Pediatric splenic infarction: Assessment of associated clinical conditions and outcome.

Pediatric splenic infarction (SI) is rare yet clinically significant. Publications regarding this complication are mostly limited to case reports. This is a retrospective study examining SI etiology, clinical presentation, management, and outcomes among children. Twenty-two patients (median age: 7.9 years) were included, mostly with pre-existing hematological diseases. Splenomegaly (72%), thrombocytopenia, and anemia were common. Most of the patients did not receive antithrombotic therapy yet only two patients experienced recurrences. During follow up 36% of patients died, however no fatalities were attributed to thrombotic or bleeding complications.

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.

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.

Venous thromboembolism characteristics, treatment and outcomes in young adults: findings from the Registro Informatizado de Enfermedad TromboEmbólica registry.

BACKGROUND: Venous thromboembolism (VTE) is rare in patients aged <21 years. Young adults aged 18 to 21 years are frequently included in adult VTE studies, whereas pediatric VTE studies include patients aged up to either 18 or 21 years. The clinical characteristics of young adult patients with VTE have not been well defined. OBJECTIVES: We aimed to highlight any unique characteristics or treatment considerations that may apply to young adult patients with VTE. METHODS: Data from the prospective, international Registro Informatizado de Enfermedad TromboEmbólica registry were used. Patients were stratified into subcohorts according to age. The clinical characteristics, risk factors, management, and outcomes of young adult patients with VTE were compared with those of adolescents aged 12 to 18 years and adults aged >21 years. RESULTS: Of 104 253 Registro Informatizado de Enfermedad TromboEmbólica patients enrolled until August 2022, 234 were adolescents and 884 were young adults. Less cases of pulmonary embolism were reported in adolescents (P < .001). Estrogen use was a common risk factor, more prevalent in adolescents and young adults (P < .001), whereas active cancer and immobilization were uncommon in both. Most patients were initially treated with low-molecular-weight heparin. VTE recurrence, major bleeding, and all-cause mortality rates were comparably low among adolescents and young adults. None of the patients aged <21 years died from VTE recurrence. CONCLUSION: Young adults have some distinctive VTE risk factors. While VTE presentation may be similar among young adults and older patients, the outcomes of patients aged <21 years are more favorable.

Anticoagulant treatment for pediatric splanchnic vein thrombosis: a systematic review and meta-analysis.

BACKGROUND: The clinical characteristics of splanchnic vein thrombosis (SVT) in pediatric patients and its optimal treatment strategies are unknown. OBJECTIVES: This study aimed to assess the effectiveness and safety of anticoagulant therapy for pediatric SVT. METHODS: MEDLINE and EMBASE databases were searched up to December 2021. We included observational and interventional studies that enrolled pediatric patients with SVT and reported anticoagulant treatment and outcomes, including rates of vessel recanalization, SVT extension, venous thromboembolism (VTE) recurrence, major bleeding, and mortality. Pooled proportions of vessel recanalization were calculated with their 95% CI. RESULTS: A total of 506 pediatric patients (aged 0-18 years) across 17 observational studies were included. The majority of patients had portal vein thrombosis (n = 308, 60.8%) or Budd-Chiari syndrome (n = 175, 34.6%). Most events were triggered by transient provoking factors. Anticoagulation (heparins and vitamin K antagonists) was prescribed in 217 (42.9%) patients, and 148 (29.2%) patients underwent vascular interventions. The overall pooled proportions of vessel recanalization were 55.3% (95% CI, 34.1%-74.7%; I2 = 74.0%) among anticoagulated patients and 29.4% (95% CI, 2.6%-86.6%; I2 = 49.0%) among non-anticoagulated patients. SVT extension, major bleeding, VTE recurrence, and mortality rates were 8.9%, 3.8%, 3.5%, and 10.0%, respectively, in anticoagulated patients and 2.8%, 1.4%, 0%, and 50.3%, respectively, in non-anticoagulated patients. CONCLUSION: In pediatric SVT, anticoagulation appears to be associated with moderate recanalization rates and a low risk of major bleeding. VTE recurrence is low and comparable to that reported in pediatric patients with other types of provoked VTE.

Cerebral sinus venous thrombosis in children with inherited bleeding disorders: A case series.

