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Background Treatment goals Conclusion Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile.The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health‐related quality of life impacted by haemophilia and its treatment.Capitalizing on the major potential of therapeutic innovations, ‘Normalization’ of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia‐imposed limitations. To achieve this—being supported by the data reviewed in this manuscript—the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community. [ABSTRACT FROM AUTHOR]

Advances in haematological therapies for people with complex or rare inherited bleeding disorders (IBD) have resulted in them living longer, retaining their natural teeth with greater expectations of function and aesthetics. Dental management strategies need to evolve to meet these challenges. Utilising low level laser diode therapy to reduce pre‐operative inflammation to reduce the intraoperative and postoperative burden on haemostasis is described in a case series of 12 patients. For these individuals who previously required further medical management to support haemostasis or experienced such prolonged haemorrhage sufficient to warrant hospital admission, haemostasis was achieved in the dental surgery such that they were able to return home with no further medical intervention or overnight stays. Global inequities in accessing novel treatments for complex or rare IBD necessitates a comprehensive understanding of the local haemostatic agents available to dentists and the most commonly used agents and techniques are described including the use of single tooth anaesthesia (STA). STA is a computerised delivery mechanism that allows routine dental procedures that would previously have required block injections needing factor replacement therapy to be undertaken safely and effectively with no additional haemostatic intervention. The challenges of inhibitors in oral surgery are explained and discussed although more research and evidence is required to establish new treatment protocols. The importance of establishing good dental health in the quality of life of people with complex or rare IBD is highlighted with respect to the dental specific impact that more novel therapies may have on people with IBD. [ABSTRACT FROM AUTHOR]

Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half‐life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas. [ABSTRACT FROM AUTHOR]

Introduction: While the dental management of patients with haemophilia has changed considerably in the last decade, haemophiliacs in Western Australia have continued to receive pre‐operative factor support for dentistry regardless of the type of dental procedure. Aim: To review the efficacy and safety of established dental protocols that reduce factor use in the dental management of patients with haemophilia and to estimate cost savings. Methods: Records of 11 patients with haemophilia that were seen in the pilot programme period were reviewed. These were cross‐referenced with previous dental and haematology notes that stated the amount and type of pre‐operative factor used. Cost savings were estimated using the Australian National Blood Authority's Product List. Results: All study participants were male, and included those with haemophilia A (n = 9), and B (n = 2). Mean age was 45 years (range 22–80). A variety of dental treatments were undertaken, and no pre‐operative factor was used. Patients on prophylaxis (n = 6) received dental treatment the same day as their regular factor administration. It was estimated AUD$26,314 was saved by not using pre‐operative factor. One patient had bleeding post‐extraction and was seen the following day to achieve haemostasis using local measures. The remaining patients had no complaints of post‐operative bleeding, and did not require any further haemostatic measures. Conclusion: This pilot programme supports data that haemophiliacs can safely receive a variety of dental treatments without the need for pre‐operative factor, and the significant cost savings of doing so. Further data is required to support this protocol for invasive dental procedures. [ABSTRACT FROM AUTHOR]

Introduction and aims: Mim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non‐FVIII measuring haemostasis assays was assessed in plasma containing Mim8. Methods: Congenital severe HA plasma was spiked with increasing concentrations of Mim8 (0–20 μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D‐dimer, anti‐Xa, heparin induced thrombocytopenia (HIT), clotting factors II–XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT. Results and conclusions: Less than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15 μg/mL Mim8 in all assays except thrombin time (−10.5%), APTT‐based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (−26.4%) and LA2 (−16.9%). At the expected therapeutic steady state levels of Mim8 (5–8 μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo. APTT‐based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management. [ABSTRACT FROM AUTHOR]

Background: The International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH‐BAT), is used during the diagnostic workup of bleeding disorders. Data on ISTH‐BAT scores in women with heavy menstrual bleeding (HMB) undergoing endometrial ablation (EA) could be essential in optimizing HMB counselling. Objective: To investigate the postsurgical incidence of amenorrhea, dysmenorrhea, quality of life, re‐intervention after EA, and ISTH‐BAT score. Methods: This study included women who have undergone EA because of HMB. During a follow‐up of 2 to 5 years, ISTH‐BAT, pictorial blood assessment chart (PBAC), and Short Form‐36 survey (SF‐36) were administered. At 10 years of follow‐up surgical re‐interventions were evaluated. Results: Seventy‐one women were included of whom 77% (n = 55) had an ISTH‐BAT score < 6, versus 23% (n = 16) ISTH‐BAT score ≥6 (mean age 46.3 versus 42.3, p = 0.004). In the ISTH‐BAT ≥6 group versus < 6 group, amenorrhea occurred in 63% (10/16) versus 82% (45/55) (p = 0.111), dysmenorrhea in 38% (6/16) versus 18% (10/55) (p = 0.111), and surgical re‐intervention in 19% (3/16) versus 25% (14/55) (p = 0.582). SF‐36 item (Bodily) pain was lower in the ISTH‐BAT ≥6 group versus < 6 (median score 58.7 vs. 80.0, p = 0.104). Conclusions: An ISTH‐BAT score ≥6 may be related to a lower amenorrhea incidence and higher dysmenorrhea rate after EA. [ABSTRACT FROM AUTHOR]

