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Management of haemophilia
SYMPOSIUM: HAEMATOLOGY
Management of haemophilia
In families with a documented history of the condition the diagnosis is often made shortly after birth by measuring the factor VIII (or IX) level in a cord blood sample. Typical laboratory findings in haemophilia include normal prothrombin (PT) and thrombin times but a prolonged activated partial thromboplastin time (APTT). The platelet count and bleeding time are normal. A specific factor assay is required to confirm the diagnosis. Where there is no documented family history of the condition, the diagnosis is often delayed until the child starts to crawl or walk and the child is noted to have significant bruising or limp. In such cases, there is a distinct possibility that non-accidental injury will be considered in the differential diagnosis. The clinical severity (phenotype) is critically determined by the level of circulating factor VIII (or IX) in the blood, and severe haemophilia is defined by a clotting factor level of less than1 IU/dl. The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis. Typically, hinge joints such as the knees, elbows and ankles are affected but bleeds may also occur in the wrist or shoulder. Bleeding into the hip joint is unusual. The affected joint is swollen and warm, and held in a position of flexion, with no external discolouration or bruising around the joint. It is unusual for an infant to suffer spontaneous haemarthroses in the first few months of life. The first joint to be affected tends to be the ankle as the child learns to crawl. The initial signs of a haemarthrosis in an infant will often be obvious discomfort and distress, accompanied by limping or reluctance to use a limb. Recurrent bleeds into a joint can result after a period of months or years to synovitis and joint damage resulting in crippling arthritis. Bleeding into muscles is also a feature of haemophilia, but this is usually a consequence of direct injury, albeit often minor. Bleeds into certain areas are particularly dangerous because of the risk of compression of neighbouring structures. Patients with inhibitory antibodies are particularly at risk in this regard, as bleeds may be more difficult to control (see below). Bleeds in the tongue can obstruct the airway, and retroperitoneal bleeding within the ilio-psoas muscle may result in femoral nerve compression, causing weakness and wasting of leg muscles. Bleeding from the gastrointestinal tract (melaena) and bleeding into the urinary tract (haematuria) may also occur. There is also a significant risk of intracranial haemorrhage in severe haemophilia which was a significant cause of mortality in the past when treatment was not so readily available. This is a particular issue for very young children and parents need to be specifically advised to seek treatment for their child if he knocks or bangs his head. Higher levels of factor VIII (or IX) above 5 IU/dl are associated with a milder form of the disease, with no spontaneous joint bleeds but a definite risk of bleeding after even relatively minor injury.
P L F Giangrande
Abstract Haemophilia is an inherited bleeding disorder associated with a deficiency of coagulation factors VIII or IX. The bleeding tendency is proportional to the degree of deficiency. The hallmark of the severe phenotype is recurrent and spontaneous bleeding into joints which can lead to crippling joint deformity and arthritis at an early age in the absence of effective treatment. The condition is inherited as an X-linked disorder although there is no family history in approximately one-third of cases and this represents a new mutation. In the absence of effective treatment, the prognosis is poor but the development of coagulation factor concentrates in the last few decades has transformed the outlook. Recombinant products are now increasingly regarded as the treatment of choice because they are free of the risk of viral infection. Conventional treatment now consists of the administration of concentrate on a prophylactic basis to prevent bleeds and hence minimize disability in the long-term. Patients with haemophilia now live essentially normal lives and life expectancy approaches that of the normal population. Inhibitors to factor VIII arise in a significant minority of patients with haemophilia A and vigilance is required in screening children for the development of this complication. Bypassing agents such as FEIBAÒ and NovoSevenÒ may be used to control bleeding in such cases and the regular administration of large doses of coagulation factor concentrate will usually result in suppression of inhibitor production. Looking to the future, it is likely that modified molecules with enhanced properties such as increased half-life will soon be available and trials of gene therapy are also underway.
Keywords antenatal diagnosis; carrier; factor VIII; factor IX; haemophilia; inhibitors; recombinant
Clinical features of haemophilia Haemophilia is a congenital disorder of coagulation and affects approximately 1 in 10000 males worldwide, with approximately 5000 patients with haemophilia in the United Kingdom. Haemophilia A is due to a deficiency of factor VIII in the circulating blood and haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by factor IX deficiency. The genes for factors VIII and IX are both located on the X chromosome and thus haemophilia is inherited as an X-linked recessive condition. The daughters of affected males are obligate carriers but the sons are normal. The phenotype remains constant within a family, so the daughter of a man with only mild haemophilia may be reassured that she will not pass on a severe form of the condition. However, approximately one-third of all cases of haemophilia arise in the absence of a previous family history and is due to a new mutation.
