The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.

A prospective surveillance study of inhibitor development in haemophilia A patients following a population switch to a third-generation B-domain-deleted recombinant factor VIII.

INTRODUCTION: Following a provincial tender, most subjects with haemophilia A in Quebec switched their treatment to a third-generation recombinant B-domain-deleted factor VIII (FVIII). AIM: Our objective was to evaluate the incidence of inhibitor development and FVIII recovery in patients following the switch of factor replacement therapy. METHODS: One hundred and thirty-five subjects were enrolled and tested for FVIII activity and inhibitors every 6 months during 1 year. Subjects with mild haemophilia A or current inhibitors were excluded. Data on demographics, bleeds and FVIII usage were collected. RESULTS: A total of 125 switchers and 10 non-switchers were enrolled. Most subjects had severe haemophilia A (95.6%) and were on prophylaxis (89.6%). Mean FVIII recovery was similar at 0, 6 and 12 months postswitch. Two switchers developed de novo inhibitors in the 6 months postswitch, one of which was transient. No recurrent inhibitor was observed. A small but significant increase in FVIII usage was observed for adult switchers and the whole cohort of switchers and non-switchers. There was an increase in the annualized bleeding rate (ABR) for non-joint bleeds for the whole cohort of switchers. However, no significant differences were observed in ABR for joint bleeds. CONCLUSION: Our surveillance study shows comparable inhibitor development to similar published studies. A significant increase in FVIII utilization was noted for the whole cohort, switchers and non-switchers. Lastly, no clinically significant changes were observed in ABR for joint bleeds, but a difference for non-joint bleed ABRs was observed in switchers.

Vaccinations are not associated with inhibitor development in boys with severe haemophilia A.

BACKGROUND: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. OBJECTIVE: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. METHODS: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. RESULTS: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. CONCLUSION: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations.

Severe bleeding diatheses in an elderly patient with combined type autoantibody against factor XIII A subunit; novel approach to the diagnosis and classification of anti-factor XIII antibodies.

INTRODUCTION: Acquired factor XIII (FXIII) deficiency due to autoantibody is a rare, severe bleeding diathesis. Its laboratory diagnosis and classification represents a difficult task. AIM: Introduction of novel approaches into the diagnosis and characterization of anti-FXIII autoantibody and demonstration of their use in the diagnosis of a patient with autoimmune FXIII deficiency. METHODS: Factor XIII activity, FXIII antigen levels and the titre of anti-FXIII-A antibody were monitored throughout the course of the disease. FXIII activity was measured by ammonia release assay; FXIII-A2 B2 complex, total and free FXIII-B concentrations were determined by ELISAs. The binding constant for the interaction of the autoantibody with recombinant FXIII-A2 (rFXIII-A2 ) and FXIII-A2 B2 was determined by surface plasmon resonance (SPR). The inhibitory capacity of IgG was expressed as the concentration exerting 50% inhibition of FXIII activation/activity (IC50). The truncation of FXIII-A by thrombin was monitored by western blotting. The inhibition of Ca2+ -induced FXIII activation and active FXIII (FXIIIa) were assessed by FXIII activity assay. RESULTS: The antibody bound to rFXIII-A2 and FXIII-A2 B2 with high affinity and accelerated the decay of supplemented FXIII concentrate. An IC50 value of 170.1 µg IgG·mL-1 indicated effective FXIII neutralization. The main neutralizing effect of the autoantibody was the inhibition of FXIIIa. After 2 months, due to combined therapeutic modalities, the autoantibody disappeared and FXIII activity significantly elevated. CONCLUSION: The anti-FXIII-A autoantibody exerted a combined effect including inhibition of FXIIIa and acceleration of FXIII decay in the plasma. IC50 and binding constant determinations added important information to the characterization of the autoantibody.

Molecular phenotype and bleeding risks of an inherited platelet disorder in a family with a RUNX1 frameshift mutation.

