Roger E. G. Schutgens

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is an ultrarare metabolic disorder characterized by congenital neutropenia and multisystem abnormalities and accumulation of 1,5-anhydro...

Light transmission aggregometry (LTA) is commonly used to diagnose platelet disorders and has a specific pattern in Glanzmann thrombasthenia (GT). As there is currently no adequate test to assess the efficacy of platelet transfusion, we explored whether LTA can be used to monitor the platelet response following platelet transfusion. We retrospectively evaluated LTA results after platelet transfusion in four patients with GT. After transfusion of two units of platelets, aggregation assessed by LTA remained reduced for all platelet agonists except ristocetin, despite a satisfactory clinical effect on hemostasis. One patient received seven units, after which a change in LTA results was observed. In this heterogeneous case cohort, the LTA response did not correlate with the clinical response after platelet transfusion in GT. To draw definitive conclusions, a study in a larger population that controls for influencing factors - such as the timing and dose of platelet transfusion and the use of a standardized LTA procedure - should be conducted.

Introduction: Glanzmann's thrombasthenia is a rare inherited platelet disorder characterized by a lack of platelet aggregation. Patients tend to be diagnosed in early childhood with treatment strategies involving a multifaceted approach to prevent and manage bleeding episodes. Unfortunately, there is currently no European consensus regarding the management of GT. Aim: This initiative aimed to gain an understanding of current clinical management of GT across Europe, with the aim of aligning best practice and improving patient outcomes. Methods: The authors, on behalf of the EAHAD Glanzmann Working Group, administered an online survey of 57 questions to European haematologists currently involved in the management of patients with GT. The survey covered topics related to diagnosis, treatment access and selection, immunization, peri‐operative management and use of second‐line therapies. Results: Responses reflected physician consensus around some topics, including peri‐operative treatment, use of recombinant factor VIIa, and concerns around antibody development. However, more varied responses were received on topics such as antibody screening (anti‐ αIIbβ3 antibodies screening conducted by ≤53% of respondents in all countries of interest except France), access to HLA‐matched platelet concentrates (none or limited for 55% of respondents) and duration of platelet transfusions for major surgery (13%–31% for 1, 2, 3 and 4 or more days of transfusions). Conclusion: Establishing comprehensive guidelines to manage GT will enhance patient outcomes by ensuring patients receive high‐quality and effective care as well as standardize care across different healthcare settings.

To illustrate the challenges in the management of women with Glanzmann thrombasthenia (GT) planning a pregnancy, we conducted a literature review and present a case series of eight women giving detailed descriptions of reproductive health problems, platelet alloimmunisation, treatment to prevent post-partum haemorrhage and neonatal outcomes. ART, assisted reproductive therapy; PPH, post-partum haemorrhage; rFVIIa, recombinant activated factor VII.

Background: Cyclic sex‐hormone fluctuation impacts clotting factor concentrations, being lowest during the follicular phase of the menstrual cycle. This pattern is unexplored in women with heavy menstrual bleeding (HMB), but potentially affects the timely diagnosis of underlying bleeding disorders. Aim: Comparing clotting factor fluctuation in the follicular versus luteal phase, between women with and without HMB. Methods: A PubMed/MEDLINE systematic review on HMB and clotting factors. Articles reporting clotting factor concentrations in premenopausal women with and without HMB were included, categorized by follicular or luteal phase if the sampling moment was specified. A meta‐analysis was performed and the effect of HMB on (cyclic) clotting factor concentrations was assessed. Results: A total of 21 out of 2158 articles were included. Clotting factors II, V, VII‐XI, fibrinogen and von Willebrand factor (VWF) during the follicular and luteal phases were reported in women with HMB. All measurements in women with HMB were performed during the follicular or unspecified phase, hindering phase‐specific assessment. Irrespective of phase, pooled measurements in women with HMB suggested elevated FVIII (pooled difference 21.8 IU/dL, 95% CI: 4.5–39.1, p = 0.01) and FV concentrations (pooled difference 15.8 IU/dL, 95% CI: 6.0–25.5, p = 0.002), but not VWF activity (pooled difference −11.0 IU/dL, 95% CI: −27.9 to 5.9, p = 0.20), compared to women without HMB. Conclusion: Based on meta‐analysis of limited data, women with HMB tend to exhibit slightly higher FVIII and FV concentrations as compared to those without. More research is needed in the follicular phase of women with HMB to assess the effect of menstrual phases on HMB.

Introduction: About 40%–70% of persons with a clinically relevant bleeding tendency who are referred to haemostasis experts are classified as having a ‘bleeding disorder of unknown cause’ (BDUC) as no biological entity can be found after extensive laboratory testing. Currently, guidelines are under development regarding diagnostic assessment and management to minimize variation in clinical practice. Aim: Investigate current practices regarding BDUC in the Netherlands. Methods: An online survey on the best BDUC definition, associated bleeding phenotype, clinical and diagnostic approaches, treatment, registration, and follow‐up was distributed amongst healthcare providers working in Dutch haemophilia treatment centres (HTCs). Results: The survey was completed by 39/54 (72%) respondents. Twenty percent did not register BDUC patients in their HTC. Healthcare professionals indicated that follow‐up should depend on bleeding phenotype severity and bleeding history, and other potential causes for an increased bleeding tendency should be excluded. Moreover, the use of laboratory tests within the routine diagnostic pathway was demonstrated to be heterogeneous. Regarding treatment, tranexamic acid was most frequently prescribed for minor and major surgical interventions (79% and 86%), dental extractions (93%) and childbirth (93%). Desmopressin was prescribed for major surgical procedures by 79%. Conclusion: Our survey shows that Dutch current practice varies but is generally in line with recent ISTH SSC recommendations. Additionally, it describes other clinically relevant topics not included in the international survey, such as follow‐up and exclusion of other causes for bleeding. This survey therefore adds to international efforts to unify BDUC definition, diagnostic approach, treatment and follow‐up, and to attain broadly supported guidelines.

Summary: Sustained remissions off‐treatment (SROTs) after tapering of thrombopoietin receptor agonists (TPO‐RAs) have been reported in 15%–50% of patients with immune thrombocytopenia (ITP). The STIP (Stop TPO‐Receptor Agonist in ITP Patients) study is a prospective trial aimed to investigate the clinical effects of romiplostim tapering. Adult patients (22/40) with ITP ≥3 months received romiplostim for 1 year, were tapered and followed for 1 year. Anti‐platelet antibodies (APAs), TPO levels and indium‐111 platelet scintigraphy were assessed before, during and after romiplostim. Censored survival analysis showed that the probability of SROT at 1 year after tapering was 23.6% (95% confidence interval: 11.0%–50.5%). Patients with SROT had higher platelet levels on romiplostim (median: 332.5 vs. 84.5 × 10⁹/L) and lower romiplostim doses at the start of tapering (median: 1.0 vs. 4.5 μg/kg) compared to those with a non‐sustained response (NSR). APAs were detected in 8/25 patients at baseline, of which 5 showed a substantial decrease during romiplostim. The indium‐111 scan revealed an improved platelet survival at the start of tapering for 50% of patients with SROT (2/4, missing n = 1) versus none with an NSR (0/14, missing n = 3). Overall, the STIP study demonstrated a probability of SROT of 23.6% in a diverse and largely chronic group of adult patients with ITP.