Genetic and molecular basis of haemophilia The factor VIII gene consists of 26 exons located at the telomeric end of the X chromosome, which range in size from 69 bp (exon 5) to 3.1 kb (exon 14) in size and which encode a mature protein is made up of 2332 amino acids. Approximately half of all cases of severe haemophilia and all cases of mild and moderate haemophilia result from heterogeneous mutations which occur throughout the FVIII gene. By far the commonest single genetic defect causing severe haemophilia is an inversion in intron-22, which is encountered in as many as 45% of people with severe
P L F Giangrande BSc MD FRCP FRCPath FRCPCH is Consultant Haematologist at the Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 21:8
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HAEMATOLOGY
haemophilia in all ethnic groups. More recently, inversions in intron 1 of the factor VIII gene have been identified as a cause of severe haemophilia and this abnormality appears to be responsible for approximately 5% of all cases of severe haemophilia. Most other cases of haemophilia are the consequence of a variety of missense mutations although a small number of cases result from gene deletions (3). The factor IX gene (F9) is also located on the long arm of the X chromosome at band Xq27, and is encoded by a stretch of DNA spanning 33.5 kb and which contains eight exons. Point mutations account for the vast majority of cases of haemophilia B.
therapy. Data also suggest that early adoption of prophylaxis may confer protection against inhibitor development. The use of implantable venous devices certainly makes early treatment of children easier although complications such as thrombosis and bacterial infection are not infrequent. Another area of active debate is whether prophylaxis should be continued in adults. Participation in sports should be positively encouraged as this is good both for social integration and also maintenance of musculoskeletal health. Suitable activities include swimming, athletics and football but rough contact sports need to be avoided. Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic peptide analogue of the endogenous pituitary hormone, vasopressin (antidiuretic hormone, ADH). It can significantly boost levels of both factor VIII and VWF in the blood and desmopressin is therefore a valuable agent for the treatment of mild and moderate haemophilia A as well as Willebrand’s disease. This product is very cheap and is completely free from the risk of transmission of viral infections. The standard dose of DDAVP for treatment of bleeding disorders is 0.3 mg/kg given by subcutaneous injection, although it may also be given by intravenous infusion. Young children seem to particularly prone to development of hyponatraemia and it is best to avoid the use of this particular agent in children under the age of 2 years. Tranexamic acid is an inhibitor of fibrinolysis and is useful as adjunctive therapy for bleeding from mucosal surfaces such as from the nose and around the teeth and gums. Aspirin and nonsteroidal anti-inflammatory agents should be avoided as they will exacerbate the bleeding tendency through inhibition of platelet function. Paracetamol is a perfectly safe alternative as it has no such action. Older patients with established arthropathy in several joints often derive considerable benefit from treatment with COX-2 inhibitors such as etoricoxib. Patients with congenital bleeding disorders should not be given intramuscular injections as this may result in haematoma formation. It is, of course, important that children receive their normal vaccinations, but these should be given via the subcutaneous route. In the future, it is likely that modified molecules with enhanced properties such as reduced immunogenicity and increased half-life will become available. Strategies for increasing the duration of activity of coagulation include covering the molecule with polyethylene glycol (PEG) and creating molecules with mutations at sites which are the natural targets for specific proteolytic inactivation. Haemophilia also provides an attractive model for correction by gene therapy and several clinical trials in both haemophilia A and B are already underway.
Treatment of haemophilia Haemophilia is a rare disorder and few non-specialist health care professionals will deal with such patients on a regular basis. Patients with congenital bleeding disorders are usually followed up within designated regional comprehensive care centres which can provide multidisciplinary care. Such a unit should also offer support to patients at home in the community as well as to other regional hospitals. There is now clear evidence that such a system of haemophilia care provides a better outcome. Plasma-derived coagulation factor concentrates were developed in the early 1970s but many patients with haemophilia were subsequently infected with either HIV and/or hepatitis C. Modern plasma-derived products are much purer and are also subjected to viral inactivation procedures so that the risk of these infections has effectively been eliminated. Recombinant factor VIII and IX concentrates are now available and any clinicians now regard these as the treatment of choice for all patients with haemophilia as they offer the best possible protection from transmission of bloodborne pathogens: it has been the policy within the UK for some years now to use these products exclusively. The articular cartilage of young children is particularly vulnerable to irreversible damage which is primarily mediated by iron release from blood which also triggers an inflammatory reaction. The administration of prophylactic infusions of coagulation factor concentrates is now generally accepted as representing the best approach to the modern management of haemophilia. Data from a recent prospective randomized controlled trial have confirmed the longstanding impression that such treatment reduces the incidence of joint bleeds and also protects against the development of joint damage. The conventional prophylactic treatment regime involves administration of 20e40 IU/kg three times weekly in the case of haemophilia A and twice weekly in haemophilia B. However, there are many variants in treatment approach and a Canadian study has suggested that once weekly treatment is a reasonable initial alternative, with escalation of the dosage if breakthrough bleeding occurs. Prophylaxis is usually embarked upon after the first or second joint bleed, which will usually be around the age of 18e24 months of age. This will initially be given by the parents at home and the child should be able to take over the task by the age of 12 years. Periodic measurement of trough levels of factor VIII is recommended as there is a clear correlation between the probability of spontaneous bleeding and time spent with a baseline level below 1%. Firm data are also available to show that prophylaxis is associated with enhanced quality of life in children. There is also evidence that the incidence of extra-articular bleeding, including intracranial haemorrhage, is also reduced among children receiving prophylactic
PAEDIATRICS AND CHILD HEALTH 21:8
Inhibitors Now that the risk of viral infection has been eliminated, the development of antibodies (inhibitors) to infused factor VIII is the major potential complication. The problem is significantly commoner in haemophilia A than in haemophilia B. Data from the UK registry indicate that around 14% of all patients with haemophilia A and 2% of those with haemophilia B will develop inhibitory antibodies at some stage. It is quite likely that this figure underestimates the true prevalence as transient and low titre inhibitors may not be detected. The development of inhibitors is typically first seen in childhood, fairly soon after a child begins to receive treatment. Periodic screening for inhibitors is an important part of haemophilia care. UK
