Factor IX replacement to cover total knee replacement surgery in haemophilia B: a single‐centre experience, 2000–2010

Summary. Total knee replacement (TKR) is a well recognized treatment for haemophilic arthropathy. Successful haemostasis can be achieved by bolus doses or continuous infusion (CI) using either recombinant (r) or plasma‐derived (pd) factor IX (FIX). We retrospectively analysed our experience of factor replacement to cover TKR in haemophilia B patients and explored factors related to FIX use during surgery. Between 2000 and 2010, 13 primary TKRs were performed in 11 haemophilia B patients. Operations were performed by the same surgeon using standard techniques. Median age was 58 years (42–79). An adjusted CI protocol was used for 5 days followed by bolus doses. FIX:C was maintained at 100 IU dL^?1 in the immediate postoperative period. There was no excess haemorrhage. There was no evidence of thrombosis or infection. All patients received mechanical thromboprophylaxis and only one chemical. CI was used in seven cases. Ten patients received pdFIX. Median hospital stay was 14 days (8–17). Median factor usage was 999 IU kg^?1 (768–1248). During CI, factor consumption was 695 IU kg^?1, 691 IU kg^?1 and 495 IU kg^?1 for Bene Fix ®, Replenine® and Haemonine, respectively. Clearance of both pdFIX and rFIX reduced during CI. All operations were uncomplicated. The decreased clearance in the CI setting reduced the amount of FIX required to maintain a therapeutic level. This reduction was greater with pdFIX and may be related to pharmacokinetic differences between pdFIX and rFIX. Given the excellent safety profile of the pdFIX products, CI of FIX and particularly pdFIX is safe, efficacious and convenient.     

Therapeutic potential of apixaban in the prevention of venous thromboembolism in patients undergoing total knee replacement surgery

Anticoagulant prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery. Despite available anticoagulant prophylaxis, patients who undergo total knee arthroplasty (TKA) have a high incidence of venous VTE. In spite of their proven efficacy, the currently available anticoagulants have limitations that driven to develop new oral agents that directly target specific factors in the coagulation cascade, such as direct thrombin inhibitors and direct Factor Xa inhibitors, in an attempt to overcome some of the drawbacks with the traditional agents. Apixaban is a potent, selective direct inhibitor of the coagulation factor Xa, recently approved in Europe for the prevention of venous thromboembolism (VTE) in adult patients after total hip replacement (THR) or total knee replacement (TKR) surgery. Apixaban has been extensively studied worldwide in about 12,000 patients in four clinical studies that have demonstrated the efficacy and safety of apixaban respect to enoxaparin for the prevention of thromboembolism after major orthopedic surgery. Three of these trials involved 7,337 patients who undergo TKR: one phase II trial (APROPOS Study) and two large phase III trials (ADVANCE 1 and ADVANCE 2 Studies). ADVANCE 1 demonstrated that when compared with enoxaparin 30 mg twice daily for efficacy, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding. ADVANCE 2 showed that apixaban was superior to the European standard dose of enoxaparin of 40 mg once daily in term of efficacy, with a similar incidence of major bleeding. This review focuses the clinical efficacy and tolerability of oral apixaban for the prevention of VTE in adult patients following TKR surgery.     

Clinical efficacy,safety and pharmacokinetic properties of the plasma‐derived factor IX concentrate Haemonine® in previously treated patients with severe haemophilia B

Summary. Plasma‐derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ^® is a high purity double‐virus inactivated human plasma‐derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open‐label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long‐term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on‐demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half‐life. Mean terminal elimination half‐life was 27.6 h and 25.0 h, mean incremental recovery (IU dL^?1/IU kg^?1) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as ‘excellent’ or ‘good’. Moreover, ‘excellent’ haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long‐term prophylaxis, TOD and when applied after minor and major surgeries.     

