Risk factors associated with invasive orthopaedic interventions in males with haemophilia enrolled in the Universal Data Collection program from 2000 to 2010.

BACKGROUND: Invasive orthopaedic interventions (IOI) are often used to control recurrent haemarthrosis, pain and loss of joint function, in males with haemophilia (Factor VIII and Factor IX deficiency). AIM: Identify risk factors associated with IOIs in males with haemophilia enrolled in the Universal Data Collection (UDC) surveillance program from 2000 until 2010. METHODS: Data were collected on IOIs performed on patients receiving care in 130 haemophilia treatment centers in the United States annually by health care providers using standardized forms. IOIs included in this study are as follows: 1) synovectomy and 2) arthrodesis or arthroplasty (A/A). Information about potential risk factors was obtained from the preceding UDC visit if available, or from the same visit if not. Patients with no reported IOI at any of their UDC visits were the reference group for the analysis. Multivariate analyses were conducted to identify independent risk factors for synovectomies and arthrodesis/arthroplasty. RESULTS: Risk factors significantly associated with the two IOI categories were age, student status, haemophilia severity, number of joint bleeds within the last 6 months, HIV or hepatitis C (HCV) status. Multivariate analyses showed patients on continuous prophylaxis were 50% less likely to have had a synovectomy and were 40% less likely to have an A/A. CONCLUSIONS: This study shows modifiable risk factors, including management of bleeding episodes with a continuous prophylactic treatment schedule are associated with a decreased likelihood of IOIs in males with haemophilia.

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.

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.

BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.

Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders.

Bleeding disorders, including haemophilia, von Willebrand disease, and platelet function abnormalities pose a substantial, ongoing management challenge. Patients with these disorders not only require treatment during bleeding events but also need effective management strategies to prepare for events ranging from minor dental procedures to major surgery and childbirth. Moreover, women with bleeding disorders often require ongoing treatment to prevent menorrhagia during childbearing years. Desmopressin (DDAVP), a synthetic derivative of the antidiuretic hormone l-arginine vasopressin, has become a well-established tool for the management of patients with bleeding disorders in a variety of clinical settings. However, despite the widespread use of DDAVP, the available clinical evidence on its efficacy and safety in these settings is limited, and there has not been a recent comprehensive review of its role in the clinical management of patients with bleeding disorders. As such, this article provides a review of the mechanism of action and pharmacokinetic properties of DDAVP, followed by a concise summary of the available evidence for its use in the treatment and prevention of bleeding.

Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease.

Type 2M von Willebrand disease (VWD) includes qualitative defects in von Willebrand factor (VWF) function, with normal multimer distribution but a defect in VWF activity with respect to platelet or collagen binding. We characterized novel VWF gene mutations found in type 2M VWD subjects enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Subjects were enrolled based on a pre-existing diagnosis of type 2M VWD. Testing included full-length gene sequencing, VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding and multimer distribution. Recombinant VWF variants were synthesized using site-directed mutagenesis and expressed in HEK293T cells. Platelet binding was measured by flow cytometry with fixed platelets and ELISA with recombinant glycoprotein Ibα (GPIbα). Four novel VWF A1 domain mutations were found in individuals with type 2M VWD: S1358N, S1387I, S1394F and Q1402P. All subjects had a history of bleeding, VWF:RCo < 40 IU dL(-1) , VWF:RCo/VWF:Ag ratios <0.6 and normal multimer distribution. No defect in expression, secretion, or multimerization was found for any of the mutations. All showed decreased binding to intact platelets, and decreased or absent binding to a mutant GPIbα construct with spontaneous VWF binding. 1387I had decreased binding to all collagen types tested. 1402P had reduced binding exclusively to type VI collagen. Type 2M VWD is a heterogeneous category comprised of both collagen- and platelet-binding defects. Understanding the precise defect for each mutation may ultimately lead to better diagnosis and treatment.

Case studies in the management of refractory bleeding in patients with haemophilia A and inhibitors.

In haemophilia patients with well-established high-titer inhibitors, even seemingly minor acute bleeding episodes or surgical procedures may become refractory to treatment and transform into limb- or life-threatening situations. In the absence of evidence-based treatment guidelines, this article presents 10 cases of difficult to control acute and surgical bleeding and offers consensus opinions regarding their management from a panel of experienced haemophilia treaters.

Critical von Willebrand factor A1 domain residues influence type VI collagen binding.

BACKGROUND: von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen. OBJECTIVES: We report here on several mutations that exclusively alter binding to type VI collagen. PATIENTS/METHODS: Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects. RESULTS: Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen. CONCLUSIONS: VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing.

Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease.