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HAEMATOLOGY
guidelines recommend screening patients every 5th exposure day, or every 3 months, until the 20th exposure then every 6e12 months thereafter. In addition, it is essential to screen a patient prior to any surgical procedure (including dental work) and if the clinical response to infused coagulation factor concentrate is unexpectedly poor. The method involved in screening for inhibitors involves incubating normal and test plasma at 37 C for 60 min both separately and as a 50:50 mixture. The activated partial thromboplastin time (APTT) is then determined on the normal plasma, test plasma and incubated mixture. The degrees of correction of the APTT of each mixture are compared and poor correction in the incubated mixture is suggestive of an inhibitor. The titre of any antibody detected may then be quantified using the Bethesda method and results are reported in Bethesda units (BU). There is no clear evidence that the risk of inhibitor development is higher amongst recipients of recombinant products compared to those who receive plasma-derived concentrates. The major determinant for inhibitor development is the underlying molecular defect and certain types of gene defects in haemophilia are undoubtedly associated with a significantly increased risk of inhibitor development. The risk of inhibitor development in patients with severe molecular defects, such as large deletions, nonsense mutations and the intron-22 inversion, is 7e10 times higher than in patients with other defects such as missense mutations, small deletions and splice site mutations. The rare patients with haemophilia B who develop inhibitory antibodies typically have large gene deletions. Subjects of AfroCaribbean origin are also more vulnerable to develop inhibitors. Whilst patients with inhibitors do not usually experience more bleeds than patients without inhibitors, the episodes can certainly be more difficult to control. The treatment plan for an affected patient has two distinct aims: to control individual bleeding episodes and to eradicate the underlying antibody through immune tolerance. The cost of both immune tolerance and the special products used in the treatment of bleeding episodes in patients with inhibitors products is enormous and can stretch a hospital budget, even in supposedly affluent countries. The choice of product is also determined by clinical considerations, including antibody titre and severity of the bleed. Knowledge of the individual patient’s previous response to specific products is also very useful. Infusions of conventional factor VIII concentrates are unlikely to be of any value in patients with inhibitor titres above 5 BU. FEIBAÒ (Baxter) is a prothrombin complex concentrate with a long track record of efficacy in controlling bleeds in patients with inhibitors. It is a plasma-derived concentrate which contains coagulation factors II, VII, IX and X which are activated in vitro during manufacture and therefore acquire the ability to generate thrombin in the absence of factor VIII. The clinical effect can only be determined by clinical observation, rather than through laboratory assays. It is important not to exceed the maximum daily dose of 200 U/kg as thromboembolism is a rare complication which has usually been reported after repeated infusion (e.g. after surgery). There is also the potential for a significant anamnestic response, with a rise in the titre of inhibitor, as the product does contain traces of factor VIII. Recombinant factor VIIa (NovoSevenÒ, NovoNordisk) is also effective in such cases. It also has a short plasma-half-life of approximately 2 h. Again, there is also no simple assay available which can be used to monitor treatment.
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Immunosuppression with, for example, steroids is of no value in the management of patients with congenital haemophilia and inhibitory antibodies. However, the production of inhibitory antibodies can be suppressed in many cases through the daily administration of high doses of coagulation factor over a long period (“immune tolerance”). This is typically required for around a year but sometimes it may be necessary to continue treatment for up to 2 years in order to achieve success. It is often necessary to insert an indwelling central venous line to facilitate treatment. The daily dose of factor VIII given for immune tolerance remains the subject of controversy following the early termination of an international trial. A typical dose is 100 IU/kg but doses in the range of 50e200 IU/kg may be employed. It is usual practice to continue treatment with the same type or brand of factor VIII product the patient was on when the inhibitor developed. If there is no early fall in the antibody titre, consideration should be given to switching to a plasma-derived product containing von Willebrand factor as there is some suggestion that these less pure products may be more effective in attaining immune tolerance. Overall, the response rate with the various current regimes is of the order of 85% and relapse is fortunately rare in successful cases. Predictors of a successful outcome include a low initial antibody titre (less than10 BU), a low historical peak inhibitor titre and early institution of treatment (an interval of less than 2 years between inhibitor diagnosis and initiation of immune tolerance). The rare patients with haemophilia B and inhibitory antibodies pose a particular challenge. These inhibitory antibodies often retain the ability to fix complement and allergic reactions may develop after infusions of concentrate. Indeed, such a reaction may be the very first manifestation of inhibitor development. The response to immune tolerance is also poor and the development of nephrotic syndrome during treatment has been reported, presumably as a result of immune-complex formation.
Carriers of haemophilia There is no need to carry out special genetic tests in daughters of men with haemophilia to determine their carrier status but the position for other women in the extended family may not be so clear. A woman who has an affected uncle, for example, may or may not be a carrier. A common and difficult problem is to be confronted with a pregnant woman with a vague history of a bleeding disorder in a distant relative. Carrier testing can take some months to perform and it may seem logical to initiate carrier testing to determine carrier status as soon as possible in girls with a family history of the condition, as this would facilitate management of pregnancy in the case of an early and unexpected pregnancy. However, testing of young children ignores the ethical and/ or legal rights of children as testing cannot be considered to have been obtained with the informed consent of the individual child concerned. These issues must be discussed openly with the family. Once the carrier status has been determined and DNA markers have been identified, it is then possible to offer antenatal diagnosis of haemophilia to pregnant women. Most female carriers of haemophilia have levels of factor VIII (or IX) within the normal range but a significant proportion will have a modest reduction in the baseline level. The baseline level is seldom lower than 20% of the normal level and should thus certainly suffice to protect against significant bleeding problems in day-to-day life.
