Haemophilia at various stages of life: design of new therapeutic strategies through an interactive course - the Kogeniale project

Abstract

Background

High-quality evidence is lacking in several areas of haemophilia treatment, in part because little time is allocated to the treatment and care of haemophilia in university education in Italy. Physicians caring for patients with haemophilia must, therefore, rely on their information on background pathophysiology and more experienced colleagues. This makes diagnostic and therapeutic choices difficult, especially when the patient has concomitant disorders or psychological issues.

Material and methods

This article describes a course to educate young physicians who were already engaged in the management of haemophilia on the emerging and unmet issues of haemophilia care and to implement existing guidelines. Physicians (n=53) already caring for patients with haemophilia in their haematology, internal medicine, or paediatric practices in Italy attended the course. Problem-solving group activity and open discussion were the methods chosen to formulate consensus statements. During the specifically designed interactive course, three clinical cases were simulated: a young child with congenital dislocation of the hip, an adolescent refusing prophylactic treatment, and an elderly man with cardiovascular disorders. The physicians were asked questions during the course and, through a Wi-Fi console, were able to answer and discuss each case interactively.

Results

Following discussion of each case, agreement was reached regarding general statements on the management of patients with severe haemophilia A in the three different age ranges considered.

Discussion

This project helped to outline useful decision-making tools for handling diagnostic and treatment issues in the field of haemophilia.

Introduction

There are 52 Haemophilia Treatment Centres in Italy, of which approximately 20% are Comprehensive Care Centres, each with three to five physicians dedicated full-time to the treatment of inherited bleeding disorders. All directors of the Italian Haemophilia Treatment Centres are members of the Italian Association of Medical Directors of Haemophilia Centres (AICE).

Twice a year, AICE organises a meeting to report on ongoing programmes and to plan new clinical studies.

It is estimated that the majority of AICE directors will retire in the next few years. There is, therefore, concern regarding the generational turnover of medical doctors dedicated to haemophilia, given current financial constraints and the weak interest of general haematologists in rare bleeding diseases. This issue will be particularly problematic for smaller single-physician-based treatment centres. Unfortunately, little time is being allocated to the treatment and care of haemophilia during university education in Italy.

To educate young physicians on the emerging and unmet issues of haemophilia care, an interactive multimedia course was organised at the Centre for Experimental Learning (CELL) in Padua: KOGENIALE (Keep On Going Exerting New Interactive And Live Experience). During this course, three clinical cases were simulated in order to analyse and solve problems related to severe haemophilia A in three specific periods of life: early childhood, adolescence, and late adulthood. The objective of this training project was to examine the different clinical problems of patients in the three different age groups.

Case 1: a young child

In most cases, the diagnosis of severe haemophilia is made in the first year of life¹. The need for early surgical interventions (due to congenital or other disorders), which are sometimes repeated at close intervals, creates a serious problem regarding the dose and frequency of replacement factor. In fact, these interventions require prolonged intensive treatment, and the risk factors for the development of inhibitors under these circumstances must be considered². The topics considered during this course were the time of starting prophylaxis, doses, risks, duration, family involvement and psychological aspects, management of paediatric disorders that interact with the clotting disease, choice of correct diagnostic procedure for a differential diagnosis, and surgical planning to improve the management of haemorrhagic risk.

Case 2: an adolescent

Young patients with haemophilia, as well as their physicians and families, face problems involving contemporaneous physical, psychological, social, and sexual changes as adolescence approaches³. One of the most frequently debated issues among doctors caring for patients in this age group who started a therapeutic regimen at an early age is whether to continue prophylaxis and, if so, for how long⁴. We, therefore, targeted the problem of rejection of prophylaxis, the importance of prophylaxis, a home programme or patient's independence in self-administration of the drug, identification of the best therapeutic approach, and evaluation of the use of secondary prophylaxis.

Case 3: and elderly adult

A direct effect of the improvement in the manufacturing processes of factor concentrate and the large-scale availability of clotting factors is that the life expectancy of patients with haemophilia has increased considerably⁵. Patients with haemophilia in the western world grow as old as people without haemophilia^6,7. In addition, haemophiliacs live long enough to develop age-related diseases including hypertension, type 2 diabetes mellitus, ischaemic coronary syndromes, cerebrovascular disorders, cancer^8,9, and complications from obesity and osteoporosis^10,11. Furthermore, because older patients with haemophilia normally did not receive prophylaxis earlier in life, they often have mixed arthropathy, with both haemophilia- and arthritis-related joint damage and consequent pain management-related problems¹². Physicians in haemophilia centres are, therefore, facing clinical challenges that they have not previously confronted. The problems we targeted in this age group were comorbidity (cardiovascular disease), inhibitor development, identification of an optimal prophylaxis regimen for surgery, cardiovascular risk prophylaxis, and management of a previously developed inhibitor.

