Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.

AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.

Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction.

BACKGROUND: Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg-1 day-1 ) and low-dose (LD) (50 IU kg-1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. METHODS: We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. RESULTS: There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non-neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]. CONCLUSION: In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority.

Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study.

INTRODUCTION: Central venous access devices (CVADs) are frequently required as stable long-lasting venous access in children with haemophilia, especially those requiring immune tolerance induction (ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter-related complications in this patient population. AIM: Detailed review of CVAD complications from the International ITI (I-ITI) study and analysis of potential risk factors for such complications. METHODS: Retrospective analysis of prospectively obtained data from the I-ITI study primarily focused on CVAD-related complications. RESULTS: A total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD-days observed on-study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD-days (interquartile ranges 0-1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters (P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram-positive infections were also significantly younger than those with Gram-negative infections (median age: 17 vs. 25 months, P < 0.0001). CONCLUSION: CVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I-ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections.

Prevalence of clinical hip abnormalities in haemophilia A and B: an analysis of the UDC database.

Clinical hip abnormalities, secondary to recurrent joint and/or muscle bleeding in persons with haemophilia, have not been well characterized and have the potential for significant morbidity. We aimed to examine the prevalence of clinical hip abnormalities in the US haemophilia population and to explore associations between these findings and putative risk factors. We conducted a study of hip abnormalities of 8192 subjects aged 2-69 years with haemophilia A and haemophilia B (54% of haemophilia A and haemophilia B are severe) currently enrolled in the Universal Data Collection (UDC) database. Associations between hip abnormality and type/severity of haemophilia A/B, current age, history of high-titre (≥ 5 BU) inhibitor (HTinh), concomitant ankle (AA) and knee arthropathy (KA), overweight and obesity and prophylaxis were examined using logistic regression. Overall prevalence of hip abnormality at the last recorded UDC visit for all subjects was 16.7%. Haemophilia A (aOR = 1.3, 1.0-1.4), severe haemophilia (aOR = 1.3, 1.0-1.5), a history of HTinh (aOR = 1.4, 1.1-1.7), and concomitant AA (aOR = 1.7, 1.4-1.9) were each independently associated with hip abnormality. Older age (45-69 years) was significantly associated with hip abnormality prevalence only in subjects with KA (aOR = 3.4, 1.9-5.9). The presence of overweight (aOR = 1.4, 1.1-1.8) and obesity (aOR = 2.1, 1.6-2.8) was associated with hip abnormality only among subjects without KA. Hip abnormality prevalence was not influenced by prophylaxis (aOR = 0.9, 0.8-1.1). These data suggest that hip abnormalities in US patients with haemophilia are associated with haemophilia severity and type, HTinh, concomitant AA and, depending on the presence or absence of KA, advancing age and obesity.

Use of global assays to understand clinical phenotype in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored.

Haemostasis prophylaxis using single dose desmopressin acetate and extended use epsilon aminocaproic acid for adenotonsillectomy in patients with type 1 von Willebrand disease.

In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them.

Clinical trial design in haemophilia.

Progress in the evidence-based care of haemophilia A and B worldwide has been historically challenged by the dearth of evaluable outcome data, including but not limited to the safety and effectiveness of therapeutic interventions. These challenges are partially rooted in the inherent difficulty of conducting prospective clinical trials and observational studies with statistically meaningful endpoints in a rare disease such as haemophilia. Despite the logistical barriers, the need for outcome data has never been more critical than in this time of expansive therapeutic advance tempered by the shrinking economic capacity to fund the rapidly increasing cost of treatment. Given that systematic analyses of published literature have been largely unsuccessful in compensating for the lack of rigorous and purposeful data collection, new approaches to clinical study design and statistical modelling are urgently needed. However, even as these are considered, the lack of broadly accepted and well-defined clinical outcome endpoints poses an additional barrier to progress. The three presentations encompassed by this paper highlight the timely need for quality data from the perspectives of the clinicians, regulatory agencies and health care funders, and describe the ongoing coordinated efforts by the international haemophilia community to further understand and dismantle the barriers to harmonized and standardized data collection on a global scale using well-defined clinical outcome endpoints.

Successful hip arthroplasty in an adult male with severe factor XI deficiency using Hemoleven®, a factor XI concentrate.

Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven® ; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15 U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10 U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients.

Recombinant activated factor VII safety and efficacy in the treatment of cranial haemorrhage in patients with congenital haemophilia with inhibitors: an analysis of the Hemophilia and Thrombosis Research Society Registry (2004-2008).

Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004-2008 database was conducted. Among 29 patients with CHwI, 56 of the reported haemorrhages met the study criteria. Of these, 75% were traumatic and 80% were extracranial (ECH). The majority (8/11, 73%) of intracranial haemorrhages (ICHs) developed spontaneously. Conversely, most ECHs (39/45, 87%) followed trauma. ICHs were treated with a median/mean of 23/58 rFVIIa infusions over a median/mean of 7/9 days while ECHs were treated with a median/mean of 1/3 infusions (P = 0.011) over a median/mean of 1/1 day. The median/mean initial rFVIIa doses for all CHs were 106/137 microg kg(-1), and were similar for ICHs and ECHs. All ECHs were effectively controlled with rFVIIa; 44/45 bleeds were controlled within 24 h, one bleed was successfully treated perioperatively, and 27 ECHs required only a single dose. Nine out of 11 ICHs were effectively treated with rFVIIa; six ICHs were controlled within 24 h, one within 72 h and in two cases haemostasis was achieved during the perioperative period. No serious treatment-associated adverse events were reported. One patient died as a result of ICH despite the reported control of bleeding. In conclusion, standard dosing of rFVIIa was found to be safe and effective in treating CH with an efficacy rate of 100% for ECH and 82% for ICH.

The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy.

The North American Immune Tolerance Registry (NAITR) began in 1992 as a project of the ISTH Factor VIII/IX Subcommittee with the goal of further determining immune tolerance induction (ITI) practices in Canada and the United States. This retrospective registry study, published in 2002, was limited in its capacity to provide definitive answers to many unresolved ITI practice issues. Nonetheless, it played a role in developing guidelines for current ITI practice and in generating hypotheses that must now be examined through rigorous prospective data collection efforts. For haemophilia A, the logical next step has been the initiation of international prospective randomized studies of ITI outcome relative to factor VIII (FVIII) dose and purity for subjects with high titre inhibitors. Both trials will additionally provide platforms for translational study of the immunology of tolerance, a prelude to the next generation of safe and effective tolerizing strategies. For the less common problem of FIX inhibitor eradication, prospective randomized studies will not be a feasible way to confirm the NAITR observations. Coordinated international efforts will still be required to prospectively collect data on ITI outcome to document new potentially effective therapeutic strategies for inhibitor eradication. These registries will hopefully also serve to identify potential subjects for scientific studies of immunology of haemophilia B-related allergic phenomena, a devastating complication of FIX antibody development.

Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project.

Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0-2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy-five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C-section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra- and extra-cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence-based recommendations for their management.

Ethical considerations in clinical investigation: exploring relevance in haemophilia research.

Painful controversy has so far been largely absent from the history of haemophilia-related clinical research. However, the investigative methods now needed to realize evidence-based clinical practice, therapeutic advance, and a progressive standard of care for patients worldwide will be accompanied by the potential for ethical dilemma and transgression. From the current vantage point, three primary ethical issues merit special consideration: (i) the therapeutic misconception inherent to all clinical research and the randomized trial in particular; (ii) high risk and potentially non-beneficial novel technology research in children; and (iii) a collaborative partnership approach to research in the developing world. This study will focus on a discussion of each of these, drawing from the research ethics literature to offer a potential template for future deliberations in clinical trial design.

Rare inherited disorders of fibrinogen.

Fibrinogen, a hexameric glycoprotein encoded by three genes - FGA, FGB, FGG - clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross-linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life-threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma-derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.

Haemophilia in the first years of life.

Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40-80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.

The use of factor VIII/von Willebrand factor concentrate for immune tolerance induction in haemophilia A patients with high-titre inhibitors: association of clinical outcome with inhibitor epitope profile.

A retrospective chart review of 11 subjects with severe haemophilia A and high-titre inhibitors who received a von Willebrand factor-containing FVIII concentrate (VWF/FVIII) for immune tolerance induction (ITI) was accompanied by B cell inhibitor epitope mapping during 10/11 treatment courses. ITI was successful or partially successful in all seven subjects who received VWF/FVIII for initial ITI, and failed in all four subjects whose ITI with this product was initiated following treatment failure using recombinant factor VIII. Variables including age at inhibitor development and age at ITI initiation, interval between inhibitor detection and ITI initiation, titre at start of ITI, and peak historical titres prior to and during ITI were not statistically significant outcome predictors in this cohort. However, the B cell epitope specificity in all four successful and in one of two partially successful ITI subjects for whom information was available included the C2 and excluded the A2 domains. Conversely, FVIII B cell epitopes in one partially successful ITI and in all three failed ITI subjects for whom data were available mapped to both the C2 and the A2 domains. The FVIII B cell epitope profile was associated with ITI outcome in this VWF/FVIII-treated cohort. Its role in predicting ITI outcome and guiding choice of FVIII product for ITI requires further study.

Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors.