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HAEMATOLOGY
However, female carriers with low levels of factor VIII (or IX) are at risk of bleeding in the setting of surgery or other invasive procedures, such as dental extractions, biopsies etc. DDAVP is often the best treatment option in carriers of haemophilia A.
traumatic delivery, instrumental delivery (e.g. mid forceps extraction) or a prolonged second stage of labour. The key points relating to management of delivery may be summarized as follows: 1. good liaison is essential between the haemophilia centre and the obstetricians, who may be based in a different hospital. A written management plan should be drawn up 2. baseline factor VIII (or IX level) should be checked at booking in, and in the third trimester (ideally at around 34 weeks) 3. fetal sex should be determined by ultrasound, and the results should be available to the obstetrician at the time of delivery 4. routine Caesarean section is not routinely indicated merely because of possible haemophilia 5. epidural anaesthesia is permitted if the factor level is more than 40 IU/dl 6. avoid the use of fetal scalp electrodes for monitoring during delivery 7. avoid vacuum extraction (Ventouse delivery) 8. check the cord factor level after birth 9. withhold intramuscular vitamin K until the result is known 10. give recombinant products to baby if forceps applied (but not routinely otherwise) 11. special observations after delivery may be warranted, including ultrasound examination of the head to exclude the possibility of intracranial bleeding 12. be aware of the risk of delayed post-partum haemorrhage in carriers. It is wise to check the factor level a few days after delivery. DDAVP may be useful after delivery. A
Management of pregnancy and care of affected neonates As a general rule, antenatal diagnosis of haemophilia is only offered where a termination of the pregnancy is being contemplated if an affected fetus were identified. It is certainly not necessary to determine the status of a male fetus simply to determine management of the pregnancy. Women will obviously require counselling about haemophilia and before they make this important decision. The general experience has been that only a minority of women subsequently takes up the offer of antenatal diagnosis with a view to termination if an affected fetus is identified. This may well reflect the fact that many women with affected relatives recognize the tremendous advances in treatment in recent years, including the wider adoption of prophylaxis and the introduction of recombinant products, which have resulted in an essentially normal life for the younger generation of haemophiliacs. Chorionic villus sampling (CVS) is the principal method used for antenatal diagnosis of haemophilia although it should not be carried out before 11 weeks of gestation as earlier biopsy may be associated with a risk of subsequent fetal limb abnormalities. Analysis of fetal DNA extracted from maternal blood as early as 7 weeks of gestation is now feasible. This permits early determination of fetal sex, thus circumventing the need for CVS when a female fetus is identified. Fetal blood sampling can be carried out when it has not been possible to establish the status of the fetus, either because DNA-based studies were not possible or they were carried out but were not informative. The levels of factor VIII and von Willebrand factor rise during normal pregnancy. The rise is particularly marked during the third trimester, when levels of factor VIII may rise to double that of the normal baseline value. By contrast, factor IX levels do not rise significantly in pregnancy and thus carriers of haemophilia B with a low baseline factor IX level are more likely to require haemostatic support to cover delivery, particularly if a Caesarean section is required. After delivery, a cord blood sample should be obtained for coagulation factor assay. It is helpful for the obstetrician to know the sex of the fetus at the time of delivery, even if the stars with regard to haemophilia is uncertain, as this fact alone may influence important decisions as the delivery progresses. Although normal vaginal delivery is still considered to be safe, it is clear that in recent years there has been a move towards Caesarean section and this has been particularly marked in North America. This is largely due to the recent recognition that the incidence of intracranial haemorrhage is higher than previously thought. Vacuum extraction should certainly be avoided as the use of this instrument is associated with a high risk of cephalhaematoma or intracranial bleeding. Recent guidelines recommend that cranial ultrasound examination should be undertaken prior to discharge in all neonates with haemophilia. It is not generally necessary to administer coagulation factor concentrates to a haemophilic neonate after a normal delivery if there is no evidence of any bleeding. Prophylactic therapy should be considered for neonates considered to be at increased at increased risk of bleeding e.g. following
PAEDIATRICS AND CHILD HEALTH 21:8
FURTHER READING Astermark J. Immune tolerance induction in patients with hemophilia A. Thromb Res 2011; 127(suppl 1): S6e9. Carcao M, Chambost H, Ljung R. Devising a best practice approach to prophylaxis in boys with severe haemophilia: evaluation of current treatment strategies. Haemophilia 2010; 16(suppl 2): 4e9. Giangrande PLF. Molecular basis of haemophilia. In: Molecular haematology. Blackwells, 2010. Hay CRM, Brown S, Collins PW, Keeling DM, Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the united kingdom Haemophilia Centre Doctors’ Organisation. Br J Haematol 2006; 133: 591e605. Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasmaderived or recombinant factor VIII concentrates; a systematic review. J Thromb Haemostasis 2010; 8: 1256e65. James AH, Hoots K. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is Caesarean delivery. Haemophilia 2010; 16: 420e4. Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Guideline. Haemophilia 2008; 14: 671e84. Ljung R. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery. Haemophilia 2010; 16: 415e9. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years. Blood 2000; 6(suppl 1): 60e7. Street AM, Ljung R, Lavery SA. Management of carriers and babies with haemophilia. Haemophilia 2008; 14(suppl 3): 181e7.