BACKGROUND: von Willebrand factor (VWF) plays a key role in coagulation by tethering platelets to injured subendothelium through binding sites for collagen and platelet GPIb. Collagen binding assays (VWF:CB), however, are not part of the routine work-up for von Willebrand disease (VWD). OBJECTIVES: This study presents data on collagen binding for healthy controls and VWD subjects to compare three different collagens. PATIENTS/METHODS: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen were examined for samples obtained from the Zimmerman Program. RESULTS: Mean VWF:CB in healthy controls was similar and highly correlated for types I, III and VI collagen. The mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen were 1.31, 1.19 and 1.21, respectively. In type 1 VWD subjects, VWF:CB was similar to VWF:Ag with mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen of 1.32, 1.08 and 1.1, respectively. For type 2A and 2B subjects, VWF:CB was uniformly low, with mean ratios of 0.62 and 0.7 for type I collagen, 0.38 and 0.4 for type III collagen, and 0.5 and 0.47 for type VI collagen. CONCLUSIONS: Normal ranges for type I, III and VI collagen are correlated, but higher values were obtained with type I collagen as compared with types III and VI. The low VWF:CB in type 2A and 2B subjects suggests that VWF:CB may also supplement analysis of multimer distribution. However, these results reflect only one set of assay conditions per collagen type and therefore may not be generalizable to all collagen assays.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open-label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate-P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4-point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half-life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL(-1) per IU kg(-1) infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg(-1) (oral surgery) to 61.2 IU VWF:RCo kg(-1) (major surgery), with a median of 10 (range, 2-55) doses administered per subject. Adverse events considered possibly treatment-related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.

Exposure and safety of higher doses of recombinant factor VIIa ≥250 µg kg(-1) in individuals with congenital haemophilia complicated by alloantibody inhibitors: the Haemophilia and Thrombosis Research Society Registry experience (2004-2008).

Recombinant factor VIIa (rFVIIa) is a well-established treatment for managing bleeding episodes in individuals with congenital haemophilia complicated by alloantibody inhibitors (CHwI). The safety and efficacy of standard dosing (90-120 µg kg(-1) every 2-3 h) are well-established; however, the desire to optimize therapy with one or more higher doses instead of multiple lower doses has created a need for evidence of the safety and efficacy of such regimens. Analysis of data from the Haemophilia and Thrombosis Research Society (HTRS) Registry was performed on episodes where doses of ≥250 µg kg(-1) were reported. From 2041 rFVIIa-treated bleeds, 172 bleeding episodes were identified in 25 individuals with CHwI who were treated with ≥1 higher doses (≥250 µg kg(-1) , ≥270 µg kg(-1) or ≥300 µg kg(-1) ) of rFVIIa between January 2004 and November 2008. Bleeds occurred in individuals ranging in age from 0.4 to 41.7 years who were predominantly non-Hispanic and white (40%) with haemophilia A (88%). Bleed types most frequently treated with higher doses of rFVIIa were spontaneous (62-65%) or traumatic (27-32%). Bleed locations most frequently treated with higher doses of rFVIIa were joint (60-68%) or muscle (20-25%). A total of 1521 rFVIIa doses were administered (median, three doses per bleed); 26% were 250 µg kg(-1) or higher (initial dose, 82%). Bleeding stopped in 93% (160/172) of bleeds treated with rFVIIa 250 µg kg(-1) or higher. No serious adverse drug-related events or thrombotic complications were reported. This data analysis from the HTRS Registry provides evidence of the safe and effective use of higher doses of rFVIIa (≥250 µg kg(-1) ) in US practice.

Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function.

BACKGROUND: Type 2M von Willebrand disease (VWD) is characterized by a qualitative defect in von Willebrand factor (VWF) and diagnosed by a disproportionate decrease in VWF ristocetin cofactor activity (VWF:RCo) as compared with VWF antigen (VWF:Ag). OBJECTIVE: We report here on the spurious diagnosis of VWD in a patient with a sequence variation in the ristocetin-binding domain of VWF. PATIENTS/METHODS: The index case had a VWF:RCo of 11 IU dL(-1), with VWF:RCo/VWF:Ag ratio of 0.09. DNA sequencing revealed a novel P1467S mutation in a known ristocetin-binding region of the A1 domain. Because of the discrepancy between the laboratory findings, consistent with type 2M VWD, and the patient's lack of bleeding symptoms, further studies were performed to determine whether this mutation affected VWF function or merely reduced its ability to interact with ristocetin. RESULTS: Studies with recombinant VWF showed normal platelet binding with botrocetin, but a significant decrease in binding in response to ristocetin. Ristocetin-induced binding to recombinant GPIb was also absent, but normal binding was seen when a gain-of-function GPIb construct was used in the absence of ristocetin. VWF function under shear stress was normal when analyzed with a cone and plate(let) analyzer. CONCLUSIONS: The decreased VWF:RCo seen with the P1467S sequence variation likely represents an artifact as a result of the use of ristocetin to measure VWF activity. The normal VWF function in other assays correlates with the lack of hemorrhagic symptoms, and suggests the need for more physiologically relevant assays of VWF function.

Genetic alteration of the D2 domain abolishes von Willebrand factor multimerization and trafficking into storage.

