Total joint arthroplasty: the final solution for knee and hip when synovitis could not be controlled

Summary.  In severely affected haemophilic patients knee and hip arthropathy is a common problem, which can leads to considerable pain and functional deficit. Surgical management, including total knee and hip arthroplasty, can be undertaken if conservative management fails. This paper reviews the functional outcome of arthroplasty in the knee and hip, the postoperative and long-term complications, and the impact of HIV. Although complications are commonly described and the surgery is technically demanding, the results of the author of this paper and the review of the literature suggest that arthroplasty of the hip and knee can be a valuable option in the management of severe haemophilic arthropathy.     

Total joint arthroplasty in haemophilia

In severely affected haemophilic patients arthropathy is a common problem which can lead to considerable pain and functional deficit. Surgical management, including total joint arthroplasty, can be undertaken if conservative management fails. A search of the literature showed that a number of studies describing the use of total knee arthroplasty (TKA) and total hip arthroplasty (THA) in haemophilia have been published, whereas shoulder, elbow and ankle arthroplasties are confined to case reports. This paper reviews the functional outcome of arthroplasty in the different joints, the postoperative and long-term complications, and the impact of HIV. Although complications are commonly described and the surgery is technically demanding, the results suggest that arthroplasty, particularly of the hip and knee, can be a valuable option in the management of severe haemophilic arthropathy.     

Clinical outcomes and patient satisfaction following total joint replacement in haemophilia – 23‐year experience in knees,hips and elbows

Summary. Joint replacement surgery is an available option for end‐stage haemophilic arthropathy. However, reports with long‐term follow‐up are limited. Moreover, patient satisfaction in this setting has never been measured. We share our institution’s experience with joint arthroplasty in haemophilic arthropathy and report on clinical outcomes and patient satisfaction. Between 1985 and 2007, 65 consecutive joints in 45 patients (mean age: 48.6; range: 22–83) underwent joint replacement surgery. Of these, 40 total knee replacements in 31 patients, 18 total hip replacements in 16 patients and 6 total elbow replacements in 3 patients were included. Average follow‐up was 10.7 years (2.4–24.3). Charts were reviewed retrospectively and patients were asked to return for clinical assessment and completion of questionnaires. According to the Knee Society clinical score, postoperative results were good to excellent in 83% of knees. According to the Harris Hip Score, results were good to excellent in 31% of hips. According to the Mayo Elbow Performance Score, results were good to excellent in 83% of elbows. Complication rates are higher than in the non‐haemophilic population, while prosthesis survival rates are lower. Patient satisfaction with pain relief is higher than satisfaction with functional improvement. For 88% of joints, patients are willing to have the same operation again. This study confirms previous knowledge on the role of total joint arthroplasty in haemophilic arthropathy. Despite high complication rates and modest functional outcomes, the operations are valuable for achieving pain relief. In general, patients find that risks are outweighed by the benefits.     

Total hip and knee arthroplasty for arthropathy in a hemophiliac

We evaluated the medium-term follow-up results, effectiveness, and suitability of arthroplasty for hemophilic arthropathy. We performed 26 total knee and 9 total hip arthroplasty operations on hemophilic patients between 1988 and 1998 under general anesthesia and appropriate hemostatic management. Postoperative treatment for hemophilic arthropathy is the same as that for osteoarthritis and rheumatoid arthritis. After their operations, patients experienced relief from pain and intra-articular bleeding in affected joints but only marginal improvement in the range of motion. In general, total joint arthroplasty is not indicated for young patients. However, arthropathy can have a severe impact on the active life of patients during their youth. For severe hemophilic arthritis, total knee and hip arthroplasty can lead to a pain-free and improved quality of life. We believe total knee and hip arthroplasty is a good solutions for hemophiliac arthropathy before severe deformity occurs. Although treated relatively young hemophilic patients, age was not considered to be a contraindication.     

