with antibodies to factor VIII, haemolysis may occur. Progressive anaemia in a patient whose blood group is A, B or AB, and who is receiving large doses of concentrate suggests the possibility of haemolysis. The haemolysis stops when factor replacement is withdrawn.
Hepatitis Hepatitis is an important complication of transfusion therapy. The risks are especially great with coagulation factor concentrates made from large pools of plasma collected from many donors. The testing of each blood donation for hepatitis B virus has greatly reduced the incidence of hepatitis B after transfusion of blood and blood products. In spite of this, many haemophilic patients still develop jaundice and it is clear that the majority of these episodes are due to neither the hepatitis A virus nor the hepatitis B virus. The diagnosis of this non A non B (NANB) hepatitis is made by a process of exclusion when a patient with acute hepatitis has no serological marker for hepatitis A, hepatitis B, cytomegalovirus or Epstein Barr virus. The agent(s) causing non A non B hepatitis have still not been isolated nor has it been possible to demonstrate antibodies in the patient's serum. There is now evidence that most large pool factor VIII concentrates are contaminated with N A N B viruses and will cause hepatitis in nearly 100K of recipients who have not been heavily transfused in the past. Unfortunately
attempts to reduce infectivity of the concentrates by heating them have not proved effective. The NHS concentrates of factor VIII and factor IX at present available have undergone a very severe heating procedure (80°C for 72 h) and are at present being evaluated. The results to date are encouraging. Because of this danger of transmitting N A N B hepatitis careful consideration should be given to the benefits and risks of transfusing large pool concentrates to any given patient; this applies especially if the patient is mildly affected and has received little in the way of concentrates in the past. In the case of mild haemophilia, von Willebrand's disease and in carriers of haemophilia, cryoprecipitate or desmopressin (DDAVP) may be the treatment of choice. In the case of mild Christmas disease plasma may be preferred to a concentrate. The clinical illness found with non A non B hepatitis is often mild but some patients experience severe symptoms and may have abnormal liver function for many months. A significant proportion go on to develop chronic liver disease and cirrhosis.
HTL VIII/ LA V/HIV injection Within the past 5 years it has become clear that the retrovirus known variously as human T cell lymphotropic virus (HTLVIII), lymphadenopathy associated virus (LAV) or human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). Those at risk of acquiring the disease include homosexual and bisexual men, recipients of infected blood or blood products and intravenous drug abusers who share contaminated needles and syringes. A survey carried out at Haemophilia Centres in the United Kingdom in August, 1985 revealed that approximately 60~ of severely affected haemophiliacs and 10~ of Christmas disease patients were positive for HIV antibody. This presumably means that they have at some time been exposed to HIV as a consequence of transfusion therapy. Patients at greatest risk were those who had received doses of commercial clotting factor concentrates prepared from large donor pools. It is predicted that approximately 5~o of sero positive haemophiliacs will go on to develop full-blown AIDS. To date (March, 1987) in the United Kingdom 24 cases of AIDS have been reported in haemophiliacs out of a total population of 5000 patients. Detailed guidelines have been drawn up giving advice on the management of patients who have AIDS or who are HIV antibody positive. Those guidelines should be consulted and followed whenever a haemophiliac is admitted to hospital especially if he is bleeding externally or if he is undergoing surgery.
Antibodies to factor VIII Approximately 12~ of severely affected haemophiliacs have antibodies to factor VIII. This is an
CURRENT ORTHOPAEDICS
important complication and makes treatment of bleeding extremely difficult. Suppression of the antibody by means of drugs such as steroids, cyclophosphamide or azathioprin has met with little success, although immune tolerance has been brought about by giving very large doses of factor VIII daily over many months. For the treatment of haemorrhagic episodes different methods have been used depending on the titre of the antibody. These methods include giving human or porcine factor VIII concentrate in large doses; administration of prothrombin complex concentrates with the aim of by-passing the factor antibodies site of action in the clotting process. Patients with Christmas disease rarely develop antibodies to factor IX; the incidence in the United Kingdom is approximately 1 2% of severely affected patients.
Thromboembolic complications Thromboembolism has been described following transfusion of prothrombin complex concentrates. Patients with liver dysfunction, neonates and patients undergoing major surgery are particularly at risk. Thrombogenicity which was thought to be due to the presence of activated coagulation factors in the preparations has been greatly reduced since the introduction, by the manufacturers, of a range of in vivo and in vitro tests for potential thrombogenicity. /
Acknowledgements The figures used in this article have been reproduced from Bleeding Disorder~R. A. Dickson 1983 in Postgraduate Textbook of Clinical Orthopaedics, by kind permission of the publishers, John Wright & Sons Limited, Bristol.