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Ó 2011 Elsevier Ltd. All rights reserved.
Management of haemophilia
In families with a documented history of the condition the diagnosis is often made shortly after birth by measuring the factor VIII (or IX) level in a cord blood sample. Typical laboratory findings in haemophilia include normal prothrombin (PT) and thrombin times but a prolonged activated partial thromboplastin time (APTT). The platelet count and bleeding time are normal. A specific factor assay is required to confirm the diagnosis. Where there is no documented family history of the condition, the diagnosis is often delayed until the child starts to crawl or walk and the child is noted to have significant bruising or limp. In such cases, there is a distinct possibility that non-accidental injury will be considered in the differential diagnosis. The clinical severity (phenotype) is critically determined by the level of circulating factor VIII (or IX) in the blood, and severe haemophilia is defined by a clotting factor level of less than1 IU/dl. The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis. Typically, hinge joints such as the knees, elbows and ankles are affected but bleeds may also occur in the wrist or shoulder. Bleeding into the hip joint is unusual. The affected joint is swollen and warm, and held in a position of flexion, with no external discolouration or bruising around the joint. It is unusual for an infant to suffer spontaneous haemarthroses in the first few months of life. The first joint to be affected tends to be the ankle as the child learns to crawl. The initial signs of a haemarthrosis in an infant will often be obvious discomfort and distress, accompanied by limping or reluctance to use a limb. Recurrent bleeds into a joint can result after a period of months or years to synovitis and joint damage resulting in crippling arthritis. Bleeding into muscles is also a feature of haemophilia, but this is usually a consequence of direct injury, albeit often minor. Bleeds into certain areas are particularly dangerous because of the risk of compression of neighbouring structures. Patients with inhibitory antibodies are particularly at risk in this regard, as bleeds may be more difficult to control (see below). Bleeds in the tongue can obstruct the airway, and retroperitoneal bleeding within the ilio-psoas muscle may result in femoral nerve compression, causing weakness and wasting of leg muscles. Bleeding from the gastrointestinal tract (melaena) and bleeding into the urinary tract (haematuria) may also occur. There is also a significant risk of intracranial haemorrhage in severe haemophilia which was a significant cause of mortality in the past when treatment was not so readily available. This is a particular issue for very young children and parents need to be specifically advised to seek treatment for their child if he knocks or bangs his head. Higher levels of factor VIII (or IX) above 5 IU/dl are associated with a milder form of the disease, with no spontaneous joint bleeds but a definite risk of bleeding after even relatively minor injury.
P L F Giangrande
Abstract Haemophilia is an inherited bleeding disorder associated with a deficiency of coagulation factors VIII or IX. The bleeding tendency is proportional to the degree of deficiency. The hallmark of the severe phenotype is recurrent and spontaneous bleeding into joints which can lead to crippling joint deformity and arthritis at an early age in the absence of effective treatment. The condition is inherited as an X-linked disorder although there is no family history in approximately one-third of cases and this represents a new mutation. In the absence of effective treatment, the prognosis is poor but the development of coagulation factor concentrates in the last few decades has transformed the outlook. Recombinant products are now increasingly regarded as the treatment of choice because they are free of the risk of viral infection. Conventional treatment now consists of the administration of concentrate on a prophylactic basis to prevent bleeds and hence minimize disability in the long-term. Patients with haemophilia now live essentially normal lives and life expectancy approaches that of the normal population. Inhibitors to factor VIII arise in a significant minority of patients with haemophilia A and vigilance is required in screening children for the development of this complication. Bypassing agents such as FEIBAÒ and NovoSevenÒ may be used to control bleeding in such cases and the regular administration of large doses of coagulation factor concentrate will usually result in suppression of inhibitor production. Looking to the future, it is likely that modified molecules with enhanced properties such as increased half-life will soon be available and trials of gene therapy are also underway.
Keywords antenatal diagnosis; carrier; factor VIII; factor IX; haemophilia; inhibitors; recombinant
Clinical features of haemophilia Haemophilia is a congenital disorder of coagulation and affects approximately 1 in 10000 males worldwide, with approximately 5000 patients with haemophilia in the United Kingdom. Haemophilia A is due to a deficiency of factor VIII in the circulating blood and haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by factor IX deficiency. The genes for factors VIII and IX are both located on the X chromosome and thus haemophilia is inherited as an X-linked recessive condition. The daughters of affected males are obligate carriers but the sons are normal. The phenotype remains constant within a family, so the daughter of a man with only mild haemophilia may be reassured that she will not pass on a severe form of the condition. However, approximately one-third of all cases of haemophilia arise in the absence of a previous family history and is due to a new mutation.