Materials and methods

Fifty-three physicians attended the KOGENIALE course in three separate 2-day sessions held between March and April 2010 at the CELL, which is a modern, multimedia, interactive, hands-on-learning environment created to offer stimulating educational programmes. It is divided into a teaching area for discussion in large groups and a training area dedicated to practical exercises in small groups, including direct, interactive clinical cases in "real-time." Each participant was provided with a personal digital assistant -a Wi-Fi console and touch screen- which was used interactively during brief surveys and tests and to view images and other materials during the discussion of the cases. The personal digital assistant recorded the participant's individual training progress and the choices made. The experiential area was a multimedia hall in which full-wall projections enabled viewing and consultation of specific features of a case and real-time interaction with the "patient" (actors portrayed a female caregiver, an adolescent, and an adult) such that the physicians attending the course could feel that they were participating in a real diagnostic-therapeutic process.

The system provided immediate educational feedback (audio and video) on the outcomes of the group's decisions. The clinical records (history, ongoing therapy, blood test results, genealogical history, etc.) and abstracts of the guidelines and recommendations most relevant to the case could be chosen and consulted through a touch-screen panel. The teaching and experiential areas were connected to each other by an audio-visual system to enable participants to watch and comment on the activities undertaken in the experiential hall from the educational area and to guide the participants in their choices.

The steering committee of the course selected three different clinical cases designed to simulate steps involved in the diagnosis and treatment of comorbidities in haemophilia.

Case 1: a young child with haemophilia and concomitant disorders

A male child (aged 9 months) was brought to the emergency department for treatment of a central nervous system haemorrhage. The child had been diagnosed at birth with congenital dislocation of the hip and was, therefore, placed in a Pavlik harness. Ecchymoses quickly developed under the straps of the brace, leading to the diagnosis of severe haemophilia A at 5 days of life. It soon became necessary to decide how to manage the clotting disorder during the various measures used to treat the dislocation¹³ (cast, progressively increasing traction, surgical osteotomy); management should be based on knowledge of the coagulation disease and application of this knowledge to the orthopaedic condition without the support of other, similar cases reported in the literature. At the age of 9 months, the child had a convulsion concomitant with fever. This was interpreted by the paediatrician as a febrile convulsion (ultrasound of the brain, negative), although a subsequent cerebral computed tomography scan revealed a subdural-focused haemorrhage, which was probably the cause of the child's symptoms.

Case 2: problems during adolescence

A boy born in 1991 started secondary prophylaxis at the age of 5 years, approximately when recombinant clotting factors became available. Prophylaxis led to a significant reduction in the number of joint bleeds, with an improvement in the patient's orthopaedic score and quality of life. However, at the age of 15 years, the teenager refused to continue secondary prophylaxis and, despite the efforts of the physicians, returned to an "on-demand" treatment regimen. In the following 2 years, he developed a target joint (left knee) and worsening of his orthopaedic score. Finally, doctors at the haemophilia centre convinced the patient to restart secondary prophylaxis; this had a positive effect on both the number of joint bleeds and the patient's quality of life. Furthermore, the patient was able to recommence sporting activities and, following a specific training course, was able to start self-administration of factor concentrate, thus rendering himself independent of his parents in the administration of his therapy.

Case 3: haemophilia and ageing problems

A 65-year old patient with haemophilia and cardiovascular disease was diagnosed with cancer of the colon after faecal occult blood was found in his stool. Surgical prophylaxis and anti-thromboembolic treatment for curative surgery were the first aspects to be discussed. The patient developed myocardial ischaemia immediately after surgery and was a candidate for percutaneous transluminal coronary angioplasty. The indication for and modality of antithrombotic-antiplatelet treatment were discussed. Coronary intervention was successful but complicated by the onset of atrial fibrillation, which is known to occur occasionally in this population.