Introduction: Inhibition of tissue factor pathway inhibitor (TFPI) is a potential new mode of action to achieve haemostasis in haemophilia A and B patients. Aim: Knowledge about potential developmental changes of TFPI levels during childhood are a prerequisite to translate adult doses of TFPI inhibitors to doses in paediatric patients. Methods: In this study we present longitudinal data for total TFPI concentrations (TFPI‐T) and TFPI activity (TFPI‐A) from 48 paediatric Haemophilia A patients in the age range from 3 to 18 years (2–12 observations per patient). Results: TFPI‐T and TFPI‐A tend to decrease over age during childhood. Lowest values were observed between 12 and <18 years. On average, TFPI‐T and TFPI‐A were lower in adolescent haemophilia patients than in adult haemophilia patients. Conclusion: In summary, the presented information on TFPI levels in children adds to the current knowledge of developmental haemostasis and it can be helpful in evaluating how children respond to haemophilia treatment including the new class of anti‐TFPI compounds. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab treatment may allow patients with hemophilia A without (PwHA) and with inhibitors (PwHA‐I) to undergo some minor surgeries, such as tooth extraction, without peri‐operative factor infusions. However, criteria for determining the necessity of factor infusions before minor surgeries are unknown. Aim: We report the peri‐operative hemostatic management and outcomes of emicizumab‐treated PwHA and PwHA‐I cases who underwent tooth extractions using our institutional protocol. Methods: We retrospectively evaluated PwHA and PwHA‐I who underwent tooth extraction with emicizumab prophylaxis at our institution. Local bleeding risk was assessed based on the method, number, and site of tooth extraction. Hemostasis was monitored peri‐operatively by rotational thromboelastometry (ROTEM). Hemostatic agents and a mouth splint were used. Results: Twenty‐nine extractions (17 interventions) were performed in eight PwHA and two PwHA‐I. Based on ROTEM, pre‐operative factor infusions were used in ten PwHA and four PwHA‐I interventions. Among nine low local bleeding risk interventions, three (33.3%) each received no infusions, one dose of factor infusion pre‐operatively, and pre‐ and post‐operative factor infusions. All eight high local bleeding risk interventions involved planned factor infusions. Absorbable hemostats were used in all extractions. A mouth splint was used in 21/25 (84.0%) PwHA and in 4/4 (100%) PwHA‐I extractions. No post‐extraction bleeding or thrombotic events occurred. Conclusions: Use of a systemic hemostatic treatment plan according to the local bleeding risk, peri‐operative coagulation status assessment using ROTEM, filling the extraction socket with hemostats, and use of a mouth splint can achieve effective and safe hemostatic management in emicizumab‐treated PwHA and PwHA‐I. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors. Aim: To investigate the effect of emicizumab dose up‐titration in PwHA with suboptimal bleeding control. Methods: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up‐titration. Adverse events (AEs) were compared between PwHA with and without dose up‐titration. Results: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up‐titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady‐state trough concentrations increased from 44.0 to 86.2 μg/mL after up‐titration. The median (interquartile range [IQR]) efficacy period prior to up‐titration was 24.6 (24.0–32.0) weeks. The model‐based annualised bleed rate for 'treated bleeds' and 'all bleeds' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow‐up of 97.1 (48.4–123.3) weeks in the up‐titration period. Incidences of injection‐site reactions and serious AEs were higher in PwHA with up‐titration; however, this was already observed in these participants before the dose up‐titration. Overall, the safety profile appeared similar between PwHA with and without up‐titration. Conclusion: The dose up‐titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The first external quality assessment (EQA) in Thrombosis and Haemostasis was elaborated over 20 years ago, and since then, several national and international EQA institutions have been established. Aim: Display the benefits of EQA programs. Methods: The spectrum of EQA action was evaluated ranges from improving the performance of the local laboratory to highlighting inadequate diagnostic tests that need to be replaced by new technologies. Results: The first result approach is related to a national management of quality in laboratories. In recent years, Brazil has invested in an EQA program to aid public policy in the laboratory area. During this period, a group of haemostasis laboratory specialists were invited to manage the results and help the Ministry of Health with applying these results as a strategy to improve laboratories. Thus, in collaboration with NEQAS‐BC, the University of Campinas – UNICAMP, established a Brazilian EQA program for Blood Coagulation. The second result approach is related to FVIII inhibitor assay performance evaluation, which is another type of EQA program benefit. Despite the assay being considered the gold standard to measure neutralised immunoglobulins for FVIII since 1975, over 40 years ago, the test still has a high coefficient of variation. Results from NEQAS‐BC and WFH IEQAS program demonstrate the inter‐laboratory variation across the United Kingdom over the last years and among emergent countries. Conclusion: The EQA programs have an important educational role in helping countries manage their public policy and in the international inquiry regarding the necessity of new technologies in haemostasis. [ABSTRACT FROM AUTHOR]

