scholarly journals Clinical case of an infant with severe hemophilia A on emicizumab

2021 ◽  
Vol 8 (3) ◽  
pp. 123-126
Author(s):  
T. A. Andreeva ◽  
I. A. Lavrichenko
Keyword(s):  
Clinical Case ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Primary Prophylaxis ◽  
Intracranial Bleeding ◽  
First Year ◽  
Severe Hemophilia ◽  
Traumatic Bleeding ◽  
Post Traumatic ◽  
First Year Of Life

Hemophilia A is an X-linked congenital bleeding disorder caused by a deficiency or absence of coagulation factor VIII. In children who are in the first year of life, bleeding into the head accounts for 12.8–17.7 % of cases, and up to 45.5 % of them are intracranial bleeding in contrast to adult patients, in whom joints are the most frequent localization of bleeding. The first 2 years of life are the most dangerous in relation tointracranial bleeding for a child with hemophilia and the provision of full preventive treatment is extremely important for this time.Aim of the study – present the first experience of using emicizumab as primary prophylaxis in a child of the first year of life with hemophilia A. A patient born in 2020 with a severe hemophilia A had two post-traumatic bleeding that required hospitalization and replacement therapy. We decided to start primary prophylaxis with emicizumab at the age of 10 months.There were not spontaneous bleedings during 8 months of emicizumab usage. Post-traumatic bleeding did not require hospitalization and additional therapy.The clinical case demonstrates that emicizumab is effective and safe in infant who have not previously received prophylactic treatment.

EFFICACY AND SAFETY OF MOROCTOCOG ALFA IN AN OPEN, MULTICENTER, PROSPECTIVE, CLINICAL STUDY IN CHILDREN 2 TO 6 YEARS OF AGE WITH SEVERE HEMOPHILIA A

2021 ◽  
Vol 100 (6) ◽  
pp. 154-161
Author(s):  
M.A. Timofeeva ◽  
◽  
V.V. Lebedev ◽  
O.I. Plaksina ◽  
N.I. Zozulya ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Hemophilia A ◽  
Prospective Clinical Study ◽  
Study Group ◽  
Haemophilia A ◽  
Severe Hemophilia ◽  
Efficacy And Safety ◽  
Prophylactic Dose ◽  
Traumatic Bleeding ◽  
Post Traumatic

The purpose of the study was to assess the efficacy, safety and pharmacokinetics of the moroctocog alfa (Octofactor) in children aged 2-6 with haemophilia A. Materials and methods of research : six patients between 2 and 6 years of age (average age 4.3±0.8 years) were included in the open multicenter prospective clinical trial. The efficacy of the drug was assessed against the background of the introduction of 30±10 IU/kg every 2–3 days, the safety was assessed by the frequency and causality of adverse reactions. Results: 7 post-traumatic bleeding was registered. The average prophylactic dose of the drug is 37.84±7.13 IU/kg. The dose of the drug for stopping bleeding was 1000 IU. 2 adverse events have been reported that are not related to moroсtocog alfa. Conclusion: the obtained data indicate the efficacy and safety of moroсtocog alfa in the study group of patients.

scholarly journals Manajemen Low Flow Anesthesia pada Pasien Kraniosinostosis dengan Hipertelorisme yang menjalani Four Box Wall Osteotomy, dan Eksisi Redundant Skin Fronto Nasal

2021 ◽  
Vol 10 (3) ◽  
pp. 172-181
Author(s):  
Syarif Afif ◽  
◽  
Dewi Yulianti Bisri ◽  
M. Sofyan Harahap ◽  
Syafruddin Gaus ◽  
...  
Keyword(s):  
Fluid Management ◽  
Coagulation Factor ◽  
Massive Bleeding ◽  
Low Flow ◽  
First Year ◽  
Inhalation Anesthesia ◽  
Good Communication ◽  
Post Operative Pain ◽  
Low Flow Anesthesia ◽  
First Year Of Life