Safety and efficacy of plasma‐derived coagulation factor IX concentrate (AlphaNine® SD) in patients with haemophilia B undergoing surgical intervention: a single institution retrospective analysis

Summary. While coagulation factor replacement is essential in surgical intervention in haemophilia B patients, few studies are available on the safety and efficacy of plasma‐derived factor IX (FIX) for haemostasis during surgery. This retrospective study examined outcomes in these patients. A total of 20 patients who underwent 29 surgical procedures at the Hemophilia Treatment Center at Orthopaedic Hospital in Los Angeles, California, were identified and their inpatient charts were reviewed and abstracted. Outcomes included pre‐ and postoperative FIX dosing, recovery of FIX, blood loss, use of blood products, safety and haemostatic response. Identified patients had mild (10%), moderate (15%) or severe (75%) haemophilia B, and average age at surgery was 48.5 years. All surgical procedures were major (orthopaedic 89.7%; abdominal 10.3%), all were completed under general anaesthesia, and average time in surgery was 3.25 h. Average hospital length of stay was 11.0 days [standard deviation (SD) = 8.5] and all patients were discharged home. All patients were treated with AlphaNine^® SD at an average dose of 254.9 IU kg^?1 (SD = 65.4) on the day of surgery and the dose was adjusted over the course of hospital stay. Mean perioperative blood loss was 255.5 mL (SD = 283.1) and blood replacement was required in only two surgeries (6.9%). FIX recovery analysis performed preoperatively related well to FIX levels obtained. Identified patients had little blood loss perioperatively and had no bleeding related complications. Plasma‐derived FIX pre‐ and postoperatively appeared to be a safe and effective treatment in haemophilia B patients undergoing surgery.     

Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey

Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty-seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg(-1), and for surgery was 100 IU kg(-1). For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85-97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65-97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage.     

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.     

A clinical study assessing the pharmacokinetics,efficacy and safety of AlphaNine®, a high‐purity factor IX concentrate,in patients with severe haemophilia B

Summary. Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine^®, a high‐purity human FIX concentrate. This open, single‐arm, multicentre, non‐randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6‐month follow‐up. The degree of haemostasis control achieved was evaluated during a 12‐month follow‐up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL^?1 per IU kg^?1 at baseline and 1.23 ± 0.34 IU dL^?1 per IU kg^?1 6 months later. Terminal half‐life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine^® were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty‐one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine^® showed a pharmacokinetic profile in agreement with that of other plasma‐derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.     

Perioperative clotting factor replacement and infection in total knee arthroplasty

Total knee arthroplasty, or replacement (TKR), is now the most commonly performed surgical procedure performed in adults with haemophilia. It is indicated when end-stage haemophilic arthropathy results in intractable pain and reduced function. In patients with haemophilia, however, there has always been a concern about the high risk of infection, which carries with it potentially catastrophic consequences. The aims of this study were to review the case series of TKR for haemophilic arthropathy published in the medical literature, comparing the published infection rates and the differing clotting factor replacement regimes employed. Nineteen retrospective case series were identified; representing 556 TKR's in 455 patients with an overall infection rate of 7.9%. Case series which maintained a high level of clotting factor replacement throughout the first two postoperative weeks, however, had an infection rate of 2.15%, significantly lower than that of case series using the clotting factor replacement regime currently recommended in the World Federation of Hemophilia guidelines (9.22% P = 0.00545). We believe this study supports the use of a high level clotting factor replacement regime, replacing clotting factors to maintain them at a higher level for a longer period of time than currently recommended in international guidelines.     

The clinical efficacy and safety of the FVIII/VWF concentrate,BIOSTATE®, in children with von Willebrand disorder: a multi‐centre retrospective review