Introduction: Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres. Aim: To explore the potential use of electronic tools to improve the delivery of GT under real‐world conditions. Methods: Considering the hub‐and‐spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients. Results: Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow‐up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered. Conclusion: Important information needs to be shared between patients and treatment centres in a real‐world GT hub‐and‐spoke model. Collecting and sharing this information in well‐organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries. [ABSTRACT FROM AUTHOR]

Introduction: Oral health is an important component of care at haemophilia treatment centres (HTCs). Correlations between oral health and inflammation suggest that proper oral health may improve joint health. Aim: To evaluate the dental habits, needs, and oral health status of paediatric patients with bleeding disorders, and identify predicters of poor oral health. Methods: From May 2016 to October 2017, consecutive paediatric HTC patients completed a 14‐question survey and were examined by dental professionals. Descriptive analyses, chi‐square tests and logistic regression models identified characteristics associated with four main dental outcomes. Results: Evaluations from 226 consecutive patients (age 1–20 years) were included. Diagnoses included haemophilia A and B (64%), von Willebrand disease (25%) and other bleeding disorders (13%). Nearly half of patients reported not brushing their teeth twice a day (44%). One‐quarter of patients did not currently have a dentist (27%), and 15% reported specific challenges with access to dental care. Oral screening demonstrated significant pathology: 89% of patients had plaque accumulation, 37% had gingivitis and 8% had lesions suggestive of dental caries. Multivariate analysis revealed that having a primary caregiver with active decay was associated with significantly higher rates of suspicious lesions (OR 4.34, CI 1.41‐13.35) and gingival erythema (OR 3.44, CI 1.63‐7.25) and lower rates of twice daily teeth brushing (OR.17, CI.08‐.37). Conclusion: Children with bleeding disorders commonly have significant dental pathology and report obstacles to dental care, posing the potential risk for morbidity. Primary caregiver dental health is strongly associated with dental pathology in children. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA‐approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12‐54 years) and 25 subjects in PERSEPT 2 (1‐11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2‐56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post‐operatively as indicated. Descriptive statistics were used for data analyses. Results: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti‐EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with haemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to predict the approximate FVIII level in severe haemophilia A patients with inhibitors on emicizumab using global haemostasis assays. Materials and methods: Patients with moderate and mild HA in the non‐bleeding state and healthy controls had FVIII levels and thrombin generation assessed. Linear regression was utilized to model the FVIII levels as a function of the thrombin generation assay parameters and to make a calibration curve of FVIII levels versus peak thrombin and endogenous thrombin potential. Patients with severe haemophilia A with inhibitors on emicizumab had thrombin generation performed in the same manner and their peak thrombin and endogenous thrombin potential results were placed on the calibration curve to calculate their FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). Results: All patients with severe HA with inhibitors on emicizumab had F8EmT >10%, suggesting they had been converted to a mild haemophilia phenotype. The patient's weight was inversely correlated to their F8EmT. Conclusion: The results from this study suggest that the F8EmT in patients with severe HA on emicizumab falls within the range of mild haemophilia which is consistent with the data noted in the emicizumab clinical trials and in vivo studies in animals. [ABSTRACT FROM AUTHOR]

Introduction: The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis. Aim: We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half‐life FIX, Alprolix®, to extravascular type IV collagen (Col4). Methods: Three mouse models of haemophilia were used: the FIX knockout as the CRM− model and two knock‐in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q) or a mutation that binds poorly to Col4 (FIXK5A). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX. Results: CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL‐FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20–40 nM) and show dose‐dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574 nM) was greater than for BeneFIX® (405 nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor. Conclusion: Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity. [ABSTRACT FROM AUTHOR]

Introduction: Central venous access devices (CVAD) are used to facilitate intravenous treatment with coagulation factor concentrates (CFCs) in haemophilia A (HA). Guidelines for perioperative CFC replacement therapy are based on single centre experiences, and the length of replacement therapy varies. Aim: The aim of this study was to evaluate whether haemostasis coverage under four days is as effective and safe as a longer period of haemostatic coverage. Methods: We identified patients with severe HA without inhibitors or major bleeds within one month of the surgery who received their first CVAD. We compared the CFC consumption and bleeds between children with ≤4 and those who received 5–7 perioperative treatment days including the day of surgery. Bleeds were recorded up to 4 days after the end of perioperative haemostatic coverage. Results: In total, 144 children met the eligibility criteria and were included in the study cohort: 34 had received haemostatic coverage for ≤4 days, while 110 had received 5–7 days of haemostatic coverage. One bleed related to the surgery occurred in both groups. Conclusion: Overall, the bleeding complications were rare. Haemostatic coverage with CFCs under ≤4 days with elective CVAD insertions was as effective as coverage for ≥5 days. [ABSTRACT FROM AUTHOR]

Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state‐of‐the‐art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady‐state haemostasis as a possible new target for prophylaxis. [ABSTRACT FROM AUTHOR]

The performance of surgery and invasive procedures in patients with haemophilia is currently facing new challenges globally. The first is the appropriate application of low‐dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resource constraint environments. The increasing availability of CFC through humanitarian aid programmes allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half‐life CFC that are increasingly available in many countries represent valuable alternatives to standard half‐life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half‐life factor IX. Third, in the era of recently introduced non‐factor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low‐dose administrations of CFC or bypassing agents. Additional factor VIII or bypassing treatment has proven to be safe and effective in association with emicizumab for major surgeries, and it was effectively given at low doses in association with fitusiran. No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A with and without inhibitors. Management of breakthrough bleeding in patients with inhibitors on emicizumab involves episodic treatment with bypassing agents (BPA), activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Thrombotic events and thrombotic microangiopathy were reported when patients on emicizumab received concomitant aPCC at relatively high doses yet such events were not reported with rFVIIa. We studied the effect of spiking various concentrations of BPA on plasma taken from patients on emicizumab. Material and Methods: Eleven patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Blood samples drawn from patients were spiked in vitro with varying concentrations of aPCC and rFVIIa. All samples were tested utilizing global haemostasis assays, thromboelastography and thrombin generation assay. Results: Thrombin generation increased with higher concentrations of spiked BPA with a normalized endogenous thrombin potential at a concentration of 0.05 IU/ml and 4 mcg/ml for aPCC and rFVIIa, respectively. Concentrations of aPCC in the range of licensed dosing led to excessive thrombin generation. Thromboelastography was not sufficiently sensitive. Conclusion: Due to the known thrombotic complications when emicizumab is used in conjunction with aPCC, there has been a large‐scale abandonment of the use of aPCC in patients on emicizumab. However, it is possible that aPCC can be used safely with emicizumab albeit with lower doses than are typically prescribed. It would be important to test this hypothesis in a clinical study. [ABSTRACT FROM AUTHOR]

The multimeric composition of the von Willebrand factor (VWF) is essential to its function, especially for platelet adhesion to the site of vascular injury, with high molecular weight multimers (HMWM) being the most active. Patient 1 is a 49-year-old patient with type 3 VWD (FVIII:C 2 IU/dL; VWF:GPIbR and VWF:Ag < 1 IU/) confirmed by molecular biology (double heterozygosity for nonsense mutations: p.Ser2079X and p.Arg2535X). [Extracted from the article]

Introduction: An increased bleeding tendency has been shown in female haemophilia carriers compared to healthy females. Bleeding assessment tools (BATs) have mainly been performed in western cultures. It is unclear how they perform in populations with different healthcare, health/wellness concepts and awareness, as well as family planning practices. Aim: To (a) describe and compare the bleeding symptoms in carriers with healthy females, particularly for bleeding after surgical abortion and intrauterine device (IUD) placement which are performed frequently for family planning in China; (b) quantify scores of International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH‐BAT) and Chinese‐BAT (C‐BAT) developed to include surgical abortion and IUD placement as separate categories in Chinese haemophilia carriers; (c) correlate bleeding scores (BS) with factor levels. Methods: We conducted a multicentre, cross‐sectional study on obligate haemophilia carriers and healthy controls using ISTH‐BAT and C‐BAT. Results: We enrolled 125 haemophilia carriers and 106 controls. Carriers, compared to controls, had significantly higher median BS (3 vs 1 by both ISTH‐BAT and C‐BAT) and lower factor level (63.5 vs 101.8 IU/dL). Bleeding after surgical abortion and IUD placement was significantly associated with carrier status. Bleeding scores from neither ISTH‐BAT nor C‐BAT showed significant correlation with factor levels. Conclusion: Haemophilia carriers in China experienced abnormal bleeding. Unique to the Chinese carriers is significant bleeding after surgical abortion (3rd highest incidence of bleeding symptom) and IUD placement (4th highest). However, both ISTH‐BAT and C‐BAT exhibited no correlation between BS and factor levels in this population and neither could identify carriers with low factor level (of <50 IU/dL). [ABSTRACT FROM AUTHOR]