References 1. Poole J G, Hershgold E J, Pappenhagen A 1964 High potency antihaemophilic factor concentrate prepared from cryoglobulin precipitate. Nature 203 : 312
309
2. Stein H, Dickson R A 1975 Reversed dynamic slings for knee flexion contractures in the haemophiliac. Journal of Bone and Joint Surgery 57A : 282
Further Reading Biggs R, Rizza C R 1984 Human Blood coagulation, Haemostasis and Thrombosis. Oxford, Blackwell Scientific Publications Bloom A L, Thomas D P 1981 Haemostasis and Thrombosis. Edinburgh, Churchill Livingstone Bloom A L 1984 Acquired immunodeficiency syndrome and other possible immunoiogical disorders in European haemophiliacs. Lancet: 1452-1455 Centers for Disease Control (1982a) Pneumocystis carinii pneumonia among persons with haemophilia A. Morbidity and Mortality Weekly Report 31 : 365 367 Centers for Disease Control (1982b) Possible transfusionassociated acquired immune deficiency syndrome (AIDS) California. Morbidity and Mortality Weekly Report 31 : 652 654 C h o o K H, Gould K G, Rees D J G, Brownlee G G 1982 Molecular cloning of the gene for human anti-haemophilic factor IX Duthie R B, Matthews J M, Rizza C R, Steel W M 1972 The Management of Musculo-skeletal problems in the haemophilias. Oxford, Blackwell Scientific Publications Gitschier J, Wood W I, Goralka T M e t al 1984 Characterization of the human factor VIII Gene. Nature 812:326 Jackson C M, Nemerson Y 1980 Blood Coagulation. Annual Review of Biochemistry 49: 765 Kasper C K 1973 Post operative thromboses in hemophilia B. New England Journal of Medicine 289 : 160 Macfarlane R G 1964 An enzyme cascade in the blood clotting mechanism : its function as a biological amplifier. Nature 202 : 498 Mannucci P M, Ruggeri Z M, Pareti F I, Capitanio A 1977a 1-deamino -8-D-arginine vasopressin : a new pharmacological approach to the management of haemophilia and von Willebrand's disease. Lancet 1 : 869-872 Ratnoff O D, Forbes C D 1984 Disorders of Hemostasis. Orlando, Florida, Grune & Stratton Inc Rizza C R, Spooner R J D 1983 Treatment of haemophilia and related disorders in Britain, Northern Ireland during 1976 80: report on behalf of the directors of haemophilia centres in the United Kingdom. British Medical Journal 286:929 933 Smith J K, Bidwell D 1979 Therapeutic materials used in the treatment of coagulation defects. Clinics in Haematology 8:183 206 Winkelman L, Owen N E, Haddon M, Smith J K 1985 Treatment of a new high specific activity factor VIII concentrate to inactivate viruses. Meeting Abstract. Thrombosis and Haemostasis 54(1): 19
C. R. R i z z a
questioning wherever possible and to ask specific questions. The patient should be asked about his responses to mild knocks and scratches and whether or not he feels he bleeds longer than normal or bruises abnormally. Some patients have difficulty in deciding what is normal and what is abnormal, in which case it may be necessary to ask them very specifically if bruising after sporting injuries was much different from that of their colleagues in the team or if bleeding from cuts is different from that in school friends or workmates. Questions about bleeding following minor operations such as dental extractions or more major surgery such as tonsillectomy, give invaluable information. Whether or not blood transfusion was required should always be recorded. Questioning about dental extraction will give more valuable information if the patient can specify the number and type of teeth removed. Tonsillectomy is a particularly useful test of the haemostatic mechanism and if the patient did not bleed following tonsillectomy, it is unlikely that he was suffering at the time from a significant haemorrhagic disorder. The site and nature of bleeding may give valuable information about the underlying defect. Platelet and vascular defects and von Willebrand's disease may cause petechial haemorrhages or ecchymoses in the skin, nosebleeds and bleeding from the mucous membranes of the mouth, gastrointestinal tract and genitourinary system. On the other hand intramuscular, intra-articular and retroperitoneal haemorrhages are seen chiefly in the severe blood coagulation defects, in particular haemophilia A and haemophilia B. A history of recurrent epistaxes is of limited diagnostic value as nosebleeds are not uncommon in childhood and may be associated with upper respiratory tract congestion. Haematuria may be due to haemophilia, anticoagulant therapy or thrombocytopenia. Bleeding
Assessment
Patients with bleeding disorders, no matter how mild, are at risk of bleeding excessively following injury or surgery and may present the clinician with a difficult problem in diagnosis. When faced with a patient who is thought to have a bleeding disorder, the clinician must ask himself two questions 1) Does the patient have a bleeding disorder? and 2) What is the nature and severity of the disorder? The first question can only be answered by taking a careful clinical history and carrying out a full clinical examination. The second question is answered by examination of the patient's blood in the laboratory to see if there is any deficiency in coagulation factors or platelets (Fig. 1) and to assess the severity of the deficiency. The importance of the clinical history cannot be stressed too much and the failure to demonstrate an abnormality in laboratory tests in the face of a strong history of haemorrhage does not rule out the diagnosis of a bleeding disorder; it suggests that the tests used were inappropriate or not sensitive to the patient's defect. Similarly, abnormal laboratory tests in a patient who has recently undergone major surgery without haemorrhage suggests that the test is reflecting some deficiency which is of little or no importance in normal haemostasis. An example of this latter situation is seen in patients suffering from factor XII (Hageman factor) deficiency who have grossly abnormal activated partial thromboplastin times but do not bleed abnormally.
Clinical history When asking a patient about his history of bleeding, it is desirable to follow the same procedure of Dr C. R. Rizza FRCP, Consultant Physician, Oxford Haemophilia
Centre, Churchill Hospital, Headington, Oxford,OX3 7LJ. Current Orthopaedics (1987) 1,299 309 © 1987 Longman Group UK Ltd
299
300
BLEEDING DISORDERS Anionic
Surface
HMWK
Kallikrein Vll
Xlla
Xll
I Tissue Factor XI
Vlla
~ Xla
Ca2+[ IX
..... ~ V l l l
mVllla
Ca 2
X
~ PL
.......... ..,..• ..... .O,~V
I~Va Ca 2+
•
Pro thrombin
ionian •
~ Th rombin
(II)
p
'l'l
(lla)
~
ii•...•...........n.mmmn........n...mm•.I ••'e••'~• ••'~'°°'~•
XIII
~Xlla
;,Fibrin
Fibrinogen
Stabilised
Fibrin
Fig.
1 - - A schematic representation of the b l o o d coagulation cascade: H M W K = High molecular w e i g h t kininogen FL = p h o s p h o l i p i d a = A c t i v a t e d factor . . . . > = Feed b a c k mechanisms
from the gastrointestinal tract m a y be a complication of any haemorrhagic disorder and enquiries should be made about the ingestion of drugs, in particular aspirin and oral anticoagulants. A history of exposure to toxic chemicals should also be sought. When enquiring about past history the patient should be asked about jaundice, hepatitis and the use of alcohol. In women attention should be paid to menorrhagia although this by itself is of little value as a diagnostic symptom. Excessive bleeding after childbirth and the need for blood transfusion should also be enquired after. Family history is important and details of haemorrhagic symptoms in other family members should be sought. This information by itself m a y give a strong hint as to the possible diagnosis. Haemophilia A and B are both sex-linked conditions. Von Willebrand's disease is autosomal dominant and the rest of the inherited disorders are autosomal recessive.