Summary. Factor replacement with BIOSTATE^®, a factor VIII (FVIII)/von Willebrand factor concentrate, forms the mainstay of treatment for children with von Willebrand disorder (VWD) in Australia and New Zealand. However, published data on the clinical efficacy and safety of BIOSTATE in the VWD paediatric population are limited. We retrospectively assessed the efficacy and safety of BIOSTATE in 43 children with VWD who received treatment for surgery, non‐surgical bleeds or continuous prophylaxis at eight paediatric haemophilia centres in Australia and New Zealand. Data were collected on patient demographics, disease history, treatment history, dosage, administration, adverse reactions, concomitant medications and excessive bleeding events. BIOSTATE provided excellent/good haemostatic efficacy in 90% of surgical procedures (n = 42) with a mean daily FVIII dose of 47 IU FVIII:C kg^?1 and a median treatment duration of 3 days. Excellent/good haemostatic efficacy was achieved in 94% of non‐surgical bleeding events (n = 72) with a mean FVIII dose of 45 IU FVIII:C kg^?1 day^?1 and a median treatment duration of 1 day. There were no bleeding events attributable to lack of efficacy. One case of nausea, possibly related to BIOSTATE administration, was reported. These results suggest that BIOSTATE is safe and effective for the treatment and prophylaxis of bleeding in children with VWD.     

Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery

We have evaluated the haemostatic efficacy of plasma derived, highly purified, solvent-detergent treated factor IX concentrate (Nanotiv®), to which a nanofiltration step has recently been added to improve safety with regard to parvovirus B19, hepatitis A and other nonlipid enveloped viruses. Thirteen surgical procedures, including eight orthopaedic operations, were carried out using continuous infusion of Nanotiv in 10 haemophilia B patients (nine severe and one mild). Tranexamic acid was used for 11 of the 13 procedures. The mean factor IX levels on the day of surgery and postoperative days 1–3 were 0.77, 0.89, 0.80 and 0.73 IU mL^–1, respectively. The haemostatic effect was rated as normal or excellent and no blood transfusions were needed. One patient had thrombophlebitis twice at the infusion site. The remaining cases received heparin, 5 units per 100 IU of Nanotiv, and had neither superficial nor deep venous thromboembolic complications. The requirement for factor IX in the four joint replacement operations was 663 IU kg^–1 during the first 9 days, which compares favourably with previous materials. Thus, continuous infusion with this highly purified factor IX concentrate with improved viral safety is effective for surgery in haemophilia B.     

Continuous intravenous infusion of a plasma-derived factor IX concentrate (Mononine®) in haemophilia B

This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset of 13 non-emergency patients 7-21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for 107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.     

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.     

A comparison between the complications and long‐term outcome of hip and knee replacement therapy in patients with and without haemophilia; a controlled retrospective cohort study

Summary. The outcomes of total knee arthroplasty (TKA) and total hip arthroplasty (THA) in patients with haemophilia have not been compared with other patient populations. The aim of this study was to compare the results of joint replacement therapy in patients with and without haemophilia retrospectively. This is a controlled retrospective cohort study. The complications and long‐term results of 21 TKAs and 6 THAs performed in 22 haemophilia patients were compared with those of 42 TKAs and 12 THAs in patients without bleeding disorders. Patients were matched for type of arthroplasty, gender, year of surgery and age. Blood loss, infection rate, revision, implant survival and function as judged by the patient were recorded. Haemarthrosis occurred in 14 (52%) of the 27 arthroplasties performed in the haemophilia patients, while four bleedings were recorded in the 54 arthroplasties in the control group (7%, P < 0.001). All bleeds occurred in TKAs. In the patient group, two infections (7%, both in TKAs) occurred compared to seven (13%, 6/7 in TKAs) in the control group (NS). In the haemophilia patients, all but one (96%) arthroplasties were still in situ at the end of follow‐up, vs. 44 (81%, NS) in the control group. For TKAs, survival was 20/21 vs. 34/42 respectively (P = 0.25). Subjective function was good in 22/27 (81%; 76% in TKAs) arthroplasties in haemophilia patients, vs. 40/54 (74%; 71% in TKAs) in controls. Haemophilia patients experienced significantly more haemarthroses, but no more infections and they have an excellent implant survival compared with non‐haemophilia controls.     

