Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1.

AIM: An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. METHODS: The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. RESULTS: The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated. CONCLUSION: This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www. CLINICALTRIALS: gov as #NCT02690714.

Utilization of a surgical database to provide care and assess perioperative treatment and outcomes in patients with bleeding disorders.

OBJECTIVES: To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019. METHODS: Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period. RESULTS: Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p = .164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p < .001), complications (14.3% vs. 12.3%; p < .001), and plan deviations (34.2% vs. 25.1%; p < .001). CONCLUSION: The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care.

Congenital Portosystemic Shunts and Liver Hemangiomas in Children: Is There an Association?

Liver hemangiomas are benign vascular tumors of infancy. They can have vascular shunting mostly arteriovenous and sometimes arterioportal or portosystemic, which improves as hemangiomas involute. In contrast, congenital portosystemic shunts are developmental vascular anomalies that may go undetected for years, with significant sequelae. We describe a child with a history of multiple cutaneous and liver hemangiomas in infancy and later diagnosis of congenital portosystemic shunt. Past experience of a similar patient and a current baby followed for liver hemangiomas with portosystemic shunts, is also shared. Literature is reviewed for known association. We suggest longer-term follow-up for babies with liver hemangiomas.

Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency.

Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

An international registry of patients with plasminogen deficiency (HISTORY).

Plasminogen deficiency is an ultra-rare multisystem disorder characterized by the development of fibrin-rich pseudomembranes on mucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported. Affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with potential life-threatening complications. Non-specific therapies are inadequate and plasminogen concentrates are not commercially available. The current understanding of plasminogen deficiency and management of disease symptoms and its progression are based on case reports/series and two small clinical trials. To date there has never been a comprehensive, international study to examine the natural history or optimal therapeutic intervention; knowledge gaps include identification of contributing factors and triggers of disease manifestations, inability to predict disease course, and insufficient real-world data for use of therapeutics. We have created an international, observational study (HISTORY) in a large cohort of persons with plasminogen deficiency and first-degree family members to address these gaps and to advance knowledge and care. HISTORY will build upon the established relationship between the Indiana Hemophilia and Thrombosis Center and the Fondazione Angelo Bianchi Bonomi, IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan and will utilize a modified version of the Prospective Rare Bleeding Disorders Database (PRO-RBDD). A biorepository containing samples from subjects with plasminogen deficiency will be established. This article describes the rationale behind the study and efforts towards its goals.

Hemophilia A with inhibitor: Immune tolerance induction (ITI) in the mirror of time.

Inhibitor (neutralizing antibodies) development remains the most significant complication in patients with severe congenital hemophilia A receiving exogenous factor VIII (FVIII). Although our understanding of the pathophysiology of inhibitor development has advanced, the knowledge gained has not yet translated into a robust decline in incidence, with the overall risk remaining at ∼30%. Immune Tolerance Induction (ITI) is the only current method to successfully eradicate an inhibitor and achieve long-term tolerance. Although current practice utilizes a wide variety of ITI regimens, identification of an optimal regimen has not emerged. Over the last decade, the number of replacement products available in hemophilia has greatly expanded. The cumulative evidence with each product for use in ITI is often lacking. Most recently emicizumab, a humanized monoclonal bi-specific antibody that substitutes for the scaffolding effect of FVIIIa was approved; this agent prevents bleeding in both inhibitor and non-inhibitor patients. The use of emicizumab will bring about a new era in care that will require clinicians to challenge current practice paradigms including use and administration of ITI. This review will summarize the main clinical ITI data and practices for patients with severe congenital hemophilia A with inhibitors (CHAwI) over the last four decades and will highlight current studies in the field, with attention to open questions.

Clinical features of children, adolescents, and adults with coexisting hypermobility syndromes and von Willebrand disease.

We present five patients with coexistent von Willebrand disease (VWD) and Ehlers-Danlos syndrome and 21 with VWD and joint hypermobility. Females outnumbered males ten to three, Beighton scores were documented in 58% (15 of 26 patients), and several patients experienced moderately severe bleeding. We believe coexistent hypermobility disorder with VWD potentially affects bleeding severity and want to raise awareness among hematologists. Evaluation by geneticists is recommended because of the varying complexities observed across the disease spectrum, and the availability of new genetic tests should lead to more accurate diagnoses for the various hypermobility disorders.