During each session of the KOGENIALE course, the participating doctors were divided into three groups: one group stayed in the theatre to watch the actors simulating patients and to interact with them; the other two groups stayed in the discussion hall to watch the simulation of the clinical case and follow the interactions of their colleagues with the patient.

The doctors in the theatre could ask questions about the patient's history and could see and read the outcomes of any laboratory tests and imaging studies (radiographs, ultrasonography, computed tomography, magnetic resonance imaging) to reach a final diagnosis and to follow the clinical course of the disease. While working through each case, doctors were challenged to consider the correct questions to ask at each step in the process. The doctors in the discussion room were also able to view (on a screen) the performance of the actors and the outcomes of all clinical and laboratory tests shown to their colleagues in the theatre.

The performance was interrupted three or four times at decision-making steps. An actor summarised the main issues of the clinical case and suggested four different solutions to the clinical problem. Doctors in the theatre made their decisions while those in the discussion room selected their choice via the personal digital assistant. At the end of the performance, all doctors met in the discussion room and decisions made by each group were compared in a discussion chaired by the author of the specific clinical case. At each decision-making step, participants chose between the possible options available. The procedure was repeated for each clinical case, with groups rotating in the hall and theatre, to allow each group to attend the performance in the theatre for each of the cases.

Eventually, the discussion of the individual cases allowed some general statements to be made on the management of patients with severe haemophilia in each of the three age ranges considered. These statements concerned clinical situations that were considered of particular importance because of the therapeutic choices and management of the patients with severe haemophilia A in the three age groups presented. The statements were subsequently considered by all participants of each the three sessions to reach a general consensus. The consensus statements on the three sessions were then collated by the steering committee.

Results

Tables IA, IIA, and IIIA list the questions raised by the three clinical cases presented (young child, adolescent and adult) with the possible answers and the percentage of participants who chose each option. In addition, a comment on the appropriateness suitability of each answer is reported in the last column of each table. The statements for which a unanimous consensus was reached are reported in Tables IB, IIB and IIIB for the management of a child, adolescent and adult, respectively.

Table IA.

Case 1: a child with haemophilia and concomitant disorders (questions raised during the course).

Question 1:What is the best diagnostic/therapeutic approach in case of febrile convulsions, considering their frequency in children less than 3 years old and an observation period of 24 hours expected in these cases?
Answer		%1	Comment
1-	Observation for the canonical 24 h for the febrile convulsions because of the absence of any neurological symptoms and the negativity of the cerebral scan. No further examination.	0	Not adequate. The absence of neurological symptoms does not exclude a small haemorrhage that could worsen. The cerebral scan is optimal for parenchymal or ventricular haemorrhages, but could be negative for subdural or subarachnoid ones.
2-	The convulsive crisis must be investigated with CT; afterwards, replacement therapy must be defined.	25.8	Not adequate. The time needed for CT could be too long, while the haemorrhage could deteriorate in the short-term if it is not stopped.
3-	Start replacement therapy and then perform CT.	74.2	Adequate choice. After a convulsive crisis in a patient with haemophilia, even in the absence of symptoms and with a negative cerebral scan, the deficient factor should be administered and then further investigations should be performed.
Question 2:What is the appropriate dose of rFVIII for treating a cerebral haemorrhage and for preventing a new one?
Answer		%1	Comment
1-	rFVIII: 50 IU/kg every 6 h for the first 24 h, every 12 h for the following 24 h then once a day until the 10th day.	7.2	Not adequate. The dose of rFVIII for a cerebral haemorrhage is 100 IU/kg.
2-	rFVIII: 100 IU/kg every 6 h for the first 24 h, every 12 h for the following 72 h then once a day until the 10th day.	11.6	Possible choice: it is important to keep the level of rFVIII around 100%. It is indispensable to quantify the rFVIII or measure the prothrombin time at least twice a day. A child's metabolism is different from an adult's and the half-life of the administered factor can vary from case to case.
3-	rFVIII: 100 IU/kg every 8 h for the first 24 h, every 12 h for the following 48 h then once a day until the 10th day.	54.1	See answer 2.
4-	rFVIII: 100 IU/kg every 4 h for the first 12 h, every 6 h for the following 12 h, every 12 h for the next 48 h then once a day until the 10th day.	27.2	See answer 2.
Question 3:What is the best surgical approach, with the lowest haemorrhagic risk, for a child with congenital hip dysplasia?
Answer		%1	Comment
1-	A single operation.	67.0	Best choice. The patient undergoes anaesthesia only once, the consumption of rFVIII is less and, if the inhibitor is developed, the patient does not have to undergo new surgery with the risk of haemorrhage.
2-	Two distinct operations in a short time frame.	3.3	The risk of haemorrhage is lower, but the risk of inhibitor onset could complicate the second surgery. rFVIII consumption is higher and the patient must undergo two anaesthetic procedures.
3-	Two distinct operations, one a few months after the other.	29.6	See answer 2. Moreover, there is no reason for waiting so long between operations.

