Emicizumab prophylaxis in infants: Single-centre experience.

The hallmark of haemophilia A (HA) therapy is prophylaxis, aimed at spontaneous bleeding prevention. Emicizumab provides a viable alternative to intravenous factor replacement therapy. However, data on its use in infants are limited. This single-centre open arm prospective study reports on emicizumab prophylaxis in infants. We included severe HA patients under 1 year who started emicizumab prophylaxis since 2018, with longitudinal follow-up. The study collected data on demographics, clinical and laboratory variables, the occurrence of bleeding events, surgeries and treatment outcomes. Of the 27 enrolled infants, whose median age at prophylaxis initiation was 7 months, 24 primarily choose to start emicizumab therapy (3/27 switched from FVIII prophylaxis due to development of FVIII inhibitors). The median age for prophylaxis initiation decreased to 3 months in 2023. Following emicizumab initiation, the median calculated ABR decreased, and no intracranial haemorrhages were observed. Thrombin generation showed a significant improvement in peak height and endogenous thrombin potential at steady state after a loading period. Our study highlights a shift towards early prophylaxis in the era of non-replacement therapies. It underscores the need for continuous evaluation and refinement of treatment approaches, emphasizing personalized care and diligent monitoring in the evolving field of paediatric haemophilia care.

Bleeding phenotype and hemostatic evaluation by thrombin generation in children with Noonan syndrome: A prospective study.

BACKGROUND: This study aimed to evaluate the bleeding phenotype and to conduct a comprehensive hemostatic evaluation in individuals with Noonan syndrome (NS), a dominantly inherited disorder caused by pathogenic variants in genes associated with the Ras/MAPK signaling pathway. METHODS: Children with a genetically confirmed diagnosis of NS underwent clinical evaluation, routine laboratory tests, platelet function testing, and thrombin generation (TG) assessment. RESULTS: The study included 24 children. The most frequently reported bleeding symptoms were easy bruising and epistaxis, while bleeding complications were observed in 15% of surgical procedures. Various hemostatic abnormalities were identified, including platelet dysfunction, von Willebrand disease, and clotting factor deficiencies. Abnormal platelet function was observed in 50% of the patients, and significantly lower TG parameters were found compared to controls. However, no significant correlation was observed between bleeding symptoms and TG results. CONCLUSIONS: The study suggests that the bleeding diathesis in NS is multifactorial, involving both platelet dysfunction and deficiencies of plasma coagulation factors. The potential role of TG assay as an ancillary tool for predicting bleeding tendencies in individuals with NS undergoing surgery warrants further investigation.

Atypical Presentations of Pediatric-Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) in children is a rare, severe thrombotic microangiopathy. This condition is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia due to reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. METHODS: A retrospective case series evaluating data collected from the medical files of 4 children diagnosed with iTTP. RESULTS: The presented case series depicts a variety of iTTP presentations: 1 case of primary iTTP, 1 case induced by Shiga toxin, 1 associated with RAS-associated autoimmune leukoproliferative disease (RALD), and 1 initial manifestation of systemic lupus erythematosus (SLE). Notably, 2 patients recovered without undergoing plasma exchange. CONCLUSION: Early ADAMTS13 testing in children with unexplained hemolysis or thrombocytopenia is crucial. The diverse underlying causes, including infections and autoimmune disorders, underscore the complexity of iTTP in the pediatric population. These cases highlight the necessity for personalized treatment approaches that consider each patient's unique clinical situation and potential alternatives or modifications to conventional therapeutic regimens.

Can T-cell and B-cell excision circles predict development of inhibitors in pediatric hemophilia A?