Introduction: Rurioctocog alfa pegol (BAX 855, TAK‐660) is a PEGylated, full‐length, recombinant factor VIII (rFVIII) with extended half‐life developed from unmodified rFVIII (antihaemophilic factor [recombinant]). Aim: To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A. Methods: This multicentre, single‐arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients' pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score. Results: Twenty‐one patients aged 16‐61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non‐haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury‐related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non‐serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment‐related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG‐ or IgM‐binding antibodies to FVIII, PEG‐FVIII or PEG. Conclusion: Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab (Hemlibra®) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. Aim: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. Methods: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. Results: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. Conclusion: The lack of data means that it is only possible to issue proposals rather than recommendations. [ABSTRACT FROM AUTHOR]

Planning and undertaking elective surgery in people with haemophilia (PWH) is most effective with the involvement of a specialist and experienced multidisciplinary team (MDT) at a haemophilia treatment centre. However, despite extensive best practice guidelines for surgery in PWH, there may exist a gap between guidelines and practical application. For this consensus review, an expert multidisciplinary panel comprising surgeons, haematologists, nurses, physiotherapists and a dental expert was assembled to develop practical approaches to implement the principles of multidisciplinary management of elective surgery for PWH. Careful preoperative planning is paramount for successful elective surgery, including dental examinations, physical assessment and prehabilitation, laboratory testing and the development of haemostasis and pain management plans. A coordinator may be appointed from the MDT to ensure that critical tasks are performed and milestones met to enable surgery to proceed. At all stages, the patient and their parent/caregiver, where appropriate, should be consulted to ensure that their expectations and functional goals are realistic and can be achieved. The planning phase should ensure that surgery proceeds without incident, but the surgical team should be ready to handle unanticipated events. Similarly, the broader MDT must be made aware of events in surgery that may require postoperative plans to be changed. Postoperative rehabilitation should begin soon after surgery, with attention paid to management of haemostasis and pain. Surgery in patients with inhibitors requires even more careful preparation and should only be undertaken by an MDT experienced in this area, at a specialized haemophilia treatment centre with a comprehensive care model. [ABSTRACT FROM AUTHOR]

Aims: To systematically review the effectiveness of on‐demand treatment with recombinant coagulation factor VIIa (rFVIIa) in congenital haemophilia with inhibitors and, if feasible, perform a meta‐analysis of the data. Materials and methods: Publications from Embase®, MEDLINE®, MEDLINE® In‐Process and the Cochrane Central Register of Controlled Trials were searched. Selected publications were reviewed for inclusion by two independent expert reviewers. Discrepancies were reconciled by a third independent reviewer. Data from selected studies were extracted using a predefined grid to ensure uniform and comparable results were captured. Results: A systematic search (cut‐off date of 2 May 2016) identified 20 studies (13 observational; seven randomized controlled trials). All studies were of sufficient quality to include in this analysis and comprised 1221 participants, with 5981 bleeds in 746 individuals treated with rFVIIa. Haemostatic overall effectiveness of the individual studies identified ranged from 68% to 100% at ≤12 hours, 86% to 96% at 13‐24 hours and 76% to 99% at 24‐48 hours with rFVIIa <100 μg/kg, with similar rates reported for the ≥250 μg/kg dose. However, heterogeneity between the studies precluded pooling of results. Conclusions: Data from the individual studies confirmed that rFVIIa is an effective therapy for the on‐demand treatment of bleeds in congenital haemophilia with inhibitors. However, the high levels of heterogeneity between studies precluded pooling of results for a valid, reliable or precise summary measure. There remains a need to implement standardized clinical definitions and measurements for the effectiveness and safety of haemophilia therapies in future clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Postinfusion ReFacto AF levels can be difficult to measure accurately due to discrepancies between one‐stage and chromogenic FVIII assays. To overcome this, the use of the ReFacto AF laboratory standard (RAFLS) is recommended, but there are discordant reports regarding its usefulness. Aim: We investigated whether calibration with RAFLS and measurement of ReFacto AF levels are influenced by the choice of reagents and patient‐specific factors in one‐stage FVIII assays. Methods: Calibration curves were generated with both the RAFLS and a plasma standard using different F8DPs and one‐stage FVIII assay reagents. This selection of reagents was then used to determine FVIII levels in the plasma of patients repeatedly treated with ReFacto AF. Results were compared with those obtained with a chromogenic assay. Results: F8DP devoid of von Willebrand factor (VWF) falsely increased the values of RAFLS pro‐coagulant activity generated using the APTT reagent. The resulting RAFLS calibration curve underestimated ReFacto AF levels to be half of their true concentration. The use of RAFLS with F8DP containing VWF reduced the discrepancy observed between the one‐stage and chromogenic FVIII assays. However, the mean difference between the two assays still varied up to 50% depending on the patient. Conclusions: The RAFLS is a suitable calibrator for one‐stage FVIII assays carried out with F8DP containing VWF. However, calibration with the RAFLS does not avoid the effect of patient‐specific variables that contribute to discrepancies between the measurements of ReFacto AF levels with one‐stage and chromogenic FVIII assays. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete. Aims/Methods: To examine the efficacy of Nuwiq® (simoctocog alfa, human‐cl rhFVIII), a 4th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A. Results: Thirty‐six patients, aged 3‐55 years, received surgical prophylaxis with Nuwiq® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as “excellent” or “good” in all but one major surgery (assessed as “moderate”). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2‐100.9) IU kg−1 for minor surgeries and 69.3 (43.3‐135.6) IU kg−1 for major surgeries. There were no serious treatment‐related adverse events, and none of the patients developed FVIII inhibitors. Conclusions: The results of this pooled analysis show that Nuwiq® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A. [ABSTRACT FROM AUTHOR]