Legend CT: computed tomography; rFVIII: recombinant factor VIII;

¹Percentage of participants who selected this answer.

Table IIA.

Case 2: problems during adolescence (questions raised during the course).

Question 1:The patient refuses to continue with prophylaxis therapy. How do you proceed?
Answer		%1	Comment
1-	Continuation of the secondary prophylaxis, as in the past, at least until completion of musculoskeletal development (18–20 years).	30.2	Best choice, both in terms of clinical efficacy (observed from positive results obtained in 10 years for bleeding and joint score) and from the psychological point of view of the patient who can visualise an end to the treatment.
2-	Continued secondary prophylaxis with a reduction of the infusion frequency from 3 to 2 times/week.	41.0	Possible option, it could be therapeutically effective and would grant a better compliance because of the reduced number of injections, but clinical results could be less positive.
3-	On-demand therapy.	28.7	Possible option if the patient is firmly determined to refuse prophylaxis. It is the least adequate choice because it has the lowest clinical efficacy.
Question 2:After 3 years of on-demand therapy, the health status of the patient has worsened. What is the best therapeutic option at this stage?
Answer		%1	Comment
1-	Restart the continued secondary prophylaxis 3 times/week and follow an autoinfusion course.	76.8	Best choice, as seen by a significant increase in the number of bleeds and worsening of the haemophilic arthropathy during the on-demand therapy.
2-	Continue with on-demand therapy.	0.0	Not recommended, as seen by the worsening of the articular disease during the 3 years in which this therapy regimen was adopted and by the marked worsening of the quality of life.
3-	Restart the continued secondary prophylaxis 2 times/week and follow an autoinfusion course.	23.2	Possible option, with a reduced number of infusions one could obtain better compliance and could re-educate the patient to continue prophylaxis, with the aim of subsequently reaching the frequency of 3 times/week (if 2 infusions are insufficient).
Question 3:How should the treatment be adapted to the patient's change of lifestyle, considering his/her desire to restart practicing sports at a competitive level, and how should a proper cost/efficacy ratio be maintained?
Answer		%1	Comment
1-	Therapy every other day keeping the same dosage per kg.	59.0	Adequate therapy for this patient. In this way the suspension period of 72 h is avoided (from Friday to Monday) and circulating FVIII levels remain adequate for the entire week with only two more infusions needed a month.
2-	Daily therapy with a lower daily dosage.	6.7	Appropriate therapy considering the almost daily sporting activity, with a good cost/efficacy ratio, but the high venipuncture frequency could be a burden.
3-	Therapy 3 times/week with higher daily dosage.	34.4	Possible therapy, but not advised, since there is a 72 h interval once a week with a higher risk of haemorrhage.

Legend FVIII: factor VIII;

¹Percentage of participants who selected this answer.

Table IIIA.

Case 3: haemophilia and problems of ageing (questions raised during the course).