Genetic and molecular basis of haemophilia The factor VIII gene consists of 26 exons located at the telomeric end of the X chromosome, which range in size from 69 bp (exon 5) to 3.1 kb (exon 14) in size and which encode a mature protein is made up of 2332 amino acids. Approximately half of all cases of severe haemophilia and all cases of mild and moderate haemophilia result from heterogeneous mutations which occur throughout the FVIII gene. By far the commonest single genetic defect causing severe haemophilia is an inversion in intron-22, which is encountered in as many as 45% of people with severe
P L F Giangrande BSc MD FRCP FRCPath FRCPCH is Consultant Haematologist at the Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 21:8
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HAEMATOLOGY
haemophilia in all ethnic groups. More recently, inversions in intron 1 of the factor VIII gene have been identified as a cause of severe haemophilia and this abnormality appears to be responsible for approximately 5% of all cases of severe haemophilia. Most other cases of haemophilia are the consequence of a variety of missense mutations although a small number of cases result from gene deletions (3). The factor IX gene (F9) is also located on the long arm of the X chromosome at band Xq27, and is encoded by a stretch of DNA spanning 33.5 kb and which contains eight exons. Point mutations account for the vast majority of cases of haemophilia B.
therapy. Data also suggest that early adoption of prophylaxis may confer protection against inhibitor development. The use of implantable venous devices certainly makes early treatment of children easier although complications such as thrombosis and bacterial infection are not infrequent. Another area of active debate is whether prophylaxis should be continued in adults. Participation in sports should be positively encouraged as this is good both for social integration and also maintenance of musculoskeletal health. Suitable activities include swimming, athletics and football but rough contact sports need to be avoided. Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic peptide analogue of the endogenous pituitary hormone, vasopressin (antidiuretic hormone, ADH). It can significantly boost levels of both factor VIII and VWF in the blood and desmopressin is therefore a valuable agent for the treatment of mild and moderate haemophilia A as well as Willebrand’s disease. This product is very cheap and is completely free from the risk of transmission of viral infections. The standard dose of DDAVP for treatment of bleeding disorders is 0.3 mg/kg given by subcutaneous injection, although it may also be given by intravenous infusion. Young children seem to particularly prone to development of hyponatraemia and it is best to avoid the use of this particular agent in children under the age of 2 years. Tranexamic acid is an inhibitor of fibrinolysis and is useful as adjunctive therapy for bleeding from mucosal surfaces such as from the nose and around the teeth and gums. Aspirin and nonsteroidal anti-inflammatory agents should be avoided as they will exacerbate the bleeding tendency through inhibition of platelet function. Paracetamol is a perfectly safe alternative as it has no such action. Older patients with established arthropathy in several joints often derive considerable benefit from treatment with COX-2 inhibitors such as etoricoxib. Patients with congenital bleeding disorders should not be given intramuscular injections as this may result in haematoma formation. It is, of course, important that children receive their normal vaccinations, but these should be given via the subcutaneous route. In the future, it is likely that modified molecules with enhanced properties such as reduced immunogenicity and increased half-life will become available. Strategies for increasing the duration of activity of coagulation include covering the molecule with polyethylene glycol (PEG) and creating molecules with mutations at sites which are the natural targets for specific proteolytic inactivation. Haemophilia also provides an attractive model for correction by gene therapy and several clinical trials in both haemophilia A and B are already underway.
Treatment of haemophilia Haemophilia is a rare disorder and few non-specialist health care professionals will deal with such patients on a regular basis. Patients with congenital bleeding disorders are usually followed up within designated regional comprehensive care centres which can provide multidisciplinary care. Such a unit should also offer support to patients at home in the community as well as to other regional hospitals. There is now clear evidence that such a system of haemophilia care provides a better outcome. Plasma-derived coagulation factor concentrates were developed in the early 1970s but many patients with haemophilia were subsequently infected with either HIV and/or hepatitis C. Modern plasma-derived products are much purer and are also subjected to viral inactivation procedures so that the risk of these infections has effectively been eliminated. Recombinant factor VIII and IX concentrates are now available and any clinicians now regard these as the treatment of choice for all patients with haemophilia as they offer the best possible protection from transmission of bloodborne pathogens: it has been the policy within the UK for some years now to use these products exclusively. The articular cartilage of young children is particularly vulnerable to irreversible damage which is primarily mediated by iron release from blood which also triggers an inflammatory reaction. The administration of prophylactic infusions of coagulation factor concentrates is now generally accepted as representing the best approach to the modern management of haemophilia. Data from a recent prospective randomized controlled trial have confirmed the longstanding impression that such treatment reduces the incidence of joint bleeds and also protects against the development of joint damage. The conventional prophylactic treatment regime involves administration of 20e40 IU/kg three times weekly in the case of haemophilia A and twice weekly in haemophilia B. However, there are many variants in treatment approach and a Canadian study has suggested that once weekly treatment is a reasonable initial alternative, with escalation of the dosage if breakthrough bleeding occurs. Prophylaxis is usually embarked upon after the first or second joint bleed, which will usually be around the age of 18e24 months of age. This will initially be given by the parents at home and the child should be able to take over the task by the age of 12 years. Periodic measurement of trough levels of factor VIII is recommended as there is a clear correlation between the probability of spontaneous bleeding and time spent with a baseline level below 1%. Firm data are also available to show that prophylaxis is associated with enhanced quality of life in children. There is also evidence that the incidence of extra-articular bleeding, including intracranial haemorrhage, is also reduced among children receiving prophylactic
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Inhibitors Now that the risk of viral infection has been eliminated, the development of antibodies (inhibitors) to infused factor VIII is the major potential complication. The problem is significantly commoner in haemophilia A than in haemophilia B. Data from the UK registry indicate that around 14% of all patients with haemophilia A and 2% of those with haemophilia B will develop inhibitory antibodies at some stage. It is quite likely that this figure underestimates the true prevalence as transient and low titre inhibitors may not be detected. The development of inhibitors is typically first seen in childhood, fairly soon after a child begins to receive treatment. Periodic screening for inhibitors is an important part of haemophilia care. UK