Laboratory tests All patients suspected of having a bleeding disorder should have estimation of haemoglobin, white cell count and platelet count. The bleeding time should be measured using the Ivy method or a modification which standardises the depth of incision by using a template. An automated device which produces a
standard cut is commercially available. The bleeding time is prolonged in quantitative or qualitative platelet deficiencies, von Willebrand's disease and following ingestion of aspirin. At present there is no simple and reliable screening test of haemostasis but there are several simple tests of clotting function which when carried out together can give a good indication of the likely diagnosis and suggest which factor should be assayed (Table 1). The definitive diagnosis will require a specific assay of the appropriate clotting factor. 1 Resultsof prothrombin time and activated partial thromboplastin time in different coagulation factor deficiencies
Table
Deficiency
Prothrombin time
APTT
Fibrinogen (factor I) Prothrombin (factor II) Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII High molecular weight kininogen Prekallikrein Factor XIII
+ + + + N N + N N N N N
+ + + N + + + + + + + N
N = Normal + = Prolonged
CURRENT ORTHOPAEDICS 301 Those assays are not easy and should be carried out by experienced staff who know how to interpret the results and provide the necessary quality control of assay and reagents. Bleeding disorders may be inherited or acquired. In general the inherited bleeding disorders are due to deficiency of one factor whereas acquired bleeding states usually show a deficiency of several coagulation factors with platelets also occasionally being involved. Table 2 shows some in vivo characteristics of blood clotting factors. This paper deals with inherited bleeding disorders and in particular classical haemophilia (haemophilia A) and Christmas disease (haemophilia B). Both these conditions can cause serious damage to the musculo-skeletal system and their management requires close collaboration with orthopaedic experts.
Classical Haemophilia (haemophilia A) and Christmas Disease (haemophilia B) Haemophilia and Christmas disease are inherited bleeding disorders which affect males and are transmitted as X-linked recessive conditions. Some female carriers may have bleeding symptoms. Bleeding in haemophilia is due to complete or partial deficiency of factor V I I I coagulant activity; in Christmas disease the bleeding is due to deficiency of factor IX. The genes for factor V I I I and factor IX lie on the X chromosomes and have recently been cloned. The factor V I I I gene is the largest known to date and is approximately 186 x 103 bases in length. The active factor V I I I produced by the gene is a glycoprotein
containing 2332 amino acids. In the case of factor IX the gene is approximately 34 x 103 bases long and codes for a mature protein containing 423 amino acids. Factor V I I I and factor IX are essential for the conversion of factor X to factor Xa, the active enzyme which converts prothrombin to thrombin in the clotting cascade. In the absence of factor VIII or IX the coagulation process is greatly delayed and thrombin generation is poor.
Prevalence Classical haemophilia is the commonest of the inherited severe bleeding disorders. In the United Kingdom the condition is present in 90 per million of the population, approximately 40% being severely affected with factor VIII level. In the case of Christmas disease the prevalence is 15 per million of the population with 30% being severely affected.
Inheritance Haemophilia and Christmas disease are passed on as X-linked conditions but it should be remembered that approximately 30% of sufferers have no previous family history of the condition. Both conditions run 'true' in a family so that all affected members of a given family will suffer from the same severity of the condition. This is important information for women carriers who are considering whether or not to have children. Because of the mode of inheritance a haemophilic male cannot pass the condition to his sons but all of his daughters will be
Table2--Some in vivoproperties of the differentclotting factors
Factor
Deficiencystate
I Afibrinogenaemia Defibrination syndrome II Prothrombindeficiency Coumarin anti-coagulanttherapy Liver disease V FactorV deficiency VII FactorVII deficiency Coumarin anti-coagulanttherapy Liver disease VIII Haemophilia von Willebrand's disease IX Christmasdisease Coumarin anti-coagulanttherapy Liver disease X FactorX deficiency Coumarin anti-coagulanttherapy Liver disease XI PTA deficiency XII Hagemandefect XIlI Fibrin stabilising factor deficiency * Higher levelsmay be required during surgery.
Plasma concentration required for haemostatis (% normal) 10 25
Half-life of transfused factor 4-6 days
Recoveryin blood (as transfused dose) 5O
40 10 15
3 days 12h
40-80 80 100
5 10
4-6 h
80-100
10 40*
8 12h
50-80
10 40*
12.-24 h
30 50
10-15 ?3O
2 days 60-80 h 60 h ?6 10 days
50 90 100
15
50 100
302
BLEEDING DISORDERS
obligatory carriers. In the case of carrier women, there is a 50: 50 chance that their sons will be affected or be normal and a 50:50 chance that their daughters will be carriers or be normal. Women in haemophilic families may wish to know if they are carriers of the condition and many when pregnant go on to request antenatal testing of the foetus to find out if it is affected. This would only be proceeded with if the woman wished abortion of an affected foetus. With regard to discovering the carrier status of a woman, a probability assessment of carrier status can be given in approximately 75~ of possible carriers by using pedigree information and assay of factor VIII coagulant activity and factor VIII-related antigen. More recently it has been possible by means of gene probing and using D N A polymorphisms to discover the carrier status with a high degree of certainty in those families which carry an appropriate polymorphism. Similar genetic methods applied to D N A obtained from chorionic villus biopsy will allow antenatal diagnosis in a proportion of women at 8-10 weeks of pregnancy. In women in whom a useful polymorphism is absent, antenatal diagnosis can still be offered by carrying out factor VIII assay on blood obtained from the foetus by foetoscopy at 17-19 weeks of pregnancy. The disadvantage of this method lies in the lateness of the termination of pregnancy in those women found to be carrying an affected son.