Total knee arthroplasty for severe haemophilic arthropathy: long-term experience in Taiwan

Summary. A number of articles have investigated the outcomes of total knee arthroplasty (TKA) and causes of prosthetic failure in patients with haemophilic arthropathy. The aims of this retrospective study were to evaluate the clinical and functional outcomes of TKA and causes of prosthetic failure in patients with haemophilic arthropathy. A consecutive series of 35 TKA in 26 patients with haemophilic arthropathy were performed between November 1985 and October 2006 by one experienced surgeon. The mean age at index operation was 34.2 years old (range: 23.4–47 years) and the mean follow‐up duration was 82.2 months (range: 12–218 months). Clinical assessment included range of flexion, range of extension and total range of motion (ROM). Functional evaluation comprised pain score and functional score by Dr. Insall’s Knee Society Clinical Rating System. The average preoperative ROM was 63.2° with flexion contracture 15°, whereas the average postoperative ROM was 79.8° with flexion contracture 5.5°. Improvement of range of flexion was 7.1° (P = 0.16); improvement of range of extension was 9.5° (P < 0.01). Average increase of total ROM was 16.6° (P = 0.02). Pain score by Knee Society was 7.1 points preoperatively and 48 points postoperatively (P < 0.01); functional score by Knee Society was 42 points preoperatively and 77.1 points postoperatively (P < 0.01). Three patients received manipulations because of an inadequate ROM. Three infection episodes were treated with debridement and one of them received arthrodesis after removal of prosthesis. Two patients received revision TKA. One of them was because of loosening of femoral component. The other one received revision TKA because of insert wear. Though improvement in range of flexion is insignificant in haemophilic arthropathy of knee after TKA, it showed significant increase in total ROM after operation, especially in improvement of flexion contracture. It also showed great pain relief and significant functional gain. Under the circumstance of acceptable infection rate and complication, TKA is an effective method to achieve pain relief and gain better function in patients with haemophilic arthropathy of knee. The data of this study confirm those previously published by many authors.     

Synovectomy for haemophilic arthropathy: 6–21 years of follow-up in 16 patients

Abstract. Objectives . To assess the efficacy of synovectomy in reducing recurrent haemarthroses and joint pain in patients suffering from haemophilic arthropathy. Moreover, to study whether synovectomy could improve joint mobility or postpone progression of joint destruction. Design . A retrospective study was conducted addressing joint-related symptoms and findings, and the need of orthopaedic surgery during follow-up. Setting . Oslo Sanitetsforenings Rheumatism Hospital/The National Hospital, the National Centre for Orthopaedic Surgery for approximately 180 Norwegians suffering from severe congenital coagulation deficiencies. Subjects . Twelve patients with haemophilia A, two patients with von Willebrand's disease and two patients with factor VII deficiency in which 21 synovectomies (nine knees. six ankles and six elbows) were performed. Main outcome measures . Joint pain, joint mobility, frequency of haemarthroses and radiographic joint scores at follow-up were compared to preoperative figures, and the number of joints in need of total joint replacement or arthrodesis was evaluated. Results . Synovectomy proved efficacious in reducing recurrent haemarthroses and joint pain in all patients. The total range of motion was not improved, but correction of extension deficiency of the knee was accomplished. The progression of arthropathy was not arrested by synovectomy as judged by the radiographic assessment; and in four patients arthroplasty of the knee, and in two patients arthrodesis of the ankle, had been performed. A major wound haemorrhage and subsequent wound rupture was seen in one patient who developed high-titred neutralizing antibodies to factor VIII. Conclusions . Synovectomy for haemophilic arthropathy is safe and efficacious in reducing recurrent haemarthroses and joint pain. Synovectomy should not be performed to improve joint mobility. The progression of the arthropathy is not arrested, and subsequently many patients will be candidates for arthroplasty or arthrodesis.     

