Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society: Part 2.

OBJECTIVES: To make recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support including future research directions. DATA SOURCES: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts. STUDY SELECTION: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support. DATA EXTRACTION/DATA SYNTHESIS: This white paper focuses on clinical understanding and limitations of current strategies to monitor anticoagulation. For each test of anticoagulation, limitations of current knowledge are addressed and future research directions suggested. CONCLUSIONS: No consensus on best practice for anticoagulation monitoring exists. Structured scientific evaluation to answer questions regarding anticoagulation monitoring and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patient receiving extracorporeal life support to a registry.

Safety of a pasteurized plasma-derived Factor VIII and von Willebrand factor concentrate: analysis of 33 years of pharmacovigilance data.

BACKGROUND: Haemate-P/Humate-P (Humate-P) is a pasteurized human plasma-derived concentrate containing both Factor VIII and von Willebrand factor for treatment of hemophilia A and von Willebrand disease (VWD). STUDY DESIGN AND METHODS: We analyzed the safety of Humate-P based on more than 33 years of postmarketing pharmacovigilance data, representing an estimated exposure of approximately 25,000 patient-years. The analysis comprises reports of potential adverse drug reactions (ADRs) from all sources, reported as part of routine pharmacovigilance at CSL Behring. ADRs considered clinically relevant or potential risks of Humate-P were identified based on defined and standardized Medical Dictionary for Regulatory Activities queries. Recognizing the limitations of spontaneous reporting, we also reviewed the literature, including clinical trials with mandatory reporting. RESULTS: From 1982 to 2015, a total of 670 postmarketing cases had been reported via pharmacovigilance, for an overall reporting rate of approximately one ADR per 3900 administered standard doses. Of these cases, 343 involved ADRs considered clinically relevant risks (33 thromboembolic complications, 97 inhibitor formation, 110 hypersensitivity or allergic reactions) or potential risks (103 suspected virus transmissions) for Humate-P. Most thromboembolic complications occurred in patients undergoing surgery or with other known risk factors. Inhibitor formation occurred mostly in patients with hemophilia A (24 cases were high titer). Most patients with hypersensitivity or allergic reactions had VWD. None of the reported suspected virus transmission cases were confirmed to be associated with Humate-P. Reported results of company-sponsored studies showed a low incidence of adverse events possibly or probably related to Humate-P. CONCLUSIONS: More than 33 years of pharmacovigilance data continue to support the safety of Humate-P.

First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study.

INTRODUCTION/BACKGROUND: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. AIM: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. PATIENTS/METHODS: Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h. RESULTS: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. CONCLUSION: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilate®): a single centre experience.

von Willebrand disease (VWD) is the commonest inherited bleeding disorder. Management of major surgery or bleeding often requires treatment with a plasma-derived (pd) VWF/FVIII containing concentrate. Wilate® is a dual-virally inactivated pd-concentrate, produced specifically for the treatment of VWD, containing physiological (1:1) ratios of VWF: FVIII. We reviewed efficacy and safety of Wilate® usage (2007-2012) at our centre including 2 years following product switching the majority of patients. Clinical and laboratory data of all adult patients treated with Wilate® during the study period were evaluated. Fifty four patients used 3 972 150 IU of Wilate® (1378 infusions) between 1/3/07 and 1/5/12. Efficacy was rated as being excellent or good in 94% of surgical episodes (n = 70; 34 patients) and 98% of bleeding/traumatic episodes (n = 46; 25 patients). Eight patients (2 636 100 IU) were managed on home treatment regimens. Two patients switched to Wilate® prophylaxis in the evaluation period, demonstrating similar efficacy to a previous product. Incremental recoveries (n = 37) were 2.24 IU dL(-1) per IU kg(-1) for FVIII:C, 2.39 IU dL(-1) per IU kg(-1) for VWF:Ag and 1.88 IU dL(-1) per IU kg(-1) for VWF:RCo. Six adverse events occurred in six patients (11.1% patients) over 1378 infusions (0.44%). Half of these were retrospectively felt to be infusion speed related. No notable accumulation of FVIII was seen in patients treated for ≥3 days. There was no treatment failure, thrombosis, transfusion transmitted infection or inhibitory VWF antibodies seen. Our findings confirm safety and efficacy of Wilate® in an adult VWD population with lack of notable FVIII accumulation.

Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate.

Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors.

The association between endothelial function and autoimmune thyroiditis induced by iodine excess.