Diagnosis The patient's clinical history and any family history may raise the suspicion of haemophilia or Christmas disease. Laboratory tests show the bleeding time and ,prothrombin time to be normal but the whole blood clotting time and activated partial thromboplastin times are prolonged. A definitive diagnosis is made by carrying out specific assays for factor VIII or factor IX. In severely affected patients the factor level will be < 1X of average normal. More mildly affected patients will have levels between 2 ~ and 25~ of normal.
Clinicalfeatures Haemophilia and Christmas disease have the same clinical features and are indistinguishable on clinical grounds. They are both characterised by prolonged bleeding, sometimes continuing for weeks, following accidents or surgery. The onset of bleeding after the injury may be delayed for hours or even days. The severity of bleeding experienced correlates well with severity of the coagulation factor deficiency (Table 3); patients with no detectable level of factor VIII or IX usually bleed severely after minor injury or even spontaneously whereas patients with levels greater than 4 - 5 ~ may lead a normal life unless they are involved in accidents or undergo surgery. Acute haemarthrosis. Bleeding into joints is a classical feature of severe haemophilia and Christmas disease (Fig. 2). On many occasions the joint bleeding seems to be spontaneous in so far as the patient cannot recall any definite injury. The onset of bleeding may be preceded by a variety of sensations in the knee including a feeling of warmth, prickling, tickling or a sensation of water trickling in the joint. If bleeding progresses those symptoms are followed in a short time by stiffness, then pain and swelling of the joint. In severe episodes pain is extreme and the joint is held in a semi-flexed position and cannot be flexed or extended. Muscle haemorrhage. Bleeding into muscles is common in severe haemophilia and Christmas disease and may sometimes be as damaging in terms of limb function as bleeding into joints. The flexor muscles of the forearm and the muscles of the calf are common sites of bleeding. In young children buttock haematomas are relatively common and are probably due to the child sitting down hard while learning to walk. In addition to destroying muscle tissue large muscle haematomas may cause pressure on neurovascular bundles and other structures. The iliacus haematoma is a particularly important type of muscle haemorrhage since it may compress the femoral nerve as it runs under the iliacus fascia and cause loss of muscle power in the quadriceps and instability of the knee (Fig. 3). The condition may be mistaken for appendicitis if it
Table 3--Relationship of plasma factor VIII level to the severity of bleeding Plasma level of factor VIII (iu/dl) >40 20 40 5 20 1-5 <1
Bleeding manifestations None Tendency to bleed after major injury. Often not diagnosed. Bleeding after minor injury and surgery. Severe bleeding after minor injury. Occasional haemarthroses and 'spontaneous' bleeding. Severe haemophilia. Spontaneous haemarthroses and muscle haemorrhages. Joint ankylosis and crippling.
Fig. 2 - - A n acute knee haemarthrosis in a patient with clinical severe haemophilia.
CURRENT ORTHOPAEDICS
Fig. 3 - - A n iliacus bleed with a palpable haematoma in the left iliac fossa (cross hatched) and an area of numbness in the femoral nerve distribution (dotted).
occurs on the right side. The diagnosis is made by finding a palpable tender mass in the iliac fossa, a hip flexion deformity and altered sensation down the front of the thigh with a diminished knee reflex. Occasionally a large muscle haematoma fails to resolve completely and following a series of re-bleeds takes on the features of a haemophilic cyst or pseudotumour. Any muscle may be involved but the commonest sites are the pelvic region, thigh and calf. Such cysts may attain a great size and cause pressure on nerves and surrounding structures and may lead to fracture of the pelvis or femur. Ultrasound or CT scanning is of value in delineating the size of haemophilic cysts and in following their progress. In addition to pseudotumours which appear to arise from muscle some seem to have their origin in bone. Chronic arthropathy. Repeated joint bleeding results in joint damage with synovial thickening, loss of cartilage, osteoporosis and eventually fibrosis or bony ankylosis (Fig. 4). In addition to the loss of joint function and mobility chronic arthropathy is usually accompanied by pain which limits the patient's day time activities, disturbs his sleep and may be difficult to control with anything but the most powerful analgesics. Haematuria. This is common and in the majority of instances is painless and not associated with infection or any other underlying pathology in the urinary tract. Occasionally large clots may form in the renal pelvis causing obstruction to urinary flow and severe clot colic.
Gastrointestinal haemorrhage. This is often associated, as in the patient without bleeding diathesis, with gastric or duodenal ulceration or some other gut pathology. In a small proportion of cases no underlying lesion can be demonstrated by endoscopy or X-ray examination. Bleeding from oesophageal varices secondary to liver disease is in our experience becoming more common. Sometimes bleeding is related to aspirin intake. Intracranial haemorrhage. This is a serious complication of haemophilia and although it is relatively uncommon it is still the commonest cause of death in haemophiliacs, accounting for 20-25~ of deaths. Most cases of intracranial haemorrhage follow some minor injury to the head. Treatment of bleeding in haemophilia and Christmas disease Bleeding in haemophilia and Christmas disease can be controlled by giving transfusions of material containing the appropriate clotting factor; factor VIII in the case of haemophilia and factor IX in the case of Christmas disease. The level of factor required to achieve haemostasis will depend on the nature and site of bleeding and the severity of the injury or surgery (Table 4). The post-transfusion level in the circulation is fairly well correlated with the size of the dose given providing the patient's weight is taken into account and providing he does not have antibodies to factor VIII or IX. In general a factor VIII increase in the patient of 2 iu/dl can be expected for every iu/kg body weight administered. In the case of Christmas disease the factor IX level increases by 1 iu/dl for each iu of factor IX/kg body weight. Such simple formulae are useful for deciding the size of initial doses but there may be considerable variation in the response in different patients and it is important to monitor the patient's response by carrying out post-transfusion assays to be sure that the desired level is being achieved.
Materials used in replacement therapy 1) Plasma. Until 1964 fresh frozen plasma was the therapeutic material most widely used in the treatment of haemophilia and Christmas disease. Minor hae-.