Cementless total hip arthroplasty for haemophilic arthropathy: follow‐up result of more than 10 years

The improvement of prophylaxis and adequate replacement of clotting factors, the quality of life and natural history of haemophilia have been significantly improved. However, significant functional impairment is inevitable. This study was performed to evaluate over 10 years clinical and radiographic outcomes of cementless total hip arthroplasty (THA) for treatment of haemophilic hip arthropathy. Between 1995 and 2003, 27cases of cementless total hip arthroplasties were performed in 23 haemophilic patients. A total of 21 cases from 17 patients were available for follow‐up analysis over 10 years. Modified Harris hip score, the range of motion of the hip joint, perioperative coagulation factor requirements and complications associated with bleeding were evaluated as part of the clinical assessment. For the radiographic assessment, fixation of component, osteolysis, loosening and other complications were evaluated. Clinically, the mean Harris hip score improved from 57 points before the operation to 94 points at the last follow‐up. The mean flexion contracture was 10° preoperatively and 0.9° at the final follow‐up. The further flexion improved from 68.4° to 90.5° after surgery. The mean monthly requirement of factor VIII reduced from 3150 units before surgery to 1800 units at the time of the last follow‐up. There were three cases of rebleeding. In one case, a progressive haemophilic pseudotumour was found. Reoperation for any reason including revision was performed in three cases. We believe that cementless THA in patient with haemophilic hip arthropathy can bring reliable pain relief and functional improvement for longer than 10 years.     

In vitro and in vivo stability of diluted recombinant factor VIII for continuous infusion use in haemophilia A

Summary.  Factor VIII (FVIII) replacement by continuous infusion (CI) is used postoperatively or after significant bleeding. For young paediatric patients, CI may require FVIII dilution. Variable stabilities of diluted full-length recombinant FVIII Kogenate^® FS (KG-FS) have been reported under different storage conditions. We investigated the recovery and stability of diluted KG-FS in vitro and in vivo . Kogenate^® FS was diluted to 50–120 U mL⁻¹ and its recovery and stability in glass vials or polypropylene syringes was determined. Furthermore, stability of KG-FS diluted to 80 U mL⁻¹'administered' via single- and double-pump mock CI systems was tested. Finally, the in vivo stability of KG-FS diluted to ∼60 U mL⁻¹ and administered postsurgically by CI with the double-pump to a paediatric patient with severe haemophilia A undergoing implantable venous access device placement was investigated. Initial KG-FS dilution resulted in a 10–20% FVIII loss; a further 25–30% loss occurred over 72 h in vials or syringes. With the double-pump, 1 h recovery was 35%, increasing to 80% by 24 h; the initial losses were because of the Y-infusion of a 10-fold larger volume of saline concomitantly with the FVIII. In vivo , CI resulted in stable FVIII activity levels within the target range. These in vitro results are important for the generation of CI guidelines for diluted KG-FS in the paediatric haemophilic population. That FVIII losses occur upon dilution and with the double-pump does not preclude use of diluted KG-FS. Indeed, stable FVIII levels were maintained when diluted KG-FS was administered by CI with the double-pump to a paediatric patient postsurgically.     

The outcome of cementless total hip arthroplasty in haemophilic hip arthropathy

Summary.  Total hip arthroplasty (THA) in haemophilic arthropathy is reported to be less successful than in non-haemophilic indications. Although preliminary results are encouraging, the survival and functional outcome of cementless THA in haemophilia are not known. The aim of this study was to analyse mid-term results of cementless THA in haemophilia. Twenty-seven consecutive cementless THAs with 23 patients performed between June 1995 and June 2003 were reviewed. Mean age at time of operation was 36 years and mean follow-up period was 92 months (range, 60–156). Radiographic assessment was done for fixation of components, loosening, osteolysis, wear and bone responses around the implants. The factor requirements, amount of transfusion and complications associated with bleeding were studied. The mean preoperative Harris hip score changed from 57 to 95.9 at the latest follow-up. The survival at mean follow-up was 95.2%. One patient with osteolysis around acetabular cup was re-operated with bone-grafting and change of polyethylene liner. One loose cup was revised with a cemented cup. All other components were deemed stable at the latest follow-up. A standardized management protocol and dedicated team approach comprising of haematologist, physicians, physical therapist, nurses and coordinators is needed for excellent results. The present retrospective study shows that the functional results of cementless THA in haemophilia are satisfactory as it happens in osteoarthritic patients according to the current literature, mainly the younger. Thus, taking into account that the majority of haemophilia patients requiring a THA are relatively young, cementless THA is currently recommended.     