The article discusses how clinicians and many laboratories are struggling to find a way for the diagnosis or exclusion of a common inherited bleeding disorder called the von Willebrand disease (VWD). According to the author, von Willebrand disease (VWD) is caused because of a deficiency of von Willebrand factor (VWF), which is necessary for effective primary haemostasis.

Introduction The thrombomodulin (TM)/activated protein C (APC) system is a key regulator of haemostasis, limiting amplification and propagation of the formed blood clot to the injury site. Dampening APC's inhibition of factor V (FV) and factor VIII (FVIII) may be a future strategy in developing next-generation therapeutic targets for haemophilia treatment. Aims To determine ex vivo the respective concentration-dependent effects of TM and a FV-stabilizing Fab on the APC regulatory pathway in severe FVIII-deficient blood and plasma. Methods Ten severe haemophilia A subjects and one healthy control were enrolled. Blood was spiked with TM (0, 1, 2.5, 5, 10, 20.0 nmol/L) and FV-stabilizing Fab (0, 3, 15, 65, 300 nmol/L). The respective effects were compared to FVIII concentrations of 3- and 10% using rotational thromboelastometry clotting time (CT) and thrombin generation analysis (TGA). Results With 1 and 2.5 nmol/L TM, 5% FVIII resulted in CT similar to the absence of TM, suggesting it completely reversed the effect of APC. Increasing TM concentrations also reduced peak thrombin generation and ETP. The addition of 300 nmol/L FV-stabilizing Fab returned CT to nearly baseline, but for most subjects was less than the effects of 3- or 10% FVIII. The FV-stabilizing Fab produced similar or greater thrombin generation compared to samples with 3- or 10% FVIII. Conclusions The FV-stabilizing Fab resulted in enhanced CT and TGA parameters consistent with FVIII levels of 3- and 10%. Additional studies need to further characterize how modulating the APC pathway may prove beneficial in developing new haemophilia drug targets. [ABSTRACT FROM AUTHOR]

Introduction Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Aim Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rh FVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes ( BEs). Methods A Phase 3, randomized, cross-over study of initial dose regimens ( IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. Results The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different ( P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rh FVIIa or host cell proteins. Conclusion The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population. [ABSTRACT FROM AUTHOR]

Introduction Family members of Von Willebrand disease ( VWD) patients may have low levels of VWF without major bleeding episodes and often remain undiagnosed. Aim The purpose of this study was to assess the utility of a modified Screening Tool in identifying previously untested reproductive age female family members of VWD patients for haemostatic evaluation. Methods Ninety-four reproductive age women including 41 previously untested family members of VWD patients, 26 previously diagnosed VWD patients and 27 healthy controls were administered a modified Screening Tool and had blood drawn for CBC, ferritin, and VWF testing. Participants completed a pictorial blood assessment chart ( PBAC) with menses. Results The modified Screening Tool was positive in 32% family members, 77% VWD patients, and 19% controls ( P < 0.001). Combined with low ferritin, the modified Screening Tool was positive in 66% family members, 92% VWD patients, and 44% controls ( P = 0.001). In family members, incorporating low ferritin with the modified Screening Tool resulted in a sensitivity of 86% (95% CI, 42-100) and negative predictive value of 93% (95% CI, 66-100). In the control group, NPV was between 92% and 95% for the modified Screening Tool and also for the modified Screening Tool combined with low ferritin or a positive PBAC. Conclusion These data in a racially diverse population suggest the usefulness of a simple, easy to administer modified Screening Tool. In conjunction with ferritin it could be used in a primary care setting to stratify reproductive age women with a family history of VWD for haemostatic evaluation. [ABSTRACT FROM AUTHOR]

A study which investigated a haemophilia A (HA) boy with inhibitor who was successfully managed for recurrent joint and muscle bleeds using activated prothrombin complex concentrate (aPCC) prophylaxis is presented. Topics covered include features of the patient, poor response of the patient after on-demand therapy, and the haemostatic effect of aPCC.

