Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment.

ABSTRACT: Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.

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.

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.

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.

Rivaroxaban treatment among children with cancer-associated thromboembolism: Real-world data.

This is the first study examining real-life data of pediatric cancer patients treated with rivaroxaban. Children with thrombocytopenia and high bleeding risk were excluded from previous clinical trials. Data regarding the safety and efficacy of rivaroxaban in pediatric cancer-associated thrombosis are scarce. Our case series included 16 children aged 7.5-17 years. Thrombus resolution rate in our study was comparable to results of previous studies. However, higher rates of thrombotic and bleeding complications were seen in our study as compared to previous reports, especially among patients with relapsed or refractory disease.

Application of a clinical decision rule and laboratory assays in pediatrics: Adult heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is rare among pediatric patients. The diagnosis of HIT depends upon clinical decision tools to assess its pretest probability, supported by laboratory evidence of anti-platelet factor 4 (anti-PF4)/heparin antibodies. AIMS: To compare the use of the 4Ts score clinical decision tool, clinical characteristics, and laboratory findings between pediatric and adult patients with suspected HIT. METHODS: We compiled all pediatric patients in our center for whom HIT testing was performed during the years 2015-2021. These were compared with a cohort of consecutive adult patients. Laboratory diagnosis of HIT was performed with particle gel immunoassay (PaGIA) as screening test and confirmed by an automated latex-enhanced immunoturbidimetric assay (LIA) and/or by functional flow cytometry assay (FCA). RESULTS: The cohort included 34 children (under 18 years) and 105 adults. Adults mostly received heparins for thromboembolism prophylaxis and treatment (72.4%, n = 76), and were more frequently treated with low-molecular-weight heparin (LMWH). Children were mostly exposed during cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO, 61.8%, n = 21), and were more frequently treated with unfractionated heparin (UFH). Compared with adults, children had significantly higher 4Ts scores. Nevertheless, adults had a slightly higher rate of a positive diagnosis of HIT. Six out of 16 adults with confirmed HIT presented with thrombosis (37.5%), whereas all three pediatric patients with HIT presented with thrombosis (p = .087). CONCLUSIONS: 4Ts scores are higher in children compared with adult patients for whom laboratory tests for HIT were obtained. A potentially higher incidence of thrombosis in children with HIT may be attributable to the severity of underlying illness.

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.

Allergy and inhibitors in hemophilia - a rare complication with potential novel solutions.

INTRODUCTION: Hemophilia is a rare bleeding disorder caused by a deficiency of the plasma coagulation factors VIII and IX (hemophilia A [HA] and hemophilia B [HB], respectively). Replacement therapy with clotting factor concentrates is the mainstay of treatment. Unlike in patients with HB, anaphylaxis in patients with HA is extremely rare. METHODS: A retrospective study of prospectively collected data on patients with hemophilia who experienced anaphylaxis was conducted in our center. Demographic and clinical data were collected, and laboratory workups that included thrombin generation were conducted. RESULTS: Our first patient underwent successful immune tolerance induction (ITI) following the administration of rituximab. The second patient was transitioned to emicizumab. The third patient receives recombinant activated VIIa (rFVIIa) on demand. Thrombin generation was performed following current medical management protocols for supporting hemostasis. DISCUSSION: Our case series illustrates the difficulty in managing patients with anaphylaxis to replacement therapy. In the era of novel therapies, such as emicizumab, the management of HA patients who experience anaphylaxis to replacement therapy is becoming easier and may obviate the need for ITI. Current treatment strategies for HB patients with such anaphylaxis, however, are limited to rFVIIa, and it continues to pose a challenge.

Essential thrombocythemia A retrospective case series.

BACKGROUND: Essential thrombocythemia (ET) is rare in children, and pediatric guidelines are lacking. Therefore, we aimed to evaluate ET diagnosis and treatment in a pediatric cohort. PROCEDURE: Data of patients with ET from three hospitals were reviewed. Molecular diagnosis included JAK2V617F, CALR, and MPL mutations. Patients were evaluated for acquired von Willebrand syndrome (AVWS). Follow-up included clinical symptoms, adverse events, and treatment. RESULTS: Twelve children (median age: 8 years, range 1-14.5) were included. Mean lag period between the first documentation of thrombocytosis until ET diagnosis was 36 months. Six patients were positive for JAK2V617F and two for CALR mutations. In six of nine patients, AVWS was diagnosed. At diagnosis, only 33% of patients started therapy with aspirin (n = 4) and hydroxyurea (n = 2). In three of eight untreated patients, therapy was added during follow-up. The cohort was followed for a median of 32.5 months (range: 4-108 months). Clinical follow-up disclosed vascular complications in 4 of 12 patients (deep vein thrombosis, n = 1; transient ischemic attack, n = 3). Two females experienced excessive bleeding; both were diagnosed with AVWS. Neither leukemia nor myelofibrosis evolved in our cohort. CONCLUSION: Increased awareness to pediatric ET is warranted, as delayed diagnosis is common. Compared to adults, AVWS may be more prevalent among children with ET.

Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation.

Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM, resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate.

[PEDIATRIC VENOUS THROMBOEMBOLISM - A COHORT STUDY IN A TERTIARY CENTER].

INTRODUCTION: Deep Venous Thrombosis (DVT) is rare among children, yet may yield high morbidity and mortality. Due to the limited data regarding pediatric DVT, its management has been adopted from adults' protocols. Recent research reported associations of DVT and strokes with genetic thrombophilia, especially in the presence of transient risk factors (e.g.: hospitalization, malignancy, central venous lines…). AIMS: To evaluate the influence of risk factors within our pediatric DVT cohort of a tertiary center upon treatment and prognosis. METHODS: Retrospective analysis of prospectively collected data at the Sheba Medical Center. RESULTS: During the period 2014-2017, 76 out of 150 cases of acute DVT diagnosed at our center were fully followed. Upper extremity DVT was most commonly observed. Malignancy and a central venous line (CVL) were the most abundant risk factors. Genetic thrombophilia was diagnosed in one third of the cases. The majority of patients were treated with low molecular weight heparin for at least 3 months and 13% continued prolonged anti-coagulation treatment. Neither thrombophilia nor cancer affected the outcome. DISCUSSION: Our results confirm previously published data indicating that malignancy and CVL are the most common risk factors associated with DVT in children, making the upper extremity the most common location of thrombosis. Neither the type of cancer nor genetic thrombophilia was found to be associated with treatment outcome, but they did influence the treatment duration. Risk factors influence the pathogenesis of DVT and influence the duration of treatment.

[HEMOPHILIA - A ROYAL DISEASE IN THE HOLY LAND].

INTRODUCTION: Hemophilia is a hereditary congenital hemorrhagic diathesis caused by mutations in blood coagulation factor VIII (FVIII) or IX (FIX) genes, causing hemophilia A and B, respectively. Most cases are familial but a significant minority is sporadic. OBJECTIVES: To examine the presenting symptoms of patients with hemophilia in Israel and identify causes for delay in diagnosis. METHODS: Retrospective analysis of data from medical files of newly diagnosed patients with hemophilia during the period from 1st January 2010 to 31s December 2017. RESULTS: During the study period 104 children had been diagnosed with hemophilia. Fifteen percent were diagnosed with hemophilia B and 85% with hemophilia A. In most familial cases the diagnosis was established by examination of aPTT and the level of the relevant clotting factor shortly after birth. Diagnosis of sporadic cases (40 cases) was performed due to suggestive clinical symptoms. Perinatal complications were observed in 6 newborns. The most common presenting symptom was disproportionate bleeding following circumcision. In 6/21 patients who experienced excessive bleeding following circumcision there was a delay in diagnosis. Severe bleeding requiring intensive care admission was observed in twelve neonates. DISCUSSION: Diagnosis of hemophilia in Israel is made at an earlier age than in Europe. This is probably due to the performance of ritual circumcision during the neonatal period. In recent years a reduction in familial cases of severe hemophilia has been noted due to genetic counseling of hemophilia carriers. In cases of excessive bleeding following circumcision aPTT and PT should be examined promptly.

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.

Inhibitors in Hemophilia: Treatment Challenges and Novel Options.