Outcomes in total elbow arthroplasty in patients with haemophilia at the University of California,San Francisco: a retrospective review

Summary. Severe haemophilic arthropathy of the elbow is a significant cause of morbidity among adults with haemophilia. However, previous reports of total elbow arthroplasty (TEA) in the haemophilic population have been based on small numbers of patients with relatively short‐term follow‐up. The records of seven total elbow arthroplasties in six adult men with haemophilia at the University of California, San Francisco who underwent TEA over a period of 25 years were retrospectively reviewed. Type of haemophilia, age at time of TEA, HIV infection status, pre‐ and postoperative range‐of‐motion (ROM) scores, complications (including infections), need for subsequent surgical revision and functional outcomes were recorded. Four patients had severe factor VIII deficiency and two patients had severe factor IX deficiency. None of the patients had an inhibitor. The mean age at the time of surgery was 34 years (range, 22–46 years) and the mean follow‐up period was 118 months (range, 37–176 months). One of the six patients had TEA in both elbows. Five of the six patients were infected with HIV. There were no immediate perioperative complications. At a mean of 19.2 months postoperatively, ROM had improved in five of seven TEAs: mean flexion had increased from 110.7° (SD = 15.0) to 120.1° (SD = 14.5), whereas mean preoperative extension increased from ?44.3° (SD = 21.5) to ?36.9° (SD = 27.0). One patient required a revision at 30 months because of ulnar component loosening. This same patient sustained a staph epidermidis infection and ultimate removal of the prosthesis 15 years postoperatively. At a mean of 118 months postoperatively, five of six patients continued to report reduced pain and preserved functionality, with ability to perform normal daily activities. TEA resulted in favourable results in six of seven procedures. Our findings support the viability of TEA for individuals with severe haemophilic arthropathy of the elbow, especially to reduce pain and preserve or restore functionality. Level of evidence .  Level IV.     

Pre-operative flexion contracture determines the functional outcome of haemophilic arthropathy treated with total knee arthroplasty

End-stage haemophiliac arthropathy can be successfully treated with total knee arthroplasty. However, the functional results may not be as good as anticipated and certain pre-op knee characteristics may alter the functional results. The purpose of this study was to evaluate the functional outcome of TKA in haemophilic patients with specific attention to final range of motion and residual flexion contracture of the joint. Twenty-one consecutive patients were retrospectively reviewed. The average age was 34 years with an average follow-up of 5.7 years. Functional status was evaluated with Hospital for Special Surgery Knee Score. Receiving Operating Characteristics analysis was used to determine the threshold of pre-operative flexion contracture degree to avoid residual knee contracture. The range of motion was increased in 16 joints and unchanged in three joints and decreased in the remaining two. Preoperative average range of motion was 37.6°, improved to 57.1° post-operatively. The average knee score increased from 27.85 (15-30) points pre-operatively to 79.42 (12-94) points at the last follow-up. The degree of pre-operative flexion contracture was found to be a good predictor for residual flexion contracture. (Specificity: 85.7%, sensitivity: 100%, cut-off: 27.5°). Total knee replacement improves the quality of life in patients with advanced haemophilic arthropathy. Statistical analysis revealed that pre-op flexion contracture of 27.5° is an important threshold. Patients should be operated before that stage to gain maximum benefit with minimal gait abnormalities.     