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label.

BACKGROUND: The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. PROCEDURE: Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery). RESULTS: The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review. CONCLUSIONS: rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.

Case Report: Respiratory lesions successfully treated with intravenous plasminogen, human-tvmh, replacement therapy in four patients with plasminogen deficiency type 1.

Plasminogen deficiency type 1 (PLGD-1, hypoplasminogenemia) is an ultra-rare, lifelong disease associated with development of fibrinous lesions in multiple organ systems. Depending on lesion location, clinical manifestations of PLGD-1 can result in acute and/or chronic respiratory airway disease which can compromise respiratory function leading to life-threatening events. Early recognition and effective treatment of airway obstruction caused by fibrinous lesions are critical to prevent morbidity due to respiratory compromise. However, physicians may not be familiar with the clinical presentation and management of PLGD-1, causing delays in diagnosis and treatment and potentially contributing to morbidity. Presented here is a case series of one adult and three pediatric patients with severe respiratory complications of PLGD-1 successfully managed by infusions of plasminogen, human-tvmh replacement therapy. Patients' respiratory symptoms were resolved or greatly improved, and treatment was generally well tolerated. In all patients, baseline plasminogen activity was substantially increased with plasminogen replacement therapy administered initially every one to two days followed by extended interval dosing as symptoms were controlled or resolved. All four described cases support the clinical benefit of replacement therapy with plasminogen, human-tvmh in the resolution of life-threatening respiratory complications associated with PLGD-1. Clinical manifestations in addition to respiratory lesions were also improved or resolved with continued treatment.

Outcomes in Children with Provoked Venous Thrombosis and Antiphospholipid Antibodies: Findings from the Kids-DOTT Trial.

Few studies have prospectively evaluated the incidence and outcomes in children with provoked venous thromboembolism (VTE) and transient or persistent antiphospholipid antibodies (aPL). We compared outcomes of patients <21 years old with a first-episode acute provoked VTE and positive aPL at diagnosis enrolled in the Kids-DOTT trial. aPL were tested at enrollment and, when positive, repeated at 6 weeks post-VTE. Subsequent testing was performed at discretion of the treating hematologist. Of 524 patients, 116 (22%) had positive aPL at enrollment. At follow-up, 70 (60%) had transient (n=66) or low titer aPL (n=4), 11 (10%) had persistent aPL meeting criteria for antiphospholipid syndrome (APS), and 35 (30%) had no repeat testing. Patients with APS were older (15.8 vs. 9.9 years, p=.014), and had a statistically significant higher risk of symptomatic recurrent VTE (18% vs. 1%, OR: 12.2 [1.4 - 108], p= .025), and a statistically non-significant but clinically meaningful difference in the risk of anticoagulant-related clinically-relevant bleeding (9% vs. 0%, OR: 20.1 [0.7 - 558], p=0.077) compared to those in the transient or low titer aPL group. In conclusion, aPL are common in young patients with acute provoked VTE and are mostly transitory and clinically insignificant. Patients with APS and provoked VTE appear to have an increased risk of recurrent VTE compared to patients with transitory or low titer aPL. Future collaborative studies should investigate the optimal VTE management of children with provoked VTE who meet criteria for APS.

Inhibitors in hemophilia: association with surgery plans and outcomes in a retrospective cohort study.

Background: The development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need for bypassing agents to achieve hemostasis. Objectives: To evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations. Methods: We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics. Results: A total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk [adjRR], 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005). Conclusion: Inhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.

Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells.