BACKGROUND: The large von Willebrand factor (VWF) propeptide (VWFpp) plays a critical role in the multimerization and regulated storage of the mature VWF protein. Although our laboratory and others have identified mutations in von Willebrand disease patients that disrupt VWF multimerization, little is known about the affect of mutations on the regulated storage of VWF. PATIENTS/METHODS: We identified a heterozygous 18 base pair, in-frame deletion in exon 12 of the VWF gene in a patient with an unusual, dimer-intense multimer pattern. This deletion results in loss of amino acids 436-442 of VWFpp, which include one cysteine. RESULTS: Through expression studies, we demonstrate reduced secretion, loss of VWF multimerization, and defective regulated storage of the variant VWF. The loss of VWF storage is secondary to loss of propeptide storage resulting from an apparently defective sorting signal on VWFpp. Suprisingly, coexpressed wild-type VWF or VWFpp functioned in trans to partially restore multimerization of VWF from the variant allele. CONCLUSIONS: The deletion of six amino acids in VWFpp results in defects in VWF processing, regulated storage, and function. Although VWFpp may usually function in a homotypic fashion, acting on its own mature VWF subunit, VWFpp may retain the ability to function in trans on VWF expressed from the variant allele.

B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII concentrate: a randomized, three-way crossover study.

BACKGROUND: Deletion of the B-domain of recombinant blood coagulation factor VIII (BDDrFVIII) increases the manufacturing yield of the product but does not impair in vitro or in vivo functionality. BDDrFVIII (ReFacto) has been developed with the additional benefit of being formulated without human albumin. OBJECTIVE: The primary objective of this three-way crossover-design study was to compare the pharmacokinetic (PK) parameters of two BDDrFVIII formulations (one reconstituted with 5 mL of sterile water, the other reconstituted with 4 mL sodium chloride 0.9% USP) with those of a plasma-derived, full-length FVIII preparation (Hemofil M) in patients with haemophilia A to determine bioequivalence. METHODS: A series of blood samples were collected over a period of 48 h after i.v. administration of each of the FVIII preparations. Plasma FVIII activity was determined using a validated chromogenic substrate assay. Plasma FVIII activity vs. time curves was characterized for a standard set of PK parameter estimates. Two parameter estimates, the maximum plasma concentration (Cmax) and the area under plasma concentration vs. time curves (AUCs), were used to evaluate bioequivalence. The two preparations were considered bioequivalent if the 90% confidence intervals for the ratio of geometric means for Cmax and AUCs fell within the bioequivalence window of 80% to 125%. RESULTS/CONCLUSION: Results show that each BDDrFVIII formulation is bioequivalent to Hemofil M and the two formulations of BDDrFVIII are bioequivalent to each other.

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.

Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg(-1) appear to be well-tolerated. Additionally, rFVIIa doses >200 mcg kg(-1) appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P).

von Willebrand disease (VWD) is characterized by insufficient von Willebrand factor (VWF) activity. It has been proposed that VWF:ristocetin cofactor (VWF:RCo) activity may be useful in evaluating the response to VWD treatment in patients who require replacement therapy. This prospective, open-label, non-randomized study evaluated the safety and efficacy of a factor VIII (FVIII)/VWF concentrate (Humate-P) used in treatment regimens based on VWF:RCo activity in subjects with VWD in situations requiring urgent and necessary surgery. This article summarizes the results for 39 subjects with 42 evaluable surgical treatment events, 100% of which were rated as excellent/good for overall efficacy (achievement of haemostasis). The median loading dose based upon VWF:RCo activity was 82.3 international units/kilogram (IU kg(-1); range 32.5-216.8 IU kg(-1)), and the median maintenance dose per infusion was 52.8 IU kg(-1) (range 24.2-196.5 IU kg(-1)) for a median of 3 days (range 1-50 days). The median number of infusions per event was 6 (range 1-67 infusions). Three unanticipated adverse events (peripheral oedema, extremity pain and pseudo-thrombocytopenia) from two surgical treatment events were reported that were potentially treatment-related. No serious drug-related adverse events (AEs) were observed, and no thrombotic events were reported in this study. This study supports the safety and efficacy of the FVIII/VWF concentrate Humate-P for the prevention of surgical haemorrhage in patients with VWD when administered in doses calculated in VWF:RCo units.

Comment on "Molecular gyroscopes and biological effects of weak extremely low-frequency magnetic fields".

A mechanism whereby reaction rates may be influenced by weak alternating magnetic fields has been suggested by Binhi and Savin [Phys. Rev. E 65, 051912 (2002)] to account for certain magnetobiological effects. It is proposed that the fields influence the probability of reaction of molecular rotators (gyroscopes) by inducing interference between eigenstates of angular momentum superposed in their wave functions. The predicted variation of reaction rate with the amplitude of the alternating field is found to be qualitatively consistent with observation. It is commented that the required interference occurs only in circumstances which are quite implausible, and that even if it were possible, the interference would not lead to a detectable magnetobiological effect.