Table 4--Approximate levels of factor VIII required for haemostasis in different lesions
Lesion Minor spontaneous haemarthrosis and muscle haematomas Severe haemarthrosis and muscle haematomas, haematomas in dangerous situations Major surgery
303
Level of factor VIII desired in patient's blood immediately after transfusion (iu/100 ml)
Dose of factor VIII (iu/kg body weight)
15-20(0 5)
10 15
20-49 (5-10) 80-100 (or less if transfusion given 8-hourly or 6-hourly)
15 20 40-50
Figures in parentheses are the approximate levels to which factor VIII will have fallen 24 hours after dose.
304
BLEEDING DISORDERS
Fig. 4 ~ ( A ) and (B) AP and lateral radiographs showing chronic haemophilic knee arthropathy. Features, in addition to secondary degenerative change, are metaphyseal/epiphyseal widening (due to local hypervascularity during growth), widening of the intercondylar notch, squaring of the lower end of the patella, and generalised osteoporosis.
morrhages and early haemarthroses could be controlled by means of fresh frozen plasma but it was extremely diffficult to maintain haemostasis following surgery with this material because of the large volume required. Plasma is now rarely used in the treatment of haemophilia but is still used in the treatment of factor V deficiency and factor XI deficiency for which there are at present no factor concentrates available. 2) Cryoprecipitate. The introduction of cryoprecipitate in 19641 was a major advance in the management of haemophilia. It was shown that the cold insoluble protein remaining after gentle thawing of frozen plasma was rich in factor VIII. By separating this material by centrifugation, a potent concentrate of factor VIII was obtained. Cryoprecipitate contains approximately 50~ of the factor VIII activity of the original plasma and 50~ of the original fibrinogen content. In addition there are large amounts of fibronectin and factor XIII. Cryoprecipitate is of no
value in the treatment of Christmas disease. The advantages of cryoprecipitate are the ease and low cost of production. Since it is not prepared from large pools of plasma, it also carries a relatively low risk of transmitting hepatitis or HIV infection. It is therefore often used for treating mildly affected patients who have had few previous transfusions, and who are at particular risk of developing hepatitis. Clearly if large doses of cryoprecipitate are given over a prolonged period the patient's exposure to infection is increased. The disadvantages of cryoprecipitate are that reconstitution is laborious and time consuming; it must be stored at - 20°C or less which makes it unsuitable for home therapy; there is considerable variation in factor VIII content from bag to bag which makes rational replacement therapy difficult. 3) Intermediate and high purity factor VIII concentrates. These concentrates are prepared using cryoprecipitate as the first step in the purification process. Thereafter
CURRENT ORTHOPAEDICS
depending on the degree of purity further steps may be added including washing with buffer, adsorption with aluminum hydroxide and precipitation with polyethylene glycol, ethanol or heparin. High purity concentrates have a specific activity usually greater than 1 iu factor VIII/mg protein and are used at a potency of 20-30 iu/ml; intermediate purity concentrates have a specific activity of 0.2 0.5 iu factor VIII/rag protein and are used at a potency of 10 20 iu/ml. As expected the greater the purity sought the greater the factor VIII toss in the manufacturing process. Most of the factor VIII used in the U K at present is of intermediate purity. All intermediate and high purity concentrates whether produced by commercial companies or by NHS laboratories are prepared from blood donations tested for anti-HIV. In addition the finished freezedried product undergoes a heating process to inactivate any HIV which may be present. The heating regime varies with the different manufacturers. The material at present prepared by the NHS fractionation laboratories is heated to 80°C for 72 h. Hopefully this degree of heating will inactivate not only HIV but also the viruses which cause hepatitis. It is already known that less severe heating such as 60°C for 72 h is not sufficient to inactivate the virus of non A non B hepatitis. Although prepared from blood donations tested for anti-HIV it should be noted that cryoprecipitate cannot be heated. 4) Prothrombin complex (II, VII, IX and X) concentrates. The chief value of these preparations is in treatment of Christmas disease. Because of their chemical characteristics all four factors tend to fractionate together although it is possible with relative ease to separate factor VII from the other three and collect it as a separate fraction for treatment of factor VII deficiency. The prothrombin complex concentrates at present used in the U K are obtained from cryoprecipitate supernatant using DEAE cellulose chromatography. Because of the long half-life of prothrombin compared with factor IX it can be seen that a patient with Christmas disease receiving heavy treatment with prothrombin complex concentrate may develop very high levels of prothrombin which may be dangerous. As with factor VIII all prothrombin complex concentrates are now prepared from donors tested for anti-HIV and have undergone a heating stage.
Management of acute haemarthroses Bleeding into joints can be an acutely painful condition. Treatment aims at controlling the bleeding and relieving the pain. Clotting factor concentrates should be administered in a dose of 10 15 iu kg/body weight as soon as possible after the onset of bleeding. For an early mild haemarthrosis a single dose may be sufficient but for severe haemorrhage, especially following injury it may be necessary to give larger doses and repeat the dose daily for several days. If pain is severe,
305
analgesic drugs such as pethidine, morphine or dextromoramide should be given, always bearing in mind the risk of inducing drug dependency. Immobilisation of the joint in a light plaster of Paris back splint also helps to diminish the pain. The majority of haemarthroses respond quickly to these simple measures and the patient can start mobilisation gently within a few days. Bleeding into muscles should be treated in a similar way. Mobilisation after haemorrhage into muscle should be gradual and gentle because of the risk of re-bleeding.
Home therapy In view of the delay and great inconvenience often caused to the patient by going to hospital for transfusion therapy, many centres have started programmes of home therapy or self-therapy for their severely affected patients. The coagulation factor is administered by the patient or a close member of his family and there seems little doubt that bleeding episodes are being treated earlier and thus loss of time from school or work has been reduced. It is too early to know if there has been a significant reduction in chronic arthropathy in patients on home therapy.