In patients with inherited bleeding disorders, thrombus development poses a challenge in balancing the management of thrombosis and bleeding. Pediatric antithrombotic therapy guidelines do not address the treatment of a thrombus in the setting of a bleeding disorder. We present a case series of four children with inherited bleeding disorders presenting with cerebral sinus venous thrombosis and bleeding, in order to summarize the different therapeutic approaches and outcomes of these patients.

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.

Real-World Data on Bleeding Patterns of Hemophilia A Patients Treated with Emicizumab.

Emicizumab (Hemlibra™) is approved for prophylaxis of hemophilia A (HA) patients. The HAVEN studies addressed bleeding reduction in emicizumab-treated patients, but real-world data on bleeding patterns during emicizumab therapy are lacking. We aimed to compare the occurrence of breakthrough bleeding at different time points, starting from emicizumab initiation. This longitudinal prospective observational cohort study included HA patients (n = 70, aged 1 month to 74.9 years) that completed at least 18 months of follow-up in our center. We analyzed the number of spontaneous and traumatic bleeds during selected time points of the study ("bleeding periods"). The percentage of traumatic and spontaneous bleeding episodes was not significantly different among "bleeding periods" (P = 0.053 and P = 0.092, respectively). Most trauma-related treated bleeds resulted from either hemarthrosis (53%) or head trauma (33%). Spontaneous bleeding episodes were mostly hemarthroses (80%). Potential associations of the patients' age, annualized bleeding rate before emicizumab treatment, and the presence of inhibitors with spontaneous bleed occurrence were analyzed with binomial logistic regression. The odds of bleeding while on emicizumab increased by a factor of 1.029 (P = 0.034) for every one year of age. Conclusions: Our real-world data revealed that the risk of bleeding persists, especially in older patients, despite therapy with emicizumab. These data may help clinicians in counselling their patients and in planning their management.

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.

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.

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.

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.

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.

Severe Protein C Deficiency due to Novel Biallelic Variants in PROC and Their Phenotype Correlation.

Severe protein C deficiency due to biallelic PROC mutations is an extremely rare thrombophilia, most commonly presenting during the neonatal period as purpura fulminans. Despite treatment, severe morbidity and mortality are frequent. The current study reports 3 unrelated patients harboring novel homozygous PROC mutations and their clinical phenotypes. We discuss how the cytoprotective activity of protein C and its role in the stabilization of endothelial barriers may account for the unique symptoms of this thrombophilia.

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.

Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients.

BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality among immunocompromised patients. Isavuconazole is a new drug that shows promise in the adult population for the treatment of IMIs. No data regarding the use of isavuconazole in pediatric patients have been published. METHODS: Patients with a diagnosis of IMI from our pediatric hemato-oncology division, treated with isavuconazole between 2010 and 2016, were identified using the hospital's computerized database. Data including demographics, clinical course, and outcome were collected. Pharmacokinetic samples were obtained from two younger patients to guide dosing. RESULTS: In total, three patients (4.5, 5, and 19 years of age) with invasive mucormycosis who were treated with isavuconazole were identified. All patients were treated with isavuconazole as a second line therapy and experienced improvement following the initiation of this treatment. CONCLUSIONS: Based on our limited clinical experience, isavuconazole may be a safe and effective treatment option for children and adolescents afflicted by IMI. Prospective clinical trials should be performed in order to evaluate the pharmakokinetics and safety of isavuconazole in the pediatric population.

An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A.

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care.

The Risk of Serious Bacterial Infection in Neutropenic Immunocompetent Febrile Children.

Only few reports have looked into the risk of invasive bacterial infection in children with neutropenia that is not malignancy related. The objective of the current study was to determine the clinical significance of neutropenia as a predictor of serious bacterial infection (SBI) in immunocompetent children. We conducted a retrospective case-control study including children 3 months to 18 years of age with fever ≥ 38°C hospitalized or presenting to the emergency department. Patients who had neutropenia ≤ 1000 ANC/µL and had a blood culture taken were matched for age with the consecutive febrile patients for whom a blood culture was taken. The main outcome was the rate of SBI. SBIs were more prevalent among the control group than in the group of children with neutropenia, 19/71 and 6/71, respectively (P = 0.0005). More children were treated with antibiotics among the control group than in the group of children with neutropenia, 39/71 and 20/71, respectively (P < 0.0001). Acute-phase reactants including CRP and platelets were higher in the control group. We concluded that immunocompetent patients with fever and moderate neutropenia do not carry a higher risk for SBIs compared with patients with fever who do not have neutropenia.