BACKGROUND: Hemophilia A (HA) therapy requires intravenous replacement infusions of factor (F) VIII concentrate. Inhibitors are high-affinity immunoglobulin G that are directed against FVIII and thereby render replacement therapy ineffective. This complication has significant prognostic implications. We aimed to examine the immune system involvement in inhibitor formation specifically T-cell excision circles (TRECs) and B-cell excision circles (KRECs), markers of new T and B cells, respectively, and examine them as surrogate markers for inhibitor formation. METHODS: Blood samples were collected from 35 children with severe HA. Children were divided into two groups: with FVIII inhibitors and without FVIII inhibitors. TRECs and KRECs were measured in peripheral blood. RESULTS: A total of 11 patients with inhibitors and 24 without were evaluated. Children with inhibitors had higher levels of TRECs however not statistically significant (p = 0.085). CjKREC levels were higher in the inhibitor patients (p = 0.003). Moreover, the sj/cjKREC ratio was lower in the inhibitor patients (p = 0.015). CONCLUSIONS: Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and loss of peripheral tolerance. Improved knowledge regarding the involvement of the immune system in the formation of FVIII inhibitors will enable better therapy tailoring in the era of non-replacement therapies. IMPACT: The etiology of FVIII inhibitor formation is multifactorial, in which the immune system plays a pivotal role. Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and production of antibodies against FVIII. Improved knowledge regarding the involvement of the immune system in the development of FVIII inhibitors will enable the identification of patients prone to inhibitor development and better therapy tailoring in the new era of non-replacement therapies.

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions.

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.

Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study.

BACKGROUND: Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia. OBJECTIVES: To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples. RESULTS: Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls. CONCLUSION: These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.

Pediatric severe factor XI deficiency: A multicenter study.

BACKGROUND: Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder. Only scarce publications address its clinical features in children. The increased prevalence of FXI deficiency in Israel enabled data collection for this large multicenter cohort study. OBJECTIVE: Some hemostatic challenges may be unique or more common in children, such as bleeding in the neonatal period or trauma-related injury. The current study was designed to explore the potential impact of these differences in children with severe FXI deficiency. METHODS: Medical files of all children with FXI level under 15% followed at five tertiary centers were evaluated. The retrieved data comprised demographic and clinical characteristics, including bleeding episodes, surgical interventions, treatment strategies, as well as laboratory features. RESULTS: Sixty children, whose median age at diagnosis was 4.2 years and their median FXI level was 4%, were included. Three children experienced triggered intracranial hemorrhage (ICH) and two children had major bleeds. No bleeding complications occurred in surgeries in which hemostatic treatment consisting mostly of tranexamic acid or fresh frozen plasma was applied (n = 45). In contrast, excessive bleeding was noted in 25% of surgical procedures performed without hemostatic preparation (p = .002). CONCLUSION: This study's findings confirm the generally favorable outcome of this rare bleeding disorder, with no spontaneous bleeds or cases of perinatal ICH. Nonetheless, proper diagnosis and adequate hemostasis in the surgical setting are imperative. Unlike previous studies in adults, our pediatric study suggests an association between the severity of FXI deficiency and bleeding tendency.

The potential role of emicizumab prophylaxis in severe von Willebrand disease.

BACKGROUND: Severe von Willebrand disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. Emicizumab is a humanized bispecific antibody, which mimics the function of coagulation factor VIII (FVIII), and it has been approved for prophylaxis in hemophilia A. METHODS: This is the first study assessing the potential future role of emicizumab as an alternative prophylactic treatment in patients with severe VWD, based upon a thrombin generation (TG) ex vivo analysis. We report 51 weeks of successful off label emicizumab prophylaxis in a child with severe VWD and recurrent hemarthroses and progressive arthropathy despite adherence to previous prophylaxis with replacement therapy. RESULTS AND CONCLUSIONS: Our work demonstrated that ex vivo spiking with emicizumab increased TG in plasma from patients with type 3 VWD. Similar TG results were observed in our treated patient, whose therapy was well tolerated without any adverse events. Both in vitro and ex vivo TG data support sufficient hemostasis without exceeding the range seen in healthy volunteers. Further collaborative studies on the efficacy and safety of emicizumab prophylaxis in severe VWD is warranted.

Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data.

INTRODUCTION: Emicizumab (Hemlibra™) is approved for prophylaxis of Haemophilia A (HA) patients with and without inhibitors. However, real-world data on emicizumab use in the elderly HA patients with concomitant cardiovascular risk factors are lacking. AIM: To evaluate the safety and efficacy of emicizumab in a real-world cohort of elderly HA patients. METHODS: A prospective longitudinal observational study on HA patients over 50 years old treated, followed and monitored during emicizumab prophylaxis was conducted. We documented any bleeding or adverse events and collected plasma samples for emicizumab levels, aPTT and thrombin generation (TG). RESULTS: Seventeen HA patients (2 with inhibitor), whose median age was 62.4 years (range: 51.5-77.1) composed the cohort, including 9/17 with multiple cardiovascular risk factors (high risk group). Seven patients had chronic HIV infection. The median follow-up of our cohort was 400 days (range 89-805, IQR 211-479 days). The median annualized bleeding rate (ABR) significantly decreased for all patients. Among patients who displayed significant bleeding tendencies, emicizumab steady state levels as well as TG were lower as compared with the group. The ABR of four patients concomitantly treated by antiplatelet agents was significantly higher compared with the rest of the cohort. Neither thrombosis nor thrombotic microangiopathy (TMA) was encountered. CONCLUSIONS: Emicizumab prophylaxis for HA patients older than 50 years including those with cardiovascular risk factors was well tolerated. As lower emicizumab and TG levels were observed among bleeding patients, we suggest that monitoring laboratory assays could be of value within this age group.