BACKGROUND: Iodine excess (IE) intake leads to lymphocyte dysfunction and contributes to autoimmune thyroiditis (AIT). Abnormal thyroid function is associated with adverse cardiovascular events, endothelial dysfunction is often an early pathophysiological feature in most cardiovascular disease. However, the relationship between iodine and the cardiovascular system is currently unclear. Therefore, the aim of this study was to investigate the effects of IE on endothelial function in mouse model. METHODS: A total of 24 NOD.H-2h4 mice were randomly divided into different groups. A sodium iodide (NaI) group supplied with 0.05% NaI water for 8 weeks. Serum levels of tumor necrosis factors α (TNFα), interleukin-6 (IL-6) and C-reactive Protein (CRP), as well as endothelin-1 (ET-1), von Willebrand factor (VWF) and thrombomodulin (THBD) were detected by Elisa. In addition, the mRNA and protein expression of these genes were measured by RT-PCR and Western blotting. RESULTS: Here, we found the urinary iodine concentration (UIC) was higher in the NaI group compared to the control group. Serum levels of ET-1, VWF, and THBD were also significantly lower in the NaI group, however, CRP serum levels are significantly increased. In aorta, the mRNA and protein expression of ET-1, VWF, THBD were downregulated, however, the expression of IL-6, CRP and TNFα mRNA and protein were upregulated in the NaI group. A correlation analysis showed negative correlation between UIC with ET-1, VWF, and THBD, similarly, negative correlation between CRP with THBD was observed. In addition, positive correlations between UIC with CRP. CONCLUSION: Collectively, in the NOD.H-2h4 mice, IE supplementation had a suppressive effect on endothelial function, and this inhibition maybe due to the increase expression of inflammatory cytokines.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). METHODS: With in vivo experiments, we established the steroid-induced osteonecrosis of the femoral head (SONFH) model using Sprague-Dawley (SD) rats (8-week-old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low-, medium- and high-dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4-week-old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX-containing serum and glucocorticoids: control group (CG); BSHX low-, medium-, and high-dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low-, medium-, and high-dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX-containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co-culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. RESULTS: BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p < 0.05, vs. control group or model group). Different concentrations of BSHX-containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX-containing serum-induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. CONCLUSION: BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.

Efficacy and safety during formulation switch of a pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by the quantitative or qualitative deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived VWF/factor VIII (FVIII) concentrates is required in patients unresponsive to desmopressin. To assess the efficacy, safety and ease of use of a new, volume-reduced (VR) formulation of VWF/FVIII concentrate Haemate(®) P in patients requiring treatment for bleeding or prophylaxis for recurrent bleeding or for invasive procedures. Pharmacoeconomic variables were also recorded. Data were analysed using descriptive statistics. This was a multicentre, prospective, observational study. Consecutively enrolled patients received Haemate(®) P VR according to their needs, and were followed for 24 months. Of the 121 patients enrolled, 25.6% had type 3 VWD and more than 40% had severe disease. All patients were followed for 2 years, for a total of 521 visits. On-demand treatment was given to 61.9% of patients, secondary long-term prophylaxis to 25.6% and prophylaxis for surgery, dental or invasive procedures to 45.5%. The response to treatment was rated as good to excellent in >93-99% of interventions. The new formulation was well tolerated by all patients with no report of drug-related adverse events. The switch to volume-reduced Haemate(®) P was easy to perform and infusion duration was decreased twofold compared with the previous formulation. Volume-reduced Haemate(®) P was at least as effective and well-tolerated as the previous formulation.

Use of Haemate(®) P as immune tolerance induction in patients with severe haemophilia A who failed previous induction attempts: a multicentre observational study.

Immune tolerance induction (ITI) can eliminate factor VIII (FVIII) inhibitory antibodies that appear during FVIII replacement therapy. If first-line ITI fails, switching to a different FVIII concentrate, especially one containing von Willebrand factor (VWF), has been advocated. The objective of the study was to assess the efficacy and safety of Haemate(®) P, a plasma-derived FVIII concentrate containing high levels of VWF, as ITI in severe haemophilia A patients who had failed at least one prior ITI attempt with a different FVIII concentrate. In this multicentre, observational study, Haemate(®) P was administered at a starting dose of 83-308 IU kg(-1) day(-1) (1500-6000 IU day(-1)). Efficacy was assessed by standard criteria (e.g. Bethesda titre, FVIII recovery and half-life), and bleeding characteristics. Nine patients from six haemophilia centres were treated with Haemate(®) P after failing one (n = 2), two (n = 5) or three (n = 2) prior ITI courses. The median time from inhibitor detection to Haemate(®) P treatment was 5.4 years. The median Haemate(®) P dose was 134 IU kg(-1), and the median treatment duration 32 months. During median of 47 months of follow-up, complete response, partial response and treatment failure were observed in one, three and five patients respectively. Five patients experienced seven adverse events (AEs), including two serious AEs (sepsis). Haemate(®) P was discontinued due to an AE in one patient with a partial response. Haemate(®) P salvage ITI resulted in complete or partial tolerization in four of nine patients (44%) who had failed previous ITI attempts using different FVIII concentrates.