Management of chronic arthropathy Treatment of chronic arthropathy is aimed at reducing pain and improving joint and muscle function. Cooperation with orthopaedic specialists and physiotherapists is essential. The mainstays of management are: l) Physiotherapy 2) Splinting of the joint 3) Correction of joint deformity by non-surgical means, e.g., reversed dynamic slings 4) Analgesics 5) Reconstructive surgery including arthroplasty 1) Physiotherapy. The function of a joint with only slight structural damage may be improved considerably by exercise aimed at improving muscle strength and range of movement. In the case of severely damaged joints with flexion contractures, physiother-. apy seems of less benefit. 2) Splinting. Damaged joints are often unstable and as a consequence prone to recurrent bleeding. Calipers will give some support to the knees and ankles. More recently splinting by means of light plastic 'supports' have been found of value for knees, ankles and elbows. Firm boots lacing above the ankles are often sufficient to reduce pain or haemorrhage in the ankles. 3) Reverse dynamic slings. A system of dynamic slings has been described 2 which has proved of value in treatment of fixed flexion contracture of the knees. The method is gentle, does not require factor replacement and may produce benefit within a few days. 4) Analgesics. Pain is common in haemophilic arthro-
306
BLEEDING DISORDERS
pathy and may be severe, disrupting the patient's day time routine and his sleep. Aspirin and aspirincontaining preparations should not be used. Paracetamol, pentazocine or dihydrocodeine should be given in the first instance. Non-steroidal anti-inflammatory drugs may give some relief but it may be necessary for the patient and his doctor to explore the various possibilities to see which suits the patient best. More powerful potentially addictive drugs such as pethidine, dextromoramide and morphine should be used with great care and only in short courses. 5) Reconstructive surgery. If all of the above measures fail to give benefit and especially if pain is severe, it may become necessary to relieve deformity and pain by surgical means. Procedures which have been found of value in the management of haemophilic joint disease include synovectomy (Fig. 5), total hip replacement, corrective osteotomy, patellectomy, knee replacement, arthrodesis of knee and ankle.
Major surgery Major surgery in a patient with haemophilia or Christmas disease can be extremely hazardous and requires close collaboration between surgeon, physician, haaematologist and laboratory staff. Before undertaking surgery it is essential to check that the patient does not have antibody to factor VIII or IX. In most instances the finding of antibody is a contraindication to surgery. A transfusion of clotting factor concentrate is administered immediately before surgery. The dose should be sufficient to raise the clotting factor level to 80-100 iu/100 ml. In the case of haemophilia this will require a dose of 40-50 iu factor VIII/kg body weight and in the case of Christmas disease a dose of 80-100iu/kg body weight. Assays are carried out immediately after the dose to make sure that a satisfactory level has been achieved. Further doses are given according to the level of factor VIII or IX in the patient's blood, the aim being to maintain the level above 40 iu/100 ml. Factor replacement is given 8hourly or 12-hourly and this is continued until wound healing is well advanced, usually 7-14 days.
Von Willebrand's Disease After haemophilia A, yon Willebrand's disease is probably the next commonest inherited bleeding disorder. There is a wide range of clinical and laboratory features and it is difficult to be sure of the prevalence of the disease. Estimates range between 30 and 100 per million of population. The condition shows autosomal dominant inheritance and affects males and females equally. It is characterised by a tendency to bleed from mucous membranes especially of the gastrointestinal tract, nose and uterus. Bleeding into muscles and joints is very uncommon and this helps to distinguish it from severe haemophilia. The skin bleeding time is prolonged and examination of the blood shows a variable reduction of the factor VIII coagulant activity and factor VIII-related antigen. There is also reduced aggregation of platelets on addition of the antibiotic ristocetin, yon Willebrand's disease has been classified into several types depending on the relative levels of factor VIII coagulant activity, factor VIII-related antigen and ristocetin co-factor, on the electrophoretic mobility of factor VIII-related antigen and analysis of the multimers of factor VIII-related antigen. The patient with yon Willebrand's disease who is undergoing major surgery will require to have his factor VIII level raised. This may be achieved by giving transfusion of cryoprecipitate or intermediate purity factor VIII concentrates. Alternatively if the level of factor VIII complex is > 10 15% of normal, the vasopressin analogue, desmopressin (DDAVP) may be used in a dose of 0.2-0.5 ~tg/kg administered by the intravenous route. Cyklokapron should be given to counter the increase of plasminogen activation brought about by DDAVP. The factor VIII response to the D D A V P may vary from patient to patient and it is therefore important to assay the patient's factor level after administration of the drug. In patient's undergoing major surgery it is desirable to maintain the level of factor VIII above 40-50% of normal until wound healing is well advanced. If blood products are used a dose of 15-20 iu/kg body weight should be given immediately before operation. Thereafter further doses are given depending on the level of factor VIII found by daily assay.
Rare Coagulation Factor Deficiencies Inherited deficiencies of coagulation factors other than factor VIII complex and factor IX are very uncommon and will be mentioned here only briefly.
Plasma thromboplastin antecedent (Factor X I PTA ) deficiency
Fig. 5--Haemophilic synovium removed at surgery. The pannus is blood and haemosiderin stained.
This condition is inherited as an autosomal recessive trait. Homozygotes tend to bleed excessively. In the majority of cases bleeding is mild and usually follows injury. Epistaxis and menorrhagia may be trouble-
CURRENT ORTHOPAEDICS
some. Laboratory testing shows a prolonged activated partial thromboplastin time and a normal prothrombin time. Specific assay for factor XI is necessary to confirm the diagnosis. Treatment of bleeding consists of giving transfusion of fresh frozen plasma.
Factor X (Stuart-Prower factor) deficiency This condition is transmitted as an autosomal recessive disease and is extremely rare. Bleeding may be severe especially in the homozygotes. The prothrombin time and activated partial thromboplastin times are prolonged as is the recalcification time in the presence of Russell's viper venom. Plasma is an effective method of treatment although for severely affected patients undergoing major surgery it may be necessary to use a prothrombin complex concentrate.