The role of physiotherapy after total knee arthroplasty in patients with haemophilia

Summary. With the availability of clotting factor concentrates, advances in surgical techniques, better implant design, and improvements in postoperative management, total knee arthroplasty has become the treatment of choice for haemophilia patients suffering from end‐stage haemophilic knee arthropathy. The success of this surgery is also dependent on close collaborations among the orthopaedic surgeon, the haematologist and the physiotherapist. Although haemophilic patients undergoing this surgery would likely benefit from a targeted rehabilitation programme, its specificities, modalities and limitations have thus far not been extensively studied. Employing the published data of rehabilitation after knee prosthesis in patients with osteoarthritis and haemophilic arthropathy along with clinical experience, the authors present a comprehensive and original review of the role of physiotherapy for patients with haemophilia undergoing knee arthroplasty.     

Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability

Summary.  Understanding the pharmacokinetics (PK) of factor VIII (FVIII) is important in the management of patients with haemophilia A. We studied the PK of FVIII in order to determine aetiological factors contributing to PK variability of FVIII in children.
Twenty children with haemophilia A (mean age 12.8 years) were administered a single bolus of 50 U kg⁻¹ of recombinant FVIII (rFVIII; Kogenate-FS^®, Bayer).
The mean incremental FVIII recovery was 1.87 (U mL⁻¹)/(U kg⁻¹) (range: 1.25–2.76) and the mean FVIII half-life was 10.7 h (range: 7.8–15.3). FVIII recovery was positively correlated with body surface area (BSA; P  = 0.04). FVIII half-life was positively correlated with preinfusion levels of von Willebrand factor antigen (VWF:Ag) ( P  = 0.0001) and was reduced in patients ( n  = 6) with very low FVIII inhibitor titres (<0.5 BU) vs. those ( n  = 14) with negative inhibitor titres ( P  = 0.06).
These observations suggest that (i) young children with haemophilia in comparison with adults have a low recovery of FVIII and that this might be explained by differences in body composition (BSA, plasma volume), (ii) levels of VWF:Ag may explain some of the differences in the half-life and clearance of FVIII and (iii) very low inhibitor titres, previously regarded as clinically insignificant, may actually be significant and should be evaluated in the context of PK studies.     

Potency and mass of factor VIII in FVIII products

Summary.  Several factor (F) VIII products of different origin and structure are being used for haemophilia A treatment worldwide. The assessment of FVIII concentration in these products is done using activity assays, which are dependent upon the assay and its modifications. To evaluate FVIII products for potency and for FVIII concentration and specific activity, three activity-based assays [activated partial thromboplastin time (APTT), intrinsic FXase and synthetic coagulation proteome] and two immunoassays (ELISA and western blotting) were used in this study with albumin-free full-length recombinant (r) FVIII as a standard. In all activity assays, products A and B (both contain full-length rFVIII) at 1 U mL⁻¹ showed potency similar to that of the 0.7 n m (1 U mL⁻¹) rFVIII standard. Product E (contains truncated rFVIII) was less potent in the APTT (83% of standard) and product C (contains plasma FVIII) was less potent in FXase assays (66%). The ELISA immunoassay revealed that the specific activity of FVIII proteins in products A–C and E varied over a wide range (3900–13 200 U mg⁻¹) and was higher for most lots when compared with the standard (5000 U mg⁻¹), whereas the specific activity of product D (contains plasma FVIII) was lower than expected (3200–4800 U mg⁻¹). (i) FVIII potency estimated in different assays gives dissimilar results; (ii) the specific activity of FVIII in various FVIII products is different and inconsistent. Thus, the administration of an equal FVIII potency in units means the administration of different amounts of FVIII protein, which may partly explain apparent discrepancies in product performance.     