Factor VIII (FVIII) inhibitors remain a serious complication of treatment for patients with haemophilia A. Immune tolerance induction (ITI) can eliminate inhibitors in the majority of patients, but there are major concerns related with this therapy. Investigators have raised the possibility that the use of FVIII/von Willebrand factor (FVIII/VWF) concentrates may improve the success rate of ITI and may shorten the duration of therapy necessary to attain tolerance. This retrospective study describes 25 patients at five institutions in the USA, who were treated with FVIII/VWF concentrate as part of their ITI. These were all patients who were considered poor prognosis because of clinical and laboratory characteristics, which made ITI less likely to be successful or because of a poor response to initial ITI with a monoclonal/recombinant FVIII concentrate. Overall success (complete tolerization) was 32% with another 40% attaining partial tolerization, but not complete tolerization. Of those patients attaining only partial tolerization, two patients ultimately discontinued ITI and had return of their high titre inhibitors. Eight percent of patients failed to attain either partial or complete tolerization and discontinued ITI. Another 24% are continuing with ITI but have titres of >10 BU. This study adds further retrospective data to the information regarding the use of FVIII/VWF concentrate in ITI.

Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach.

Currently, the only proven strategy for achieving antigen-specific tolerance to factor VIII (FVIII) is immune tolerance induction (ITI) therapy. This paper discusses our current knowledge of the host and treatment factors, as well as supportive care initiatives, known or suspected to influence the outcome of ITI in the treatment of inhibitors arising in patients with severe hemophilia A. Among these, questions surrounding the choice of therapeutic product and/or dosing regimen generate the most controversy, given the lack of a definitive evidence-based approach to either. Furthermore, the potential for central venous access device (CVAD) and intercurrent bleeding complications to impact the ultimate success of ITI remains unclear. The ongoing clinical trials designed to further clarify several of these polarizing issues are reviewed. This paper also explores the current and future role of immune modulation in possible salvage, ancillary or primary alternative tolerance induction strategies. The special cases of low titer/ responding inhibitors and inhibitors developing in mild hemophilia A patients are considered. Finally, this paper summarizes the currently recommended approach to ITI and makes the case for a move from empiric therapeutics to a risk-stratified evidence-based approach to FVIII inhibitor eradication.

Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.

A North American registry for rare bleeding disorders [factor (F)II, factor (F)VII, factor (F)X, factor (F)V, factor (F)XIII, fibrinogen deficiencies and dysfibrinogenemias] was established to gather information about disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment and prophylaxis strategies, as well as disease- and treatment-related complications. Questionnaires were sent to 225 hemophilia treatment centers in the USA and Canada. Among 26% of responding centers, 294 individuals [4.4% of the registered children (200/4583) and 2.4% of adults (94/3809)] were diagnosed with one or more of the rare bleeding disorders (RBDs) included in this survey. The ethnic distribution for each disorder paralleled that of the general US population with the exception of the disproportionately large number of Latinos with FII deficiency. Only 5.4% of affected individuals were genotyped. An abnormal preoperative bleeding screen most often led to diagnosis. The most common coagulopathy was FVII deficiency; however, 40% of homozygous patients were asymptomatic. FX and FXIII deficiencies caused the most severe bleeding manifestations. Among all RBDs, the most common sites of bleeding were skin and mucus membranes. Multiple products were used to treat hemorrhage; however, half of the bleeding episodes required no therapy. The majority of patients suffered no long-term complications from hemorrhage. Treatment-related complications included viral seroconversion, anemia, allergic reactions and venous access device-related events. This registry provides the most comprehensive information to date about North American individuals with RBDs and could serve as an important resource for both basic scientist and clinician.

Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study.

The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.

The North American Immune Tolerance Registry: practices, outcomes, outcome predictors.

The North American Immune Tolerance Registry was initiated to study of immune tolerance (ITT) in Canada and the United States with respect to: 1) therapeutic regimens in use for haemophilia A (HA) and B (HB) inhibitor patients; 2) therapeutic outcomes; 3) potential predictors of successful outcome and 4) complications of therapy. Data on 188 ITT courses was collected by questionnaire from 60 haemophilia centers from 1993-99. Among the completed courses, the overall success rate was 70% (115/164) for all HA and 31% (5/16) for all HB. Outcome parameters noted to be predictive of ITT success for all HA were 1) pre-ITT induction (p = 0.003), 2) ITT peak (p = 0.007) and 3) historical pre ITT peak (p = 0.04) inhibitor titres. An inverse correlation between total daily dose (units/kg/day) and success: (80% with under 50; 71% with 50-99; 73% with 100-199; and 41% with > or = 200, p = 0.01) was found. Outcome predictors were not evaluable for HB, although adverse reactions to therapy, including nephrotic syndrome, and access complications were more common among failed courses. Infection most often complicated the use of access catheters. These results are discussed within the context of the international ITT registry and upcoming prospective ITT study.