Question 1:What is the best pre-operative anti-haemorrhagic and/or antithrombotic prophylaxis?
Answer		%1	Comment
1-	Recombinant FVIII boluses + elastic compression stockings.	0.0	Not adequate. Both the FVIII boluses and the use of elastic compression stockings leave the patient exposed to a risk of thrombosis.
2-	Recombinant FVIII in continuous infusion + elastic compression stockings.	0.0	Not adequate. Although the continuous infusion optimises the dosage to maintain the FVIII levels in safe margins, elastic compression stockings are more indicated for patients with inhibitors.
3-	Recombinant FVIII boluses + prophylactic doses of LMWH.	67.7	Not adequate. The administration of recombinant FVIII in boluses is a valid alternative, but it exposes the patient to alternate periods of over- and underdosage that result in suboptimal treatment, from both the anti-haemorrhagic and anti-thrombotic aspects.
4-	Recombinant FVIII in continuous infusion + prophylactic doses of LMWH.	32.3	Best choice. LMWH is justified by age, kind of surgery, previous diagnostic suspicion. The continuous infusions also allow reduced costs.
Question 2:Is it possible to perform coronarography?
Answer		%1	Comment
1-	Yes.	96.3	After the patient has been given appropriate prophylaxis with recombinant FVIII, he/she may undergo this procedure, which is certainly more useful than risky.
2-	No.	3.7
Question 3:What is the best prophylactic treatment when undergoing coronarography?
Answer		%1	Comment
1-	Aspirin therapy; it is advised to avoid DES.	7.4	Not adequate. Prophylaxis with rFVIII is fundamental.
2-	Therapy with full dose rFVIII with full heparinisation and aspirin; it is advised to avoid DES.	55.1	Adequate choice: rFVIII to correct the haemostatic defect, associated with heparin at therapeutic doses for the procedure and aspirin from the start. As for other patients with a high risk of thrombosis, the use of DES is avoided, if possible.
3-	Therapy with rFVIII according to the post-operative scheme and aspirin; DES should be avoided.	37.5	Not adequate. In this case rFVIII must be prescribed at full doses, at least during the acute periprocedural phase and for the period of potential double anti-aggregation. For this procedure, it is advisable to use heparin (at the discretion of the cardiologist).
Question 4:What therapeutic approach would you suggest for the long-term, considering the patient's complex clinical picture?
Answer		%1	Comment
1-	Suspend prophylaxis with rFVIII.	11.7	Not adequate. It is a theoretically valid option, based on the hypothesis that the coagulopathy confers natural protection against the thromboembolic risk. However, no evidence has yet been found to support this theory.
2-	Continue with aspirin therapy together with prophylaxis with rFVIII.	66.3	Adequate therapy. The current most accepted treatment for these patients is to normalise the coagulopathy with prophylaxis and then treat the patient as if he/she was not coagulopathic. In this particular case, because of the atrial fibrillation, it is advisable to use prophylaxis with aspirin rather than with dicoumarols, because the patient can be treated without risks of bringing him/her to a FVIII level higher than 5% and not higher than 30% as suggested with the dicoumarol treatment.
3-	Switch oral anticoagulant therapy together with prophylaxis with rFVIII.	16.2	Not adequate. The current most accepted treatment is to normalise coagulopathy with prophylaxis and then treat the patient as if he/she was not coagulopathic.
4-	Suspend prophylaxis with rFVIII and continue with aspirin therapy.	6.0	Not adequate. Although anti-aggregant therapy could be an acceptable choice for prophylaxis of cardiac embolism, it is not feasible in a haemophilic patient in the absence of an appropriate anti- haemorrhagic prophylaxis.

Legend DES: drug-eluting stent; LMWH: low molecular weight heparin; FVIII: factor VIII; rFVIII: recombinant factor VIII;

¹Percentage of participants who selected this answer.

Table IB.

Management of paediatric patients with severe haemophilia A.

A. Severe bleeding episode or major surgery as reason for first FVIII treatment in a PUP
A.1.	The dose of the first infusion of rFVIII should be established according to the age and body weight of the patient.
A.2.	The doses of subsequent infusions of rFVIII should be established according to the observed in vivo recovery of FVIII and the target trough level of FVIII.
A.3.	If high FVIII doses and/or frequent boluses are required to maintain the target trough level of FVIII, administration by continuous infusion is recommended.
B. Treatment modality after resolution of a severe bleeding episode in PUPs
B.1.	Continued prophylactic treatment is indicated because a severe, spontaneous haemorrhage as the first clinical manifestation is indicative of an important bleeding tendency. After a severe traumatic bleed, continuation of prophylactic treatment is also indicated to prevent recurrences.
B.2.	The prophylactic regimen must be established to maintain the FVIII at measurable levels (minimum frequency: standard regimen 3 times weekly).
B.3.	Continuation of prophylactic treatment has the possible benefit of reducing the risk of inhibitor development after intensive treatment.
C. Treatment modality after a major surgical procedure in PUPs
C.1.	Continuation of prophylactic treatment has the possible benefit of reducing the risk of inhibitor development after surgery and intensive treatment with FVIII, particularly in those cases in which there are other risk factors for inhibitor development (mutations, family history of inhibitors). The choice of a prophylactic regimen must be discussed and agreed upon with the family, considering the available venous access and compliance (minimum frequency: 1 infusion/week).
C.2.	The bleeding tendency, type of venous access and compliance of the caregivers (escalating regimen) are useful to select the most appropriate prophylactic regimen.
D. Inhibitor development during FVIII treatment for a severe bleeding episode
D.1.	Development of a low titre inhibitor: increase the dose of FVIII (frequent, high-dose boluses or continuous infusion), monitor the circulating levels and continue with the high-dose prophylaxis once the acute phase has passed.
D.2	Development of a high titre inhibitor: treat the bleeding with rFVIIa, start ITI promptly, possible prophylaxis of bleeding with by-passing agents if the bleeding is severe (e.g., to prevent the risk of recurrence after cerebral bleeding) or frequent (repeated joint bleeds).