Emicizumab prophylaxis: Prospective longitudinal real-world follow-up and monitoring.

INTRODUCTION: Real-world data on prophylaxis of severe haemophilia A (HA) patients treated by emicizumab are scarce. AIM: To study the efficacy and safety of longitudinal emicizumab prophylaxis and assess laboratory monitoring correlations in a large patient cohort. METHODS: HA patients with and without FVIII inhibitors, initiating emicizumab prophylaxis, were prospectively enrolled. Bleeding, adverse events and surgeries were documented. FVIII inhibitors, emicizumab levels and thrombin generation (TG) were sequentially measured. RESULTS: A total of 107 patients, including 58 children (whose median (IQR) age was 6 (1-11) years) with severe HA, composed the study cohort. Twenty-nine per cent (31/107) of our HA patients had FVIII inhibitors. Patients were followed for a median of 67 weeks (up to 144 weeks). Fifty-three patients, whose median follow-up was 53 weeks, experienced zero bleeds. Most bleeds (94%) among children were trauma-related, whereas 61% of adults sustained spontaneous joint bleeds. Four patients experienced major bleeds, with a fatal outcome in one infant, who also presented with central venous line thrombosis. No other serious adverse events were encountered. Seven patients have decided to stop emicizumab treatment for various reasons. Emicizumab plasma levels increased after emicizumab prophylaxis initiation, and values were maintained during follow-up, in all but one patient, suspected of anti-drug antibodies. A significant reduction of FVIII inhibitor levels was noted among inhibitor patients. TG was increased and sustained yet could not prognosticate bleeding risk. CONCLUSION: Emicizumab prophylaxis was mostly well tolerated, although 50% of patients experienced breakthrough bleeds. Routine TG monitoring is not obligatory, and further studies are warranted in selected patient populations.

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients-Lessons from Wide Genome Analyses.

INTRODUCTION: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. AIM: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. METHODS: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. RESULTS: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. CONCLUSION: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning.

Emicizumab treatment and monitoring in a paediatric cohort: real-world data.

Real-world data on emicizumab use and monitoring in paediatric severe haemophilia A (HA) patients are scarce. We therefore sought to evaluate safety, efficacy, and laboratory monitoring of emicizumab prophylaxis in a cohort of 40 children with severe HA, including 22 non-inhibitor patients and nine infants younger than one year. Bleeding, trauma, adverse events, and surgeries were documented during a median follow-up of 45 weeks. Emicizumab levels, activated partial thromboplastin time (aPTT) values, and thrombin generation were measured before and during therapy. Twenty patients experienced zero bleeds. All bleeding was trauma-related, and bleeding risk was positively correlated with the length of emicizumab prophylaxis. Sixteen surgical interventions were performed in 12 patients, with no thrombotic complications or thrombotic microangiopathy. Prolonged aPTT values normalised after emicizumab initiation, correlating with an increase in emicizumab plasma levels. Elevation in the thrombin generation was observed following emicizumab prophylaxis, with lower values recorded in younger infants. Emicizumab prophylaxis was safe and well tolerated. As all bleedings were trauma-related, laboratory monitoring could not predict bleeding risk. Our results do not support routine thrombin generation monitoring in children treated by emicizumab, yet further studies are warranted in the context of surgical procedures.

Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort.