INTRODUCTION: Inherited defects in RUNX1 are important causes of platelet function disorders. AIM: Our goals were to evaluate RUNX1-related platelet disorders among individuals evaluated for uncharacterized, inherited platelet function disorders and test a proof of concept that bleeding risks could be quantitatively estimated for typical families with an inherited platelet function disorder. METHODS: Index cases with an uncharacterized inherited platelet function disorder were subjected to exome sequencing with confirmation of RUNX1 mutations by Sanger sequencing. Laboratory findings were obtained from medical records and persistence of platelet non-muscle myosin heavy chain IIB (MYH10), a biomarker of RUNX1 defects, was assessed by Western blotting. Bleeding histories were assessed using standardized assessment tools. Bleeding risks were estimated as odds ratios (OR) using questionnaire data for affected individuals compared to controls. RESULTS: Among 12 index cases who had their exomes sequenced, one individual from a family with eight study participants had a c.583dup in RUNX1 that segregated with the disease and was predicted to cause a frameshift and RUNX1 haploinsufficiency. Unlike unaffected family members (n = 2), affected family members (n = 6) had increased bleeding scores and abnormal platelet aggregation and dense granule release responses to agonists but only some had thrombocytopenia and/or dense granule deficiency. This family's mutation was associated with persistence of MYH10 in platelets and increased risks (OR 11-440) for wound healing problems and mild bleeding symptoms, including bleeding interfering with lifestyle in women. CONCLUSION: Inherited platelet dysfunction due to a RUNX1 haploinsufficiency mutation significantly increases bleeding risks.

Pilot study of once-a-day prophylaxis for youth and young adults with severe haemophilia A.

INTRODUCTION: Standard prophylaxis has been shown to be an effective treatment for severe haemophilia A. According to pharmacokinetic principles, daily factor infusions of smaller doses can maintain similar trough factor VIII (FVIII) levels, and perhaps the same protection as standard prophylaxis. AIM: This multicentre study examined the feasibility of daily prophylaxis for youth and young adults with severe haemophilia A in Montreal and Toronto. METHODS: Bleeding rates, joint status, quality of life and physical activity were monitored for 14 patients during this study. At baseline, subjects continued their regular treatment regimen and switched to daily prophylaxis after 4 months; nine had begun daily prophylaxis before enrolment. Additional visits occurred at 8 and 12 months which included a physical examination, inhibitor testing, HJHS and FISH assessments, the CHO-KLAT/Haemo-QoL-A and PDPAR. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication ver.II and perceived difficulty questions at the end of study. RESULTS AND CONCLUSIONS: There were no significant changes in quality of life except for concerns with the demanding daily infusion schedule. The number of bleeds did not statistically differ from the initial 4 months of the study to the last 8 months. Monthly bleeding rates from the year prior to the study and during the intervention phase were not statistically different. It was also found that daily prophylaxis used 24% less FVIII compared to standard prophylaxis. Taking all of this into account, we have found that providing daily prophylaxis is feasible and that it is feasible to prospectively study daily prophylaxis in youth and young adults.

Generic and disease-specific quality of life among youth and young men with Hemophilia in Canada.

BACKGROUND: This study was undertaken to explore the longitudinal patterns of health-related quality of life (HRQoL) among youth and young adults with Hemophilia A (HA) over a 3-year period. This report presents the baseline characteristics of the study cohort. METHODS: Males, 14 to 29 years of age, with predominantly severe HA were recruited from six treatment centres in Canada. Subjects completed a comprehensive survey. HRQoL was measured using: the CHO-KLAT2.0 (youth), Haemo-QoL-A (young adults) and the SF-36v2 (all). RESULTS: 13 youth (mean age = 15.7, range = 12.9-17.9 years) and 33 young adults (mean age = 23.6; range = 18.4 -28.7 years) with moderate (7 %) and severe (93 %) HA were enrolled. All were on a prophylactic regimen with antihemophilic factor (Helixate FS®) during the study. The youth had minimal joint damage (mean HJHS = 5.2) compared to young adults (mean HJHS = 13.3). The mean HRQoL scores for youth were: 79.2 (SD = 11.9) for the CHO-KLAT, and 53.0 (5.5) and 52.3 (6.8) for the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores respectively. The mean HRQoL scores for young adults were: 85.8 (9.5) for the Haemo-Qol-A, and 50.8 (6.4) and 50.9 (8.8) for PCS and MCS respectively. PCS and MCS scores were comparable to published Canadian norms, however significant differences were found for the domains of Physical Functioning and Bodily Pain. The disease-specific HRQoL scores were weakly correlated with the PCS for youth (CHO-KLAT vs. PCS r = 0.28, p = 0.35); and moderately correlated for the MCS (r = 0.39, p = 0.19). Haemo-QoL-A scores for young adults were strongly correlated with the PCS (r = 0.53, p = 0.001); and weakly correlated with the MCS (r = 0.26, p = 0.13). Joint status as assessed by HJHS was correlated with PCS scores. A history of lifelong prophylaxis resulted in better PCS but worse MCS scores. CONCLUSION: Despite having hemophilia, the youth in this cohort have minimal joint disease and good HRQoL. The young adults demonstrated more joint disease and slightly worse HRQoL in the domains of physical functioning and pain. The data presented here provide new information to inform the selection of Health Related Quality of Life (HRQoL) instruments for use in future clinical trials involving persons with hemophilia. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01034904. Study funded by CSL Behring Canada.

Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study.

INTRODUCTION: In persons with severe haemophilia A (pwshA), infused factor VIII (FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor (VWF) level or age; however, FVIII pharmacokinetics (PK) has not been well studied in pwshA during exercise. AIM: To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. METHODS: Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen (VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. RESULTS: For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise (P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. CONCLUSION: Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities.

Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody.

INTRODUCTION: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. AIM: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. METHODS: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2 B2 ) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2 B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+ -induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. RESULTS: FXIII activity, FXIII-A2 B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2 B2 with equally high affinity (Kd ~10-8 ). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+ -induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. CONCLUSION: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.

Incidence of hypotension and acute hypotensive transfusion reactions following platelet concentrate transfusions.

BACKGROUND AND OBJECTIVES: Platelet concentrates (PCs) are associated with transfusion reactions involving hypotension, particularly bradykinin-mediated acute hypotensive transfusion reactions. This study aims to determine the incidence of hypotensive events and more specifically acute hypotensive transfusion reaction associated with PC transfusions. We also sought to ascertain whether these reactions are associated with elevated bradykinin levels. MATERIALS AND METHODS: This is a prospective descriptive study of PCs administered at Sainte-Justine Hospital over 28 months. All PCs administered during this period were screened for hypotension through review of all transfusion-associated reaction reports (TARRs) sent to the blood bank. All residual PC bags were returned to the blood bank. TARRs associated with hypotension were reviewed by adjudicators that established the imputability of the PC transfusion to the reaction. Bradykinin levels were sampled in the first 168 PC bags returned to the blood bank. Levels were compared between PCs associated with hypotension and control PCs not associated with hypotension. RESULTS: A total of 3672 PC bags were returned to the blood bank; 25 PCs were associated with hypotension. Adjudicators ascertained that five hypotensive events were imputable to PCs of which one was an acute hypotensive transfusion reaction (incidence: 0·03%). Bradykinin level in the latter PC was 10 pg/ml, whereas levels were 226·2 ± 1252 pg/ml in the 143 control PCs. CONCLUSION: Our results show a low incidence of hypotension after PC transfusion. We identified only one acute hypotensive transfusion reaction. No correlation between bradykinin level and the occurrence of acute hypotensive reactions could be observed given that only one event was identified.

Experience with central venous access devices (CVADs) in the Canadian hemophilia primary prophylaxis study (CHPS).

INTRODUCTION: Haemophilia A treatment with factor VIII concentrates requires frequent venipunctures; a central venous access device (CVAD) may be required to facilitate reliable venous access, especially in young children. While CVADs provide reliable venous access, complications such as infection and thrombosis may occur. AIM: The aim of this study was to assess CVAD use in the Canadian Hemophilia Primary Prophylaxis Study (CHPS), a single-arm, multi-centre prospective study whereby factor use is tailored to individual prophylactic need. METHODS: Participants received a tailored, escalating dose, prophylaxis regimen of increasing frequency of FVIII infusions: step-1: 50 IU kg(-1) once weekly; step-2: 30 IU kg(-1) twice weekly; and step-3: 25 IU kg(-1) on alternate days, according to their level of bleeding. CVAD insertion was at the discretion of the local health care team. Details regarding CVAD use during this protocol were analysed. RESULTS: Fifty six boys were enrolled, 21 required 25 CVADs due to difficult venous access. CVADs were inserted at a median age of 1.3 years (range: 0.6-2.1) and were removed at a median age of 8.7 years (range 6.3-11.8). Six participants experienced non-life threatening CVAD-complications, the most frequent being device malfunction requiring CVAD replacement (n = 4). Two boys were shown to have CVAD-associated thrombosis detected on routine imaging; one required removal due to infusion difficulties and the other was asymptomatic and did not require device removal. No CVAD-related infections were documented. CONCLUSION: Our study shows that the CHPS tailored prophylaxis regimen is associated with a decreased requirement for CVADs and with few device-related complications.

Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010.

The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL(-1) ). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg(-1)  day(-1) X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99-1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14-27.17) and 5.08 (95% CI: 1.11-23.31) respectively. ID according to FVIII concentrate used was: Advate (®) 18/50 (36%), Kogenate FS(®) or Helixate FS(®) 15/36 (42%), Wilate(®) 0/11 and Xyntha(®) 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11-122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08-18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure.

Product-dependent anti-factor VIII antibodies.

The development of anti-factor (F)VIII antibodies in haemophilia A (HA) subjects undergoing replacement therapy has been well documented. The correlation between antibody development and the FVIII product used for replacement therapy remains a subject of discussion. The aim of this study was to evaluate the presence of anti-FVIII antibodies towards three commercial rFVIII products in 34 HA subjects' plasmas. Antibodies were quantitated by a Multiplex Fluorescence Immunoassay. All plasmas contained anti-FVIII antibodies at variable concentrations ranging from 50 nm to 570 µm. Eleven of the 20 HA subjects treated with one (r)FVIII product contained inhibitory anti-FVIII antibodies (0.8-3584 BU). The inhibitory antibody titre and the molar concentrations of total antibody were mildly correlated (r(2) = 0.6). Pronounced differences in antibody recognition with the three rFVIII products were observed. For the group treated with Product 'A', the titre towards this product was 2.4-fold higher than that observed with another full-length rFVIII-containing product (Product 'B') and almost four-fold higher than that measured with a B domain-less rFVIII product (Product 'C'). For the group of 14 HA subjects treated with FVIII other than Product 'A', only one showed higher antibody titre when measured with this product. Our data suggest that the development of anti-FVIII antibodies is biased towards the product used for treatment and that a significant fraction of antibodies bind to the B domain of FVIII.

Stereological analysis of subchondral angiogenesis induced by chitosan and coagulation factors in microdrilled articular cartilage defects.

OBJECTIVE: Cartilage repair elicited by bone marrow stimulation can be enhanced by a chitosan-glycerol phosphate (GP)/blood implant, through mechanisms involving therapeutic inflammatory angiogenesis. The implant is formed by in situ coagulation, which can be accelerated by adding coagulation factors. We hypothesized that coagulation factors enhance acute subchondral angiogenesis in repairing drilled defects. DESIGN: Full-thickness cartilage defects were created bilaterally in 12 skeletally mature rabbit knee trochlea, microdrilled, then allowed to bleed as a control (N = 6) or treated with chitosan-GP/blood implant (N = 6), or implant solidified with thrombin (IIa), tissue factor (TF) with recombinant human factor VIIa (rhFVIIa), or rhFVIIa alone (N = 4 each condition). At 3 weeks post-operative, quantitative stereology was used to obtain blood vessel length (L(V)), surface (S(V)), and volume (V(V)) density at systematic depths in two microdrill holes per defect. Collagen type I, type II and glycosaminoglycan (GAG) percent stain in non-mineralized repair tissue were analysed by histomorphometry. RESULTS: All drill holes were healing, and showed a depth-dependent increase in granulation tissue blood vessel density (Lv, Sv, and Vv, P < 0.005). Residual chitosan implant locally suppressed blood vessel ingrowth into the granulation tissue, whereas holes completely cleared of chitosan amplified angiogenesis vs microdrill-only (P = 0.049), an effect enhanced by IIa. Chitosan implant suppressed strong Col-I, Col-II, and GAG accumulation that occurred spontaneously in drill-only bone defects (P < 0.005) and coagulation factors did not alter this effect. CONCLUSIONS: Subchondral angiogenesis is promoted by chitosan implant clearance. Chitosan implant treatment suppresses fibrocartilage scar tissue formation, and promotes bone remodeling, which allows more blood vessel migration and woven bone repair towards the cartilage lesion area.

Immune tolerance induction in haemophilia A patients with inhibitors by treatment with recombinant factor VIII: a retrospective non-interventional study.