Craniosynostosis is a case that diagnosed in the first year of life and can need surgical in young age. Craniosynostosis is a part of hypertelorism with incidence rate around 20%. Boy, 13 years old with hypertelorism had undergone multiple surgery for correction of hypertelorism before. Patient was planned to advance surgical correction of four box wall osteotomy which consist frontal part correction and part of it is release craniosynostosis in coronal suture. Risk of massive bleeding because patient already in teen age and length of surgery can be prolonged. Difficult airway management due to fascial deformity, use of low flow anesthesia to preserve temperature and reduce inhalation anesthesia usage, intraoperative fluid management in consideration maintenance and replacement blood loss and post operative pain management has become another consideration. Covid-19 as part of problems post operatively being known before extubation made the process is delayed. Massive bleeding needs massive transfusion protocol to speed up blood availability. Blood product such as PRC, FFP and TC should be available because coagulation factor is part of consideration. Anesthesia management in hypertelorism with four box wall osteotomy need good communication between anesthesiologist, neurosurgeon, plastic surgeon and pediatric intensivist to reduce perioperative risk including covid-19 in pandemic era.

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Joint Damage ◽  
Coagulation Factor ◽  
The United States ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

Long-Term Venous Access Catheters and Infections in Patients with Severe Hemophilia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4117-4117
Author(s):  
Janet A. Harrison ◽  
Jerry S. Powell
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Significant Risk ◽  
Clinical Decision ◽  
Primary Prophylaxis ◽  
Venous Access ◽  
Secondary Prophylaxis ◽  
Catheter Placement ◽  
Severe Hemophilia

Abstract Treatment of hemophilia A or B with factor concentrates requires uncomplicated venous access, and frequently this access uses venous access catheters, which have been associated with increased frequency of thrombophlebitis and catheter related infections. Reports have estimated the incidence of infection as 8.3% to 55%. A prospective multi-center study was undertaken to determine the rates of these complications associated with venous access catheters in patients with severe hemophilia. Inclusion criteria were: severe hemophilia, age 6 months to 70 years, and non-emergent need for a long-term venous access catheter. Excluded were catheters inserted for less than 28 days or in a femoral site, and other medical conditions compromising expected survival. 53 subjects (48 hemophilia A, 5 hemophilia B) were enrolled by nine hemophilia treatment centers, with 3 subjects receiving repeat catheter insertions, for a total of 56 catheter experiences. Factor replacement was given to all subjects during catheter placement. Families were trained in catheter use according to individual center practices, and each subject was followed at least monthly in the clinic or by telephone. 54 catheters were placed by a physician in an operating room under sterile conditions; antibiotics were used for catheter placement for 18 subjects. The ages at placement ranged from 10 months to 59 years (mean 8.9 years). Most of the Catheter types were Port-a-Cath (n = 43), 6 Broviac, 4 Hickman, and 3 PICC. The reasons for the catheters varied: primary prophylaxis, 10, secondary prophylaxis, 23, immune tolerance, 17, and for treatment after surgery or trauma, 6. Five subjects were positive for hepatitis C, 2 subjects for hepatitis B, and one for HIV. Of the 53 subjects, 10 have had catheter related infections. The infections were detected 19 to 762 days after catheter insertion (mean 272.7 days). Two subjects had recurrent infections, 4 and 3 respectively. The ages of the subjects at the time of infection ranged from 1.8 to 13.9 years old (mean = 5 years). The peripheral blood cultures and the catheter tip (if removed) cultures revealed a variety of different bacteria and one fungus (candida albicans). Perhaps surprisingly, staphylococcus epidermidis was found in only 2 subjects, and no case of s. aureus was detected. Klebsiella was cultured from 3 subjects who experienced infections. No subjects died during the study. Eight catheters were removed for reasons determined by the responsible clinician: 6 for infection, 1 by accident, 1 was no longer needed. Nine of the 10 subjects with infections received antibiotics. Of the 6 Broviacs, 2 subjects experienced infections (33%). Of the 43 Port-a-Caths, 8 subjects experienced infections (18.6%). The 2 subjects with repeated infections both had Port-a-Caths, and the first infections occurred at 354 and 120 days, respectively. Of the 17 subjects on immune tolerance, 2 subjects experienced infections (not significantly different from the larger cohort). No subjects experienced thrombophlebitis or other catheter failure. In summary, the results of this study demonstrate that long-term venous access catheter use in patients with severe hemophilia: 1) is associated with significant risk of catheter related infections, particularly in children, 2) that these infections can be managed clinically in most cases, with appropriate clinical monitoring, and, 3) the risk of thrombophlebitis is quite low. These data should assist to evaluate the risks and benefits of the clinical decision to use venous access catheters in patients with severe hemophilia.