A French Real-World Evidence Study Evaluating the Efficacy, Safety, and Pharmacokinetic Parameters of rVIII-SingleChain in Patients with Hemophilia A Receiving Prophylaxis.

BACKGROUND: rVIII-SingleChain is a recombinant factor VIII (FVIII) with increased binding affinity to von Willebrand factor compared with other FVIII products. rVIII-SingleChain is indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A. OBJECTIVES: To collect real-world evidence data from patients treated with rVIII-SingleChain to confirm the efficacy and safety established in the clinical trial program and carry out a population pharmacokinetic (PK) analysis. METHODS: This interim analysis includes data, collected between January 2018 - September 2021, from patients treated with rVIII-SingleChain prophylaxis at French Hemophilia Treatment centers. Data on annualized bleeding rates, dosing frequency, and consumption before and after switching to rVIII-SingleChain were recorded. A population PK analysis was also conducted to estimate PK parameters. RESULTS: Overall, 43 patients switched to prophylaxis with rVIII-SingleChain either from a previous prophylaxis regimen or from on-demand treatment. Following the switch to rVIII-SingleChain, patients maintained excellent bleed control. After switching to rVIII-SingleChain, most patients maintained or reduced their regimen. Interestingly, a majority of patients treated >2 ×/weekly with a standard half-life FVIII reduced both injection frequency and FVIII consumption with rVIII-SingleChain. A PK analysis revealed a lower clearance of rVIII-SingleChain (1.9 vs. 2.1 dL/h) and a longer half-life both in adolescents/adults (n = 28) and pediatric (n = 6) patients (15.5 and 11.9 hours, respectively vs. 14.5 and 10.3 hours) than previously reported. CONCLUSIONS: Patients who switched to rVIII-SingleChain prophylaxis demonstrated excellent bleed control and a reduction in infusion frequency. A population PK analysis revealed improved PK parameters compared with those reported in the clinical trial.

Efficacy and safety of von Willebrand factor concentrate almost devoid of factor VIII (Wilfactin®) in paediatric patients under 6 years of age with severe von Willebrand disease.

BACKGROUND: Plasma-derived von Willebrand factor (VWF) (Wilfactin®, LFB, France) was developed for prophylaxis and treatment of haemorrhages in both adults and adolescents with von Willebrand disease (VWD). Replacement therapy in paediatric patients is a key element of the clinical trial programme. MATERIAL AND METHODS: Patients aged <6 years with severe VWD were enrolled in a multinational, open-label study to evaluate the in vivo recovery for Wilfactin®, and its efficacy in preventing and treating bleeding episodes and during surgery. Overall haemostatic efficacy based on a 4-point scale was assessed by investigators. The treatment period ≥18 months investigated the long-term safety. RESULTS: Nine patients, including 7 with type 3 VWD were exposed to treatment with Wilfactin® for up to 4.2 years. Recovery of VWF in 7 patients (n=5 type 3, n=1 type 2, n=1 type 1) was 1.8±0.4 IU/dL per IU/kg. Of the 62 bleeds, 89% were controlled with one (73%) or two (16%) infusions of Wilfactin®. The median dose per infusion was 54 IU/kg. A factor VIII dose was co-administered in 1.6% of bleeds. "Excellent"/"Good" haemostatic efficacy was achieved in 90.3% of episodes. Six patients underwent 11 minor surgical interventions. Treatment duration was 1 day (range: 1-6 days) with a dose administered 30-60 minutes before procedure of 56 IU/kg (range: 41-106 IU/kg). Haemostasis was rated as "Excellent" in all surgeries. During 4-year prophylactic treatment in one patient, breakthrough bleeds were reported in 2.2% of infusions. No VWF inhibitors, thromboembolic events or allergic/anaphylactic-type reactions were observed following a total exposure of 770 days. DISCUSSION: The results show that Wilfactin® provides a safe and effective treatment in patients <6 years of age with severe VWD.

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study.

For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate(®) is a plasma-derived, human, von Willebrand factor-stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate(®) in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate(®) dose change. All inhibitors developed under on-demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate(®). Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22-inversions or large deletions. Octanate(®) was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate(®) in prophylaxis and treatment of bleeding were generally rated as 'excellent', and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (± 0.6) % IU(-1) kg(-1) . These interim results indicate Octanate(®) to be an efficacious, well-tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.

Clinical assessment of Optivate®, a high-purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A.

Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor-screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high-purity FVIII product with von Willebrand factor, Optivate(®). Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long-term studies. Seventy previously treated patients with severe haemophilia A, with ≥ 20 exposure days, were recruited into two long-term, multicentre, open-label studies. The protocols were virtually identical. Patients received Optivate(®) either prophylactically or on-demand. A mean of 159.0 EDs were experienced over 11,320 infusions. Under both conditions, Optivate(®) was well tolerated. Only 10% of patients experienced a treatment-related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on-demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on-demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate(®) in both prophylactic and on-demand management of patients with haemophilia A.

[Proteins influencing the blood coagulation]. / Proteine mit Einfluss auf die Blutgerinnung.

This review describes some natural proteins, which can be employed, either as factor concentrates derived from human plasma or as recombinant drug, to modulate the coagulation system. I will address some biochemical characteristics and the physiological role of von Willebrand factor, the coagulation factors of the extrinsic and intrinsic pathways, and the physiological anticoagulant protein C. In addition, I will detail the pharmacological compounds, which are available for influencing or substituting the coagulation proteins: desmopressin (DDAVP), single coagulation factor concentrates, prothrombin complex concentrates, and protein C concentrate. In particular, I will address some treatment topics of general medical interest, such as the treatment of massive bleeding, the correction of the coagulopathy induced by vitamin K-antagonists in patients with cerebral haemorrhage, and of the coagulopathy of meningococcemia. Finally, I will describe some properties and practical clinical applications of the recombinant anticoagulans lepirudin and bivalirudin, which are derived from hirudin, the natural anticoagulant of the medical leech.

Effectiveness and safety of hFVIII/VWF concentrate (Voncento®) in patients with inherited von Willebrand disease requiring surgical procedures: the OPALE multicentre observational study.

BACKGROUND: In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento® (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD. MATERIALS AND METHODS: The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento® who underwent surgery. RESULTS: In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1-9), the pre-operative loading dose was 41 IU VWF:RCo kg-1 (range: 18-147), and the total dose was 63 (range: 18-594). During major surgeries, the number of infusions was 4 (range: 1-23), the pre-operative loading dose was 43 (range: 25-66) IU VWF: RCo kg-1, and the total dose was 155 (range: 40-575). The median FVIII:C levels ranged from 78 to 165 IU dL-1 during 5 days after minor surgeries and from 86 and 167 IU dL-1 during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL-1 and between 34 and 76 IU dL-1 after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as "excellent" or "good" in 99% of patients. No thrombotic events related to Voncento® were recorded. DISCUSSION: The present study suggests that Voncento® is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.

Treatment and prevention of acute bleedings in von Willebrand disease--efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate.

For many patients with von Willebrand disease (VWD), the replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is the treatment of choice. To evaluate clinical efficacy, safety and tolerability of Wilate, an albumin-free VWF/FVIII concentrate with a ratio of the two haemostatic moieties of approximately 1 to 1, a prospective clinical programme has been designed. The dataset on the treatment and prevention of bleedings is derived from 44 patients (20 males and 24 females) of all VWD types. Thousand and ninety five bleeding episodes were treated with an overall efficacy rating of excellent or good in 96%. The median dose per treatment day was 26 IU FVIII:C per kg. Eighty-one per cent of bleeds were stopped within 1 or 2 days. Gastrointestinal (GI) bleeds needed higher doses (mean 44 IU kg(-1)) and longer treatment (mean 4 days). Efficacy and dosing data from eight children of 12 or less years of age did not differ significantly from the overall study population. Nineteen patients, including six children, were treated prophylactically for more than 3 months (mean 14.8, range 3-46) with a mean prophylactic dose of 27.4 IU kg(-1) and a mean frequency of 1.9 infusions per week. A drop of bleeding frequency from a mean of 4.5 to 1.4 bleeds per month was observed. The overall tolerability was very good. Adverse drug reactions were rare and were mild or moderate in their intensity. The large prospective clinical dataset shows that Wilate is efficacious and safe in the treatment and prevention of haemorrhages in all VWD types in both adult and paediatric patients.

Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?

Most patients with congenital von Willebrand disease (VWD) undergoing major surgical procedures require prophylactic replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates. Venous thromboembolism has been reported in such patients, as a result of a combination of various treatments (i.e., type of surgery, progressive increase of post-infusion FVIII plasma levels) and/or patient-related thrombotic risk factors. On the whole, the literature data show that venous thromboembolic complications in surgical VWD patients who have been prophylactically treated with VWF/FVIII concentrates are extremely rare. Indeed, only 11 cases have been reported in the literature, mostly occurring during orthopedic procedures. Thus, in absence of a widely accepted consensus and adequate prospective studies, we advise that the need for thromboprophylaxis in such patients should be evaluated individually, after a careful risk/benefit analysis.