Factor VII deficiency This condition is rare and is probably transmitted as an autosomal recessive trait. The prothrombin time is prolonged but the activated partial thromboplastin time is normal. Specific assay of factor VII is required for the diagnosis. Bleeding from the gastrointestinal tract, epistaxis and menorrhagia may be troublesome. Severely affected patients may suffer haemarthroses and severe crippling. Treatment consists of giving fresh frozen plasma, a prothrombin complex concentrate or a factor VII concentrate. The factor has a short half-life ( ~ 6 h) and it may be necessary to give transfusions three times daily.
Factor V deficiency This is an autosomal recessive condition. It is very rare. Bleeding symptoms are usually mild and include epistaxis, gastrointestinal haemorrhage, menorrhagia and bleeding from cuts and scratches. Associated congenital abnormalities involving the kidneys and heart have been found. The patient's prothrombin time is prolonged and the skin bleeding time may be abnormal. Treatment consists of giving transfusions of fresh frozen plasma.
Prothrombin deficiency This is inherited as an autosomal recessive condition and is very rare. Bleeding is from mucous membranes and after injury. The prothrombin time is prolonged. Treatment consists of giving transfusions of fresh frozen plasma. There is a long half-life of prothrombin in the circulation (3-4 days) and transfusions twice weekly are therefore sufficient even for major surgery.
Congenital afibrinogenaemia This is an autosomal recessive condition. There is often a history of consanguinity in the family. Surprisingly, despite having very low levels of fibri-
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nogen and blood which is completely incoagulable, affected people may have only slight bleeding problems. Bleeding usually follows injury and surgery. Females may suffer menorrhagia. Haemarthrosis is extremely uncommon. The whole blood clotting time, activated partial thromboplastin time, prothrombin time and thrombin time are infinitely prolonged and fibrinogen cannot be detected in the plasma. Bleeding responds to transfusions of plasma or cryoprecipitate. Transfusions need be given only once or twice a week because of the long half-life of fibrinogen (4-6 days).
Dysfibrinogenaemia This is a qualitative abnormality of fibrinogen and is rare. Many variants have been described. In general, bleeding is very mild, and many sufferers have experienced thromboembolism rather than bleeding. The thrombin time, prothrombin time and activated partial thromboplastin time are all prolonged. If treatment is necessary plasma should be given.
Factor XIII deficiency This is one of the more common of the rare bleeding disorders. Factor XIII is a precursor of plasma transglutaminase and is necessary for stabilisation of the fibrin clot. The mode of transmission of the deficiency is not known for certain. Homozygotes suffer lifelong bleeding which may be severe. Typically there is excessive bleeding following separation of the umbilical cord, prolonged bleeding after injury or surgery, bruising and muscle haematomas. Delayed wound healing is common as is bleeding into the central nervous system; there is a tendency to abortion. The diagnosis is made by finding the patient's fibrin clots soluble in 5M urea or 1% monochloracetic acid. Normal fibrin clots are resistant to those agents. Treatment of bleeding consists of giving transfusions of plasma, cryoprecipitate or one of the factor XIII concentrates now available. In view of the high risk of intracranial haemorrhage, severely affected patients should be given prophylactic treatment. Because of the long half-life of factor XIII (6-10 days) a dose of cryoprecipitate every 2-3 weeks should suffice.
Complications of Transfusion Therapy Transfusion with blood or blood products carries the risk of several possible complications. Until recently these were considered to be relatively unimportant compared to the benefits of treatment and so were rarely considered as contraindication to therapy. The emergence of hepatitis and infection with HIV has meant that this point of view has had to be modified and careful thought must be given to the balance of benefits and risks before administration of any blood products, especially to mildly affected patients.
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BLEEDING DISORDERS
Hypervolaemia This is a well-known and potentially life-threatening compiication of treatment with whole plasma, especially when large volumes are transfused rapidly. With the advent of potent factor concentrates it is now rarely seen. If large volumes are to be used it is wise to give a diuretic prophylactically.
Allergic reaction Allergic reactions following transfusion with plasma or plasma factor concentrates are uncommon but may be severe and life-threatening. Reactions may occur during or within 1-2 h of administration of a dose and consist of backache, headache, rigor, tightness of chest, wheeze, urticaria and itching. If a reaction occurs the dose should be stopped and an antihistamine given intravenously. For more severe reactions steroids or subcutaneous adrenaline may be required. If a patient is known to have adverse reactions to plasma concentrates he should be given antihistamine prophylactively following which the factor concentrate should be given cautiously.
Haemolysis Most factor VIII concentrate contains small amounts of blood group isoagglutinins which seem to be of little significance when average size doses are used in treatment. If large doses of concentrate are given, for example in the management of patients with antibodies to factor VIII, haemolysis may occur. Progressive anaemia in a patient whose blood group is A, B or AB, and who is receiving large doses of concentrate suggests the possibility of haemolysis. The haemolysis stops when factor replacement is withdrawn.
Hepatitis Hepatitis is an important complication of transfusion therapy. The risks are especially great with coagulation factor concentrates made from large pools of plasma collected from many donors. The testing of each blood donation for hepatitis B virus has greatly reduced the incidence of hepatitis B after transfusion of blood and blood products. In spite of this, many haemophilic patients still develop jaundice and it is clear that the majority of these episodes are due to neither the hepatitis A virus nor the hepatitis B virus. The diagnosis of this non A non B (NANB) hepatitis is made by a process of exclusion when a patient with acute hepatitis has no serological marker for hepatitis A, hepatitis B, cytomegalovirus or Epstein Barr virus. The agent(s) causing non A non B hepatitis have still not been isolated nor has it been possible to demonstrate antibodies in the patient's serum. There is now evidence that most large pool factor VIII concentrates are contaminated with N A N B viruses and will cause hepatitis in nearly 100K of recipients who have not been heavily transfused in the past. Unfortunately
attempts to reduce infectivity of the concentrates by heating them have not proved effective. The NHS concentrates of factor VIII and factor IX at present available have undergone a very severe heating procedure (80°C for 72 h) and are at present being evaluated. The results to date are encouraging. Because of this danger of transmitting N A N B hepatitis careful consideration should be given to the benefits and risks of transfusing large pool concentrates to any given patient; this applies especially if the patient is mildly affected and has received little in the way of concentrates in the past. In the case of mild haemophilia, von Willebrand's disease and in carriers of haemophilia, cryoprecipitate or desmopressin (DDAVP) may be the treatment of choice. In the case of mild Christmas disease plasma may be preferred to a concentrate. The clinical illness found with non A non B hepatitis is often mild but some patients experience severe symptoms and may have abnormal liver function for many months. A significant proportion go on to develop chronic liver disease and cirrhosis.