Hemophilia A (HA) and hemophilia B (HB) are rare congenital severe bleeding disorders, that may be controlled by proper administration of adequate prophylaxis with factor VIII (FVIII), and factor IX (FIX) concentrates, respectively, to prevent joint damage due to recurrent bleeding. However, approximately 30% of patients develop inhibitory antibodies that render factor replacement therapy ineffective. Due to the high variability of patients' bleeding tendency, there is a need to "individually tailor treatment" for this unique group of patients. While replacement therapy with FVIII or FIX can be used for treating HA or HB patients with low responding inhibitors, hemophilia patients with high-responding inhibitors are treated with bypassing agents. Unfortunately, the Bethesda assay applied for inhibitor measurement in most laboratories does not fully predict either bleeding tendency or therapy response. Immune tolerance induction (ITI) may eradicate most inhibitors, yet treatment is challenging during bleeding episodes. The role of bypassing agents and their various treatment strategies still deserves attention. Recently, new nonreplacement therapies have emerged for patients with hemophilia including patients with inhibitors. Adequate monitoring of bypassing therapy and of the new nonreplacement therapies in inhibitor patients is extremely challenging, thus global hemostatic assays are increasingly used to assess clot formation. This review aims to summarize the current treatment and monitoring challenges for inhibitor patients; in this perspective, we will discuss our institutional approach for optimal decision-making and individual therapy tailoring.

Hemostasis in the Very Young.

Hemostasis is a dynamic process that starts in utero. The coagulation system evolves with age, as evidenced by marked physiological differences in the concentration of the majority of hemostatic proteins in early life compared with adulthood. This concept, known as "developmental hemostasis," has important biological and clinical implications. Overall, impaired platelet function, along with physiologically reduced levels of vitamin K-dependent and contact coagulation factors, may cause poorer clot firmness even in healthy neonates. However, increased activity of von Willebrand factor and low levels of coagulation inhibitors that promote hemostasis counterbalance the delicate and immature hemostatic system. Since this hemostatic system has little reserve capacity, preterm neonates or sick infants are extremely vulnerable and predisposed to either hemorrhagic or thrombotic complications. This review will address the concept and manifestations of developmental hemostasis with respect to clinical disease phenotypes. It will discuss bleeding diagnosis in neonates, dealing especially with the devastating complications of intracerebral and pulmonary hemorrhage in preterm infants. Neonates, especially the sickest preterm ones, are also extremely susceptible to thrombotic complications; thus, thrombosis in neonates will be reviewed, with special focus on arterial ischemic perinatal stroke. Based on the concept of developmental hemostasis, the phenotypes of clinically relevant bleeding or thrombotic disorders among neonates may differ from those of older infants and children. Treatment options for these conditions will be suggested and reviewed.

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.

From thrombasthenia to next generation thrombocytopenia: Neonatal alloimmune thrombocytopenia induced by maternal Glanzmann thrombasthenia.

BACKGROUND: Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of platelet function caused by mutations in the genes coding for integrin αIIbß3. The aim of this study was to examine the outcome of newborns of GT mothers, with emphasis on thrombocytopenia and bleeding manifestations and their relation to maternal antiplatelet antibodies. PROCEDURE: Medical files of all female patients with GT treated in a single tertiary center from 1999 to 2017 were searched for details on pregnancy and birth. The medical files of their newborns were retrieved, and data on the postnatal course were collected. RESULTS: Nine babies were born to five patients with GT at our center during the study period. Three of the nine newborns had severe thrombocytopenia, and all three were offspring of GT mothers who were positive for antiplatelet antibodies. CONCLUSION: Pregnant GT patients should be examined for platelet antibodies. Assessment and management protocols (including treatment with intravenous immunoglobulins) for fetal and neonatal alloimmune thrombocytopenia should be considered.

Rare bleeding disorders-old diseases in the era of novel options for therapy.

Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of less than one per 2000 according to the European Union or one per 1250 according to the USA. Congenital rare bleeding disorders RBD are reported in most populations, with incidence varying from 1 in 5000 (Hemophilia A), 1:30,000 (Hemophilia B) to much rarer (1:500,000 for FVII deficiency, 1-3 million for Prothrombin or FXIII deficiency). Acquired Hemophilia A is also a rare bleeding disorder with estimated frequency of 1 in million. Most RBDs are inherited as autosomal recessive (AR); however, heterozygous carriers with varying degrees of corresponding factor deficiency may render an unpredictable propensity for bleeding. In patients with bleeding symptoms, laboratory assessment and especially molecular techniques currently enable accurate diagnosis and may provide tools for prenatal and family counseling. Currently hemostasis control is mainly based upon replacement of the missing coagulation factors (unless presence of inhibitors renders it impossible), however future gene therapy and disruptive, non-replacement alternatives may be promising for patients with RBD.

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.