Introduction Successful outcomes in dental management for patients with inherited bleeding disorders require close collaboration between haematology teams and dentists. Aim To review outcomes of an interdisciplinary pathway for dental procedures by assessing adequacy and appropriateness of haemostatic management. Methods Two hundred dental procedures in 30 patients with inherited bleeding disorders were included. A Dental Bleeding Risk Assessment and Treatment Tool (De BRATT) was developed to identify four categories of bleeding risk (no risk, low, moderate and high risk of bleeding) in relation to the severity of the bleeding disorder and the invasiveness of dental procedure. The adequacy and appropriateness of haemostatic therapy provided in relation to the bleeding risk was assessed with reference to the published literature. Treatment was classified as appropriate, over or under-treatment. Bleeding complication was the primary outcome. Results A high level of dental disease was noted, with 83% of patients having at least one decayed tooth and 46.7% having chronic gum disease. A total of 59.1% of the dental procedures in patients with mild bleeding disorders were over-treated ( n = 65/110) and 8.9% in patients with severe disorders had an extended duration of treatment ( n = 7/79). One bleeding complication was observed in a patient with Von Willebrand's disease and severe thrombocytopenia. All other procedures (99.5%) were uneventful. Conclusion De BRATT enables a risk-based approach for the management of dental procedures in patients with inherited bleeding disorders. The tool facilitates a comprehensive evaluation of bleeding risk with the potential to minimize unnecessary treatment and aid interdisciplinary communication among different clinical teams. [ABSTRACT FROM AUTHOR]

Von Willebrand disease ( VWD) is an inherited haemorrhagic disorder caused by a quantitative or qualitative defect of von Willebrand factor ( VWF), a multimeric plasma glycoprotein that plays a key role in platelet adhesion to the subendothelium and acts as a carrier of factor VIII ( FVIII) in blood. Patients with VWD experience bleeding symptoms that are mainly localized in mucous membranes and soft tissues, and their severity depends on the degree of the primary reduction in VWF and the secondary deficiency of FVIII in plasma. Because VWD patients are also at increased risk of perioperative bleeding, a prophylactic treatment aimed to correct the dual haemostatic defect (i.e. VWF and FVIII) is warranted. This review summarizes knowledge on the current management of patients undergoing major surgery, focusing on the peri-surgical laboratory monitoring of replacement therapy with VWF/ FVIII concentrates. We suggest to monitor plasma levels of FVIII coagulant activity in the postoperative period rather than a surrogate maker of platelet-binding VWF activity as the ristocetin cofactor assay and its recent modifications. [ABSTRACT FROM AUTHOR]

Introduction Previous guidelines recommend that FXI:C levels should be used to monitor FXI replacement in factor XI ( FXI) deficiency. However, FXI:C levels do not correlate with bleeding tendency in this disorder and may not be the optimal test by which to monitor and determine further treatment in the postoperative period. Aim To assess whether the thrombin generation assay ( TGA) and rotational thromboelastometry can be used to monitor FXI replacement peri-operatively in FXI deficiency and to determine if changes in FXI:C levels correlate with changes in thrombin generation and clot formation parameters following treatment with solvent-detergent fresh frozen plasma ( SD- FFP). Methods The TGA and rotational thromboelastometry were used to measure thrombin generation and clot formation in 11 adults with FXI deficiency who were treated with either SD- FFP ( n = 8) or FXI concentrate ( n = 3) as prophylaxis peri-operatively. Blood samples were taken pre- and 30 min post-treatment. Results Global haemostasis assays can be used to measure the effect of FXI replacement with SD- FFP or FXI concentrate in FXI deficiency. Both treatment types improved thrombin generation and clot formation. However, the remaining response to treatment at 24 h post SD- FFP was variable and changes in FXI:C levels were not predictive of changes in thrombin generation/thromboelastometry parameters after treatment with SD- FFP. Conclusion Global haemostasis assays may provide a more reliable means of monitoring SD- FFP treatment with the potential to prevent individuals receiving unnecessary treatment, however, their clinical use in decision making needs to be tested in a larger prospective study. [ABSTRACT FROM AUTHOR]