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guidelines recommend screening patients every 5th exposure day, or every 3 months, until the 20th exposure then every 6e12 months thereafter. In addition, it is essential to screen a patient prior to any surgical procedure (including dental work) and if the clinical response to infused coagulation factor concentrate is unexpectedly poor. The method involved in screening for inhibitors involves incubating normal and test plasma at 37 C for 60 min both separately and as a 50:50 mixture. The activated partial thromboplastin time (APTT) is then determined on the normal plasma, test plasma and incubated mixture. The degrees of correction of the APTT of each mixture are compared and poor correction in the incubated mixture is suggestive of an inhibitor. The titre of any antibody detected may then be quantified using the Bethesda method and results are reported in Bethesda units (BU). There is no clear evidence that the risk of inhibitor development is higher amongst recipients of recombinant products compared to those who receive plasma-derived concentrates. The major determinant for inhibitor development is the underlying molecular defect and certain types of gene defects in haemophilia are undoubtedly associated with a significantly increased risk of inhibitor development. The risk of inhibitor development in patients with severe molecular defects, such as large deletions, nonsense mutations and the intron-22 inversion, is 7e10 times higher than in patients with other defects such as missense mutations, small deletions and splice site mutations. The rare patients with haemophilia B who develop inhibitory antibodies typically have large gene deletions. Subjects of AfroCaribbean origin are also more vulnerable to develop inhibitors. Whilst patients with inhibitors do not usually experience more bleeds than patients without inhibitors, the episodes can certainly be more difficult to control. The treatment plan for an affected patient has two distinct aims: to control individual bleeding episodes and to eradicate the underlying antibody through immune tolerance. The cost of both immune tolerance and the special products used in the treatment of bleeding episodes in patients with inhibitors products is enormous and can stretch a hospital budget, even in supposedly affluent countries. The choice of product is also determined by clinical considerations, including antibody titre and severity of the bleed. Knowledge of the individual patient’s previous response to specific products is also very useful. Infusions of conventional factor VIII concentrates are unlikely to be of any value in patients with inhibitor titres above 5 BU. FEIBAÒ (Baxter) is a prothrombin complex concentrate with a long track record of efficacy in controlling bleeds in patients with inhibitors. It is a plasma-derived concentrate which contains coagulation factors II, VII, IX and X which are activated in vitro during manufacture and therefore acquire the ability to generate thrombin in the absence of factor VIII. The clinical effect can only be determined by clinical observation, rather than through laboratory assays. It is important not to exceed the maximum daily dose of 200 U/kg as thromboembolism is a rare complication which has usually been reported after repeated infusion (e.g. after surgery). There is also the potential for a significant anamnestic response, with a rise in the titre of inhibitor, as the product does contain traces of factor VIII. Recombinant factor VIIa (NovoSevenÒ, NovoNordisk) is also effective in such cases. It also has a short plasma-half-life of approximately 2 h. Again, there is also no simple assay available which can be used to monitor treatment.
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Immunosuppression with, for example, steroids is of no value in the management of patients with congenital haemophilia and inhibitory antibodies. However, the production of inhibitory antibodies can be suppressed in many cases through the daily administration of high doses of coagulation factor over a long period (“immune tolerance”). This is typically required for around a year but sometimes it may be necessary to continue treatment for up to 2 years in order to achieve success. It is often necessary to insert an indwelling central venous line to facilitate treatment. The daily dose of factor VIII given for immune tolerance remains the subject of controversy following the early termination of an international trial. A typical dose is 100 IU/kg but doses in the range of 50e200 IU/kg may be employed. It is usual practice to continue treatment with the same type or brand of factor VIII product the patient was on when the inhibitor developed. If there is no early fall in the antibody titre, consideration should be given to switching to a plasma-derived product containing von Willebrand factor as there is some suggestion that these less pure products may be more effective in attaining immune tolerance. Overall, the response rate with the various current regimes is of the order of 85% and relapse is fortunately rare in successful cases. Predictors of a successful outcome include a low initial antibody titre (less than10 BU), a low historical peak inhibitor titre and early institution of treatment (an interval of less than 2 years between inhibitor diagnosis and initiation of immune tolerance). The rare patients with haemophilia B and inhibitory antibodies pose a particular challenge. These inhibitory antibodies often retain the ability to fix complement and allergic reactions may develop after infusions of concentrate. Indeed, such a reaction may be the very first manifestation of inhibitor development. The response to immune tolerance is also poor and the development of nephrotic syndrome during treatment has been reported, presumably as a result of immune-complex formation.
Carriers of haemophilia There is no need to carry out special genetic tests in daughters of men with haemophilia to determine their carrier status but the position for other women in the extended family may not be so clear. A woman who has an affected uncle, for example, may or may not be a carrier. A common and difficult problem is to be confronted with a pregnant woman with a vague history of a bleeding disorder in a distant relative. Carrier testing can take some months to perform and it may seem logical to initiate carrier testing to determine carrier status as soon as possible in girls with a family history of the condition, as this would facilitate management of pregnancy in the case of an early and unexpected pregnancy. However, testing of young children ignores the ethical and/ or legal rights of children as testing cannot be considered to have been obtained with the informed consent of the individual child concerned. These issues must be discussed openly with the family. Once the carrier status has been determined and DNA markers have been identified, it is then possible to offer antenatal diagnosis of haemophilia to pregnant women. Most female carriers of haemophilia have levels of factor VIII (or IX) within the normal range but a significant proportion will have a modest reduction in the baseline level. The baseline level is seldom lower than 20% of the normal level and should thus certainly suffice to protect against significant bleeding problems in day-to-day life.