Legend FVIII: factor VIII; PUP: previously untreated patient; rFVIIa: activated recombinant factor VII; rFVIII: recombinant factor VIII.

Table IIB.

Management of adolescents with severe haemophilia A.

A. Non-compliance with prophylactic regimens
A.1.	It is advisable to seek the intervention of a clinical psychologist for good management of the interpersonal dynamics within the family starting with the initial diagnosis, particularly for sporadic forms.
A.2.	Parents, particularly the mother, should try to avoid conveying a sense of uncertainty or fear to their child.
A.3.	The patient's participation in group activities with other subjects with similar disorders can be of great help for his introduction into various social settings.
A.4.	In patients with particularly difficult venous accesses or non-compliant patients, it can be suggested that prophylaxis be continued with less frequent, but monitored, doses – once or twice a week - with the aim of increasing the dose if the protocol is not clinically or pharmacokinetically adequate. It is always preferable to switch rapidly to higher doses.
B. Viral safety of FVIII products
B.1.	The perceived risk of viral transmission through plasma-derived concentrates is still high among the relatives of patients with haemophilia, and a recombinant factor is the first choice for PUPs.
B.2.	The risk of transmitting an emerging virus is very low.
B.3.	There is no short-term clinical endpoint demonstrating infection by new variant Creutzfeldt-Jakob disease with the exception of a few cases described in the UK.
C. Secondary prophylaxis
C.1.	Secondary prophylaxis reduces the frequency of bleeds and produces a clear improvement in quality of life.
C.2.	However, following the development of haemophilic arthropathy, secondary prophylaxis cannot repair already present bone and cartilage lesions although it may slow their progression.
D. Self-infusion
D.1.	Training to perform self-infusions must be encouraged through specific courses organised in haemophilia centres.
D.2.	The current regional laws, passed in the 1970s, are obsolete and should be updated.
D.3.	It is preferable to organise individual training courses in which adolescents learn to carry out their own therapy, although some of the theory about the disease can be explained in group sessions, which are also useful for encouraging patients to meet.
E. Sporting activities
E.1.	Haemophilic patients should not be prevented from carrying out sporting activities. On the contrary, they should be encouraged to do so, because physical activity may also reduce the incidence of bleeding episodes by increasing muscle tone. Of course, extreme sports, such as boxing and motocross, should be avoided.
E.2.	Prophylaxis reduces the risk of spontaneous and traumatic joint bleeds.
E.3.	Physical training should be adapted to the personality of the patient, and prophylaxis should be individualised.
E.4.	The psychological consequence of forbidding sports should be considered. A balance must be reached between the patient's wishes, the risks associated with the sporting activity, and the costs to reduce these risks.

Legend PUP: previously untreated patient.

Table IIIB.

Management of adults with severe haemophilia A.