Introduction Primary factor VIII ( FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life ( T1/2) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy. Aims To determine immunogenicity, pharmacokinetics ( PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII ( BAX 855) based on full-length recombinant FVIII ( ADVATE) in paediatric previously treated patients ( PTPs) with severe haemophilia A. Methods PTPs <12 years without history of FVIII inhibitors received twice-weekly infusions of 50 ± 10 IU kg−1 BAX 855 for ≥50 exposure days. Prophylactic dose increases to ≤80 IU kg−1 were allowed under predefined conditions. PK was evaluated after single infusions of 60 ± 5 IU kg−1. Results T1/2 and mean residence time were extended 1.3- to 1.5-fold compared to ADVATE ( n = 31), depending on the analysis used. The point estimate for the mean annualized bleeding rate in 66 subjects receiving a median of 1.9 weekly infusions of 51.3 IU kg−1 of BAX 855 each was 3.04 (median 2.0); 1.10 (median 0) for joint and 1.16 (median 0) for spontaneous bleeds. Overall, 38% of subjects had zero bleeds. No bleeds were severe. Haemostatic efficacy was rated excellent or good for 90% of bleeds; 91% were treated with one or two infusions. In 8/14 subjects all target joints resolved. No subject developed FVIII inhibitors or persistent binding antibodies that affected safety or efficacy. No adverse reactions occurred. Conclusion Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Background Continuous infusion ( CI) of recombinant FVIII ( rFVIII) concentrates has been reported as an effective and safe method to achieve haemostasis during major surgeries or severe bleeding events. For more effective and safer CI, better understanding of in vivo recovery ( IVR) and clearance ( CL) issues is imperative. Objective We investigated the following factors affecting IVR and CL using univariate and multivariate regression analyses during 47 CIs in 34 patients: rFVIII concentrate type, haemophilia severity, blood type, the presence of hepatitis C virus ( HCV) or human immunodeficiency virus ( HIV), age and body mass index ( BMI). Results The mean IVR was 1.64 ± 0.49 IU dL−1 per IU kg−1, and the mean CL during CI was 3.56 ± 1.57 mL h−1 kg−1. The univariate and multivariate regression analyses showed that the CL of octocog alfa was significantly lower than that of rurioctocog alfa ( P = 0.043 and 0.0034, respectively). There was a significant difference in BMI in the univariate and multivariate regression analyses ( P = 0.0403 and 0.0376, respectively). Conclusions This study indicated that CL during CI was potentially affected by the type of rFVIII concentrate used and BMI. [ABSTRACT FROM AUTHOR]

Introduction This study was conducted to evaluate the current implementation of outcome measures in routine clinical haemophilia practice and to explore and appreciate the perception of the relevance of such measures by treaters. Methods A survey was completed by 19 of the 26 physicians involved in the European Haemophilia Therapy Strategy Board ( EHTSB). Employing an extensive inventory of outcome measures used in patients with haemophilia, information was collected about the frequency of data collection and the subjective appreciation of their importance during clinic review. Results The survey revealed that most treaters currently collect data that are mainly related to the haemostatic treatment (consumption of concentrates) and the bleeding symptoms (number and location of bleeds) in a non-uniform and non-standardized way. By contrast, functional, physical and quality of life scorings are rarely used and show considerable heterogeneity between treaters. Also, many disparities emerged between practice and perception, in particular quality of life data that are perceived as being important but for most of the time are not collected. Conclusions This survey represents, in our view, the first attempt to evaluate the actual utilization of outcome measures in haemophilia care. While the value of outcome measures is appreciated, they are not assessed regularly. Therefore, there is a need to include appropriate performance indicators (outcome measures) of haemophilia care in routine clinical practice. Consensus recommendations to provide a framework for achieving this aim are provided. [ABSTRACT FROM AUTHOR]

Introduction High-titre factor VIII ( FVIII) inhibitors complicate peri-operative haemostasis. Recombinant porcine FVIII (r- pFVIII) may provide an alternative haemostatic agent for high-risk procedures and allow FVIII activity monitoring. Aim Devise an effective haemostatic plan for repair of a progressively symptomatic aortic coarctation in a 5-year-old male with immune tolerance induction ( ITI) refractory high-titre FVIII inhibitors. Methods Preprocedure human FVIII inhibitor titre was 58 Bethesda Units mL−1 ( BU) and cross-reacted to neutralize porcine FVIII at 30 BU. Daily ITI with plasma-derived FVIII concentrate was supplemented with anti-B-cell and anti-plasma cell immunotherapy to reduce FVIII inhibitor titres. Potential haemostatic agents were evaluated in comparative ex vivo thrombin generation assays ( TGA). Results Four weeks after immunosuppression, human and porcine inhibitor titres declined to 16 and 2 BU respectively. TGA with r- pFVIII was less robust than with activated prothrombin complex concentrate ( aPCC); however, r- pFVIII was selected for cardiac surgery to secure the ability to assay FVIII levels throughout this high-bleeding risk procedure. Haemostasis with r- pFVIII was excellent; initial trough FVIII activity levels ranged from 0.81-1.17 IU mL−1. On postoperative day 3, peak and trough levels markedly declined suggesting a rising porcine inhibitor titre. Postprocedure prophylaxis was transitioned to aPCC, informed by TGA. Conclusions R- pFVIII provided effective peri-procedural haemostasis with no adverse events. Rapid neutralization of r- pFVIII after the first 60 hours, despite intensive immune suppression, accentuates the importance of careful monitoring. Use of TGA can support bypassing agent selection for convalescence. The comparative cost of r- pFVIII may limit its use to high morbidity clinical scenarios. [ABSTRACT FROM AUTHOR]