Treatment of inherited protein C deficiency by replacement therapy with the French purified plasma-derived protein C concentrate (PROTEXEL)

BACKGROUND/OBJECTIVES: A multicentre retrospective study was performed to assess the efficacy/safety of a French purified plasma-derived protein C (PC) concentrate in inherited PC deficiency. MATERIALS AND METHODS: Nine patients were enrolled, five children aged < 5 weeks, among whom four with a severe deficiency were homozygous, and four patients < 37 years with PC levels ranging 14-25%, including one compound heterozygous. RESULTS: Thirty replacement therapy courses were recorded with mean PC dosages ranging between 24-90 IU/kg/day for prophylactic courses and 51-209 IU/kg/day for treatment courses. Recoveries varied between 0.8 and 1.12% IU/kg in preventive situations and between 1.09 and 1.91% IU/kg for treatment courses; 23 treatment courses were performed in patients aged 1 day to 18 years, 19 out of 23 treatments resulted in complete recovery with no sequelae. Treatment efficacy was difficult to assess in four out of 23 cases because the thrombotic event was not confirmed in one case and due to late treatment initiation in the three other cases. Seven prophylactic treatments were used either in association of vitamin K antagonists or to prevent thrombotic events due to vitamin K antagonist introduction or withdrawal. The safety assessed during 914 infusions was excellent. No abnormal bleeding was reported, including with high doses, during surgery, with heparin therapy. CONCLUSIONS: Replacement therapy with this French PC concentrate is safe and effective in patients with inherited PC deficiency.     

An open clinical study assessing the efficacy and safety of Factor IX Grifols®, a high‐purity Factor IX concentrate,in patients with severe haemophilia B

Summary. Factor IX Grifols^® is a new high‐purity plasma‐derived FIX concentrate with two specific pathogen elimination steps. Until this study was performed, there were no detailed reports with an adequate number of patients on the clinical evaluation of this product. To determine the efficacy and safety of Factor IX Grifols^® for replacement therapy in previously treated patients with severe haemophilia B, this open, multicentre and non‐randomized study included 25 male subjects over the age of 12 with severe haemophilia B. Patients underwent prophylaxis and treatment of bleeding episodes with Factor IX Grifols^® for 1 year. The clinical efficacy and safety of this product were assessed. Forty percent of the patients were children and adolescents (12–17 years old). During the 12 months follow‐up, 1 446 000 IU of Factor IX Grifols^® were administered in 961 infusions (range 12–83 infusions per patient): 31% for prophylaxis and 69% for bleeding episodes. Only five major bleeding events were reported in two patients. These haemorrhages were successfully treated with a mean of 2900 IU per bleed (range 1500–4000 IU), and 1–3 infusions per bleed. The average time elapsed from the first infusion to resolution of bleeding was 43 h (median). Overall, haemostasis was rated as excellent or good by the investigator in 96% of the infusions. No product‐related adverse events were reported. Factor IX Grifols^® is an effective and safe Factor IX concentrate and can be considered as a first line option for replacement therapy in haemophilia B patients.     

Prevention of major venous thromboembolism following total hip or knee replacement: a randomized comparison of low-molecular-weight heparin with unfractionated heparin (ECHOS Trial).

AIM: Venous thromboembolism remains a frequent complication after total hip or knee replacement surgery despite routine prophylaxis. However, the ability of pharmacologic thromboprophylaxis to prevent major venous thromboembolism, defined as proximal deep vein thrombosis, and/or pulmonary embolism, and/or death, has not been previously validated. METHODS: In a double-blind randomized study, 2018 patients, undergoing either total hip or knee replacement surgery, were allocated to receive subcutaneous preoperative reviparin (4,200 anti Xa IU) once daily or 7,500 IU unfractionated heparin twice daily, for a minimum of 11 days. The primary efficacy outcome was major venous thromboembolism, defined as the composite of venographically confirmed proximal deep vein thrombosis, and/or symptomatic pulmonary embolism and death, recorded up to day 14. RESULTS: The primary efficacy outcome was assessed in 1,628 patients and demonstrated a significant reduction in the reviparin group (3.4% [28 of 813 patients] compared with unfractionated heparin (5.5% [45 of 815]) (odds ratio, 0.61; 95% confidence interval, 0.38 to 0.99, P=0.04) by day 11 to 14. A significant reduction in venous thromboembolism was maintained up to 6-8 weeks (3.4% [28 of 813 reviparin patients] versus 5.6% [46 of 815 unfractionated heparin patients]) (odds ratio, 0.6; 95% confidence interval, 0.37 to 0.97, P=0.03). Major bleeding events occurred in 9 reviparin-treated patients (0.9%) and in 12 unfractionated heparin-treated patients (1.2%). CONCLUSIONS: Prophylaxis with reviparin significantly reduces the risk of major venous thromboembolism compared with unfractionated heparin in patients undergoing elective hip or knee replacement without increasing the risk of bleeding.     