A.	Knee replacement in patients aged less than 60 years who have no risk factors for thrombosis
A.1.	About 60% of adults with haemophilia have chronic haemophilic arthropathy and could benefit from modern prosthetic surgery (total or compartmental implants).
A.2.	Antithrombotic prophylaxis is advisable even if clinically manifested thromboses are rarely reported.
A.3.	Treatment with FVIII should be monitored to avoid unnecessary, excessively high peak levels.
A.4.	Rapid mobilisation and rehabilitation, with appropriate prophylaxis with FVIII infusions.
B.	Knee replacement in patients older than 60 years who have risk factors for thrombosis
B.1.	Antithrombotic prophylaxis is advisable: LMWH at prophylactic doses started at least 6 hours after the operation and continued for at least 10–15 days and until complete mobilisation.
B.2.	Treatment with FVIII should be monitored to avoid unnecessary, excessively high peak levels.
B.3.	Rapid mobilisation and rehabilitation, with appropriate prophylaxis with infusions of FVIII.
C.	Cancer
C.1.	The haemophilic patient should be managed in exactly the same way as patients without clotting disorders, once the haemostatic defect has been completely corrected.
C.2.	Invasive diagnostic or therapeutic procedures: administration of FVIII during and possibly also after the procedure, if necessary.
C.3.	Chemotherapy- or radiotherapy-related thrombocytopenia: prophylaxis with FVIII if the platelet count is below 30,000/μL.
C.4.	Cancer surgery: postoperative antithrombotic prophylaxis with LMWH. Treatment with FVIII should be monitored to avoid unnecessary, excessively high peak levels (continuous infusion is advisable).
D.	Acute coronary syndrome
D.1.	The haemophilic patient should be managed in exactly the same way as patients without clotting disorders once the haemostatic defect has been completely corrected.
D.2.	Full-dose replacement therapy during coronarography, percutaneous interventions and stenting, maintaining the levels of FVIII high (80%) also during heparin therapy. Continuous infusion is advisable.
D.3.	Treatment with FVIII, maintaining levels of 30% during dual antiplatelet therapy for cardiological indications.
D.4.	Prophylaxis with FVIII, maintaining a level of 5% during single anti-aggregation therapy.
E.	Atrial fibrillation
E.1.	The haemophilic patient should be managed in exactly the same way as patients without clotting disorders, once the haemostatic defect has been completely corrected.
E.2.	If CHADS2/cardio-embolic risk is low: aspirin + prophylaxis with FVIII maintaining a level of 5%, independently of the right coronary artery.
E.3.	If CHADS2/cardio-embolic risk high: warfarin + high-dose prophylaxis.

Legend FVIII: factor VIII; LMWH: low molecular weight heparin.

Discussion

The first clinical case concerned a child with congenital dislocation of the hip and severe haemophilia A. The problem of inadequate blood clotting had to be faced during the various occasions in which measures were used for the management of the dislocation¹³. The treatment was based on the knowledge of the bleeding disorder and application of this knowledge to the orthopaedic condition.

Some clinical events that are common in small children, such as febrile convulsions, may constitute a serious problem for the management of haemophilic patients. On the one hand, data in the literature indicate that febrile convulsions are common between 6 months and 5 years of life, occurring in 2% to 5% of children with a temperature greater than 38 °C, although they are usually benign and resolve rapidly^14,15. On the other hand, the cumulative incidence of cerebral haemorrhage in haemophilic patients (children and adults) is 2.9% to 7.5%; in children, particularly those younger than 6 months, cerebral haemorrhage can present as convulsions^16,17. Notably, in the case of replacement therapy for cerebral haemorrhage, there is a lack of data indicating the optimal dose of clotting factor, the frequency of administration, when to use high-dose therapy, and if and when to start prophylaxis.

The second clinical case focused on problems that may arise in an adolescent patient with haemophilia as well as the importance of prophylaxis. According to some authors¹⁸ and on the basis of recent guidelines published in the British Journal of Haematology¹⁹, prophylaxis should be continued at least until complete development of the bone and joints, because joint bleeds occur less frequently once growth has been completed¹⁸. Indeed, switching to on-demand treatment in these patients could lead to an increase in the number of haemorrhages and, consequently, joint damage. It has, therefore, been proposed that prophylaxis should last indefinitely²⁰. Furthermore, UK guidelines recommend restarting prophylaxis if joint bleeds become frequent¹⁹. Unfortunately, few studies have been designed to compare haemorrhagic risk and progression of joint disease in patients who continue prophylaxis and in those who suspend it, with the aim of identifying candidates for continued prophylaxis⁴. However, two Dutch studies demonstrated an increase in bleeding among patients who suspended prophylaxis^21,22.