The co effect of prophylaxis and radiosynovectomy on bleeding episodes in haemophilic synovitis

Summary.  Prophylactic substitution treatment and radiosynoviorthosis have a leading role in preventing irreversible haemophilic arthropathy. The aim of the study was to evaluate the effects of prophylaxis treatment and radiosynovectomy on the length of intervals between subsequent haemorrhages in haemophilic patients. Thirty-three joints were treated with radiosynovectomy in 28 patients with bleeding disorders. ⁹⁰Y colloid was used in knees and ¹⁸⁶Re colloid for elbows, shoulders and ankles. Twenty patients were on prophylaxis. Joint X-rays were evaluated on the Pettersson scale between 0 (normal) and 13 (severe joint destruction). During an observation period (range 6–44 months) bleeding episodes were recorded and data statistically analysed. Before radiosynovectomy, increasing intensity of the prophylaxis 10% lengthens intervals between two haemorrhages by 1% ( P  < 0.05). In patients with a Pettersson score higher than nine, intervals between bleedings are shorter by 73% ( P  < 0.05), in comparison with patients with lower Pettersson scores of 0–5. After radiosynovectomy, the length of the first non-bleeding interval increased by 120% (to 60 days) in comparison with the intervals before the procedure ( P  < 0.001). But, in the following year and half, every subsequent non-bleeding interval was 8% shorter ( P  < 0.1). In that period, prophylaxis shortened the non-bleeding interval by 1.7% ( P  < 0.05) per 10% increase of its intensity. Radiosynovectomy is more efficient in patients with less affected joints and is less efficient in younger patients. Prophylaxis reduced time between the bleedings episodes after isotope application. Before radiosynovectomy, prophylaxis reduces the number of haemorrhages. Our findings support data previously published by Rodriguez-Merchan et al. [ J Thromb Haemost , 5 (2007) P-W-126].     

Orthopaedic outcome of total knee replacement in Haemophilia A

A consecutive series of 16 patients with classical Haemophilia underwent 21 total knee replacements between 1989 and 1997 for haemophilic arthropathy. The patients received Factor VIII replacement therapy via continuous infusion, and fibrin glue was used to facilitate haemostasis. Three different types of prostheses were used. A follow-up evaluation was undertaken between 2 and 10 years after the operation (mean 5.6 years) and two patients with infection were excluded. Knee scores averaged 77.5 (pre-operative 24. 1) and functional scores averaged 84.4 (preoperative 23.2). There were no cases with aseptic loosening of the prosthesis. Complications included one early deep infection controlled by conversion of the TKR into an arthrodesis, one case of late septic loosening that had to be re-operated upon, one case of patellar dislocation, two cases of stiff knee (fibro-arthrosis) that required manipulation under anaesthesia, one postoperative hepatitis, one superficial infection treated by incision and drainage and four febrile patients with no clear source of infection, who responded to antibiotics alone. In conclusion, TKR offers haemophilic patients a long-lasting improvement of their quality of life and we therefore advocate its use with the appropriate indications.     

Orthopaedic manifestations of the hip in haemophilia – impaction bone grafting used in revision total hip arthroplasty in a haemophilic patient

The condition of haemophilia presents many challenges to the orthopaedic surgeon. Two such challenges include the haemophilic pseudotumour, a rare complication occurring in 1-2% of haemophiliacs, and the phenomenon of aseptic loosening of arthroplasty implants. This report presents a case involving the separate management of a pseudotumour and revision hip arthroplasty in the same hip using impaction bone grafting.     

Preliminary results for the use of knee mega‐endoprosthesis in the treatment of musculoskeletal complications of haemophilia