BACKGROUND: Emicizumab is a bispecific antibody that bridges factor IXa and factor X to restore hemostasis in patients with hemophilia A (HA). Its efficacy and safety have been proven in multicenter trials. However, real world data regarding its use in very young children are currently lacking. Ancillary test results for monitoring emicizumab's hemostatic effect and their clinical correlations are scarce. METHODS: Children with HA and inhibitors treated by emicizumab were prospectively followed at our center. Laboratory follow-up included rotational thromboelastometry (ROTEM) and thrombin generation (TG), prior to and during treatment. RESULTS: Eleven children whose median age was 26 months were treated by emicizumab and followed for a median of 36 weeks. During follow-up, none experienced hemarthrosis or any other spontaneous bleeds. For 7/11 patients, emicizumab prophylaxis was sufficient to maintain hemostasis without additional supplemental therapy. Only 4/11 patients were occasionally treated with recombinant activated FVII for trauma. Two minor surgeries were safely performed without supplemental therapy while another procedure was complicated by major bleeding. TG parameters improved for all patients, correlating with their clinical status. Interestingly, the lowest TG values were obtained for patients experiencing bleeding episodes, while ROTEM parameters in all patients were close to the normal range. CONCLUSIONS: This study confirms the safety and efficacy of emicizumab in reducing bleeds in young children with HA with inhibitors, including infants. However, surgeries warrant caution as emicizumab prophylaxis may not be sufficient for some procedures. TG may more accurately reflect the hemostasis state than ROTEM in pediatric patients treated with emicizumab.

A novel approach using ancillary tests to guide treatment of Glanzmann thrombasthenia patients undergoing surgical procedures.

BACKGROUND: Glanzmann thrombasthenia (GT) is a disorder of platelet function. Standard therapy includes platelet transfusions, which may be hampered by antiplatelet antibodies. AIMS: To assess potential correlation between bleeding and number of active platelets in GT patients undergoing surgery. Clinical peri- operative patients' hemostasis was compared with flow cytometry analysis (FC), and whole blood clot formation. METHODS: GT patients undergoing surgery were included. Blood counts, platelet activation studies, FC and rotational thromboelastography (ROTEM) were performed as ancillary tests to estimate the effectiveness of treatment. RESULTS: A total of 4 GT patients undergoing 5 surgeries were included. Consecutive FC analysis following platelet transfusions showed gradual decrease of donor platelets with a nadir of 3280 platelets in patients who experienced no post procedural bleeding following minor procedures. After major surgery, bleeding occurred when donor platelets decreased to 2600-4280. Decline in donor platelets was associated with reduced clot firmness as noted by ROTEM. CONCLUSION: Results suggest that very low number of active donor platelets may suffice to achieve proper hemostasis in certain procedures. Our study points to the potential role of consecutive FC examinations to demonstrate the number of donor platelets as an ancillary tool for decision making in GT patients undergoing surgery.

Treatment tailoring for factor V deficient patients and perioperative management using global hemostatic coagulation assays.

INTRODUCTION: Congenital factor V deficiency (FVD) is a rare bleeding disorder with an estimated incidence of 1 in 1000,000 in the general population. Since the common coagulation tests do not correlate with the bleeding tendency there is an unmet need to predict FVD patients' bleeding hazard prior to surgical interventions. AIM: To optimize treatment prior to surgical interventions, using global coagulation assays, thrombin generation (TG) and rotating thromboelastogram (ROTEM). METHODS: Our cohort included 5 patients with FVD, 4 severe and one mild. Two of them underwent TG and ROTEM prior to surgical interventions, including ex vivo spiking assays using bypass agents and platelets spiking. RESULTS: All five patients exhibited prolonged PT and PTT, non-dependent on their bleeding tendency. Patient 1, who demonstrated severe bleeding phenotype, underwent surgery treated by combination of APCC (FEIBA) and platelet transfusion. Therapy was guided by global tests (TG as well as ROTEM) results. During the pre and post-operative period neither excessive bleeding nor any thrombosis was noted. In contrast, TG and ROTEM analysis of patient 4 has lead us to perform the surgery without any blood products' support. Indeed, the patient did not encounter any bleeding. CONCLUSION: Global coagulation assays may be useful ancillary tools guiding treatment decisions in FVD patients undergoing surgical procedures.

Alternative treatment options for pediatric hemophilia B patients with high-responding inhibitors: A thrombin generation-guided study.

