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.

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.

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.

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.

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.

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.

Cancer associated thrombosis in pediatric patients.

The etiology of pediatric cancer associated thrombosis (CAT) is multifactorial and may reflect pro-coagulant alterations of the hemostatic system induced by presence of cancer itself or by therapeutic chemotherapy, tumor mass effects, tumor thrombi, and inherited thrombophilia. Age, diagnosis of hematological malignancy and presence of a central venous line significantly increase the risk of thrombosis. With over 80% cure rates of childhood cancer, strategies for prevention as well as for early diagnosis and optimal treatment of (thromboembolism) TE in children with malignancies are of major importance. Currently use of therapeutic low molecular heparin (LMWH) still prevails, as prospective studies and real world data regarding Direct oral anticoagulant (DOAC) use for treatment or prevention of pediatric CAT are scarce. The following review will address the epidemiology, etiology and risk factors for CAT in children, and describe the presently available evidence associated with anticoagulant therapy and prevention strategies.

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.

Invasive Fusariosis in Pediatric Hematology/Oncology and Stem Cell Transplant Patients: A Report from the Israeli Society of Pediatric Hematology-Oncology.

Invasive Fusarium species infections in immunocompromised patients occur predominantly in those with hematological malignancies. Survival rates of 20−40% were reported in adults, but data in children are limited. Our retrospective, nationwide multicenter study of invasive fusariosis in pediatric hematology/oncology and stem cell transplant (SCT) patients identified twenty-two cases. Underlying conditions included hematological malignancies (n = 16; 73%), solid tumors (n = 2), and non-malignant hematological conditions (n = 4). Nineteen patients (86%) were neutropenic, nine (41%) were SCT recipients, and seven (32%) received corticosteroids. Sixteen patients (73%) had disseminated fusariosis, five had local infection, and one had isolated fungemia. Fifteen patients (68%) had skin involvement and eight (36%) had a bloodstream infection. Four patients (18%) presented with osteoarticular involvement and four with pulmonary involvement. Nineteen patients (86%) received combination antifungal therapy upfront and three (14%) received single-agent treatment. Ninety-day probability of survival was 77%: four of the five deaths were attributed to fusariosis, all in patients with relapsed/refractory acute leukemias. Ninety-day probability of survival for patients with relapsed/refractory underlying malignancy was 33% vs. 94% in others (p < 0.001). Survival rates in this largest pediatric population-based study were strikingly higher than those reported in adults, demonstrating that invasive fusariosis is a life-threatening but salvageable condition in immunosuppressed children.

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.

Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study.

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1-19 years diagnosed with ALL between 2003-2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

Cancer-associated thrombosis in pediatric patients.

Childhood malignancy and especially acute lymphoblastic leukemia are increasingly associated with thromboembolism. The etiology of pediatric cancer associated thrombosis is multifactorial and may reflect a tumor mass effect, tumor thrombi, alterations of the hemostatic system, treatment-related hazards (e.g. procoagulant changes induced by chemotherapy), presence of central venous lines and comorbidities (e.g. inherited thrombophilia). With over 80% cure rates of childhood cancer, strategies for prevention as well as for early diagnosis and optimal treatment of thromboembolism in children with malignancies are of major importance. While the use of therapeutic low molecular weight heparin prevails, prospective studies regarding guidelines for treatment or prevention are currently lacking. This review will address the epidemiology, etiology and risk factors for thrombosis, describe the presently available evidence associated with current therapy, and offer a glimpse into future treatment options.

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.

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.

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.

[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.

[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.

Low Concentrations of Recombinant Factor VIIa May Improve the Impaired Thrombin Generation of Glanzmann Thrombasthenia Patients.

INTRODUCTION: Glanzmann thrombasthenia (GT) is a rare bleeding disorder. The disease is caused by the lack or dysfunction of platelet membrane glycoprotein IIb/IIIa (integrin αIIbß3) which is essential for platelet aggregation. Bleeding episodes are usually managed by platelet transfusions. Recombinant activated factor VII (rFVIIa) is a common adjunct or alternative treatment option. OBJECTIVE: This article evaluates GT patients' response to increasing concentrations of rFVIIa using an ex vivo thrombin generation assay to elaborate the knowledge in which rFVIIa treats a platelet dysfunction for bleeding episodes and preoperative management. MATERIALS AND METHODS: Twenty-four GT patients in a non-bleeding state were enrolled into the study. Thrombin generation was measured in platelet-rich plasma (PRP) in the presence of 0.7 to 7.0 µg/mL rFVIIa. Clinical data of rFVIIa used to treat GT patients' bleeding episodes was collected, and patients' follow-up course was documented. RESULTS: Thrombin generation was significantly decreased in GT patients compared with controls. An individual response to rFVIIa spiking was noted in GT patients' PRP. In the majority of patients, a significant improvement in thrombin generation was already demonstrated with low concentrations (0.7 µg/mL) of rFVIIa. CONCLUSION: Thrombin generation is improved in the majority of GT patients following ex vivo spiking with rFVIIa. The magnitude of this improvement is individual and was noted at low concentrations of rFVIIa. There is a need for a prospective clinical trial to find the optimal doses or rFVIIa for treatment of GT patients.

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.

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.