Pre-operative synovial hyperaemia in haemophilia patients undergoing total knee replacement and the effects of genicular artery embolization: A retrospective cohort study

Aim

Haemophilia is characterized by recurrent joint bleeding caused by a lack of clotting factor VIII or IX. Due to repeated joint bleeding, end-stage arthropathy occurs in relatively young patients. A total knee replacement (TKR) can be a solution. However, TKR may be complicated by perioperative and postoperative bleeds despite clotting factor therapy. The aim of this study was to evaluate the prevalence of pre-operative synovial hyperaemia and the effects of Genicular Artery Embolization on synovial hyperaemia and 3-month postoperative joint bleeding.

Methods

In this retrospective cohort study, all patients with haemophilia who underwent periarticular catheter angiography between 2009 and 2020 were evaluated after written informed consent. Synovial hyperaemia on angiography was scored by an interventional radiologist.

Results

Thirty-three angiography procedures in 24 patients were evaluated. Median age was 54.4 years (IQR 48.4–65.9). Preoperative synovial hyperaemia was observed in 21/33 joints (64%). Moderate and severe synovial hyperaemia was observed in 10/33 joints (30%). Synovial hyperaemia decreased in 13/15 (87%) joints after embolization. Three-month postoperative joint bleeding occurred in 5/32 joints: in 2/18 joints (11%) without synovial hyperaemia and in 3/14 joints (21%) with mild synovial hypertrophy. Non-embolized and embolized joints did not differ regarding 3-month postoperative bleeding (P = .425). No complications were observed after embolization.

Conclusion

One-third of patients with haemophilia requiring a TKR had moderate or severe synovial hyperaemia which can be reduced safely by Genicular Artery Embolization prior to TKR. Three-month postoperative bleeding appears to occur independently of the presence of residual mild synovial hyperaemia.     

Ten‐year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.     

Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion

In this study we explore the feasibility of high-purity double-inactivated concentrates by continuous infusion for the treatment of haemophiliacs in a group of patients undergoing different surgical procedures. The patients were enrolled in the study on the basis of their transfusion history, which was well known due to their long-term follow up at our Haemophilia Center. We did not perform a pre-operative pharmacokinetic study because one of the aims of this study was to demonstrate that continuous infusion can become a first choice standard treatment in patients with haemophilia. Fourteen haemophilia A and one haemophilia B patients who needed at least 5 days of replacement therapy were monitored for haemostatic efficacy, post-operative factor VIII and factor IX levels and evaluated for safety and flexibility of the products. The infusion rate of 3 IU kg-1 h-1 was demonstrated to be sufficient to ensure haemostasis and patients did not need additional bolus infusion during the post-operative period. Our study demonstrates the safety and feasibility of high-purity concentrates in patients undergoing surgery by continuous infusion, also in the absence of a previous pharmacokinetic study.     

Clinical observation on safety and efficacy of a plasma‐ and albumin‐free recombinant factor VIII for on‐demand treatment of Chinese patients with haemophilia A

Summary. Recombinant FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma‐ and albumin‐free recombinant FVIII (rAHF‐PFM, ADVATE^®), as the third generation rFVIII, virtually eliminates the risk of blood‐borne disease transmission by excluding all human blood derived additives throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE^® in Chinese patients with haemophilia A. Fifty‐eight patients enrolled and received ADVATE^® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%) had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty‐four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per‐protocol. A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE^® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE^®. Overall, response to the first ADVATE^® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE^® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE^® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A.