Little is known about the challenging treatment of pediatric patients with hemophilia B and inhibitors due to disease rarity. We describe three patients diagnosed in childhood and followed up to 9 years. All three had allergic reactions to Factor IX, but two were later safely treated for bleeding episodes with activated prothrombin complex concentrates (APCC = FEIBA). The third was given only recombinant activated Factor VIIa. Based on ex vivo thrombin generation analysis, a new alternative treatment of combined bypassing agents was administered for bleeding episodes and several minor surgical procedures with no treatment-associated adverse events or thrombosis.

Combination of hemostatic therapies for treatment of patients with hemophilia A and inhibitors.

BACKGROUND: Therapy application and monitoring of patients with hemophilia A (HA) and inhibitors are challenging. In the current study, combined FVIII - bypass therapy was implemented for a cohort of severe HA patients with inhibitors. METHODS: Plasma of 15 HA patients with inhibitors was spiked ex vivo with FVIII, rFVIIa, FEIBA and their combinations and thrombin generation (TG) was studied. Some patients who experienced hemarthroses or required minor surgeries were treated by a combined concomitant administration of FVIII+FEIBA as IV bolus doses. RESULTS: TG spiking studies showed individual responses not correlated to inhibitor titer. Combinations of agents augmented TG as compared to any single agent, while combined FVIII+FEIBA yielded the highest TG, supporting it as a potential treatment. Following emergent successful surgery of child treated by concomitant FVIII+FEIBA, a total of 396 episodes in 7/15 patients were treated with concomitant FVIII+FEIBA. Five patients were treated for bleeding episodes only, whereas 2 were children undergoing immune tolerance induction (ITI) with FEIBA prophylaxis. Four minor surgeries were performed on FVIII+FEIBA repeated infusions. Neither thrombosis nor any other adverse events were documented. CONCLUSION: A combination of FVIII+FEIBA may be effective and safe as an alternative treatment option for some high-responding inhibitor patients.

Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes.

Background: Using emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated. Objectives: To study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis. Methods: Patients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs). Results: Of 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance. Conclusion: Our longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.

Management of surgery in persons with hemophilia A receiving emicizumab prophylaxis: data from a national hemophilia treatment center.

Background: Persons with hemophilia A may require surgical procedures. Real-world data on invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis are limited. Objectives: To evaluate the safety of invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis and their outcomes in a longitudinally followed cohort. Methods: Data from medical records of persons with hemophilia A with and without factor VIII (FVIII) inhibitors longitudinally followed at our tertiary center, who received emicizumab prophylaxis and underwent all types of invasive procedures, were retrieved. Outcomes of interest were bleeding and thrombotic complications. Results: Overall, 35 patients underwent 56 invasive procedures, 18 (32.1%) were major. The median age was 36.3 years (IQR, 8.8-55.9 years); 12 patients (34.3%) were younger than 18 years at the time of procedure; 17 (48.6%) were patients with FVIII inhibitors. Among major procedures, orthopedic surgeries prevailed. All patients who underwent major procedures received factor replacement with either recombinant activated factor VII (patients with inhibitors) or FVIII (patients without inhibitors). Factor concentrates were administered prior to 32 (84.2%) of the minor procedures. Repeated doses were given according to international expert opinion recommendations and patients' condition.There were 7 bleeding events in 6 patients, 5 were major bleeds, including 1 patient who underwent a minor procedure without factor replacement. None of the patients experienced a thrombotic complication. Conclusion: Invasive procedures can be performed safely in patients receiving emicizumab prophylaxis with close surveillance after surgery. Factor concentrates may be advised in selected patients undergoing minor procedures.

Women with Hemophilia: Case Series of Reproductive Choices and Review of Literature.

Aim Very little is known regarding reproductive choices, pregnancy, and delivery of women with moderate to severe hemophilia. Our aim was to describe our experience with three hemophiliac women and their journey to achieve motherhood. Methods Medical charts of women with moderate to severe hemophilia A treated at our center were evaluated. Data regarding choices of conception, pregnancy course, mode of delivery, and pregnancy outcomes were obtained. Results Three women are presented. Whereas patient 1 chose to adopt her first child and later had twins through egg donations and a surrogate mother, patient 2 underwent spontaneous pregnancy and delivered via cesarean section. Patient 3 preferred in vitro fertilization and preimplantation genetic diagnosis to avoid hemophilia and hemophilia carriership in her offspring. Conclusion The appropriate means to achieve parenthood for women with moderate to severe hemophilia should be individualized and requires support of a comprehensive multidisciplinary team.