Interferon-Gamma (IFN-γ) Secretion Defect in Peripheral Blood Mononuclear Cells (PBMCs) from Severe Hemophilia A (HA) Patients Prior to Therapeutic Exposure To Factor VIII (FVIII) Concentrates.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3093-3093
Author(s):  
Joan Cox Gill ◽  
Karen Stephany ◽  
Craig Helsell
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Membrane Lipids ◽  
Coagulation Factor ◽  
Cytokine Secretion ◽  
Foreign Protein ◽  
Subject Group ◽  
Severe Hemophilia ◽  
Adult Control ◽  
Ifn Γ

Abstract The recent availability of highly purified recombinant coagulation factor concentrates to treat hemorrhages in hemophilic patients is thought to circumvent perturbations in immune function by preventing chronic intravenous exposure to multiple foreign protein antigens. We previously reported a PHA-induced IFN-γ secretion defect in severe hemophilia A patients who had been exposed exclusively to highly purified coagulation factor VIII concentrates. We now report the results of cytokine secretion in response to PHA in cultured PBMCs from severe hemophilia A patients never exposed to FVIII concentrates. PBMCs were isolated from whole blood from three severe HA patients, 3 age-matched normal boys, 3 boys with severe hemophilia B and an adult control. Cells were stained with PKH26 (Sigma), a fluorescent dye with aliphatic tails that intercalate into membrane lipids; cells were than washed and cultured in complete media in wells of microtiter plates with and without PHA. Cells were harvested at 5 days and proliferation detected by loss of membrane PKH26 staining detected by flow cytometry. Cytokines secreted into the supernatants of 48 hour and 5 day cultures were measured by ELISA assays (BD Pharmingen). PBMCs from severe HA patients proliferated normally in response to PHA but failed to secrete IFN-γ when compared to normal boys and boys with severe HB: PBMC Proliferation and Secretion of IFN-γ in Response to PHA Subject Group HA HB Normal Boys Adult Control PHA Proliferation (% unstained cells) M± 1SD 79.3 ±3.7 78.2±13.3 95.4±1.5 89.3±5.3 INF-γ Secretion (pg/mL) M± 1 SD 6.7±4.7 429.0±464 69.1±32.4 770.1±148.7 The severe HA patients did not have improvement in INF-γ secretion following therapeutic exposure to FVIII concentrates. Addition of physiologic concentrations of FVIII or FIX to cultures with or without PHA did not alter the results of proliferation or cytokine secretion regardless of the inhibitor history of the patients. (1 HA and 1 HB patient developed high responder inhibitors.) Secretion of IL-4, IL-5 and IL-10 were moderately decreased in some HA patients as well. In summary, we have confirmed an INF-γ secretion defect in PBMCs from patients with HA in spite of normal proliferation in response to PHA. The defect is not present in HB or normal age-matched control subjects and is not corrected by addition of FVIII to cultures. We conclude that the defect is not due to exposure to intravenous foreign antigens. The precise clinical significance and any possible relation to the higher risk of inhibitor development in HA will require further investigation. PBMC Proliferation and Secretion of IFN-γ in Response to PHA Subject Group HA HB Normal Boys Adult Control PHA Proliferation (% unstained cells) M± 1SD 79.3 ±3.7 78.2±13.3 95.4±1.5 89.3±5.3 INF-γ Secretion (pg/mL) M± 1 SD 6.7±4.7 429.0±464 69.1±32.4 770.1±148.7

Most Factor VIII B Domain Missense Mutations Are Unlikely to Be Causative Mutations for Hemophilia A: Implications for Factor VIII Genetic Analysis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 513-513
Author(s):  
Kyoichi Ogata ◽  
Steven W. Pipe
Keyword(s):  
Amino Acid ◽  
Factor Viii ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Causative Mutation ◽  
Factor V ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Single Chain