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However, female carriers with low levels of factor VIII (or IX) are at risk of bleeding in the setting of surgery or other invasive procedures, such as dental extractions, biopsies etc. DDAVP is often the best treatment option in carriers of haemophilia A.
traumatic delivery, instrumental delivery (e.g. mid forceps extraction) or a prolonged second stage of labour. The key points relating to management of delivery may be summarized as follows: 1. good liaison is essential between the haemophilia centre and the obstetricians, who may be based in a different hospital. A written management plan should be drawn up 2. baseline factor VIII (or IX level) should be checked at booking in, and in the third trimester (ideally at around 34 weeks) 3. fetal sex should be determined by ultrasound, and the results should be available to the obstetrician at the time of delivery 4. routine Caesarean section is not routinely indicated merely because of possible haemophilia 5. epidural anaesthesia is permitted if the factor level is more than 40 IU/dl 6. avoid the use of fetal scalp electrodes for monitoring during delivery 7. avoid vacuum extraction (Ventouse delivery) 8. check the cord factor level after birth 9. withhold intramuscular vitamin K until the result is known 10. give recombinant products to baby if forceps applied (but not routinely otherwise) 11. special observations after delivery may be warranted, including ultrasound examination of the head to exclude the possibility of intracranial bleeding 12. be aware of the risk of delayed post-partum haemorrhage in carriers. It is wise to check the factor level a few days after delivery. DDAVP may be useful after delivery. A
Management of pregnancy and care of affected neonates As a general rule, antenatal diagnosis of haemophilia is only offered where a termination of the pregnancy is being contemplated if an affected fetus were identified. It is certainly not necessary to determine the status of a male fetus simply to determine management of the pregnancy. Women will obviously require counselling about haemophilia and before they make this important decision. The general experience has been that only a minority of women subsequently takes up the offer of antenatal diagnosis with a view to termination if an affected fetus is identified. This may well reflect the fact that many women with affected relatives recognize the tremendous advances in treatment in recent years, including the wider adoption of prophylaxis and the introduction of recombinant products, which have resulted in an essentially normal life for the younger generation of haemophiliacs. Chorionic villus sampling (CVS) is the principal method used for antenatal diagnosis of haemophilia although it should not be carried out before 11 weeks of gestation as earlier biopsy may be associated with a risk of subsequent fetal limb abnormalities. Analysis of fetal DNA extracted from maternal blood as early as 7 weeks of gestation is now feasible. This permits early determination of fetal sex, thus circumventing the need for CVS when a female fetus is identified. Fetal blood sampling can be carried out when it has not been possible to establish the status of the fetus, either because DNA-based studies were not possible or they were carried out but were not informative. The levels of factor VIII and von Willebrand factor rise during normal pregnancy. The rise is particularly marked during the third trimester, when levels of factor VIII may rise to double that of the normal baseline value. By contrast, factor IX levels do not rise significantly in pregnancy and thus carriers of haemophilia B with a low baseline factor IX level are more likely to require haemostatic support to cover delivery, particularly if a Caesarean section is required. After delivery, a cord blood sample should be obtained for coagulation factor assay. It is helpful for the obstetrician to know the sex of the fetus at the time of delivery, even if the stars with regard to haemophilia is uncertain, as this fact alone may influence important decisions as the delivery progresses. Although normal vaginal delivery is still considered to be safe, it is clear that in recent years there has been a move towards Caesarean section and this has been particularly marked in North America. This is largely due to the recent recognition that the incidence of intracranial haemorrhage is higher than previously thought. Vacuum extraction should certainly be avoided as the use of this instrument is associated with a high risk of cephalhaematoma or intracranial bleeding. Recent guidelines recommend that cranial ultrasound examination should be undertaken prior to discharge in all neonates with haemophilia. It is not generally necessary to administer coagulation factor concentrates to a haemophilic neonate after a normal delivery if there is no evidence of any bleeding. Prophylactic therapy should be considered for neonates considered to be at increased at increased risk of bleeding e.g. following
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FURTHER READING Astermark J. Immune tolerance induction in patients with hemophilia A. Thromb Res 2011; 127(suppl 1): S6e9. Carcao M, Chambost H, Ljung R. Devising a best practice approach to prophylaxis in boys with severe haemophilia: evaluation of current treatment strategies. Haemophilia 2010; 16(suppl 2): 4e9. Giangrande PLF. Molecular basis of haemophilia. In: Molecular haematology. Blackwells, 2010. Hay CRM, Brown S, Collins PW, Keeling DM, Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the united kingdom Haemophilia Centre Doctors’ Organisation. Br J Haematol 2006; 133: 591e605. Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasmaderived or recombinant factor VIII concentrates; a systematic review. J Thromb Haemostasis 2010; 8: 1256e65. James AH, Hoots K. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is Caesarean delivery. Haemophilia 2010; 16: 420e4. Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Guideline. Haemophilia 2008; 14: 671e84. Ljung R. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery. Haemophilia 2010; 16: 415e9. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years. Blood 2000; 6(suppl 1): 60e7. Street AM, Ljung R, Lavery SA. Management of carriers and babies with haemophilia. Haemophilia 2008; 14(suppl 3): 181e7.
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