Other problems arise when dealing with the complex psychological period that characterises adolescence. Adolescents frequently refuse treatment, which is considered too rigid and restrictive; the physician may, therefore, need to re-evaluate whether to use on-demand therapy instead of prophylaxis. Moreover, because adolescents tend to focus on the present rather the future, it can be difficult for adolescent haemophiliacs to accept sacrifices (such as those deriving from a prophylaxis infusion regimen) to prevent hypothetical, future joint damage²³. Indeed, a recent study conducted in 147 haemophilia centres showed that compliance with prophylaxis is proportional to the age of the patients, with compliance being maximal up to 12 years (90% adherence to therapy) and minimal during the period of adolescence from 13 to 18 years (54% adherence to therapy)²⁴. However, because published data strongly indicate that prophylaxis should not be abandoned during the growth period, adolescents should be encouraged to be autonomous regarding their treatment through instruction courses that enable the youngsters to administer their factor concentrate themselves, thereby improving compliance¹⁹.

Another issue that continues to be debated is the possible benefit of secondary prophylaxis started in adolescent patients who already have established degenerative joint disease. In fact, there are only a few retrospective studies on this issue, almost all of which concern small cohorts of patients^25–27, and one recent prospective crossover study with a short follow-up (6 months)²⁸. A detailed review of these studies was performed by Coppola et al⁴; in all of the studies there were significant reductions in the number of total bleeds and joint bleeds in patients receiving secondary prophylaxis. These benefits were associated with a wide variability in the increase in consumption of concentrates and costs. Fischer et al.²⁶ also showed that long-term secondary prophylaxis started in adulthood may slow, but cannot stop, the progression of haemophilic joint disease. Tagliaferri et al.²⁷ demonstrated a significant improvement in the orthopaedic score of patients who started secondary prophylaxis in adolescence and improved quality of life in both adolescents and adults. Furthermore, there are two ongoing prospective studies on this issue: an Italian observational study, the Prophylaxis vs On-Demand Therapy Through Economic Report (POTTER) study²⁹ and a randomised trial being conducted in the USA (the SPINART trial)³⁰. An interim analysis of the POTTER study at 4 years showed significant reductions in the total number of bleeds, the number of joint bleeds, and the physical examination score (Gilbert score) in the group of patients managed with prophylaxis compared with the group receiving on-demand treatment²⁹.

Although there is still a lack of evidence from long-term, controlled, prospective studies³¹, it has been demonstrated that prophylaxis at any age reduces the number of joint bleeds. There are physical and psychological limitations to prophylaxis, but the improvement in quality of life counterbalances both these limitations and the higher costs of prophylaxis compared to on-demand treatment²⁷.

With the possible exception of the last few years^18,32, the focus of haemophilia research has been mainly to assess the optimal regimen to treat and prevent joint bleeds; to reduce and possibly prevent inhibitor development; to treat bleeds and induce tolerance in inhibitor patients; and to treat patients with blood-borne viral infections^33–37. Age-related diseases have not been extensively addressed in the haemophilic population; therefore, our third case was used to focus on these diseases.

In recent years, remarkable progress has been made in the field of antithrombotic and antineoplastic treatment. In this regard, newer, more potent and selective drugs have been introduced, allowing a broader population of patients to be treated with more aggressive multiple treatment regimens. Physicians caring for haemophilic patients may now face difficult new challenges, such as assessing the risk-to-benefit ratio and feasibility of, for example, double antiplatelet treatment for cardiac stenting³⁸, extended antithrombotic prophylaxis of postoperative venous thromboembolism³⁹, and the use of vitamin K antagonists in patients with atrial fibrillation⁴⁰. Limited information on these issues has been collected in the past and mainly in patients with mild haemophilia.

Conclusion

Doctors treating haemophilic patients must often tackle difficult clinical situations in the absence of high-quality evidence and, therefore, have to rely on their knowledge of the pathophysiology of the conditions and extensive discussion of opinions and cases with experienced colleagues.

The ultimate objective of the KOGENIALE project was to use of these techniques to address three clinical scenarios. Through a randomly rotated assignment involving an interactive problem-solving group activity or open discussion and formal scoring of case-driven questions, consensus statements on issues relevant to patients with haemophilia of different ages were formulated. It is hoped that this will be a useful tool for young physicians treating patients with haemophilia and concomitant disorders.

Steering committee

The steering committee was composed of Alfonso Iorio, Maria Messina, Massimo Morfini, Elena Santagostino, and Annarita Tagliaferri. Massimo Morfini and Elena Santagostino designed the course, supervised the project, and led the general discussion. Alfonso Iorio, Maria Messina and Annarita Tagliaferri prepared the cases regarding the elderly adult, child, and adolescent, respectively; instructed the actors for performance; and led the relative case discussions. All the authors took part in drafting this manuscript and approved its final version.