Radiation-induced inhibition of rapamycin-sensitive pathway and its effect on the cellular response to radiation were studied in the human breast cancer cell line MCF-7. Both radiation and rapamycin shared molecular targets and induced similar physiologic responses. Each of these treatments increased immunostaining of mammalian target of rapamycin (mTOR) in the nucleus, and radiation led to decreased phosphorylation of its autophosphorylation site Ser2481. In addition to dephosphorylation of established mTOR downstream effectors 4E-binding protein 1 and p70 ribosomal S6 kinase, both treatments decreased the level of eukaryotic initiation factor 4G. Experiments with the potentiometric dye, JC-1, revealed an oligomycin-dependent increase in mitochondrial membrane potential following radiation or rapamycin treatment, suggesting that both lead to reversal of F0F1ATPase activity. Both radiation and rapamycin induced sequestration of cytoplasmic material in autophagic vacuoles. In both cases, appearance of autophagic vacuoles involved the participation of microtubule-associated protein 1 light chain 3 (LC3). Transient cotransfection of green fluorescent protein-LC3 with either wild-type or dominant-negative mTOR further showed that inactivation of mTOR pathway is sufficient to induce autophagy in these cells. Finally, administration of rapamycin in combination with radiation led to enhanced mitochondria hyperpolarization, p53 phosphorylation, and increased cell death. Taken together, these experiments show that radiation-induced inhibition of rapamycin-sensitive pathway in MCF-7 cells causes changes in mitochondria metabolism, development of autophagy, and an overall decrease in cell survival.

Adenovirus infection in hospitalized immunocompetent children.

This study investigated the clinical features of immunocompetent children with adenovirus infection requiring hospitalization. The files of 78 children (mean age 17 +/- 10 months) with community-acquired adenovirus infection admitted over a 2-year period were reviewed. The children were referred after 5.7 +/- 3.4 days of illness, all with fever (mean peak 39.8 +/- 0.8 degrees C). Temperature normalized after 3.5 +/- 2 days. Duration of hospitalization (mean, 7.0 +/- 3.9 days) correlated with lethargy, lung crackles, cracked lips, hypoxia, impaired liver tests, and high serum lactic dehydrogenase (LDH) concentration at admission. Serum LDH concentrations and hypoxemia predicted 70% of the variance in hospital stay. All patients recovered. Adenovirus infection may cause considerable morbidity, even in immunocompetent children. Disease severity, defined by duration of hospitalization, correlates with serum LDH concentrations and oxygen saturation at admission.

Eukaryotic initiation factor 2α--a downstream effector of mammalian target of rapamycin--modulates DNA repair and cancer response to treatment.

In an effort to circumvent resistance to rapamycin--an mTOR inhibitor--we searched for novel rapamycin-downstream-targets that may be key players in the response of cancer cells to therapy. We found that rapamycin, at nM concentrations, increased phosphorylation of eukaryotic initiation factor (eIF) 2α in rapamycin-sensitive and estrogen-dependent MCF-7 cells, but had only a minimal effect on eIF2α phosphorylation in the rapamycin-insensitive triple-negative MDA-MB-231 cells. Addition of salubrinal--an inhibitor of eIF2α dephosphorylation--decreased expression of a surface marker associated with capacity for self renewal, increased senescence and induced clonogenic cell death, suggesting that excessive phosphorylation of eIF2α is detrimental to the cells' survival. Treating cells with salubrinal enhanced radiation-induced increase in eIF2α phosphorylation and clonogenic death and showed that irradiated cells are more sensitive to increased eIF2α phosphorylation than non-irradiated ones. Similar to salubrinal--the phosphomimetic eIF2α variant--S51D--increased sensitivity to radiation, and both abrogated radiation-induced increase in breast cancer type 1 susceptibility gene, thus implicating enhanced phosphorylation of eIF2α in modulation of DNA repair. Indeed, salubrinal inhibited non-homologous end joining as well as homologous recombination repair of double strand breaks that were induced by I-SceI in green fluorescent protein reporter plasmids. In addition to its effect on radiation, salubrinal enhanced eIF2α phosphorylation and clonogenic death in response to the histone deacetylase inhibitor--vorinostat. Finally, the catalytic competitive inhibitor of mTOR--Ku-0063794--increased phosphorylation of eIF2α demonstrating further the involvement of mTOR activity in modulating eIF2α phosphorylation. These experiments suggest that excessive phosphorylation of eIF2α decreases survival of cancer cells; making eIF2α a worthy target for drug development, with the potential to enhance the cytotoxic effects of established anti-neoplastic therapies and circumvent resistance to rapalogues and possibly to other drugs that inhibit upstream components of the mTOR pathway.