HTL VIII/ LA V/HIV injection Within the past 5 years it has become clear that the retrovirus known variously as human T cell lymphotropic virus (HTLVIII), lymphadenopathy associated virus (LAV) or human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). Those at risk of acquiring the disease include homosexual and bisexual men, recipients of infected blood or blood products and intravenous drug abusers who share contaminated needles and syringes. A survey carried out at Haemophilia Centres in the United Kingdom in August, 1985 revealed that approximately 60~ of severely affected haemophiliacs and 10~ of Christmas disease patients were positive for HIV antibody. This presumably means that they have at some time been exposed to HIV as a consequence of transfusion therapy. Patients at greatest risk were those who had received doses of commercial clotting factor concentrates prepared from large donor pools. It is predicted that approximately 5~o of sero positive haemophiliacs will go on to develop full-blown AIDS. To date (March, 1987) in the United Kingdom 24 cases of AIDS have been reported in haemophiliacs out of a total population of 5000 patients. Detailed guidelines have been drawn up giving advice on the management of patients who have AIDS or who are HIV antibody positive. Those guidelines should be consulted and followed whenever a haemophiliac is admitted to hospital especially if he is bleeding externally or if he is undergoing surgery.
Antibodies to factor VIII Approximately 12~ of severely affected haemophiliacs have antibodies to factor VIII. This is an
CURRENT ORTHOPAEDICS
important complication and makes treatment of bleeding extremely difficult. Suppression of the antibody by means of drugs such as steroids, cyclophosphamide or azathioprin has met with little success, although immune tolerance has been brought about by giving very large doses of factor VIII daily over many months. For the treatment of haemorrhagic episodes different methods have been used depending on the titre of the antibody. These methods include giving human or porcine factor VIII concentrate in large doses; administration of prothrombin complex concentrates with the aim of by-passing the factor antibodies site of action in the clotting process. Patients with Christmas disease rarely develop antibodies to factor IX; the incidence in the United Kingdom is approximately 1 2% of severely affected patients.
Thromboembolic complications Thromboembolism has been described following transfusion of prothrombin complex concentrates. Patients with liver dysfunction, neonates and patients undergoing major surgery are particularly at risk. Thrombogenicity which was thought to be due to the presence of activated coagulation factors in the preparations has been greatly reduced since the introduction, by the manufacturers, of a range of in vivo and in vitro tests for potential thrombogenicity. /
Acknowledgements The figures used in this article have been reproduced from Bleeding Disorder~R. A. Dickson 1983 in Postgraduate Textbook of Clinical Orthopaedics, by kind permission of the publishers, John Wright & Sons Limited, Bristol.
References 1. Poole J G, Hershgold E J, Pappenhagen A 1964 High potency antihaemophilic factor concentrate prepared from cryoglobulin precipitate. Nature 203 : 312
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2. Stein H, Dickson R A 1975 Reversed dynamic slings for knee flexion contractures in the haemophiliac. Journal of Bone and Joint Surgery 57A : 282
Further Reading Biggs R, Rizza C R 1984 Human Blood coagulation, Haemostasis and Thrombosis. Oxford, Blackwell Scientific Publications Bloom A L, Thomas D P 1981 Haemostasis and Thrombosis. Edinburgh, Churchill Livingstone Bloom A L 1984 Acquired immunodeficiency syndrome and other possible immunoiogical disorders in European haemophiliacs. Lancet: 1452-1455 Centers for Disease Control (1982a) Pneumocystis carinii pneumonia among persons with haemophilia A. Morbidity and Mortality Weekly Report 31 : 365 367 Centers for Disease Control (1982b) Possible transfusionassociated acquired immune deficiency syndrome (AIDS) California. Morbidity and Mortality Weekly Report 31 : 652 654 C h o o K H, Gould K G, Rees D J G, Brownlee G G 1982 Molecular cloning of the gene for human anti-haemophilic factor IX Duthie R B, Matthews J M, Rizza C R, Steel W M 1972 The Management of Musculo-skeletal problems in the haemophilias. Oxford, Blackwell Scientific Publications Gitschier J, Wood W I, Goralka T M e t al 1984 Characterization of the human factor VIII Gene. Nature 812:326 Jackson C M, Nemerson Y 1980 Blood Coagulation. Annual Review of Biochemistry 49: 765 Kasper C K 1973 Post operative thromboses in hemophilia B. New England Journal of Medicine 289 : 160 Macfarlane R G 1964 An enzyme cascade in the blood clotting mechanism : its function as a biological amplifier. Nature 202 : 498 Mannucci P M, Ruggeri Z M, Pareti F I, Capitanio A 1977a 1-deamino -8-D-arginine vasopressin : a new pharmacological approach to the management of haemophilia and von Willebrand's disease. Lancet 1 : 869-872 Ratnoff O D, Forbes C D 1984 Disorders of Hemostasis. Orlando, Florida, Grune & Stratton Inc Rizza C R, Spooner R J D 1983 Treatment of haemophilia and related disorders in Britain, Northern Ireland during 1976 80: report on behalf of the directors of haemophilia centres in the United Kingdom. British Medical Journal 286:929 933 Smith J K, Bidwell D 1979 Therapeutic materials used in the treatment of coagulation defects. Clinics in Haematology 8:183 206 Winkelman L, Owen N E, Haddon M, Smith J K 1985 Treatment of a new high specific activity factor VIII concentrate to inactivate viruses. Meeting Abstract. Thrombosis and Haemostasis 54(1): 19