Immune tolerance induction (ITI) can overcome inhibitory factor VIII (FVIII) antibodies in haemophilia A patients receiving FVIII replacement therapy. The objective was to evaluate the use of sucrose-formulated, full-length recombinant FVIII (rFVIII-FS) for ITI therapy. Patients (<8 years at ITI start) with severe haemophilia A and a peak inhibitor titre >5 Bethesda units (BU) who underwent ITI with any rFVIII-FS dose for ≥ 9 months (or until success) were eligible for this retrospective study. Efficacy analyses included descriptions of ITI treatment regimens and outcomes; ITI success was determined solely at the discretion of the investigator. Safety analyses included assessment of adverse events. Of 51 enrolled patients, 32 [high dose (≥ 85 IU kg(-1) day(-1)), n = 21; low dose, n = 11] were eligible for analysis. ITI was successful in 69% (22/32) of patients (high dose, 66.7%; low dose, 72.7%) after a median of 1.4 years (range, 0.1-3.6 years). Influencing factors for ITI success were start of ITI <1 year after inhibitor detection and an inhibitor titre <10 BU at ITI start. All patients successfully tolerized with ITI continued to receive rFVIII-FS prophylaxis as maintenance therapy, with no inhibitor recurrence from the end of ITI until study enrolment. Use of rFVIII-FS for ITI was effective and well tolerated; success rates were similar to those in published studies.

Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada.

BACKGROUND/OBJECTIVES: Tailored primary prophylaxis (TPP) is a reduced-intensity treatment program for hemophiliacs with the goal of preventing arthropathy. Our primary aim was to evaluate the joint outcomes of treated subjects using magnetic resonance imaging (MRI) and physical examination as outcome measures. METHODS: Ankles, elbows and knees (index joints) of 24 subjects (median [range] age at start of therapy, 1.6 [1-2.5] years) with severe hemophilia A enrolled in the Canadian Hemophilia Primary Prophylaxis Study (CHPS) were examined by MRI at a median age of 8.8 years (range 6.2-11.5 years). Subjects were treated with TPP using a recombinant factor VIII concentrate, starting once weekly and escalating in frequency and dose according to frequency of bleeding. RESULTS: Osteochondral changes (cartilage loss/subchondral bone damage) were detected in 9% (13/140) of the index joints and 50% (12/24) of study subjects. Osteochondral changes were restricted to joints with a history of clinically reported joint bleeding. Soft tissue changes were detected in 31% (20/65) of index joints with no history of clinically reported bleeding (ankles 75% (12/16); elbows 19% (6/32); and knees 12% (2/17)). In these apparently 'bleed free' index joints hemosiderin deposition was detected by MRI in 26% (17/65) of joints (ankles 63% (10/16); elbows 16% (5/32), and knees 12% (2/17)). CONCLUSION: TPP did not completely avoid the development of MRI-detected structural joint changes in hemophilic boys in this prospective study. A longer period of follow-up is required for assessment of the longitudinal course of these early changes in hemophilic arthropathy, detected using a sensitive imaging technique (MRI).

The effect of cooling on coagulation and haemostasis: should "Ice" be part of treatment of acute haemarthrosis in haemophilia?

Repeated haemarthroses and the consequences of blood in the joint contribute to blood induced joint disease (BIJD) in people with haemophilia (PWH). Prevention of bleeding, through medical management, is the standard of care in developed countries, but is not universally available due to financial and other barriers. Ice application, as part of R.I.C.E. (Rest, Ice, Compression, Elevation) or alone, is commonly recommended as an adjunct treatment to decrease bleeding, pain, tissue metabolism, oedema, and inflammation. This article will review evidence regarding local cooling by commonly used ice application methods, to decrease the temperature of the skin and intra-articular (IA) joint space and the resultant effects on haemostasis and coagulation. The general literature was reviewed for articles in English describing temperatures achievable in the skin and IA space using clinically relevant ice protocols, and the effect of cooling on haemostasis and coagulation. The literature demonstrates that typical methods of ice application can cool both the skin and IA space. Published, general literature studies have also consistently demonstrated that experimental cooling of blood and/or tissue, both in vitro and in vivo in humans and in animal models, can significantly impair coagulation and prolong bleeding. In PWH with acute haemarthrosis, ice application has potential to increase haemorrhage morbidity by further impairing coagulation and haemostasis. Ice has not been shown to improve overall outcome, stop bleeding nor swelling from haemarthrosis. Although ice can help manage acute, haemarthrosis-related pain, there are other available interventions that will not impair coagulation and haemostasis.