Abstract Hemophilia A results from the quantitative or qualitative deficiency of coagulation factor VIII (FVIII). FVIII is synthesized as a single-chain polypeptide of approximately 280 kDa with the domain structure A1-A2-B-A3-C1-C2. Whereas the A and C domains exhibit ~40% amino acid identity to each other and to the A and C domains of coagulation factor V, the B domain is not homologous to any known protein and is dispensable for FVIII cofactor activity. Missense mutations in the FVIII B domain have been described in patients with variable phenotypes of hemophilia A. According to the NCBI SNPs (single nucleotide polymorphism) database, 22 SNPs are reported within FVIII, 11 of which occur within the B domain. FVIII B domain variant D1241E has been reported as a missense mutation associated with mild or severe hemophilia A, yet this mutation is also present in the NCBI SNPs database. We hypothesize that D1241E and most other reported B domain missense mutations are not the causative mutation for hemophilia A in these patients but represent SNPs or otherwise non-pathologic mutations. To investigate this, we analyzed 7 B domain missense mutations that were previously found in hemophilia A patients (T751S, V993L, H1047Y, D1241E, T1353A, P1641L and S1669L). Comparative analysis showed that the amino acids at these positions are not conserved in all species and in some cases, the amino acid substitution reported in hemophilia patients is represented in the native sequence in other species. Analysis with PolyPhen Software showed that only H1047Y mutation was considered as “possibly damaging”, while the others were considered as “benign”. To investigate this further, we constructed seven plasmid vectors containing these B domain missense mutations. The synthesis and secretion of FVIII wild-type (WT) and these seven mutants were compared after transient DNA transfection into COS-1 monkey cells in vitro. Analysis of the FVIII clotting activity and antigen levels in the conditioned medium demonstrated that all mutants had FVIII activity and antigen levels similar to FVIII WT. Further, FVIII WT, H1047Y and D1241E mutants were introduced into a FVIII exon 16 knock-out mouse model of hemophilia A by hydrodynamic tailvein injection in vivo. The mouse plasma was analyzed at 24 hrs for activity and antigen expression. Mutants H1047Y and D1241E expressed at 211 mU/mL and 224 mU/mL activity with FVIII antigen levels of 97 ng/mL and 118 ng/mL, respectively, similar to FVIII WT. These results suggested that H1047Y and D1241E mutants did not lead to impairments in secretion or functional activity. We conclude that most missense mutations within the FVIII B domain would be unlikely to lead to severe hemophilia A and that the majority of such missense mutations represent polymorphisms or non-pathologic mutations. Investigators should search for additional potentially causative mutations elsewhere within the FVIII gene when B domain missense mutations are identified.

Immunogenicity of BAX 855 in Previously Treated Patients with Congenital Severe Hemophilia Α

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2594-2594
Author(s):  
Frank Michael Horling ◽  
Peter Allacher ◽  
Herwig Koppensteiner ◽  
Werner Engl ◽  
Fritz Scheiflinger ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neutralizing Antibodies ◽  
Research Funding ◽  
Hemophilia A ◽  
De Novo ◽  
Coagulation Factor ◽  
Severe Hemophilia ◽  
Increased Risk ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Background and objectives BAX 855 (Antihemophilic Factor [Recombinant] pegylated, rurioctocog alfa pegol) is an extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) modified with polyethylene glycol (PEG) (Turecek et al., 2012). It was recently approved in the US and Japan for on-demand treatment of bleeding events and for prophylactic treatment for patients with congenital severe hemophilia A. The efficacy and safety of BAX 855 were extensively studied during clinical development of this compound (Konkle et al., 2015). The assessment of BAX855 immunogenicity was of particular interest because the development of neutralizing antibodies (FVIII inhibitors) is the most serious complication following replacement therapies with FVIII products. FVIII inhibitors develop in about 20-32% of previously untreated patients (Gouw SC et al., 2013) and with a rate of 1.55- 3.8 per 1000 patients per year in previously treated patients (Kempton CL, 2010) with severe hemophilia A. To fully understand the potential of BAX855 to induce antibody responses, both FVIII inhibitors and total FVIII-binding antibodies were assessed. Furthermore, potential antibody development against PEG-FVIII, PEG and CHO proteins was investigated. Methods The clinical protocols (ClinicalTrials.gov identifier: NCT02585960, NCT02210091, NCT01736475, NCT01913405, NCT01945593, NCT01599819, NCT02615691) and the methods used for antibody analytics (Whelan et al 2013; Lubich et al 2016) were previously described. ELISA technologies were used for the analysis of total binding antibodies, the Nijmegen modification of the Bethesda assay was used for the detection of FVIII inhibitors. Correlation analyses were done to assess any potential correlation between the development of antibodies and potential adverse events. Results None of the 243 subjects (6 PUPs and 237 PTPs) included in the analysis developed FVIII inhibitors (≥ 0.6 BU/mL) A total of 44 subjects tested positive for binding antibodies against FVIII, PEG-FVIII or PEG at single time points. 28 of these 44 subjects showed pre-existing antibodies against FVIII, PEG-FVIII, or PEG prior to first exposure to BAX 855, which disappeared during the study. 13 subjects who tested negative at screening developed transient antibodies against FVIII, PEG-FVIII, or PEG at one or two consecutive study visits after exposure to BAX 855. Antibodies were transient and not detectable at subsequent visits or at completion of the study. Five subjects showed positive results for binding antibodies at study completion or at the time of the data cutoff. No conclusion can be drawn whether these antibodies are of transient or persistent nature. There was no confirmed causal relationship between the appearance of binding antibodies against FVIII, PEG or PEG-FVIII and adverse events, nor was there an impact on hemostatic efficacy in any of the 44subjects. No subject had pre-existing antibodies or developed de novo antibodies to CHO proteins during the study at any time point. Conclusion Our data indicate that BAX855 did not show an increased risk for PTPs to develop FVIII inhibitors. We did not see any FVIII inhibitor development in PUPs, but the small number of overall exposures does not allow general conclusions for PUPs. Importantly, the data suggest that BAX855 did not induce immune responses associated with impaired treatment efficacy or with altered PK parameters. Disclosures Horling: Shire: Employment. Allacher:IMC Krems: Research Funding. Koppensteiner:Shire: Employment. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Scheiflinger:Shire: Employment, Research Funding. Abbuehl:Baxalta (now part of Shire): Employment. Reipert:Shire: Employment.