Complications of haemophilia in the knee region are rare and difficult to treat. Use of surgical treatments such as total knee arthroplasty cannot satisfactorily restore knee function in patients with these complications, which include massive haemophilic pseudotumour, fracture around the knee and haemarthrosis. To analyse the postoperative results of patients suffering from complications of haemophilia and treated with a knee mega‐endoprosthesis, to discuss and compare this type of surgical management with other types of treatments used in similar cases. We retrospectively analyse the surgical results of patients who were treated with a knee mega‐endoprosthesis for complications of haemophilia. Three severe haemophilic arthritic knees, of which two were combined with femoral condylar fractures, were treated in a one‐stage surgery, and another two knees which presented with massive haemophilic pseudotumours and bony defects were treated in a two‐stage operation. Mean age at time of surgery was 28.5 years old and mean follow‐up time was 22.8 months; the mega‐endoprosthesis surgery was successfully performed in four cases and the mean range of motion increased from 29.5° preoperatively to 96.75° postoperatively. The Knee society score function score value increased from 25 to 82.5. One knee was amputated because of uncontrollable recurrent haemorrhage. Roentgenograms did not show any signs of loosening of the prostheses. Use of Mega‐endoprosthesis in the treatment of complications of haemophilia can offer patients suffering from massive pseudotumours with bone defect, severe contracture knee haemophilic arthritis and fractures around a haemophilic knee a viable treatment option.     

Successful angiographic embolization of recurrent elbow and knee joint bleeds in seven patients with severe haemophilia

Summary.  In haemophilic joints with high-grade arthropathy, bleeds occur that do not respond to replacement therapy of the deficient coagulation factor. The reason may be pathologically reactive angiogenesis in chronic synovitis. Seven patients with severe haemophilia A or haemophilia B experienced recurrent massive bleeds of one elbow joint or knee joint in the absence of trauma. After initial application of factor VIII or IX (fVIII/fIX; 50 IU kg⁻¹ bodyweight), there was only slow and never complete relief of symptoms. Despite intensive secondary prophylaxis maintaining the plasma level of factor concentrate at minimum 50%, new massive bleeds at the same location occurred. Vascular bleeding was suspected. Angiography of the arteries was performed via the femoral artery. Vessels identified as potential bleeding sources were embolized with embolization fluid (ONYX) in eight joints (six elbow and two knee joints). Under low-dose prophylactic treatment (15 IU fVIII or fIX per kg bodyweight for three times per week), no recurrent severe bleed unresponsive to coagulation factor replacement occurred after a mean observation time of 16 months after embolization. The consumption of factor concentrate decreased to one-third of the amount consumed before embolization. In conclusion, angiographic embolization with a non-adhesive liquid embolic agent might be considered as a promising therapeutic and coagulation factor saving option in joint bleeds not responding to replacement of coagulation factor to normal levels.     

Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors

Summary.  Patients with severe haemophilia A and an inhibitor may become refractory to FEIBA and/or recombinant factor VIIa (rFVIIa). Sequential therapy with both products has been reported in such patients. In this pilot study, we examined the safety and efficacy of combined rFVIIa and FEIBA therapy in patients with haemophilia A and inhibitors during bleeding episodes. We also tried to evaluate whether thrombin generation (TG), by various mixtures of these agents, can serve as a guide for tailoring therapy. TG was measured in plasma taken from eight haemophilia A patients. Increasing concentrations of rFVIIa, FEIBA or both were added ex vivo to the plasmas, and TG was induced by recalcification. Since low concentrations of rFVIIa and FEIBA had either an additive or a synergistic effect in all patients, the lowest combination, yielding TG comparable or lower than TG achieved with either FEIBA 100 U kg⁻¹ or rFVIIa 160 μg kg⁻¹ alone, was selected for the treatment of bleeding episodes. Five patients with a high titre of an inhibitor (8–1300 BU), including one previously refractory to infusions of rFVIIa at doses up to 400 μg kg⁻¹ X4 daily, were treated with combinations of 30–70 μg kg⁻¹ rFVIIa and 20–30 U kg⁻¹ FEIBA during a total number of 400 bleeding episodes with excellent haemostatic effect. No adverse events and no DIC were observed following these infusions. Concomitant infusion of low-dose rFVIIa and low-dose FEIBA, seems to be safe, efficacious and economical in patients refractory to rFVIIa and probably other haemophilia A patients with an inhibitor.