scholarly journals Detection of Intron22 Mutations in Iraqi Female Carriers in Wasit City with Hemophilia A

2017 ◽  
pp. 13-24
Author(s):  
Maysoon Mohammed Hassan
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Gene Identification ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Intron 1 ◽  
Detection Mechanisms ◽  
Female Carriers ◽  
Chromosomal Recombination

The background:One of the prevalent main concerns in the medical world is the identification of Intron22 mutations in the Factor VIII gene carried by Iraqi patient in Wasit town, in Iraq suffering Hemophilia A (classical hemophilia) which is related to a X-chromosome recessive haemorrhage afflictions as the result of a flaw in the coagulation factor VIII (FVIII). It is essentially related with F8 mutations of Intron22 in version which forms the most typical kind of mutations of blood afflictions worldwide involving half the patients suffering from severe Hemophilia A that possesses mutations, in addition to Intron 1 inversion suffered by 5% of severe Hemophilia A patients.All of the inversion mutations are suffered mainly by males,and uncommonly by females due to the intra chromosomal recombination among the homologous areas, in inversion 1 or 22, with extragenic copy posited the telomeric to the Factor VIII gene. Unfortunately, there is an absence in Iraq on researches pertaining blood affliction gene identification in persons who carries the Intron22 mutations exception in the current research.Aims of study:The objectives of the research is to to analyze through the detection mechanisms, the existence of Intron 22 mutations in the Factor VIII gene of 10 Hemophilia A Iraqi carriers cohort families. The hypothesis and anticipated result is that there will be a minimal margin of hazardous possibility for the recurrence. The hereditary F8 mutation is unknown to be present on the maternal side of the patient sufferer due to the possibilty of germline mosaics that exists within the community.

scholarly journals Atypical presentation of metastatic disease in patients with stage 4S neuroblastoma of the observation group: description of the clinical case

2020 ◽  
Vol 7 (3) ◽  
pp. 125-131
Author(s):  
L. A. Smirnova ◽  
D. Yu. Kachanov ◽  
A. P. Shcherbakov ◽  
D. G. Akhaladze ◽  
M. V. Teleshova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Metastatic Disease ◽  
Malignant Tumor ◽  
Clinical Case ◽  
Favorable Outcome ◽  
First Year ◽  
Atypical Presentation ◽  
Observation Group ◽  
Atypical Metastasis ◽  
First Year Of Life

The most common extracranial solid malignant tumor of childhood – neuroblastoma (NB) is characterized by the presence of two metastatic forms (stages 4 and 4S). Stage 4S is described to have metastatic spread to the liver, skin, and minimal bone marrow invasion. Certain rare localisations of NB metastases (pleura, testicles, and others) may not worsen the prognosis in children of the first year of life in the absence of severe bone marrow invasion and metastases to the skeletal bones. The article describes a clinical case of retroperitoneal NB with atypical metastasis to the pleura in a child of the first months of life with a favorable outcome with a minimum amount of chemotherapy.

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